Timing of Occurrence Is the Most Important Characteristic of Spot Sign.

PubMed

Wang, Binli; Yan, Shenqiang; Xu, Mengjun; Zhang, Sheng; Liu, Keqin; Hu, Haitao; Selim, Magdy; Lou, Min

2016-05-01

Most previous studies have used single-phase computed tomographic angiography to detect the spot sign, a marker for hematoma expansion (HE) in spontaneous intracerebral hemorrhage. We investigated whether defining the spot sign based on timing on perfusion computed tomography (CTP) would improve its specificity for predicting HE. We prospectively enrolled supratentorial spontaneous intracerebral hemorrhage patients who underwent CTP within 6 hours of onset. Logistic regression was performed to assess the risk factors for HE and poor outcome. Predictive performance of individual CTP spot sign characteristics were examined with receiver operating characteristic analysis. Sixty-two men and 21 women with spontaneous intracerebral hemorrhage were included in this analysis. Spot sign was detected in 46% (38/83) of patients. Receiver operating characteristic analysis indicated that the timing of spot sign occurrence on CTP had the greatest area under receiver operating characteristic curve for HE (0.794; 95% confidence interval, 0.630-0.958; P=0.007); the cutoff time was 23.13 seconds. On multivariable analysis, the presence of early-occurring spot sign (ie, spot sign before 23.13 seconds) was an independent predictor not only of HE (odds ratio=28.835; 95% confidence interval, 6.960-119.458; P<0.001), but also of mortality at 3 months (odds ratio =22.377; 95% confidence interval, 1.773-282.334; P=0.016). Moreover, the predictive performance showed that the redefined early-occurring spot sign maintained a higher specificity for HE compared with spot sign (91% versus 74%). Redefining the spot sign based on timing of contrast leakage on CTP to determine early-occurring spot sign improves the specificity for predicting HE and 3-month mortality. The use of early-occurring spot sign could improve the selection of ICH patients for potential hemostatic therapy. © 2016 American Heart Association, Inc.

Timing of occurrence is the most important characteristic of spot sign

PubMed Central

Xu, Mengjun; Zhang, Sheng; Liu, Keqin; Hu, Haitao; Selim, Magdy; Lou, Min

2016-01-01

Background and Purpose Most previous studies have used single-phase CT angiography (CTA) to detect the spot sign, a marker for hematoma expansion (HE) in spontaneous intracerebral hemorrhage (SICH). We investigated whether defining the spot sign based on timing on perfusion CT (CTP) would improve its specificity for predicting HE. Methods We prospectively enrolled supratentorial SICH patients, who underwent CTP within 6 h of onset. Logistic regression were performed to assess the risk factors for HE and poor outcome. Predictive performance of individual CTP spot sign characteristics were examined with receiver operating characteristic (ROC) analysis. Results Sixty-two men and 21 women with SICH were included in this analysis. Spot sign was detected in 46% (38/83) patients. ROC analysis indicated that the timing of spot sign occurrence on CTP had the greatest AUC for HE (0.794; 95% CI, 0.630-0.958; P=0.007); the cutoff time was 23.13 seconds. On multivariable analysis, the presence of early-occurring spot sign (EOSS; i.e. spot sign before 23.13 seconds) was an independent predictor, not only of HE (OR=28.835; 95% CI, 6.960-119.458; P<0.001), but also of mortality at 3 months (OR=22.377; 95% CI, 1.773-282.334; P=0.016). Moreover, the predictive performance showed that the redefined EOSS maintained a higher specificity for HE compared to spot sign (91% vs 74%). Conclusions Redefining the spot sign based on timing of contrast leakage on CTP to determine EOSS, improves the specificity for predicting HE and 3-month mortality. The use of EOSS could improve the selection of ICH patients for potential hemostatic therapy. PMID:27026627

Large-scale filament formation inhibits the activity of CTP synthetase

PubMed Central

Barry, Rachael M; Bitbol, Anne-Florence; Lorestani, Alexander; Charles, Emeric J; Habrian, Chris H; Hansen, Jesse M; Li, Hsin-Jung; Baldwin, Enoch P; Wingreen, Ned S; Kollman, Justin M; Gitai, Zemer

2014-01-01

CTP Synthetase (CtpS) is a universally conserved and essential metabolic enzyme. While many enzymes form small oligomers, CtpS forms large-scale filamentous structures of unknown function in prokaryotes and eukaryotes. By simultaneously monitoring CtpS polymerization and enzymatic activity, we show that polymerization inhibits activity, and CtpS's product, CTP, induces assembly. To understand how assembly inhibits activity, we used electron microscopy to define the structure of CtpS polymers. This structure suggests that polymerization sterically hinders a conformational change necessary for CtpS activity. Structure-guided mutagenesis and mathematical modeling further indicate that coupling activity to polymerization promotes cooperative catalytic regulation. This previously uncharacterized regulatory mechanism is important for cellular function since a mutant that disrupts CtpS polymerization disrupts E. coli growth and metabolic regulation without reducing CTP levels. We propose that regulation by large-scale polymerization enables ultrasensitive control of enzymatic activity while storing an enzyme subpopulation in a conformationally restricted form that is readily activatable. DOI: http://dx.doi.org/10.7554/eLife.03638.001 PMID:25030911

Acceptance of Combined Coronary CT Angiography and Myocardial CT Perfusion versus Conventional Coronary Angiography in Patients with Coronary Stents—Intraindividual Comparison

PubMed Central

Martus, Peter; Laule, Michael; Dewey, Marc; Schönenberger, Eva

2015-01-01

Objectives To evaluate how well patients with coronary stents accept combined coronary computed tomography angiography (CTA) and myocardial CT perfusion (CTP) compared with conventional coronary angiography (CCA). Background While combined CTA and CTP may improve diagnostic accuracy compared with CTA alone, patient acceptance of CTA/CTP remains to be defined. Methods A total of 90 patients with coronary stents prospectively underwent CTA/CTP (both with contrast agent, CTP with adenosine) and CCA as part of the CARS-320 study. In this group, an intraindividual comparison of patient acceptance of CTA, CTP, and CCA was performed. Results CTP was experienced to be significantly more painful than CTA (p<0.001) and was associated with a higher frequency of dyspnea (p<0.001). Comparison of CTA/CTP with CCA revealed no significant differences in terms of pain (p = 0.141) and comfort (p = 0.377). Concern before CTA/CTP and CCA and overall satisfaction were likewise not significantly different (p = 0.097 and p = 0.123, respectively). Nevertheless, about two thirds (n = 60, 68%) preferred CTA/CTP to CCA (p<0.001). Moreover, patients felt less helpless during CTA/CTP than during CCA (p = 0.026). Lack of invasiveness and absence of pain were the most frequently mentioned advantages of CTA/CTP over CCA in our patient population. Conclusions CCA and combined CTA/CTP are equally well accepted by patients; however, more patients prefer CTA/CTP. CTP was associated with more intense pain than CTA and more frequently caused dyspnea than CTA alone. Trial Registration ClinicalTrials.gov NCT00967876 PMID:26327127

Effects of Collagen Tripeptide Supplement on Photoaging and Epidermal Skin Barrier in UVB-exposed Hairless Mice.

PubMed

Pyun, Hee-Bong; Kim, Minji; Park, Jieun; Sakai, Yasuo; Numata, Noriaki; Shin, Jin-Yeong; Shin, Hyun-Jung; Kim, Do-Un; Hwang, Jae-Kwan

2012-12-01

Collagen tripeptide (CTP) is a functional food material with several biological effects such as improving dry skin and wound and bone fracture healing. This study focused on the anti-photoaging effects of CTP on a hairless mouse model. To evaluate the effects of CTP on UVB-induced skin wrinkle formation in vivo, the hairless mice were exposed to UVB radiation with oral administration of CTP for 14 weeks. Compared with the untreated UVB control group, mice treated with CTP showed significantly reduced wrinkle formation, skin thickening, and transepidermal water loss (TEWL). Skin hydration and hydroxyproline were increased in the CTP-treated group. Moreover, oral administration of CTP prevented UVB-induced MMP-3 and -13 activities as well as MMP-2 and -9 expressions. Oral administration of CTP increased skin elasticity and decreased abnormal elastic fiber formation. Erythema was also decreased in the CTP-treated group. Taken together, these results strongly suggest that CTP has potential as an anti-photoaging agent.

Effects of Collagen Tripeptide Supplement on Photoaging and Epidermal Skin Barrier in UVB-exposed Hairless Mice

PubMed Central

Pyun, Hee-Bong; Kim, Minji; Park, Jieun; Sakai, Yasuo; Numata, Noriaki; Shin, Jin-Yeong; Shin, Hyun-Jung; Kim, Do-Un; Hwang, Jae-Kwan

2012-01-01

Collagen tripeptide (CTP) is a functional food material with several biological effects such as improving dry skin and wound and bone fracture healing. This study focused on the anti-photoaging effects of CTP on a hairless mouse model. To evaluate the effects of CTP on UVB-induced skin wrinkle formation in vivo, the hairless mice were exposed to UVB radiation with oral administration of CTP for 14 weeks. Compared with the untreated UVB control group, mice treated with CTP showed significantly reduced wrinkle formation, skin thickening, and transepidermal water loss (TEWL). Skin hydration and hydroxyproline were increased in the CTP-treated group. Moreover, oral administration of CTP prevented UVB-induced MMP-3 and -13 activities as well as MMP-2 and -9 expressions. Oral administration of CTP increased skin elasticity and decreased abnormal elastic fiber formation. Erythema was also decreased in the CTP-treated group. Taken together, these results strongly suggest that CTP has potential as an anti-photoaging agent. PMID:24471092

Shortened Mean Transit Time in CT Perfusion With Singular Value Decomposition Analysis in Acute Cerebral Infarction: Quantitative Evaluation and Comparison With Various CT Perfusion Parameters.

PubMed

Murayama, Kazuhiro; Katada, Kazuhiro; Hayakawa, Motoharu; Toyama, Hiroshi

We aimed to clarify the cause of shortened mean transit time (MTT) in acute ischemic cerebrovascular disease and examined its relationship with reperfusion. Twenty-three patients with acute ischemic cerebrovascular disease underwent whole-brain computed tomography perfusion (CTP). The maximum MTT (MTTmax), minimum MTT (MTTmin), ratio of maximum and minimum MTT (MTTmin/max), and minimum cerebral blood volume (CBV) (CBVmin) were measured by automatic region of interest analysis. Diffusion weighted image was performed to calculate infarction volume. We compared these CTP parameters between reperfusion and nonreperfusion groups and calculated correlation coefficients between the infarction core volume and CTP parameters. Significant differences were observed between reperfusion and nonreperfusion groups (MTTmin/max: P = 0.014; CBVmin ratio: P = 0.038). Regression analysis of CTP and high-intensity volume on diffusion weighted image showed negative correlation (CBVmin ratio: r = -0.41; MTTmin/max: r = -0.30; MTTmin ratio: r = -0.27). A region of shortened MTT indicated obstructed blood flow, which was attributed to the singular value decomposition method error.

CTP synthase forms cytoophidia in the cytoplasm and nucleus

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

Gou, Ke-Mian; State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193; Chang, Chia-Chun

2014-04-15

CTP synthase is an essential metabolic enzyme responsible for the de novo synthesis of CTP. Multiple studies have recently showed that CTP synthase protein molecules form filamentous structures termed cytoophidia or CTP synthase filaments in the cytoplasm of eukaryotic cells, as well as in bacteria. Here we report that CTP synthase can form cytoophidia not only in the cytoplasm, but also in the nucleus of eukaryotic cells. Both glutamine deprivation and glutamine analog treatment promote formation of cytoplasmic cytoophidia (C-cytoophidia) and nuclear cytoophidia (N-cytoophidia). N-cytoophidia are generally shorter and thinner than their cytoplasmic counterparts. In mammalian cells, both CTP synthasemore » 1 and CTP synthase 2 can form cytoophidia. Using live imaging, we have observed that both C-cytoophidia and N-cytoophidia undergo multiple rounds of fusion upon glutamine analog treatment. Our study reveals the coexistence of cytoophidia in the cytoplasm and nucleus, therefore providing a good opportunity to investigate the intracellular compartmentation of CTP synthase. - Highlights: • CTP synthase forms cytoophidia not only in the cytoplasm but also in the nucleus. • Glutamine deprivation and Glutamine analogs promotes cytoophidium formation. • N-cytoophidia exhibit distinct morphology when compared to C-cytoophidia. • Both CTP synthase 1 and CTP synthase 2 form cytoophidia in mammalian cells. • Fusions of cytoophidia occur in the cytoplasm and nucleus.« less

Neutron transport analysis for nuclear reactor design

DOEpatents

Vujic, Jasmina L.

1993-01-01

Replacing regular mesh-dependent ray tracing modules in a collision/transfer probability (CTP) code with a ray tracing module based upon combinatorial geometry of a modified geometrical module (GMC) provides a general geometry transfer theory code in two dimensions (2D) for analyzing nuclear reactor design and control. The primary modification of the GMC module involves generation of a fixed inner frame and a rotating outer frame, where the inner frame contains all reactor regions of interest, e.g., part of a reactor assembly, an assembly, or several assemblies, and the outer frame, with a set of parallel equidistant rays (lines) attached to it, rotates around the inner frame. The modified GMC module allows for determining for each parallel ray (line), the intersections with zone boundaries, the path length between the intersections, the total number of zones on a track, the zone and medium numbers, and the intersections with the outer surface, which parameters may be used in the CTP code to calculate collision/transfer probability and cross-section values.

Neutron transport analysis for nuclear reactor design

DOEpatents

Vujic, J.L.

1993-11-30

Replacing regular mesh-dependent ray tracing modules in a collision/transfer probability (CTP) code with a ray tracing module based upon combinatorial geometry of a modified geometrical module (GMC) provides a general geometry transfer theory code in two dimensions (2D) for analyzing nuclear reactor design and control. The primary modification of the GMC module involves generation of a fixed inner frame and a rotating outer frame, where the inner frame contains all reactor regions of interest, e.g., part of a reactor assembly, an assembly, or several assemblies, and the outer frame, with a set of parallel equidistant rays (lines) attached to it, rotates around the inner frame. The modified GMC module allows for determining for each parallel ray (line), the intersections with zone boundaries, the path length between the intersections, the total number of zones on a track, the zone and medium numbers, and the intersections with the outer surface, which parameters may be used in the CTP code to calculate collision/transfer probability and cross-section values. 28 figures.

A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study

PubMed Central

Park, Won; Hrycaj, Pawel; Jeka, Slawomir; Kovalenko, Volodymyr; Lysenko, Grygorii; Miranda, Pedro; Mikazane, Helena; Gutierrez-Ureña, Sergio; Lim, MieJin; Lee, Yeon-Ah; Lee, Sang Joon; Kim, HoUng; Yoo, Dae Hyun; Braun, Jürgen

2013-01-01

Objectives To compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS). Methods Phase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed. Results Geometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean Cmax,ss was 147.0  μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively. Conclusions The PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30. PMID:23687259

Enhanced bone formation in the vicinity of porous β-TCP scaffolds exhibiting slow release of collagen-derived tripeptides.

PubMed

Kamikura, Keita; Minatoya, Tsutomu; Terada-Nakaishi, Michiko; Yamamoto, Shoko; Sakai, Yasuo; Furusawa, Toshitake; Matsushima, Yuta; Unuma, Hidero

2017-09-01

It has been experimentally proven that orally ingested collagen-derived tripeptides (Ctp) are quickly absorbed in the body and effectively promote the regeneration of connective tissues including bone and skin. Ctp are capable to activate osteoblasts and fibroblasts, which eventually promotes tissue regeneration. Based on these findings, a hypothesis was formulated in this study that direct delivery of Ctp to bone defect would also facilitate tissue regeneration as well as oral administration. To test the hypothesis, we prepared a bone augmentation material with the ability to slowly release Ctp, and investigated its in vivo bone regeneration efficacy. The implant material was porous β-tricalcium phosphate (β-TCP) scaffold which was coated with a co-precipitated layer of bone-like hydroxyapatite and Ctp. The β-TCP was impregnated with approximately 0.8%(w/w) Ctp. Then, the Ctp-modified β-TCP was implanted into bone defects of Wistar rats to evaluate in vivo efficacy of Ctp directly delivered from the material to the bone defects. The control was pristine porous β-TCP. In vitro tests showed that Ctp were steadily released from the co-precipitated layer for approximately two weeks. The Ctp-modified scaffolds significantly promoted new bone formation in vivo in their vicinity as compared with pristine β-TCP scaffolds; 6 weeks after the implantation, Ctp-modified scaffolds promoted twice as much bone formation as the control implants. Consequently, we achieved the slow and steady release of Ctp, and found that direct delivery of Ctp from implant materials was effective for bone regeneration as well as oral administration. A β-TCP scaffold capable of slowly releasing bone-enhancing substances significantly promoted bone formation.

Evaluating blood-brain barrier permeability in delayed cerebral infarction after aneurysmal subarachnoid hemorrhage.

PubMed

Ivanidze, J; Kesavabhotla, K; Kallas, O N; Mir, D; Baradaran, H; Gupta, A; Segal, A Z; Claassen, J; Sanelli, P C

2015-05-01

Patients with SAH are at increased risk of delayed infarction. Early detection and treatment of delayed infarction remain challenging. We assessed blood-brain barrier permeability, measured as permeability surface area product, by using CTP in patients with SAH with delayed infarction. We performed a retrospective study of patients with SAH with delayed infarction on follow-up NCCT. CTP was performed before the development of delayed infarction. CTP data were postprocessed into permeability surface area product, CBF, and MTT maps. Coregistration was performed to align the infarcted region on the follow-up NCCT with the corresponding location on the CTP maps obtained before infarction. Permeability surface area product, CBF, and MTT values were then obtained in the location of the subsequent infarction. The contralateral noninfarcted region was compared with the affected side in each patient. Wilcoxon signed rank tests were performed to determine statistical significance. Clinical data were collected at the time of CTP and at the time of follow-up NCCT. Twenty-one patients with SAH were included in the study. There was a statistically significant increase in permeability surface area product in the regions of subsequent infarction compared with the contralateral control regions (P < .0001). However, CBF and MTT values were not significantly different in these 2 regions. Subsequent follow-up NCCT demonstrated new delayed infarction in all 21 patients, at which time 38% of patients had new focal neurologic deficits. Our study reveals a statistically significant increase in permeability surface area product preceding delayed infarction in patients with SAH. Further investigation of early permeability changes in SAH may provide new insights into the prediction of delayed infarction. © 2015 by American Journal of Neuroradiology.

Description of the datasets for the experiments in the paper "solving the multi-vehicle multi-covering tour problem".

PubMed

Pham, Tuan Anh; Hà, Minh Hoàng; Nguyen, Xuan Hoai

2018-06-01

This data article contains data related to the research article entitled, "Solving the multi-vehicle multi-covering tour problem" (Pham et al., 2017) [4]. All data of this article was generated from instances kroA100, kroB100, kroC100, kroD100, kroA200, and kroB200 from TSPLIB. It can be downloaded from public repository. This data can be used as benchmarks for the covering tour problem (CTP) variants, such as m -CTP- p , m -CTP, mm -CTP- p , mm -CTP, mm -CTP-o, mm -CTP-wo. We tested our algorithm on these data and results are shown in Pham et al. (2017) [4].

Low dose CT perfusion in acute ischemic stroke.

PubMed

Murphy, Amanda; So, Aaron; Lee, Ting-Yim; Symons, Sean; Jakubovic, Raphael; Zhang, Liying; Aviv, Richard I

2014-12-01

The purpose of this investigation is to determine if CT perfusion (CTP) measurements at low doses (LD = 20 or 50 mAs) are similar to those obtained at regular doses (RD = 100 mAs), with and without the addition of adaptive statistical iterative reconstruction (ASIR). A single-center, prospective study was performed in patients with acute ischemic stroke (n = 37; 54% male; age = 74 ± 15 years). Two CTP scans were performed on each subject: one at 100 mAs (RD) and one at either 50 or 20 mAs (LD). CTP parameters were compared between the RD and LD scans in regions of ischemia, infarction, and normal tissue. Differences were determined using a within-subjects ANOVA (p < 0.05) followed by a paired t test post hoc analysis (p < 0.01). At 50 mAs, there was no significant difference between cerebral blood flow (CBF), cerebral blood volume (CBV), or time to maximum enhancement (Tmax) values for the RD and LD scans in the ischemic, infarcted, or normal contralateral regions (p < 0.05). At 20 mAs, there were significant differences between the RD and LD scans for all parameters in the ischemic and normal tissue regions (p > 0.05). CTP-derived CBF and CBV are not different at 50 mAs compared to 100 mAs, even without the addition of ASIR. Current CTP protocols can be modified to reduce the effective dose by 50 % without altering CTP measurements.

Configurable Multi-Purpose Processor

NASA Technical Reports Server (NTRS)

Valencia, J. Emilio; Forney, Chirstopher; Morrison, Robert; Birr, Richard

2010-01-01

Advancements in technology have allowed the miniaturization of systems used in aerospace vehicles. This technology is driven by the need for next-generation systems that provide reliable, responsive, and cost-effective range operations while providing increased capabilities such as simultaneous mission support, increased launch trajectories, improved launch, and landing opportunities, etc. Leveraging the newest technologies, the command and telemetry processor (CTP) concept provides for a compact, flexible, and integrated solution for flight command and telemetry systems and range systems. The CTP is a relatively small circuit board that serves as a processing platform for high dynamic, high vibration environments. The CTP can be reconfigured and reprogrammed, allowing it to be adapted for many different applications. The design is centered around a configurable field-programmable gate array (FPGA) device that contains numerous logic cells that can be used to implement traditional integrated circuits. The FPGA contains two PowerPC processors running the Vx-Works real-time operating system and are used to execute software programs specific to each application. The CTP was designed and developed specifically to provide telemetry functions; namely, the command processing, telemetry processing, and GPS metric tracking of a flight vehicle. However, it can be used as a general-purpose processor board to perform numerous functions implemented in either hardware or software using the FPGA s processors and/or logic cells. Functionally, the CTP was designed for range safety applications where it would ultimately become part of a vehicle s flight termination system. Consequently, the major functions of the CTP are to perform the forward link command processing, GPS metric tracking, return link telemetry data processing, error detection and correction, data encryption/ decryption, and initiate flight termination action commands. Also, the CTP had to be designed to survive and operate in a launch environment. Additionally, the CTP was designed to interface with the WFF (Wallops Flight Facility) custom-designed transceiver board which is used in the Low Cost TDRSS Transceiver (LCT2) also developed by WFF. The LCT2 s transceiver board demodulates commands received from the ground via the forward link and sends them to the CTP, where they are processed. The CTP inputs and processes data from the inertial measurement unit (IMU) and the GPS receiver board, generates status data, and then sends the data to the transceiver board where it is modulated and sent to the ground via the return link. Overall, the CTP has combined processing with the ability to interface to a GPS receiver, an IMU, and a pulse code modulation (PCM) communication link, while providing the capability to support common interfaces including Ethernet and serial interfaces boarding a relatively small-sized, lightweight package.

Analytical similarity assessment of rituximab biosimilar CT-P10 to reference medicinal product

PubMed Central

Lee, Kyoung Hoon; Kim, Yeon Jung; Kang, Hyun Ah; Kim, Sung Hwan; Lee, So Jung; Lim, Ki Jung; Jung, Soon Kwan; Chang, Shin Jae

2018-01-01

ABSTRACT CT-P10 (Truxima™) was recently approved as the world's first rituximab biosimilar product in the European Union (EU) and South Korea. To demonstrate biosimilarity of CT-P10 with the reference medicinal product (RMP), extensive 3-way similarity assessment has been conducted between CT-P10, EU-Rituximab and US-Rituximab, focusing on the physicochemical and biological quality attributes. A multitude of state-of-the-art analyses revealed that CT-P10 has identical primary and higher order structures compared to the original product. Purity/impurity profiles of CT-P10 measured by the levels of aggregates, fragments, non-glycosylated form and process-related impurities were also found to be comparable with those of RMPs. In terms of the post-translational modification, CT-P10 contains slightly less N-terminal pyro-glutamate variant, which has been known not to affect product efficacy or safety. Oligosaccharide profiling has revealed that, although CT-P10 contains the same conserved glycan species and relative proportion with the RMPs, the content of total afucosylated glycan in CT-P10 was slightly higher than in EU- or US-Rituximab. Nevertheless, the effect of the observed level of afucosylation in CT-P10 drug product on Fc receptor binding affinity or antibody-dependent cell-mediated cytotoxicity was found to be negligible based on the spiking study with highly afucosylated sample. Arrays of biological assays representative of known and putative mechanisms of action for rituximab have shown that biological activities of CT-P10 are within the quality range of RMPs. Recent results of clinical studies have further confirmed that the CT-P10 exhibits equivalent clinical efficacy and safety profiles compared to EU- and US-Rituximab. The current 3-way similarity assessment together with clinical study results confidently demonstrate that CT-P10 is highly similar with EU- and US-Rituximab in terms of physicochemical properties, biological activities, efficacy, and safety for its final approval as a biosimilar product. PMID:29469653

Analytical similarity assessment of rituximab biosimilar CT-P10 to reference medicinal product.

PubMed

Lee, Kyoung Hoon; Lee, Jihun; Bae, Jin Soo; Kim, Yeon Jung; Kang, Hyun Ah; Kim, Sung Hwan; Lee, So Jung; Lim, Ki Jung; Lee, Jung Woo; Jung, Soon Kwan; Chang, Shin Jae

2018-04-01

CT-P10 (Truxima™) was recently approved as the world's first rituximab biosimilar product in the European Union (EU) and South Korea. To demonstrate biosimilarity of CT-P10 with the reference medicinal product (RMP), extensive 3-way similarity assessment has been conducted between CT-P10, EU-Rituximab and US-Rituximab, focusing on the physicochemical and biological quality attributes. A multitude of state-of-the-art analyses revealed that CT-P10 has identical primary and higher order structures compared to the original product. Purity/impurity profiles of CT-P10 measured by the levels of aggregates, fragments, non-glycosylated form and process-related impurities were also found to be comparable with those of RMPs. In terms of the post-translational modification, CT-P10 contains slightly less N-terminal pyro-glutamate variant, which has been known not to affect product efficacy or safety. Oligosaccharide profiling has revealed that, although CT-P10 contains the same conserved glycan species and relative proportion with the RMPs, the content of total afucosylated glycan in CT-P10 was slightly higher than in EU- or US-Rituximab. Nevertheless, the effect of the observed level of afucosylation in CT-P10 drug product on Fc receptor binding affinity or antibody-dependent cell-mediated cytotoxicity was found to be negligible based on the spiking study with highly afucosylated sample. Arrays of biological assays representative of known and putative mechanisms of action for rituximab have shown that biological activities of CT-P10 are within the quality range of RMPs. Recent results of clinical studies have further confirmed that the CT-P10 exhibits equivalent clinical efficacy and safety profiles compared to EU- and US-Rituximab. The current 3-way similarity assessment together with clinical study results confidently demonstrate that CT-P10 is highly similar with EU- and US-Rituximab in terms of physicochemical properties, biological activities, efficacy, and safety for its final approval as a biosimilar product.

A disruption of ctpA encoding carboxy-terminal protease attenuates Burkholderia mallei and induces partial protection in CD1 mice.

PubMed

Bandara, Aloka B; DeShazer, David; Inzana, Thomas J; Sriranganathan, Nammalwar; Schurig, Gerhardt G; Boyle, Stephen M

2008-09-01

Burkholderia mallei is the etiologic agent of glanders in solipeds (horses, mules and donkeys), and incidentally in carnivores and humans. Little is known about the molecular mechanisms of B. mallei pathogenesis. The putative carboxy-terminal processing protease (CtpA) of B. mallei is a member of a novel family of endoproteases involved in the maturation of proteins destined for the cell envelope. All species and isolates of Burkholderia carry a highly conserved copy of ctpA. We studied the involvement of CtpA on growth, cell morphology, persistence, and pathogenicity of B. mallei. A sucrose-resistant strain of B. mallei was constructed by deleting a major portion of the sacB gene of the wild type strain ATCC 23344 by gene replacement, and designated as strain 23344DeltasacB. A portion of the ctpA gene (encoding CtpA) of strain 23344DeltasacB was deleted by gene replacement to generate strain 23344DeltasacBDeltactpA. In contrast to the wild type ATCC 23344 or the sacB mutant 23344DeltasacB, the ctpA mutant 23344DeltasacBDeltactpA displayed altered cell morphologies with partially or fully disintegrated cell envelopes. Furthermore, relative to the wild type, the ctpA mutant displayed slower growth in vitro and less ability to survive in J774.2 murine macrophages. The expression of mRNA of adtA, the gene downstream of ctpA was similar among the three strains suggesting that disruption of ctpA did not induce any polar effects. As with the wild type or the sacB mutant, the ctpA mutant exhibited a dose-dependent lethality when inoculated intraperitoneally into CD1 mice. The CD1 mice inoculated with a non-lethal dose of the ctpA mutant produced specific serum immunoglobulins IgG1 and IgG2a and were partially protected against challenge with wild type B. mallei ATCC 23344. These findings suggest that CtpA regulates in vitro growth, cell morphology and intracellular survival of B. mallei, and a ctpA mutant protects CD1 mice against glanders.

Effect of increasing the sampling interval to 2 seconds on the radiation dose and accuracy of CT perfusion of the head and neck.

PubMed

Tawfik, Ahmed M; Razek, Ahmed A; Elhawary, Galal; Batouty, Nihal M

2014-01-01

To evaluate the effect of increasing the sampling interval from 1 second (1 image per second) to 2 seconds (1 image every 2 seconds) on computed tomographic (CT) perfusion (CTP) of head and neck tumors. Twenty patients underwent CTP studies of head and neck tumors with images acquired in cine mode for 50 seconds using sampling interval of 1 second. Using deconvolution-based software, analysis of CTP was done with sampling interval of 1 second and then 2 seconds. Perfusion maps representing blood flow, blood volume, mean transit time, and permeability surface area product (PS) were obtained. Quantitative tumor CTP values were compared between the 2 sampling intervals. Two blinded radiologists compared the subjective quality of CTP maps using a 3-point scale between the 2 sampling intervals. Radiation dose parameters were recorded for the 2 sampling interval rates. No significant differences were observed between the means of the 4 perfusion parameters generated using both sampling intervals; all P >0.05. The 95% limits of agreement between the 2 sampling intervals were -65.9 to 48.1) mL/min per 100 g for blood flow, -3.6 to 3.1 mL/100 g for blood volume, -2.9 to 3.8 seconds for mean transit time, and -10.0 to 12.5 mL/min per 100 g for PS. There was no significant difference between the subjective quality scores of CTP maps obtained using the 2 sampling intervals; all P > 0.05. Radiation dose was halved when sampling interval increased from 1 to 2 seconds. Increasing the sampling interval rate to 1 image every 2 seconds does not compromise the image quality and has no significant effect on quantitative perfusion parameters of head and neck tumors. The radiation dose is halved.

Following DNA chain extension and protein conformational changes in crystals of a Y-family DNA polymerase via Raman crystallography.

PubMed

Espinoza-Herrera, Shirly J; Gaur, Vineet; Suo, Zucai; Carey, Paul R

2013-07-23

Y-Family DNA polymerases are known to bypass DNA lesions in vitro and in vivo. Sulfolobus solfataricus DNA polymerase (Dpo4) was chosen as a model Y-family enzyme for investigating the mechanism of DNA synthesis in single crystals. Crystals of Dpo4 in complexes with DNA (the binary complex) in the presence or absence of an incoming nucleotide were analyzed by Raman microscopy. (13)C- and (15)N-labeled d*CTP, or unlabeled dCTP, were soaked into the binary crystals with G as the templating base. In the presence of the catalytic metal ions, Mg(2+) and Mn(2+), nucleotide incorporation was detected by the disappearance of the triphosphate band of dCTP and the retention of *C modes in the crystal following soaking out of noncovalently bound C(or *C)TP. The addition of the second coded base, thymine, was observed by adding cognate dTTP to the crystal following a single d*CTP addition. Adding these two bases caused visible damage to the crystal that was possibly caused by protein and/or DNA conformational change within the crystal. When d*CTP is soaked into the Dpo4 crystal in the absence of Mn(2+) or Mg(2+), the primer extension reaction did not occur; instead, a ternary protein·template·d*CTP complex was formed. In the Raman difference spectra of both binary and ternary complexes, in addition to the modes of d(*C)CTP, features caused by ring modes from the template/primer bases being perturbed and from the DNA backbone appear, as well as features from perturbed peptide and amino acid side chain modes. These effects are more pronounced in the ternary complex than in the binary complex. Using standardized Raman intensities followed as a function of time, the C(*C)TP population in the crystal was maximal at ∼20 min. These remained unchanged in the ternary complex but declined in the binary complexes as chain incorporation occurred.

Development of oral CTL vaccine using a CTP-integrated Sabin 1 poliovirus-based vector system.

PubMed

Han, Seung-Soo; Lee, Jinjoo; Jung, Yideul; Kang, Myeong-Ho; Hong, Jung-Hyub; Cha, Min-Suk; Park, Yu-Jin; Lee, Ezra; Yoon, Cheol-Hee; Bae, Yong-Soo

2015-09-11

We developed a CTL vaccine vector by modification of the RPS-Vax system, a mucosal vaccine vector derived from a poliovirus Sabin 1 strain, and generated an oral CTL vaccine against HIV-1. A DNA fragment encoding a cytoplasmic transduction peptide (CTP) was integrated into the RPS-Vax system to generate RPS-CTP, a CTL vaccine vector. An HIV-1 p24 cDNA fragment was introduced into the RPS-CTP vector system and a recombinant poliovirus (rec-PV) named vRPS-CTP/p24 was produced. vRPS-CTP/p24 was genetically stable and efficiently induced Th1 immunity and p24-specific CTLs in immunized poliovirus receptor-transgenic (PVR-Tg) mice. In challenge experiments, PVR-Tg mice that were pre-immunized orally with vRPS-CTP/p24 were resistant to challenge with a lethal dose of p24-expressing recombinant vaccinia virus (rMVA-p24). These results suggested that the RPS-CTP vector system had potential for developing oral CTL vaccines against infectious diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rust fungal effectors mimic host transit peptides to translocate into chloroplasts.

PubMed

Petre, Benjamin; Lorrain, Cécile; Saunders, Diane G O; Win, Joe; Sklenar, Jan; Duplessis, Sébastien; Kamoun, Sophien

2016-04-01

Parasite effector proteins target various host cell compartments to alter host processes and promote infection. How effectors cross membrane-rich interfaces to reach these compartments is a major question in effector biology. Growing evidence suggests that effectors use molecular mimicry to subvert host cell machinery for protein sorting. We recently identified chloroplast-targeted protein 1 (CTP1), a candidate effector from the poplar leaf rust fungus Melampsora larici-populina that carries a predicted transit peptide and accumulates in chloroplasts and mitochondria. Here, we show that the CTP1 transit peptide is necessary and sufficient for accumulation in the stroma of chloroplasts. CTP1 is part of a Melampsora-specific family of polymorphic secreted proteins. Two members of that family, CTP2 and CTP3, also translocate in chloroplasts in an N-terminal signal-dependent manner. CTP1, CTP2 and CTP3 are cleaved when they accumulate in chloroplasts, while they remain intact when they do not translocate into chloroplasts. Our findings reveal that fungi have evolved effector proteins that mimic plant-specific sorting signals to traffic within plant cells. © 2015 John Wiley & Sons Ltd.

Engineered cytidine triphosphate synthetase with reduced product inhibition.

PubMed

Zhu, Mengzhu; Sun, Wujin; Wang, Yan; Meng, Jie; Zhang, Dalu; Guo, Ting; Ouyang, Pingkai; Ying, Hanjie; Xie, Jingjing

2014-07-01

Cytidine triphosphate (CTP) synthetase (CTPS) (EC number 6.3.4.2) is a key enzyme involved in de novo synthesis of CTP. It catalyzes the rate-limiting step of the process due to the product inhibition effects on the enzyme. In this study, a novel CTPS from Corynebacterium glutamicum ATCC 13032 (CgCTPS) was cloned, expressed and characterized. A series of mutagenesis in its N-terminal ammonia ligase (ALase) domain was performed in order to reduce CTP product inhibition. All single mutation variants (D160E, E162A, E168K) lowered product inhibition by lowering the enzyme's binding affinity for CTP. The homology model of CgCTPS showed that D160E mutant caused steric hindrance for the pyrimidine ring of CTP stacking, E162A disrupted the hydrogen bond between CTP ribose and side chain and D168K caused minor localized structure perturbations of CTP binding pocket. The triple mutant of CTPS (D160E-E162A-E168K) with halved Km, doubled Vmax and the 23.5-fold increased IC50 for CTP shows a potential for use in industrial-scale CTP production by its better performance in enzyme kinetics and product inhibition. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Medical cannabis and mental health: A guided systematic review.

PubMed

Walsh, Zach; Gonzalez, Raul; Crosby, Kim; S Thiessen, Michelle; Carroll, Chris; Bonn-Miller, Marcel O

2017-02-01

This review considers the potential influences of the use of cannabis for therapeutic purposes (CTP) on areas of interest to mental health professionals, with foci on adult psychopathology and assessment. We identified 31 articles relating to the use of CTP and mental health, and 29 review articles on cannabis use and mental health that did not focus on use for therapeutic purposes. Results reflect the prominence of mental health conditions among the reasons for CTP use, and the relative dearth of high-quality evidence related to CTP in this context, thereby highlighting the need for further research into the harms and benefits of medical cannabis relative to other therapeutic options. Preliminary evidence suggests that CTP may have potential for the treatment of PTSD, and as a substitute for problematic use of other substances. Extrapolation from reviews of non-therapeutic cannabis use suggests that the use of CTP may be problematic among individuals with psychotic disorders. The clinical implications of CTP use among individuals with mood disorders are unclear. With regard to assessment, evidence suggests that CTP use does not increase risk of harm to self or others. Acute cannabis intoxication and recent CTP use may result in reversible deficits with the potential to influence cognitive assessment, particularly on tests of short-term memory. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cannabis for therapeutic purposes and public health and safety: a systematic and critical review.

PubMed

Sznitman, Sharon R; Zolotov, Yuval

2015-01-01

The use of Cannabis for Therapeutic Purposes (CTP) has recently become legal in many places. These policy and legal modifications may be related to changes in cannabis perceptions, availability and use and in the way cannabis is grown and sold. This may in turn have effects on public health and safety. To better understand the potential effects of CTP legalization on public health and safety, the current paper synthesizes and critically discusses the relevant literature. Twenty-eight studies were identified by a comprehensive search strategy, and their characteristics and main findings were systematically reviewed according to the following content themes: CTP and illegal cannabis use; CTP and other public health issues; CTP, crime and neighbourhood disadvantage. The research field is currently limited by a lack of theoretical and methodological rigorous studies. The review shows that the most prevalent theme of investigation so far has been the relation between CTP and illegal cannabis use. In addition, the literature review shows that there is an absence of evidence to support many common concerns related to detrimental public health and safety effects of CTP legalization. Although lack of evidence provides some reassurance that CTP legalization may not have posed a substantial threat to public health and safety, this conclusion needs to be examined in light of the limitations of studies conducted so far. Furthermore, as CTP policy continues to evolve, including incorporation of greater commercialization, it is possible that the full effects of CTP legalization have yet to take place. Ensuring study quality will allow future research to better investigate the complex role that CTP plays in relation to society at large, and public health and safety in particular. Copyright © 2014 Elsevier B.V. All rights reserved.

Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study

PubMed Central

Yoo, Dae Hyun; Prodanovic, Nenad; Jaworski, Janusz; Miranda, Pedro; Ramiterre, Edgar; Lanzon, Allan; Baranauskaite, Asta; Wiland, Piotr; Abud-Mendoza, Carlos; Oparanov, Boycho; Smiyan, Svitlana; Kim, HoUng; Lee, Sang Joon; Kim, SuYeon; Park, Won

2017-01-01

Objectives To assess the efficacy and safety of switching from the infliximab reference product (RP; Remicade) to its biosimilar CT-P13 (Remsima, Inflectra) or continuing CT-P13 in patients with rheumatoid arthritis (RA) for an additional six infusions. Methods This open-label extension study recruited patients with RA who had completed the 54-week, randomised, parallel-group study comparing CT-P13 with RP (PLANETRA; NCT01217086). CT-P13 (3 mg/kg) was administered intravenously every 8 weeks from weeks 62 to 102. All patients received concomitant methotrexate. Endpoints included American College of Rheumatology 20% (ACR20) response, ACR50, ACR70, immunogenicity and safety. Data were analysed for patients who received CT-P13 for 102 weeks (maintenance group) and for those who received RP for 54 weeks and then switched to CT-P13 (switch group). Results Overall, 302 of 455 patients who completed the PLANETRA study enrolled into the extension. Of these, 158 had received CT-P13 (maintenance group) and 144 RP (switch group). Response rates at week 102 for maintenance versus switch groups, respectively, were 71.7% vs 71.8% for ACR20, 48.0% vs 51.4% for ACR50 and 24.3% vs 26.1% for ACR70. The proportion of patients with antidrug antibodies was comparable between groups (week 102: 40.3% vs 44.8%, respectively). Treatment-emergent adverse events occurred in similar proportions of patients in the two groups during the extension study (53.5% and 53.8%, respectively). Conclusions Comparable efficacy and tolerability were observed in patients who switched from RP to its biosimilar CT-P13 for an additional year and in those who had long-term CT-P13 treatment for 2 years. Trial registration number NCT01571219; Results. PMID:27130908

Activation and inhibition of CTP synthase from Trypanosoma brucei, the causative agent of African sleeping sickness.

PubMed

Steeves, Craig H; Bearne, Stephen L

2011-09-15

CTP Synthase from Trypanosoma brucei (TbCTPS) catalyzes the conversion of UTP to CTP and is a recognized target for the development of antiprotozoal agents. GTP activates glutamine-dependent CTP formation catalyzed by TbCTPS at concentrations below 0.2 mM, but inhibits this activity at concentrations above 0.2 mM. TbCTPS catalyzes ammonia-dependent CTP formation, which is inhibited by purine derivatives such as GTP, guanosine, caffeine, and uric acid with IC(50) values of 460, 380, 480, and 100 μM, respectively. These observations suggest that the purine ring may serve as a useful scaffold for the development of inhibitors of trypanosomal CTP synthase. Copyright © 2011 Elsevier Ltd. All rights reserved.

Are dispensaries indispensable? Patient experiences of access to cannabis from medical cannabis dispensaries in Canada.

PubMed

Capler, Rielle; Walsh, Zach; Crosby, Kim; Belle-Isle, Lynne; Holtzman, Susan; Lucas, Philippe; Callaway, Robert

2017-09-01

In 2001, Canada established a federal program for cannabis for therapeutic purposes (CTP). Medical cannabis dispensaries (dispensaries) are widely accessed as a source of CTP despite storefront sales of cannabis being illegal. The discrepancy between legal status and social practice has fuelled active debate regarding the role of dispensaries. The present study aims to inform this debate by analysing CTP user experiences with different CTP sources, and comparing dispensary users to those accessing CTP from other sources. We compared sociodemographic characteristics, health related factors and patterns of cannabis use of 445 respondents, 215 who accessed CTP from dispensaries with 230 who accessed other sources. We compared patients' ratings of CTP sources (dispensaries, Health Canada's supplier, self-production, other producer, friend or acquaintance, street dealer) for quality and availability of product, safety and efficiency of access, cost, and feeling respected while accessing. Patients using dispensaries were older, more likely to have arthritis and HIV/AIDS, and less likely to have mental health conditions than those not using dispensaries. Those accessing dispensaries used larger quantities of cannabis, placed greater value on access to specific strains, and were more likely to have legal authorization for CTP. Dispensaries were rated equally to or more favourably than other sources of CTP for quality, safety, availability, efficiency and feeling respected, and less favourably than self-production and other producer for cost. Given the high endorsement of dispensaries by patients, future regulations should consider including dispensaries as a source of CTP and address known barriers to access such as cost and health care provider support. Further research should assess the impact of the addition of licensed producers on the role and perceived value of dispensaries within the Canadian medical cannabis system. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of a realistic, dynamic digital brain phantom for CT perfusion validation

NASA Astrophysics Data System (ADS)

Divel, Sarah E.; Segars, W. Paul; Christensen, Soren; Wintermark, Max; Lansberg, Maarten G.; Pelc, Norbert J.

2016-03-01

Physicians rely on CT Perfusion (CTP) images and quantitative image data, including cerebral blood flow, cerebral blood volume, and bolus arrival delay, to diagnose and treat stroke patients. However, the quantification of these metrics may vary depending on the computational method used. Therefore, we have developed a dynamic and realistic digital brain phantom upon which CTP scans can be simulated based on a set of ground truth scenarios. Building upon the previously developed 4D extended cardiac-torso (XCAT) phantom containing a highly detailed brain model, this work consisted of expanding the intricate vasculature by semi-automatically segmenting existing MRA data and fitting nonuniform rational B-spline surfaces to the new vessels. Using time attenuation curves input by the user as reference, the contrast enhancement in the vessels changes dynamically. At each time point, the iodine concentration in the arteries and veins is calculated from the curves and the material composition of the blood changes to reflect the expected values. CatSim, a CT system simulator, generates simulated data sets of this dynamic digital phantom which can be further analyzed to validate CTP studies and post-processing methods. The development of this dynamic and realistic digital phantom provides a valuable resource with which current uncertainties and controversies surrounding the quantitative computations generated from CTP data can be examined and resolved.

Noise characteristics of CT perfusion imaging: how does noise propagate from source images to final perfusion maps?

NASA Astrophysics Data System (ADS)

Li, Ke; Chen, Guang-Hong

2016-03-01

Cerebral CT perfusion (CTP) imaging is playing an important role in the diagnosis and treatment of acute ischemic strokes. Meanwhile, the reliability of CTP-based ischemic lesion detection has been challenged due to the noisy appearance and low signal-to-noise ratio of CTP maps. To reduce noise and improve image quality, a rigorous study on the noise transfer properties of CTP systems is highly desirable to provide the needed scientific guidance. This paper concerns how noise in the CTP source images propagates to the final CTP maps. Both theoretical deviations and subsequent validation experiments demonstrated that, the noise level of background frames plays a dominant role in the noise of the cerebral blood volume (CBV) maps. This is in direct contradiction with the general belief that noise of non-background image frames is of greater importance in CTP imaging. The study found that when radiation doses delivered to the background frames and to all non-background frames are equal, lowest noise variance is achieved in the final CBV maps. This novel equality condition provides a practical means to optimize radiation dose delivery in CTP data acquisition: radiation exposures should be modulated between background frames and non-background frames so that the above equality condition is satisïnAed. For several typical CTP acquisition protocols, numerical simulations and in vivo canine experiment demonstrated that noise of CBV can be effectively reduced using the proposed exposure modulation method.

Perceptions of cannabis as a stigmatized medicine: a qualitative descriptive study

PubMed Central

2013-01-01

Background Despite its increasing prevalence and acceptance among the general public, cannabis use continues to be viewed as an aberrant activity in many contexts. However, little is known about how stigma associated with cannabis use affects individuals who use cannabis for therapeutic purposes (CTP) and what strategies these individuals employ to manage associated stigma. The aim of this Canadian study was to describe users’ perceptions of and responses to the stigma attached to using CTP. Methods Twenty-three individuals who were using CTP for a range of health problems took part in semi-structured interviews. Transcribed data were analyzed using an inductive approach and comparative strategies to explore participants’ perceptions of CTP and identify themes. Results Participant experiences of stigma were related to negative views of cannabis as a recreational drug, the current criminal sanctions associated with cannabis use, and using cannabis in the context of stigmatizing vulnerability (related to existing illness and disability). Strategies for managing the resulting stigma of using CTP included: keeping CTP ‘undercover’; educating those who did not approve of or understand CTP use; and using cannabis responsibly. Conclusions Understanding how individuals perceive and respond to stigma can inform the development of strategies aimed at reducing stigma associated with the use of CTP and thereby address barriers faced by those using this medicine. PMID:23414118

Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair

DOE PAGES

Andres, Sara N.; Appel, C. Denise; Westmoreland, James W.; ...

2015-01-12

Ctp1 (also known as CtIP or Sae2) collaborates with Mre11-Rad50-Nbs1 to initiate repair of DNA double-strand breaks (DSBs), but its functions remain enigmatic. In this paper, we report that tetrameric Schizosaccharomyces pombe Ctp1 contains multivalent DNA-binding and DNA-bridging activities. Through structural and biophysical analyses of the Ctp1 tetramer, we define the salient features of Ctp1 architecture: an N-terminal interlocking tetrameric helical dimer-of-dimers (THDD) domain and a central intrinsically disordered region (IDR) linked to C-terminal 'RHR' DNA-interaction motifs. The THDD, IDR and RHR are required for Ctp1 DNA-bridging activity in vitro, and both the THDD and RHR are required for efficientmore » DSB repair in S. pombe. Finally, our results establish non-nucleolytic roles of Ctp1 in binding and coordination of DSB-repair intermediates and suggest that ablation of human CtIP DNA binding by truncating mutations underlie the CtIP-linked Seckel and Jawad syndromes.« less

Inventory of File WAFS_blended_2014102006f06.grib2

Science.gov Websites

) [%] 004 700 mb CTP 6 hour fcst In-Cloud Turbulence [%] spatial ave,code table 4.15=3,#points=1 005 700 mb CTP 6 hour fcst In-Cloud Turbulence [%] spatial max,code table 4.15=3,#points=1 006 600 mb CTP 6 hour fcst In-Cloud Turbulence [%] spatial ave,code table 4.15=3,#points=1 007 600 mb CTP 6 hour fcst In

Intravenous thrombolysis in ischemic stroke with unknown onset using CT perfusion.

PubMed

Cortijo, E; García-Bermejo, P; Calleja, A I; Pérez-Fernández, S; Gómez, R; del Monte, J M; Reyes, J; Arenillas, J F

2014-03-01

Acute ischemic stroke patients with unclear onset time presenting >4.5 h from last-seen-normal (LSN) time are considered late patients and excluded from i.v. thrombolysis. We aimed to evaluate whether this subgroup of patients is different from patients presenting >4.5 h from a witnessed onset, in terms of eligibility and response to computed tomography perfusion (CTP)-guided i.v. thrombolysis. We prospectively studied consecutive acute non-lacunar middle cerebral artery (MCA) ischemic stroke patients presenting >4.5 h from LSN. All patients underwent multimodal CT and were considered eligible for i.v. thrombolysis according to CTP criteria. Two patient groups were established based on the knowledge of the stroke onset time. We compared the proportion of candidates suitable for intravenous thrombolysis between both groups, and their outcome after thrombolytic therapy. Among 147 MCA ischemic stroke patients presenting >4.5 h from LSN, stroke onset was witnessed in 74 and unknown in 73. Thirty-seven (50%) patients in the first group and 32 (44%) in the second met CTP criteria for thrombolysis (P = 0.7). Baseline variables were comparable between both groups with the exception of age, which was higher in the unclear onset group. The rates of early neurological improvement (54.1% vs 46.9%), 2-h MCA recanalization (43.5% vs 37%), symptomatic hemorrhagic transformation (3% vs 0%) and good 3-month functional outcome (62.2% vs 56.3%) did not differ significantly between both groups. Delayed stroke patients with unknown onset time were no different than patients >4.5 h regarding eligibility and response to CTP-based i.v. thrombolysis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Novel P1B-type Mn2+-transporting ATPase Is Required for Secreted Protein Metallation in Mycobacteria*

PubMed Central

Padilla-Benavides, Teresita; Long, Jarukit E.; Raimunda, Daniel; Sassetti, Christopher M.; Argüello, José M.

2013-01-01

Transition metals are central for bacterial virulence and host defense. P1B-ATPases are responsible for cytoplasmic metal efflux and play roles either in limiting cytosolic metal concentrations or in the maturation of secreted metalloproteins. The P1B-ATPase, CtpC, is required for Mycobacterium tuberculosis survival in a mouse model (Sassetti, C. M., and Rubin, E. J. (2003) Genetic requirements for mycobacterial survival during infection. Proc. Natl. Acad. Sci. U.S.A. 100, 12989–12994). CtpC prevents Zn2+ toxicity, suggesting a role in Zn2+ export from the cytosol (Botella, H., Peyron, P., Levillain, F., Poincloux, R., Poquet, Y., Brandli, I., Wang, C., Tailleux, L., Tilleul, S., Charriere, G. M., Waddell, S. J., Foti, M., Lugo-Villarino, G., Gao, Q., Maridonneau-Parini, I., Butcher, P. D., Castagnoli, P. R., Gicquel, B., de Chastellièr, C., and Neyrolles, O. (2011) Mycobacterial P1-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe 10, 248–259). However, key metal-coordinating residues and the overall structure of CtpC are distinct from Zn2+-ATPases. We found that isolated CtpC has metal-dependent ATPase activity with a strong preference for Mn2+ over Zn2+. In vivo, CtpC is unable to complement Escherichia coli lacking a functional Zn2+-ATPase. Deletion of M. tuberculosis or Mycobacterium smegmatis ctpC leads to cytosolic Mn2+ accumulation but no alterations in other metals levels. Whereas ctpC-deficient M. tuberculosis is sensitive to extracellular Zn2+, the M. smegmatis mutant is not. Both ctpC mutants are sensitive to oxidative stress, which might explain the Zn2+-sensitive phenotype of the M. tuberculosis ctpC mutant. CtpC is a high affinity/slow turnover ATPase, suggesting a role in protein metallation. Consistent with this hypothesis, mutation of CtpC leads to a decrease of Mn2+ bound to secreted proteins and of the activity of secreted Fe/Mn-superoxide dismutase, particularly in M. smegmatis. Alterations in the assembly of metalloenzymes involved in redox stress response might explain the sensitivity of M. tuberculosis ctpC mutants to oxidative stress and growth and persistence defects in mice infection models. PMID:23482562

Collision and phonation threshold pressures before and after loud, prolonged vocalization in trained and untrained voices.

PubMed

Enflo, Laura; Sundberg, Johan; McAllister, Anita

2013-09-01

The phonation threshold pressure (PTP) is defined as the lowest subglottal pressure needed for obtaining and sustaining vocal fold oscillation. It has been found to increase during vocal fatigue. In the present study, PTP is measured together with the threshold pressure needed for vocal fold collision; henceforth, the collision threshold pressure (CTP). PTP and CTP are compared before and after loud, prolonged vocalization in singer and nonsinger voices. Ten subjects repeated the vowel sequence /a, e, i, o, u/ at a Sound Pressure Level of at least 80 dB at 0.3 m for 20 minutes. Audio and electroglottography signals were recorded before and after this exercise. At the same time, oral pressure was registered while the subjects produced a diminuendo repeating the syllable /pa:/, thus acquiring an approximate of the subglottal pressure. CTP and PTP increased significantly after the vocal loading in the nonsinger subjects. On the other hand, singers reported no substantial effect of the exercise, and most singers had a mean after-to-before ratio close to 1 for both CTP and PTP. Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo.

PubMed

Bapiro, T E; Frese, K K; Courtin, A; Bramhall, J L; Madhu, B; Cook, N; Neesse, A; Griffiths, J R; Tuveson, D A; Jodrell, D I; Richards, F M

2014-07-15

The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS(G12D); p53(R172H); pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo.

Comparable Immune Function Inhibition by the Infliximab Biosimilar CT-P13: Implications for Treatment of Inflammatory Bowel Disease.

PubMed

Lim, Ki Jung; Lee, So Jung; Kim, Sunghwan; Lee, Su Yeon; Lee, Min Seob; Park, Yoon A; Choi, Eun Jin; Lee, Eun Beom; Jun, Hwang Keun; Cho, Jong Moon; Lee, SooYoung; Kwon, Ki Sung; Lim, Byung Pil; Jeon, Myung-Shin; Shin, Eui Cheol; Choi, Yong Sung; Fudim, Ella; Picard, Orit; Yavzori, Miri; Ben-Horin, Shomron; Chang, Shin Jae

2017-05-01

CT-P13 is the first biosimilar monoclonal antibody to infliximab, and was recently approved in the European Union, Japan, Korea, and USA for all six indications of infliximab. However, studies directly assessing the biologic activity of CT-P13 versus inflximab in the context of inflammatory bowel disease [IBD] are still scanty. In the present study, we aimed to compare the biological activities of CT-P13 and infliximab with specific focus on intestinal cells so as to gain insight into the potential biosimilarity of these two agents for treatment of IBD. CT-P13 and infliximab were investigated and compared by in vitro experiments for their neutralisation ability of soluble tumour necrosis factor alpha [sTNFα] and membrane-bound tumour necrosis factor alpha [mTNFα], suppression of cytokine release by reverse signalling, induction of regulatory macrophages and wound healing, and antibody-dependent cell cytotoxicity [ADCC]. CT-P13 showed similar biological activities to infliximab as gauged by neutralisation of soluble TNFα, as well as blockade of apoptosis and suppression of pro-inflammatory cytokines in intestinal Caco-2 cells. Infliximab and CT-P13 equally induced apoptosis and outside-to-inside signals through transmembrane TNFα [tmTNFα]. Moreover, regulatory macrophage induction and ensuing wound healing were similarly exerted by CT-P13 and infliximab. However, neither CT-P13 nor infliximab exerted any significant ADCC of ex vivo-stimulated peripheral blood monocytes or lamina propria mononuclear cells from IBD patients. These findings indicate that CT-P13 and infliximab exert highly similar biological activities in intestinal cells, and further support a mechanistic comparability of these two drugs in the treatment of IBD. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study

PubMed Central

Park, Won; Yoo, Dae Hyun; Miranda, Pedro; Brzosko, Marek; Wiland, Piotr; Gutierrez-Ureña, Sergio; Mikazane, Helena; Lee, Yeon-Ah; Smiyan, Svitlana; Lim, Mie-Jin; Kadinov, Vladimir; Abud-Mendoza, Carlos; Kim, HoUng; Lee, Sang Joon; Bae, YunJu; Kim, SuYeon; Braun, Jürgen

2017-01-01

Objectives To investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS). Methods This open-label extension study recruited patients with AS who completed a 54-week, randomised controlled study comparing CT-P13 with RP (PLANETAS). CT-P13 (5 mg/kg) was administered intravenously every 8 weeks from week 62 to week 102. Efficacy end points included the proportion of patients achieving Assessment of SpondyloArthritis international Society (ASAS)20. Antidrug antibodies (ADAs) were measured using an electrochemiluminescent method. Data were analysed for patients treated with CT-P13 in the main PLANETAS study and the extension (maintenance group) and those who were switched to CT-P13 during the extension study (switch group). Results Overall, 174 (82.9%) of 210 patients who completed the first 54 weeks of PLANETAS and agreed to participate in the extension were enrolled. Among these, 88 were maintained on CT-P13 and 86 were switched to CT-P13 from RP. In these maintenance and switch groups, respectively, ASAS20 response rates at week 102 were 80.7% and 76.9%. ASAS40 and ASAS partial remission were also similar between groups. ADA positivity rates were comparable (week 102: 23.3% vs 27.4%). Adverse events led to treatment discontinuation during the extension study in 3 (3.3%) and 4 (4.8%) patients, respectively. Conclusions This is the first study to show that switching from RP to its biosimilar CT-P13 is possible without negative effects on safety or efficacy in patients with AS. In the maintenance group, CT-P13 was effective and well tolerated over 2 years of treatment. Trial registration number NCT01571206; Results. PMID:27117698

Diagnostic accuracy of semi-automatic quantitative metrics as an alternative to expert reading of CT myocardial perfusion in the CORE320 study.

PubMed

Ostovaneh, Mohammad R; Vavere, Andrea L; Mehra, Vishal C; Kofoed, Klaus F; Matheson, Matthew B; Arbab-Zadeh, Armin; Fujisawa, Yasuko; Schuijf, Joanne D; Rochitte, Carlos E; Scholte, Arthur J; Kitagawa, Kakuya; Dewey, Marc; Cox, Christopher; DiCarli, Marcelo F; George, Richard T; Lima, Joao A C

To determine the diagnostic accuracy of semi-automatic quantitative metrics compared to expert reading for interpretation of computed tomography perfusion (CTP) imaging. The CORE320 multicenter diagnostic accuracy clinical study enrolled patients between 45 and 85 years of age who were clinically referred for invasive coronary angiography (ICA). Computed tomography angiography (CTA), CTP, single photon emission computed tomography (SPECT), and ICA images were interpreted manually in blinded core laboratories by two experienced readers. Additionally, eight quantitative CTP metrics as continuous values were computed semi-automatically from myocardial and blood attenuation and were combined using logistic regression to derive a final quantitative CTP metric score. For the reference standard, hemodynamically significant coronary artery disease (CAD) was defined as a quantitative ICA stenosis of 50% or greater and a corresponding perfusion defect by SPECT. Diagnostic accuracy was determined by area under the receiver operating characteristic curve (AUC). Of the total 377 included patients, 66% were male, median age was 62 (IQR: 56, 68) years, and 27% had prior myocardial infarction. In patient based analysis, the AUC (95% CI) for combined CTA-CTP expert reading and combined CTA-CTP semi-automatic quantitative metrics was 0.87(0.84-0.91) and 0.86 (0.83-0.9), respectively. In vessel based analyses the AUC's were 0.85 (0.82-0.88) and 0.84 (0.81-0.87), respectively. No significant difference in AUC was found between combined CTA-CTP expert reading and CTA-CTP semi-automatic quantitative metrics in patient based or vessel based analyses(p > 0.05 for all). Combined CTA-CTP semi-automatic quantitative metrics is as accurate as CTA-CTP expert reading to detect hemodynamically significant CAD. Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.

The Pseudomonas aeruginosa Periplasmic Protease CtpA Can Affect Systems That Impact Its Ability To Mount Both Acute and Chronic Infections

PubMed Central

Seo, Jin

2013-01-01

Proteases play important roles in the virulence of Pseudomonas aeruginosa. Some are exported to act on host targets and facilitate tissue destruction and bacterial dissemination. Others work within the bacterial cell to process virulence factors and regulate virulence gene expression. Relatively little is known about the role of one class of bacterial serine proteases known as the carboxyl-terminal processing proteases (CTPs). The P. aeruginosa genome encodes two CTPs annotated as PA3257/Prc and PA5134/CtpA in strain PAO1. Prc degrades mutant forms of the anti-sigma factor MucA to promote mucoidy in some cystic fibrosis lung isolates. However, nothing is known about the role or importance of CtpA. We have now found that endogenous CtpA is a soluble periplasmic protein and that a ctpA null mutant has specific phenotypes consistent with an altered cell envelope. Although a ctpA null mutation has no major effect on bacterial growth in the laboratory, CtpA is essential for the normal function of the type 3 secretion system (T3SS), for cytotoxicity toward host cells, and for virulence in a mouse model of acute pneumonia. Conversely, increasing the amount of CtpA above its endogenous level induces an uncharacterized extracytoplasmic function sigma factor regulon, an event that has been reported to attenuate P. aeruginosa in a rat model of chronic lung infection. Therefore, a normal level of CtpA activity is critical for T3SS function and acute virulence, whereas too much activity can trigger an apparent stress response that is detrimental to chronic virulence. PMID:24082078

Collaborative trial validation studies of real-time PCR-based GMO screening methods for detection of the bar gene and the ctp2-cp4epsps construct.

PubMed

Grohmann, Lutz; Brünen-Nieweler, Claudia; Nemeth, Anne; Waiblinger, Hans-Ulrich

2009-10-14

Polymerase Chain Reaction (PCR)-based screening methods targeting genetic elements commonly used in genetically modified (GM) plants are important tools for the detection of GM materials in food, feed, and seed samples. To expand and harmonize the screening capability of enforcement laboratories, the German Federal Office of Consumer Protection and Food Safety conducted collaborative trials for interlaboratory validation of real-time PCR methods for detection of the phosphinothricin acetyltransferase (bar) gene from Streptomyces hygroscopicus and a construct containing the 5-enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium tumefaciens sp. strain CP4 (ctp2-cp4epsps), respectively. To assess the limit of detection, precision, and accuracy of the methods, laboratories had to analyze two sets of 18 coded genomic DNA samples of events LLRice62 and MS8 with the bar method and NK603 and GT73 with the ctp2-cp4epsps method at analyte levels of 0, 0.02, and 0.1% GM content, respectively. In addition, standard DNAs were provided to the laboratories to generate calibration curves for copy number quantification of the bar and ctp2-cp4epsps target sequences present in the test samples. The study design and the results obtained are discussed with respect to the difficult issue of developing general guidelines and concepts for the collaborative trial validation of qualitative PCR screening methods.

Lexical retrieval in discourse: An early indicator of Alzheimer's dementia

PubMed Central

Pekkala, Seija; Wiener, Debra; Himali, Jayandra J.J.; Beiser, Alexa S.; Obler, Loraine K.; Liu, Yulin; McKee, Ann; Auerbach, Sanford; Seshadri, Sudha; Wolf, Philip A.; Au, Rhoda

2014-01-01

We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS), and written description of the Cookie Theft Picture (CTP). Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7–9 years prior to death and FAS and BNT only at 2–4 years. These results suggest that lexical-retrieval deficits in written discourse serve as an early indicator of AD. PMID:23985011

Lexical retrieval in discourse: an early indicator of Alzheimer's dementia.

PubMed

Pekkala, Seija; Wiener, Debra; Himali, Jayandra J; Beiser, Alexa S; Obler, Loraine K; Liu, Yulin; McKee, Ann; Auerbach, Sanford; Seshadri, Sudha; Wolf, Philip A; Au, Rhoda

2013-12-01

We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS) and written description of the Cookie Theft Picture (CTP). Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7-9 years prior to death and FAS and BNT only at 2-4 years. These results suggest that lexical-retrieval deficits in written discourse serve as an early indicator of AD.

Identification and Characterization of the Nuclear Isoform of Drosophila melanogaster CTP:Phosphocholine Cytidylyltransferase

USDA-ARS?s Scientific Manuscript database

CTP:phosphocholine cytidylyltransferase (CCT) catalyzes the conversion of phosphocholine and cytidine 5'-triphosphate (CTP) to CDP-choline for the eventual synthesis of phosphatidylcholine (PC). The enzyme is regulated by reversible association with cellular membranes, with the rate of catalysis in...

Quantification of the Effect of Shuttling on Computed Tomography Perfusion Parameters by Investigation of Aortic Inputs on Different Table Positions From Shuttle-Mode Scans of Lung and Liver Tumors.

PubMed

Ghosh, Payel; Chandler, Adam G; Hobbs, Brian P; Sun, Jia; Rong, John; Hong, David; Subbiah, Vivek; Janku, Filip; Naing, Aung; Hwu, Wen-Jen; Ng, Chaan S

The aim of this study was to quantify the effect of shuttling on computed tomography perfusion (CTp) parameters derived from shuttle-mode body CT images using aortic inputs from different table positions. Axial shuttle-mode CT scans were acquired from 6 patients (10 phases, 2 nonoverlapping table positions 1.4 seconds apart) after contrast agent administration. Artifacts resulting from the shuttling motion were corrected with nonrigid registration before computing CTp maps from 4 aortic levels chosen from the most superior and inferior slices of each table position scan. The effect of shuttling on CTp parameters was estimated by mean differences in mappings obtained from aortic inputs in different table positions. Shuttling effect was also quantified using 95% limits of agreement of CTp parameter differences within-table and between-table aortic positions from the interaortic mean CTp values. Blood flow, permeability surface, and hepatic arterial fraction differences were insignificant (P > 0.05) for both within-table and between-table comparisons. The 95% limits of agreement for within-table blood volume (BV) value deviations obtained from lung tumor regions were less than 4.7% (P = 0.18) compared with less than 12.2% (P = 0.003) for between-table BV value deviations. The 95% limits of agreement of within-table deviations for liver tumor regions were less than 1.9% (P = 0.55) for BV and less than 3.2% (P = 0.23) for mean transit time, whereas between-table BV and mean transit time deviations were less than 11.7% (P < 0.01) and less than 14.6% (P < 0.01), respectively. Values for normal liver tissue regions were concordant. Computed tomography perfusion parameters acquired from aortic levels within-table positions generally yielded higher agreement than mappings obtained from aortic levels between-table positions indicating differences due to shuttling effect.

Computed Tomographic Perfusion Predicts Poor Outcomes in a Randomized Trial of Endovascular Therapy.

PubMed

Wannamaker, Robert; Guinand, Taurian; Menon, Bijoy K; Demchuk, Andrew; Goyal, Mayank; Frei, Donald; Bharatha, Aditya; Jovin, Tudor G; Shankar, Jai; Krings, Timo; Baxter, Blaise; Holmstedt, Christine; Swartz, Richard; Dowlatshahi, Dar; Chan, Richard; Tampieri, Donatella; Choe, Hana; Burns, Paul; Gentile, Nina; Rempel, Jeremy; Shuaib, Ashfaq; Buck, Brian; Bivard, Andrew; Hill, Michael; Butcher, Kenneth

2018-06-01

In the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times), patients with large vessel occlusions and small infarct cores identified with computed tomography (CT)/CT angiography were randomized to endovascular therapy or standard of care. CT perfusion (CTP) was obtained in some cases but was not used to select patients. We tested the hypothesis that patients with penumbral CTP patterns have higher rates of good clinical outcome. All CTP data acquired in ESCAPE patients were analyzed centrally using a semiautomated perfusion threshold-based approach. A penumbral pattern was defined as an infarct core <70 mL, penumbral volume >15 mL, and a total hypoperfused volume:core volume ratio of >1.8. The primary outcome was good functional outcome at 90 days (modified Rankin Scale score, 0-2). CTP was acquired in 138 of 316 ESCAPE patients. Penumbral patterns were present in 116 of 128 (90.6%) of patients with interpretable CTP data. The rate of good functional outcome in penumbral pattern patients (53 of 114; 46%) was higher than that in nonpenumbral patients (2 of 12; 17%; P =0.041). In penumbral patients, endovascular therapy increased the likelihood of a good clinical outcome (34 of 58; 57%) compared with those in the control group (19 of 58; 33%; odds ratio, 2.68; 95% confidence interval, 1.25-5.76; P =0.011). Only 3 of 12 nonpenumbral patients were randomized to the endovascular group, preventing an analysis of treatment effect. The majority of patients with CTP imaging in the ESCAPE trial had penumbral patterns, which were associated with better outcomes overall. Patients with penumbra treated with endovascular therapy had the greatest odds of good functional outcome. Nonpenumbral patients were much less likely to achieve good outcomes. © 2018 American Heart Association, Inc.

Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo

PubMed Central

Bapiro, T E; Frese, K K; Courtin, A; Bramhall, J L; Madhu, B; Cook, N; Neesse, A; Griffiths, J R; Tuveson, D A; Jodrell, D I; Richards, F M

2014-01-01

Background: The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRASG12D; p53R172H; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. Methods: LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. Results: In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. Conclusions: GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo. PMID:24874484

Reference materials for cellular therapeutics.

PubMed

Bravery, Christopher A; French, Anna

2014-09-01

The development of cellular therapeutics (CTP) takes place over many years, and, where successful, the developer will anticipate the product to be in clinical use for decades. Successful demonstration of manufacturing and quality consistency is dependent on the use of complex analytical methods; thus, the risk of process and method drift over time is high. The use of reference materials (RM) is an established scientific principle and as such also a regulatory requirement. The various uses of RM in the context of CTP manufacturing and quality are discussed, along with why they are needed for living cell products and the analytical methods applied to them. Relatively few consensus RM exist that are suitable for even common methods used by CTP developers, such as flow cytometry. Others have also identified this need and made proposals; however, great care will be needed to ensure any consensus RM that result are fit for purpose. Such consensus RM probably will need to be applied to specific standardized methods, and the idea that a single RM can have wide applicability is challenged. Written standards, including standardized methods, together with appropriate measurement RM are probably the most appropriate way to define specific starting cell types. The characteristics of a specific CTP will to some degree deviate from those of the starting cells; consequently, a product RM remains the best solution where feasible. Each CTP developer must consider how and what types of RM should be used to ensure the reliability of their own analytical measurements. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Compliance through pollution prevention opportunity assessments at Edwards AFB -- Development, results and lessons learned

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

Beutelman, H.P.; Lawrence, A.

1999-07-01

Edwards Air Force Base (AFB), located in the Mojave Desert of southern California, is required to comply with environmental requirements for air pollution emissions, hazardous waste disposal, and clean water. The resources required to meet these many compliance requirements represents an ever increasing financial burden to the base, and to the Department of Defense. A recognized superior approach to environmental management is to achieve compliance through a proactive pollution prevention (P2) program which mitigates, and when possible, eliminates compliance requirements and costs, while at the same time reducing pollution released to the environment. At Edwards AFB, the Environmental Management Officemore » P2 Branch developed and implemented a strategy that addresses this concept, better known as Compliance Through Pollution Prevention (CTP2). At the 91st AWMA Annual Meeting and Exhibition, Edwards AFB presented a paper on its strategy and implementation of its CTP2 concept. Part of that strategy and implementation included accomplishment of process specific focused P2 opportunity assessments (OAs). Starting in 1998, Edwards AFB initiated a CTP2 OA project where OAs were targeted on those operational processes, identified as compliance sites, that contributed most to the compliance requirements and costs at Edwards AFB. The targeting of these compliance sites was accomplished by developing a compliance matrix that prioritized processes in accordance with an operational risk management approach. The Edwards AFB CTP2 PPOA project is the first of its kind within the Air Force Material Command, and is serving as a benchmark for establishment of the CTP2 OA process.« less

Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study.

PubMed

Park, Won; Yoo, Dae Hyun; Miranda, Pedro; Brzosko, Marek; Wiland, Piotr; Gutierrez-Ureña, Sergio; Mikazane, Helena; Lee, Yeon-Ah; Smiyan, Svitlana; Lim, Mie-Jin; Kadinov, Vladimir; Abud-Mendoza, Carlos; Kim, HoUng; Lee, Sang Joon; Bae, YunJu; Kim, SuYeon; Braun, Jürgen

2017-02-01

To investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS). This open-label extension study recruited patients with AS who completed a 54-week, randomised controlled study comparing CT-P13 with RP (PLANETAS). CT-P13 (5 mg/kg) was administered intravenously every 8 weeks from week 62 to week 102. Efficacy end points included the proportion of patients achieving Assessment of SpondyloArthritis international Society (ASAS)20. Antidrug antibodies (ADAs) were measured using an electrochemiluminescent method. Data were analysed for patients treated with CT-P13 in the main PLANETAS study and the extension (maintenance group) and those who were switched to CT-P13 during the extension study (switch group). Overall, 174 (82.9%) of 210 patients who completed the first 54 weeks of PLANETAS and agreed to participate in the extension were enrolled. Among these, 88 were maintained on CT-P13 and 86 were switched to CT-P13 from RP. In these maintenance and switch groups, respectively, ASAS20 response rates at week 102 were 80.7% and 76.9%. ASAS40 and ASAS partial remission were also similar between groups. ADA positivity rates were comparable (week 102: 23.3% vs 27.4%). Adverse events led to treatment discontinuation during the extension study in 3 (3.3%) and 4 (4.8%) patients, respectively. This is the first study to show that switching from RP to its biosimilar CT-P13 is possible without negative effects on safety or efficacy in patients with AS. In the maintenance group, CT-P13 was effective and well tolerated over 2 years of treatment. NCT01571206; 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/.

Appropriate use of CT perfusion following aneurysmal subarachnoid hemorrhage: a Bayesian analysis approach.

PubMed

Killeen, R P; Gupta, A; Delaney, H; Johnson, C E; Tsiouris, A J; Comunale, J; Fink, M E; Mangat, H S; Segal, A Z; Mushlin, A I; Sanelli, P C

2014-03-01

In recent years CTP has been used as a complementary diagnostic tool in the evaluation of delayed cerebral ischemia and vasospasm. Our aim was to determine the test characteristics of CTP for detecting delayed cerebral ischemia and vasospasm in SAH, and then to apply Bayesian analysis to identify subgroups for its appropriate use. Our retrospective cohort comprised consecutive patients with SAH and CTP performed between days 6 and 8 following aneurysm rupture. Delayed cerebral ischemia was determined according to primary outcome measures of infarction and/or permanent neurologic deficits. Vasospasm was determined by using DSA. The test characteristics of CTP and its 95% CIs were calculated. Graphs of conditional probabilities were constructed by using Bayesian techniques. Local treatment thresholds (posttest probability of delayed cerebral ischemia needed to initiate induced hypertension, hypervolemia, and hemodilution or intra-arterial therapy) were determined via a survey of 6 independent neurologists. Ninety-seven patients with SAH were included in the study; 39% (38/97) developed delayed cerebral ischemia. Qualitative CTP deficits were seen in 49% (48/97), occurring in 84% (32/38) with delayed cerebral ischemia and 27% (16/59) without. The sensitivity, specificity, and positive and negative predictive values (95% CI) for CTP were 0.84 (0.73-0.96), 0.73 (0.62-0.84), 0.67 (0.51-0.79), and 0.88 (0.74-0.94), respectively. A subgroup of 57 patients underwent DSA; 63% (36/57) developed vasospasm. Qualitative CTP deficits were seen in 70% (40/57), occurring in 97% (35/36) with vasospasm and 23% (5/21) without. The sensitivity, specificity, and positive and negative predictive values (95% CI) for CTP were 0.97 (0.92-1.0), 0.76 (0.58-0.94), 0.88 (0.72-0.95), and 0.94 (0.69-0.99), respectively. Treatment thresholds were determined as 30% for induced hypertension, hypervolemia, and hemodilution and 70% for intra-arterial therapy. Positive CTP findings identify patients who should be carefully considered for induced hypertension, hypervolemia, and hemodilution and/or intra-arterial therapy while negative CTP findings are useful in guiding a no-treatment decision.

Pilot study comparing the Childhood Arthritis & Rheumatology Research Alliance (CARRA) systemic Juvenile Idiopathic Arthritis Consensus Treatment Plans.

PubMed

Kimura, Yukiko; Grevich, Sriharsha; Beukelman, Timothy; Morgan, Esi; Nigrovic, Peter A; Mieszkalski, Kelly; Graham, T Brent; Ibarra, Maria; Ilowite, Norman; Klein-Gitelman, Marisa; Onel, Karen; Prahalad, Sampath; Punaro, Marilynn; Ringold, Sarah; Toib, Dana; Van Mater, Heather; Weiss, Jennifer E; Weiss, Pamela F; Schanberg, Laura E

2017-04-11

To assess the feasibility of studying the comparative effectiveness of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans (CTPs) for systemic Juvenile Idiopathic Arthritis (JIA) using an observational registry. Untreated systemic JIA patients enrolled in the CARRA Registry were begun on one of 4 CTPs chosen by the treating physician and patient/family (glucocorticoid [GC] alone; methotrexate [MTX] ± GC; IL1 inhibitor [IL1i] ± GC; IL6 inhibitor [IL6i] ± GC). The primary outcome of clinical inactive disease (CID) without current GC use was assessed at 9 months. clinicaltrials.gov NCT01697254; first registered 9/28/12 (retrospectively enrolled). Thirty patients were enrolled at 13 sites; eight patients were started on a non-biologic CTP (2 GC, 6 MTX) and 22 patients on a biologic CTP (12 IL1i, 10 IL6i) at disease onset. Demographic and disease features were similar between CTP groups. CTP choice appeared to segregate by site preference. CID off GC was achieved by 37% (11 of 30) including 11/22 (50%) starting a biologic CTP compared to 0/8 starting a non-biologic CTP (p = 0.014). There were four serious adverse events: two infections, one appendicitis and one macrophage activation syndrome. The CARRA systemic JIA CTP pilot study demonstrated successful implementation of CTPs using the CARRA registry infrastructure. Having demonstrated feasibility, a larger study using CTP response to better determine the relative effectiveness of treatments for new-onset systemic JIA is now underway.

Quantification of myocardial blood flow using dynamic 320-row multi-detector CT as compared with ¹⁵O-H₂O PET.

PubMed

Kikuchi, Yasuka; Oyama-Manabe, Noriko; Naya, Masanao; Manabe, Osamu; Tomiyama, Yuuki; Sasaki, Tsukasa; Katoh, Chietsugu; Kudo, Kohsuke; Tamaki, Nagara; Shirato, Hiroki

2014-07-01

This study introduces a method to calculate myocardium blood flow (MBF) and coronary flow reserve (CFR) using the relatively low-dose dynamic 320-row multi-detector computed tomography (MDCT), validates the method against (15)O-H₂O positron-emission tomography (PET) and assesses the CFRs of coronary artery disease (CAD) patients. Thirty-two subjects underwent both dynamic CT perfusion (CTP) and PET perfusion imaging at rest and during pharmacological stress. In 12 normal subjects (pilot group), the calculation method for MBF and CFR was established. In the other 13 normal subjects (validation group), MBF and CFR obtained by dynamic CTP and PET were compared. Finally, the CFRs obtained by dynamic CTP and PET were compared between the validation group and CAD patients (n = 7). Correlation between MBF of MDCT and PET was strong (r = 0.95, P < 0.0001). CFR showed good correlation between dynamic CTP and PET (r = 0.67, P = 0.0126). CFRCT in the CAD group (2.3 ± 0.8) was significantly lower than that in the validation group (5.2 ± 1.8) (P = 0.0011). We established a method for measuring MBF and CFR with the relatively low-dose dynamic MDCT. Lower CFR was well demonstrated in CAD patients by dynamic CTP. • MBF and CFR can be calculated using dynamic CTP with 320-row MDCT. • MBF and CFR showed good correlation between dynamic CTP and PET. • Lower CFR was well demonstrated in CAD patients by dynamic CTP.

Assessing the short- and long-term prognosis of patients with cirrhosis and acute variceal bleeding.

PubMed

Sempere, L; Palazón, J M; Sánchez-Payá, J; Pascual, S; de Madaria, E; Poveda, M J; Carnicer, F; Zapater, P; Pérez-Mateo, M

2009-04-01

to evaluate the efficacy of various indicators in predicting short- and long-term survival in patients with cirrhosis and acute variceal bleeding. prognostic indicators were calculated for a cohort of 201 cirrhotic patients with acute variceal bleeding hospitalized in our center, a third-level teaching hospital. The studied variables were: age, sex, etiology of cirrhosis, endoscopic findings, previous variceal bleeding episodes, human immunodeficiency virus (HIV) infection, hepatocellular carcinoma (HCC), infection during episode, and Child-Turcotte-Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores within 24 hours of bleeding onset. Patients were followed up for at least 6 months until death, liver transplantation, or end of observation. median follow-up was 66.85 weeks (range 0-432.4). The 6-week, 3-month, 12-month and 36-month mortality rates were 22.9, 24.9, 34.3, and 39.8%, respectively. Age >= 65 years, presence of HCC, CTP score >=10, and MELD score >= 18 were the variables associated with mortality in the multivariate analysis. The accuracy of MELD scores as predictors of 6-week, 3-month, 12-month, and 36-month mortality was better than that of CTP scores (c-statistics: 6 week MELD 0.804, CTP 0.762; 3-month MELD 0.794, CTP 0.760; 12-month MELD 0.766, CTP 0.741; 36 month MELD 0.737, CTP 0.717). MELD and CTP scores together with age and a diagnosis of hepatocellular carcinoma are useful indicators to assess the short- and long-term prognosis of patients with acute variceal bleeding.

Phenotypes of gene disruptants in relation to a putative mitochondrial malate-citrate shuttle protein in citric acid-producing Aspergillus niger.

PubMed

Kirimura, Kohtaro; Kobayashi, Keiichi; Ueda, Yuka; Hattori, Takasumi

2016-09-01

The mitochondrial citrate transport protein (CTP) functions as a malate-citrate shuttle catalyzing the exchange of citrate plus a proton for malate between mitochondria and cytosol across the inner mitochondrial membrane in higher eukaryotic organisms. In this study, for functional analysis, we cloned the gene encoding putative CTP (ctpA) of citric acid-producing Aspergillus niger WU-2223L. The gene ctpA encodes a polypeptide consisting 296 amino acids conserved active residues required for citrate transport function. Only in early-log phase, the ctpA disruptant DCTPA-1 showed growth delay, and the amount of citric acid produced by strain DCTPA-1 was smaller than that by parental strain WU-2223L. These results indicate that the CTPA affects growth and thereby citric acid metabolism of A. niger changes, especially in early-log phase, but not citric acid-producing period. This is the first report showing that disruption of ctpA causes changes of phenotypes in relation to citric acid production in A. niger.

Accuracy of Computed Tomographic Perfusion in Diagnosis of Brain Death: A Prospective Cohort Study.

PubMed

Sawicki, Marcin; Sołek-Pastuszka, Joanna; Chamier-Ciemińska, Katarzyna; Walecka, Anna; Bohatyrewicz, Romuald

2018-05-04

BACKGROUND This study was designed to determine diagnostic accuracy of computed tomographic perfusion (CTP) compared to computed tomographic angiography (CTA) for the diagnosis of brain death (BD). MATERIAL AND METHODS Whole-brain CTP was performed in patients diagnosed with BD and in patients with devastating brain injury with preserved brainstem reflexes. CTA was derived from CTP datasets. Cerebral blood flow (CBF) and volume (CBV) were calculated in all brain regions. CTP findings were interpreted as confirming diagnosis of BD (positive) when CBF and CBV in all ROIs were below 10 mL/100 g/min and 1.0 mL/100 g, respectively. CTA findings were interpreted using a 4-point system. RESULTS Fifty brain-dead patients and 5 controls were included. In brain-dead patients, CTP results revealed CBF 0.00-9.98 mL/100 g/min and CBV 0.00-0.99 mL/100 g, and were thus interpreted as positive in all patients. CTA results suggested 7 negative cases, providing 86% sensitivity. In the non-brain-dead group, CTP results revealed CBF 2.37-37.59 mL/100 g/min and CBV 0.73-2.34 mL/100 g. The difference between values of CBF and CBV in the brain-dead and non-brain-dead groups was statistically significant (p=0.002 for CBF and p=0.001 for CBV). CTP findings in all non-brain-dead patients were interpreted as negative. This resulted in a specificity of 100% (95% CI, 0.31-1.00) for CTP in the diagnosis of BD. In all non-brain-dead patients, CTA revealed preserved intracranial filling and was interpreted as negative. This resulted in a specificity of 100% (95% CI, 0.31-1.00) for CTA in diagnosis of BD. CONCLUSIONS Whole-brain CTP seems to be a highly sensitive and specific method in diagnosis of BD.

The effect of sprinting after each set of heavy resistance training on the running speed and jumping performance of young basketball players.

PubMed

Tsimahidis, Konstantinos; Galazoulas, Christos; Skoufas, Dimitrios; Papaiakovou, Georgios; Bassa, Eleni; Patikas, Dimitrios; Kotzamanidis, Christos

2010-08-01

The purpose of this study was to investigate the effect of a 10-week heavy resistance combined with a running training program on the strength, running speed (RS), and vertical jump performance of young basketball players. Twenty-six junior basketball players were equally divided in 2 groups. The control (CON) group performed only technical preparation and the group that followed the combined training program (CTP) performed additionally 5 sets of 8-5 repetition maximum (RM) half squat with 1 30-m sprint after each set. The evaluation took place before training and after the 5th and 10th weeks of training. Apart from the 1RM half squat test, the 10- and 30-m running time was measured using photocells and the jump height (squat, countermovement jump, and drop jump) was estimated taking into account the flight time. The 1RM increased by 30.3 +/- 1.5% at the 10th week of training for the CTP group (p < 0.05), whereas the CON group showed no significant increase (1.1 +/- 1.6%, p > 0.05). In general, all measured parameters showed a statistically significant increase after the 5th and 10th weeks (p < 0.05), in contrast to the CON group (p > 0.05). This suggests that the applied CTP is beneficial for the strength, RS, and jump height of young basketball players. The observed adaptations in the CTP group could be attributed to learning factors and to a more optimal transfer of the strength gain to running and jumping performance.

Integrated controls and health monitoring for chemical transfer propulsion

NASA Technical Reports Server (NTRS)

Millis, Marc G.; Binder, Michael P.

1990-01-01

NASA is reviewing various propulsion technologies for exploring space. The requirements are examined for one enabling propulsion technology: Integrated Controls and Health Monitoring (ICHM) for Chemical Transfer Propulsion (CTP). Functional requirements for a CTP-ICHM system are proposed from tentative mission scenarios, vehicle configurations, CTP specifications, and technical feasibility. These CTP-ICHM requirements go beyond traditional reliable operation and emergency shutoff control to include: (1) enhanced mission flexibility; (2) continuously variable throttling; (3) tank-head start control; (4) automated prestart and post-shutoff engine check; (5) monitoring of space exposure degradation; and (6) product evolution flexibility. Technology development plans are also discussed.

Direct comparison of rest and adenosine stress myocardial perfusion CT with rest and stress SPECT

PubMed Central

Okada, David R.; Ghoshhajra, Brian B.; Blankstein, Ron; Rocha-Filho, Jose A.; Shturman, Leonid D.; Rogers, Ian S.; Bezerra, Hiram G.; Sarwar, Ammar; Gewirtz, Henry; Hoffmann, Udo; Mamuya, Wilfred S.; Brady, Thomas J.; Cury, Ricardo C.

2010-01-01

Introduction We have recently described a technique for assessing myocardial perfusion using adenosine-mediated stress imaging (CTP) with dual source computed tomography. SPECT myocardial perfusion imaging (SPECT-MPI) is a widely utilized and extensively validated method for assessing myocardial perfusion. The aim of this study was to determine the level of agreement between CTP and SPECT-MPI at rest and under stress on a per-segment, per-vessel, and per-patient basis. Methods Forty-seven consecutive patients underwent CTP and SPECT-MPI. Perfusion images were interpreted using the 17 segment AHA model and were scored on a 0 (normal) to 3 (abnormal) scale. Summed rest and stress scores were calculated for each vascular territory and patient by adding corresponding segmental scores. Results On a per-segment basis (n = 799), CTP and SPECT-MPI demonstrated excellent correlation: Goodman-Kruskall γ = .59 (P < .0001) for stress and .75 (P < .0001) for rest. On a per-vessel basis (n = 141), CTP and SPECT-MPI summed scores demonstrated good correlation: Pearson r = .56 (P < .0001) for stress and .66 (P < .0001) for rest. On a per-patient basis (n = 47), CTP and SPECT-MPI demonstrated good correlation: Pearson r = .60 (P < .0001) for stress and .76 (P < .0001) for rest. Conclusions CTP compares favorably with SPECT-MPI for detection, extent, and severity of myocardial perfusion defects at rest and stress. PMID:19936863

Comprehensive Study of Educational Technology Programs Authorized from 1989-1992. Volume IV: California Technology Project.

ERIC Educational Resources Information Center

Far West Lab. for Educational Research and Development, San Francisco, CA.

This report, the fourth in a series of six, describes the evaluative studies conducted during Phase II of the California Educational Technology Assessment Program, the California Technology Project (CTP), and the CTP Regional Consortia. The report begins with background information on the CTP, starting with the earlier statewide network of…

Biased visualization of hypoperfused tissue by computed tomography due to short imaging duration: improved classification by image down-sampling and vascular models.

PubMed

Mikkelsen, Irene Klærke; Jones, P Simon; Ribe, Lars Riisgaard; Alawneh, Josef; Puig, Josep; Bekke, Susanne Lise; Tietze, Anna; Gillard, Jonathan H; Warburton, Elisabeth A; Pedraza, Salva; Baron, Jean-Claude; Østergaard, Leif; Mouridsen, Kim

2015-07-01

Lesion detection in acute stroke by computed-tomography perfusion (CTP) can be affected by incomplete bolus coverage in veins and hypoperfused tissue, so-called bolus truncation (BT), and low contrast-to-noise ratio (CNR). We examined the BT-frequency and hypothesized that image down-sampling and a vascular model (VM) for perfusion calculation would improve normo- and hypoperfused tissue classification. CTP datasets from 40 acute stroke patients were retrospectively analysed for BT. In 16 patients with hypoperfused tissue but no BT, repeated 2-by-2 image down-sampling and uniform filtering was performed, comparing CNR to perfusion-MRI levels and tissue classification to that of unprocessed data. By simulating reduced scan duration, the minimum scan-duration at which estimated lesion volumes came within 10% of their true volume was compared for VM and state-of-the-art algorithms. BT in veins and hypoperfused tissue was observed in 9/40 (22.5%) and 17/40 patients (42.5%), respectively. Down-sampling to 128 × 128 resolution yielded CNR comparable to MR data and improved tissue classification (p = 0.0069). VM reduced minimum scan duration, providing reliable maps of cerebral blood flow and mean transit time: 5 s (p = 0.03) and 7 s (p < 0.0001), respectively). BT is not uncommon in stroke CTP with 40-s scan duration. Applying image down-sampling and VM improve tissue classification. • Too-short imaging duration is common in clinical acute stroke CTP imaging. • The consequence is impaired identification of hypoperfused tissue in acute stroke patients. • The vascular model is less sensitive than current algorithms to imaging duration. • Noise reduction by image down-sampling improves identification of hypoperfused tissue by CTP.

Clinical Use of CT Perfusion For Diagnosis and Prediction of Lesion Growth in Acute Ischemic Stroke

PubMed Central

Huisa, Branko N; Neil, William P; Schrader, Ronald; Maya, Marcel; Pereira, Benedict; Bruce, Nhu T; Lyden, Patrick D

2012-01-01

Background and Purpose CT perfusion (CTP) mapping in research centers correlates well with diffusion weighted imaging (DWI) lesions and may accurately differentiate the infarct core from ischemic penumbra. The value of CTP in real-world clinical practice has not been fully established. We investigated the yield of CTP– derived cerebral blood volume (CBV) and mean transient time (MTT) for the detection of cerebral ischemia and ischemic penumbra in a sample of acute ischemic stroke (AIS) patients. Methods We studied 165 patients with initial clinical symptoms suggestive of AIS. All patients had an initial non-contrast head CT, CT Perfusion (CTP), CT angiogram (CTA) and follow up brain MRI. The obtained perfusion images were used for image processing. CBV, MTT and DWI lesion volumes were visually estimated and manually traced. Statistical analysis was done using R-2.14.and SAS 9.1. Results All normal DWI sequences had normal CBV and MTT studies (N=89). Seventy-three patients had acute DWI lesions. CBV was abnormal in 23.3% and MTT was abnormal in 42.5% of these patients. There was a high specificity (91.8%)but poor sensitivity (40.0%) for MTT maps predicting positive DWI. Spearman correlation was significant between MTT and DWI lesions (ρ=0.66, p>0.0001) only for abnormal MTT and DWI lesions>0cc. CBV lesions did not correlate with final DWI. Conclusions In real-world use, acute imaging with CTP did not predict stroke or DWI lesions with sufficient accuracy. Our findings argue against the use of CTP for screening AIS patients until real-world implementations match the accuracy reported from specialized research centers. PMID:23253533

Early whole-brain CT perfusion for detection of patients at risk for delayed cerebral ischemia after subarachnoid hemorrhage.

PubMed

Malinova, Vesna; Dolatowski, Karoline; Schramm, Peter; Moerer, Onnen; Rohde, Veit; Mielke, Dorothee

2016-07-01

OBJECT This prospective study investigated the role of whole-brain CT perfusion (CTP) studies in the identification of patients at risk for delayed ischemic neurological deficits (DIND) and of tissue at risk for delayed cerebral infarction (DCI). METHODS Forty-three patients with aneurysmal subarachnoid hemorrhage (aSAH) were included in this study. A CTP study was routinely performed in the early phase (Day 3). The CTP study was repeated in cases of transcranial Doppler sonography (TCD)-measured blood flow velocity (BFV) increase of > 50 cm/sec within 24 hours and/or on Day 7 in patients who were intubated/sedated. RESULTS Early CTP studies revealed perfusion deficits in 14 patients, of whom 10 patients (72%) developed DIND, and 6 of these 10 patients (60%) had DCI. Three of the 14 patients (21%) with early perfusion deficits developed DCI without having had DIND, and the remaining patient (7%) had neither DIND nor DCI. There was a statistically significant correlation between early perfusion deficits and occurrence of DIND and DCI (p < 0.0001). A repeated CTP was performed in 8 patients with a TCD-measured BFV increase > 50 cm/sec within 24 hours, revealing a perfusion deficit in 3 of them (38%). Two of the 3 patients (67%) developed DCI without preceding DIND and 1 patient (33%) had DIND without DCI. In 4 of the 7 patients (57%) who were sedated and/or comatose, additional CTP studies on Day 7 showed perfusion deficits. All 4 patients developed DCI. CONCLUSIONS Whole-brain CTP on Day 3 after aSAH allows early and reliable identification of patients at risk for DIND and tissue at risk for DCI. Additional CTP investigations, guided by TCD-measured BFV increase or persisting coma, do not contribute to information gain.

Value of Computed Tomographic Perfusion-Based Patient Selection for Intra-Arterial Acute Ischemic Stroke Treatment.

PubMed

Borst, Jordi; Berkhemer, Olvert A; Roos, Yvo B W E M; van Bavel, Ed; van Zwam, Wim H; van Oostenbrugge, Robert J; van Walderveen, Marianne A A; Lingsma, Hester F; van der Lugt, Aad; Dippel, Diederik W J; Yoo, Albert J; Marquering, Henk A; Majoie, Charles B L M

2015-12-01

The utility of computed tomographic perfusion (CTP)-based patient selection for intra-arterial treatment of acute ischemic stroke has not been proven in randomized trials and requires further study in a cohort that was not selected based on CTP. Our objective was to study the relationship between CTP-derived parameters and outcome and treatment effect in patients with acute ischemic stroke because of a proximal intracranial arterial occlusion. We included 175 patients who underwent CTP in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN). Association of CTP-derived parameters (ischemic-core volume, penumbra volume, and percentage ischemic core) with outcome was estimated with multivariable ordinal logistic regression as an adjusted odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale. Interaction between CTP-derived parameters and treatment effect was determined using multivariable ordinal logistic regression. Interaction with treatment effect was also tested for mismatch (core <70 mL; penumbra core >1.2; penumbra core >10 mL). The adjusted odds ratio for improved functional outcome for ischemic core, percentage ischemic core, and penumbra were 0.79 per 10 mL (95% confidence interval: 0.71-0.89; P<0.001), 0.82 per 10% (95% confidence interval: 0.66-0.90; P=0.002), and 0.97 per 10 mL (96% confidence interval: 0.92-1.01; P=0.15), respectively. No significant interaction between any of the CTP-derived parameters and treatment effect was observed. We observed no significant interaction between mismatch and treatment effect. CTP seems useful for predicting functional outcome, but cannot reliably identify patients who will not benefit from intra-arterial therapy. © 2015 American Heart Association, Inc.

Comparison of CT perfusion summary maps to early diffusion-weighted images in suspected acute middle cerebral artery stroke.

PubMed

Benson, John; Payabvash, Seyedmehdi; Salazar, Pascal; Jagadeesan, Bharathi; Palmer, Christopher S; Truwit, Charles L; McKinney, Alexander M

2015-04-01

To assess the accuracy and reliability of one vendor's (Vital Images, Toshiba Medical, Minnetonka, MN) automated CT perfusion (CTP) summary maps in identification and volume estimation of infarcted tissue in patients with acute middle cerebral artery (MCA) distribution infarcts. From 1085 CTP examinations over 5.5 years, 43 diffusion-weighted imaging (DWI)-positive patients were included who underwent both CTP and DWI <12 h after symptom onset, with another 43 age-matched patients as controls (DWI-negative). Automated delay-corrected postprocessing software (DC-SVD) generated both infarct "core only" and "core+penumbra" CTP summary maps. Three reviewers independently tabulated Alberta Stroke Program Early CT scores (ASPECTS) of both CTP summary maps and coregistered DWI. Of 86 included patients, 36 had DWI infarct volumes ≤70 ml, 7 had volumes >70 ml, and 43 were negative; the automated CTP "core only" map correctly classified each as >70 ml or ≤70 ml, while the "core+penumbra" map misclassified 4 as >70 ml. There were strong correlations between DWI volume with both summary map-based volumes: "core only" (r=0.93), and "core+penumbra" (r=0.77) (both p<0.0001). Agreement between ASPECTS scores of infarct core on DWI with summary maps was 0.65-0.74 for "core only" map, and 0.61-0.65 for "core+penumbra" (both p<0.0001). Using DWI-based ASPECTS scores as the standard, the accuracy of the CTP-based maps were 79.1-86.0% for the "core only" map, and 83.7-88.4% for "core+penumbra." Automated CTP summary maps appear to be relatively accurate in both the detection of acute MCA distribution infarcts, and the discrimination of volumes using a 70 ml threshold. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

CT myocardial perfusion imaging: current status and future perspectives.

PubMed

Yang, Dong Hyun; Kim, Young-Hak

2017-07-01

Computed tomography myocardial perfusion (CTP) combined with coronary computed tomography angiography (CCTA) may constitute a "1-stop shop" for the noninvasive diagnosis of hemodynamically significant coronary stenosis during a single CT examination. CTP shows high diagnostic performance and provides incremental value over CCTA for the detection of hemodynamically significant coronary stenosis in patients with a high Agatston calcium score or coronary artery stents. Future studies should determine the optimal protocol and clinical value of CTP for guiding revascularization strategy and prognostication. In this article, we review the current status and future perspectives of CTP, focusing on technical considerations, clinical applications, and future research topics.

Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.

PubMed

Manns, Michael; Samuel, Didier; Gane, Edward J; Mutimer, David; McCaughan, Geoff; Buti, Maria; Prieto, Martín; Calleja, José Luis; Peck-Radosavljevic, Markus; Müllhaupt, Beat; Agarwal, Kosh; Angus, Peter; Yoshida, Eric M; Colombo, Massimo; Rizzetto, Mario; Dvory-Sobol, Hadas; Denning, Jill; Arterburn, Sarah; Pang, Phillip S; Brainard, Diana; McHutchison, John G; Dufour, Jean-François; Van Vlierberghe, Hans; van Hoek, Bart; Forns, Xavier

2016-06-01

Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. Gilead Sciences. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synergistic use of MODIS cloud products and AIRS radiance measurements for retrieval of cloud parameters

NASA Astrophysics Data System (ADS)

Li, J.; Menzel, W.; Sun, F.; Schmit, T.

2003-12-01

The Moderate-Resolution Imaging Spectroradiometer (MODIS) and Atmospheric Infrared Sounder (AIRS) measurements from the Earth Observing System's (EOS) Aqua satellite will enable global monitoring of the distribution of clouds. MODIS is able to provide at high spatial resolution (1 ~ 5km) the cloud mask, surface and cloud types, cloud phase, cloud-top pressure (CTP), effective cloud amount (ECA), cloud particle size (CPS), and cloud water path (CWP). AIRS is able to provide CTP, ECA, CPS, and CWP within the AIRS footprint with much better accuracy using its greatly enhanced hyperspectral remote sensing capability. The combined MODIS / AIRS system offers the opportunity for cloud products improved over those possible from either system alone. The algorithm developed was applied to process the AIRS longwave cloudy radiance measurements; results are compared with MODIS cloud products, as well as with the Geostationary Operational Environmental Satellite (GOES) sounder cloud products, to demonstrate the advantage of synergistic use of high spatial resolution MODIS cloud products and high spectral resolution AIRS sounder radiance measurements for optimal cloud retrieval. Data from ground-based instrumentation at the Atmospheric Radiation Measurement (ARM) Program Cloud and Radiation Test Bed (CART) in Oklahoma were used for the validation; results show that AIRS improves the MODIS cloud products in certain cases such as low-level clouds.

Characterization of cytidylyltransferase enzyme activity through high performance liquid chromatography.

PubMed

Brault, James P; Friesen, Jon A

2016-10-01

The cytidylyltransferases are a family of enzymes that utilize cytidine 5'-triphosphate (CTP) to synthesize molecules that are typically precursors to membrane phospholipids. The most extensively studied cytidylyltransferase is CTP:phosphocholine cytidylyltransferase (CCT), which catalyzes conversion of phosphocholine and CTP to cytidine diphosphocholine (CDP-choline), a step critical for synthesis of the membrane phospholipid phosphatidylcholine (PC). The current method used to determine catalytic activity of CCT measures production of radiolabeled CDP-choline from (14)C-labeled phosphocholine. The goal of this research was to develop a CCT enzyme assay that employed separation of non-radioactive CDP-choline from CTP. A C18 reverse phase column with a mobile phase of 0.1 M ammonium bicarbonate (98%) and acetonitrile (2%) (pH 7.4) resulted in separation of solutions of the substrate CTP from the product CDP-choline. A previously characterized truncated version of rat CCTα (denoted CCTα236) was used to test the HPLC enzyme assay by measuring CDP-choline product formation. The Vmax for CCTα236 was 3850 nmol/min/mg and K0.5 values for CTP and phosphocholine were 4.07 mM and 2.49 mM, respectively. The HPLC method was applied to glycerol 3-phosphate cytidylyltransferase (GCT) and CTP:2-C-methyl-D-erythritol-4-phosphate cytidylyltransferase synthetase (CMS), members of the cytidylyltransferase family that produce CDP-glycerol and CDP-methylerythritol, respectively. Copyright © 2016 Elsevier Inc. All rights reserved.

Absolute Cerebral Blood Flow Infarction Threshold for 3-Hour Ischemia Time Determined with CT Perfusion and 18F-FFMZ-PET Imaging in a Porcine Model of Cerebral Ischemia

PubMed Central

Cockburn, Neil; Kovacs, Michael

2016-01-01

CT Perfusion (CTP) derived cerebral blood flow (CBF) thresholds have been proposed as the optimal parameter for distinguishing the infarct core prior to reperfusion. Previous threshold-derivation studies have been limited by uncertainties introduced by infarct expansion between the acute phase of stroke and follow-up imaging, or DWI lesion reversibility. In this study a model is proposed for determining infarction CBF thresholds at 3hr ischemia time by comparing contemporaneously acquired CTP derived CBF maps to 18F-FFMZ-PET imaging, with the objective of deriving a CBF threshold for infarction after 3 hours of ischemia. Endothelin-1 (ET-1) was injected into the brain of Duroc-Cross pigs (n = 11) through a burr hole in the skull. CTP images were acquired 10 and 30 minutes post ET-1 injection and then every 30 minutes for 150 minutes. 370 MBq of 18F-FFMZ was injected ~120 minutes post ET-1 injection and PET images were acquired for 25 minutes starting ~155–180 minutes post ET-1 injection. CBF maps from each CTP acquisition were co-registered and converted into a median CBF map. The median CBF map was co-registered to blood volume maps for vessel exclusion, an average CT image for grey/white matter segmentation, and 18F-FFMZ-PET images for infarct delineation. Logistic regression and ROC analysis were performed on infarcted and non-infarcted pixel CBF values for each animal that developed infarct. Six of the eleven animals developed infarction. The mean CBF value corresponding to the optimal operating point of the ROC curves for the 6 animals was 12.6 ± 2.8 mL·min-1·100g-1 for infarction after 3 hours of ischemia. The porcine ET-1 model of cerebral ischemia is easier to implement then other large animal models of stroke, and performs similarly as long as CBF is monitored using CTP to prevent reperfusion. PMID:27347877

TU-EF-204-02: Hiigh Quality and Sub-MSv Cerebral CT Perfusion Imaging

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

Li, Ke; Niu, Kai; Wu, Yijing

2015-06-15

Purpose: CT Perfusion (CTP) imaging is of great importance in acute ischemic stroke management due to its potential to detect hypoperfused yet salvageable tissue and distinguish it from definitely unsalvageable tissue. However, current CTP imaging suffers from poor image quality and high radiation dose (up to 5 mSv). The purpose of this work was to demonstrate that technical innovations such as Prior Image Constrained Compressed Sensing (PICCS) have the potential to address these challenges and achieve high quality and sub-mSv CTP imaging. Methods: (1) A spatial-temporal 4D cascaded system model was developed to indentify the bottlenecks in the current CTPmore » technology; (2) A task-based framework was developed to optimize the CTP system parameters; (3) Guided by (1) and (2), PICCS was customized for the reconstruction of CTP source images. Digital anthropomorphic perfusion phantoms, animal studies, and preliminary human subject studies were used to validate and evaluate the potentials of using these innovations to advance the CTP technology. Results: The 4D cascaded model was validated in both phantom and canine stroke models. Based upon this cascaded model, it has been discovered that, as long as the spatial resolution and noise properties of the 4D source CT images are given, the 3D MTF and NPS of the final CTP maps can be analytically derived for a given set of processing methods and parameters. The cascaded model analysis also identified that the most critical technical factor in CTP is how to acquire and reconstruct high quality source images; it has very little to do with the denoising techniques often used after parametric perfusion calculations. This explained why PICCS resulted in a five-fold dose reduction or substantial improvement in image quality. Conclusion: Technical innovations generated promising results towards achieving high quality and sub-mSv CTP imaging for reliable and safe assessment of acute ischemic strokes. K. Li, K. Niu, Y. Wu: Nothing to disclose. G.-H. Chen: Research funded, GE Healthcare; Research funded, Siemens AX.« less

Comparison of the pharmacokinetics and safety of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, Phase I study.

PubMed

Park, Won; Lee, Sang Joon; Yun, Jihye; Yoo, Dae Hyun

2015-01-01

To compare the pharmacokinetics (PK), safety and tolerability of biosimilar infliximab (CT-P13 [Remsima(®), Inflectra(®)]) with two formulations of the reference medicinal product (RMP) (Remicade(®)) from either Europe (EU-RMP) or the USA (US-RMP). This was a double-blind, three-arm, parallel-group study (EudraCT number: 2013-003173-10). Healthy subjects received single doses (5 mg/kg) of CT-P13 (n = 71), EU-RMP (n = 71) or US-RMP (n = 71). The primary objective was to compare the PK profiles for the three formulations. Assessments of comparative safety and tolerability were secondary objectives. Baseline demographics were well balanced across the three groups. Primary end points (Cmax, AUClast and AUCinf) were equivalent between all formulations (CT-P13 vs EU-RMP; CT-P13 vs US-RMP; EU-RMP vs US-RMP). All other PK end points supported the high similarity of the three treatments. Tolerability profiles of the formulations were similar. The PK profile of CT-P13 is highly similar to EU-RMP and US-RMP. All three formulations were equally well tolerated.

A Phenotypic Based Target Screening Approach Delivers New Antitubercular CTP Synthetase Inhibitors.

PubMed

Esposito, Marta; Szadocka, Sára; Degiacomi, Giulia; Orena, Beatrice S; Mori, Giorgia; Piano, Valentina; Boldrin, Francesca; Zemanová, Júlia; Huszár, Stanislav; Barros, David; Ekins, Sean; Lelièvre, Joel; Manganelli, Riccardo; Mattevi, Andrea; Pasca, Maria Rosalia; Riccardi, Giovanna; Ballell, Lluis; Mikušová, Katarína; Chiarelli, Laurent R

2017-06-09

Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds. To this purpose the publically available GlaxoSmithKline antimycobacterial compound set was assayed, uncovering a series of 4-(pyridin-2-yl)thiazole derivatives which efficiently inhibit the Mycobacterium tuberculosis PyrG enzyme activity, one of them showing low activity against the human CTP synthetase. The three best compounds were ATP binding site competitive inhibitors, with K i values ranging from 3 to 20 μM, but did not show any activity against a small panel of different prokaryotic and eukaryotic kinases, thus demonstrating specificity for the CTP synthetases. Metabolic labeling experiments demonstrated that the compounds directly interfere not only with CTP biosynthesis, but also with other CTP dependent biochemical pathways, such as lipid biosynthesis. Moreover, using a M. tuberculosis pyrG conditional knock-down strain, it was shown that the activity of two compounds is dependent on the intracellular concentration of the CTP synthetase. All these results strongly suggest a role of PyrG as a target of these compounds, thus strengthening the value of this kind of approach for the identification of new scaffolds for drug development.

Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of model for end-stage liver disease: Analysis of data from the Hepa-C registry.

PubMed

Fernández Carrillo, Carlos; Lens, Sabela; Llop, Elba; Pascasio, Juan Manuel; Crespo, Javier; Arenas, Juan; Fernández, Inmaculada; Baliellas, Carme; Carrión, José Antonio; de la Mata, Manuel; Buti, Maria; Castells, Lluís; Albillos, Agustín; Romero, Manuel; Turnes, Juan; Pons, Clara; Moreno-Planas, José María; Moreno-Palomares, José Javier; Fernández-Rodriguez, Conrado; García-Samaniego, Javier; Prieto, Martín; Fernández Bermejo, Miguel; Salmerón, Javier; Badia, Ester; Salcedo, Magdalena; Herrero, José Ignacio; Granados, Rafael; Blé, Michel; Mariño, Zoe; Calleja, José Luis

2017-06-01

Direct-acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa-C registry investigated the effectiveness and safety of interferon-free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child-Turcotte-Pugh [CTP] class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End-Stage Liver Disease (MELD) score alone (cut-off 18) was the best predictor of survival. Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810-1822). © 2017 by the American Association for the Study of Liver Diseases.

A comparison of Aqua MODIS ice and liquid water cloud physical and optical properties between collection 6 and collection 5.1: Pixel-to-pixel comparisons

NASA Astrophysics Data System (ADS)

Yi, Bingqi; Rapp, Anita D.; Yang, Ping; Baum, Bryan A.; King, Michael D.

2017-04-01

We compare differences in ice and liquid water cloud physical and optical properties between Aqua Moderate Resolution Imaging Spectroradiometer (MODIS) collection 6 (C6) and collection 5.1 (C51). The C6 cloud products changed significantly due to improved calibration, improvements based on comparisons with the Cloud-Aerosol Lidar with Orthogonal Polarization, treatment of subpixel liquid water clouds, introduction of a roughened ice habit for C6 rather than the use of smooth ice particles in C51, and more. The MODIS cloud products form a long-term data set for analysis, modeling, and various purposes. Thus, it is important to understand the impact of the changes. Two cases are considered for C6 to C51 comparisons. Case 1 considers pixels with valid cloud retrievals in both C6 and C51, while case 2 compares all valid cloud retrievals in each collection. One year (2012) of level-2 MODIS cloud products are examined, including cloud effective radius (CER), optical thickness (COT), water path, cloud top pressure (CTP), cloud top temperature, and cloud fraction. Large C6-C51 differences are found in the ice CER (regionally, as large as 15 μm) and COT (decrease in annual average by approximately 25%). Liquid water clouds have higher CTP in marine stratocumulus regions in C6 but lower CTP globally (-5 hPa), and there are 66% more valid pixels in C6 (case 2) due to the treatment of pixels with subpixel clouds. Simulated total cloud radiative signatures from C51 and C6 are compared to Clouds and the Earth's Radiant Energy System Energy Balanced And Filled (EBAF) product. The C6 CREs compare more closely with the EBAF than the C51 counterparts.

Reversible hemispheric hypoperfusion in two cases of SMART syndrome.

PubMed

Wai, Karmen; Balabanski, Anna; Chia, Nicholas; Kleinig, Timothy

2017-09-01

Stroke-like migraine attacks after radiation therapy (SMART) syndrome manifests as prolonged episodes of cortical dysfunction, years after cranial irradiation. We present two cases demonstrating reversible hemispheric hypoperfusion. Case 1 presented with left hemispheric symptoms following previous similar episodes. CT perfusion (CTP) demonstrated reversible hemispheric hypoperfusion; subsequent investigations were consistent with SMART syndrome. Case 2 presented following the third episode of a hemispheric syndrome with near-identical CTP abnormalities. L-arginine was administered with rapid reversal of clinical and CTP abnormalities. We conclude that SMART syndrome may demonstrate significant hypoperfusion on hyperacute CTP without subsequent infarction. Impaired cerebrovascular autoregulation probably contributes to cortical dysfunction in SMART syndrome. L-arginine warrants investigation as a potential treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cuts, cancellations and the closed time path: The soft leptogenesis example

NASA Astrophysics Data System (ADS)

Garbrecht, Björn; Ramsey-Musolf, Michael J.

2014-05-01

By including all leading quantum-statistical effects at finite temperature, we show that no net asymmetry of leptons and sleptons is generated from soft leptogenesis, save the possible contribution from the resonant mixing of sneutrinos. This result contrasts with different conclusions appearing in the literature that are based on an incomplete inclusion of quantum statistics. We discuss vertex and wave-function diagrams as well as all different possible kinematic cuts that nominally lead to CP-violating asymmetries. The present example of soft leptogenesis may therefore serve as a paradigm in order to identify more generally applicable caveats relevant to alternative scenarios for baryogenesis and leptogenesis, and it may provide useful guidance in constructing viable models. For the vertex contributions, the intermediate on-shell particle is an out-of equilibrium singlet neutrino N (see Fig. 3). In this case, even when the subtraction of RIS is performed correctly, On the other hand, when the RIS that is to be subtracted corresponds to a particle that is in equilibrium, such as the scalar Higgs doublet H1 in Section 4 (see Fig. 7), no asymmetry is generated in first place. This type of subtraction of equilibrium RIS and the consequent vanishing of the CPV asymmetry has been missed in the context of a different model in Ref. [9]. Alternatively, there exists a way of deriving the leptogenesis kinetic equations following a set of rules that intrinsically respect the unitary evolution of the system while sidestepping the pitfalls of the RIS procedure: the Closed Time Path (CTP) formalism [10-15]. Rather than formulating the problem in terms of S-matrix elements and classical particle distribution functions, the evolution of Green functions of the quantum fields is calculated. In particular, the imaginary parts of self-energies correspond to the inclusive decay and production rates that are necessary in order to track the evolution of the asymmetry. This way, the somewhat heuristic procedure of RIS subtraction can be avoided [16-31].In the present work, we calculate the source terms for the asymmetry using the CTP formalism. As our main result, we demonstrate that the resulting asymmetry of the lepton number vanishes even when taking into account quantum statistical corrections. In particular, the corrections associated with the internal lines precisely cancel those associated with the final states that are included in Refs. [6-8]. Consequently, the sum of the lepton and slepton asymmetries is zero.

Systematic design for trait introgression projects.

PubMed

Cameron, John N; Han, Ye; Wang, Lizhi; Beavis, William D

2017-10-01

Using an Operations Research approach, we demonstrate design of optimal trait introgression projects with respect to competing objectives. We demonstrate an innovative approach for designing Trait Introgression (TI) projects based on optimization principles from Operations Research. If the designs of TI projects are based on clear and measurable objectives, they can be translated into mathematical models with decision variables and constraints that can be translated into Pareto optimality plots associated with any arbitrary selection strategy. The Pareto plots can be used to make rational decisions concerning the trade-offs between maximizing the probability of success while minimizing costs and time. The systematic rigor associated with a cost, time and probability of success (CTP) framework is well suited to designing TI projects that require dynamic decision making. The CTP framework also revealed that previously identified 'best' strategies can be improved to be at least twice as effective without increasing time or expenses.

Safety and feasibility of leadless pacemaker in patients undergoing atrioventricular node ablation for atrial fibrillation.

PubMed

Yarlagadda, Bharath; Turagam, Mohit K; Dar, Tawseef; Jangam, Pragna; Veerapaneni, Vaishnavi; Atkins, Donita; Bommana, Sudharani; Friedman, Paul; Deshmukh, Abhishek J; Doshi, Rahul; Reddy, Vivek Y; Dukkipati, Srinivas R; Natale, Andrea; Lakkireddy, Dhanunjaya

2018-03-01

Atrioventricular node (AVN) ablation and permanent pacing is an established strategy for rate control in the management of symptomatic atrial fibrillation (AF). Leadless pacemakers (LPs) can overcome some of the short-term and long-term limitations of conventional transvenous pacemakers (CTPs). The purpose of this study was to compare the feasibility and safety of LP with those of single-chamber CTP in patients with AF undergoing AVN ablation. We conducted a multicenter observational study of patients undergoing AVN ablation and pacemaker implantation (LP vs single-chamber CTP) between February 2014 and November 2016. The primary efficacy end points were acceptable sensing (R wave ≥5.0 mV) and pacing thresholds (≤2.0 V at 0.4 ms) at follow-up. Safety end points included device-related major and minor (early ≤1 month, late >1 month) adverse events. A total of 127 patients with LP (n = 60) and CTP (n = 67) were studied. The median follow-up was 12 months (interquartile range 12-18 months). Ninety-five percent of the LP group and 97% of the CTP group met the primary efficacy end point at follow-up (57 of 60 vs 65 of 67; P = .66). There was 1 major adverse event (loss of pacing and sensing) in the LP group and 2 (lead dislodgement) in the CTP group (1 of 60 vs 2 of 67; P = 1.00). There were 6 minor adverse events (5 early and 1 late) in the LP group and 3 (early) in the CTP group (6 of 60 vs 3 of 67; P = .30). Our results demonstrate the feasibility and safety of LP compared with CTP in patients undergoing AVN ablation for AF. Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

A proposed procedure for derivation of regulatory values for carcinogenic airborne polycyclic aromatic hydrocarbons (PAHs) based on coal tar pitch (CTP) volatiles.

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

Foureman, G.L.; Smith, R.L.

A procedure for estimating upper bound lifetime human cancer risk from air levels of six common carcinogenic polycyclic aromatic hydrocarbons (PAHs), termed APAHs of concern, is proposed. These PAHs are benzo(a)pyrene, benz(a)anthracene, benzo(b)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-c,d)pyrene, and chrysene. In application, this proposed procedure would regard any given air level obtained for a APAH of concern to originate from a standard mixture of coal tar pitch (CTP). The given air level for the APAHs of concern is then related to a corresponding air level of CTP and thence, to an inhalation unit cancer risk calculated for CTP. Reference values for the proceduremore » are the relative and absolute PAH composition of a CTP standard (SRM-1597) and the inhalation unit cancer risk. Qualitative characterization of the results are a vital part of the procedure especially when more than one APAH of concern{at} is being considered. Toxic equivalency factors (TEFs) may be used as an evaluative tool in characterization of the procedure and outcome. Limitations of this proposed procedure include the uneven database for the reference values and the inability to consider air samples inclusive of another common carcinogenic PAH, dibenz(a,h)anthracene, due to its lack of documentation in CTP and high TEF« less

Clinical experience with infliximab biosimilar Remsima (CT-P13) in inflammatory bowel disease patients

PubMed Central

Jahnsen, Jørgen

2016-01-01

Many reference biological therapies have now reached or are near to patent expiry, and therefore a number of biosimilars have been or will be developed. The term biosimilar can be defined as a biotherapeutic product that is similar in efficacy, safety and quality to the licensed reference product. Biosimilars may lead to a reduced price and significant cost savings for the health community and hopefully more patients globally will have easier access to biological therapy when indicated. CT-P13, which is a TNF-alfa inhibitor, is the first monoclonal antibody biosimilar being used in clinical practice. The drug is approved for all indications as an innovator product although clinical efficacy has only been demonstrated in rheumatic diseases. Until now the number of patients with inflammatory bowel disease (IBD) treated with CT-P13 is confined, but experience is continuously growing. Based on current data, CT-P13 seems to be efficacious and generally well tolerated in IBD especially in patients who are naïve to biological therapy. Knowledge with regard to interchangeability between CT-P13 and the originator infliximab is however, still rather sparse and more data are desired. Immunogenicity and long-term safety related to CT-P13 are other areas of great importance and good and reliable postmarketing pharmacovigilance is therefore required in the coming years. PMID:27134662

Stability of radiomic features in CT perfusion maps

NASA Astrophysics Data System (ADS)

Bogowicz, M.; Riesterer, O.; Bundschuh, R. A.; Veit-Haibach, P.; Hüllner, M.; Studer, G.; Stieb, S.; Glatz, S.; Pruschy, M.; Guckenberger, M.; Tanadini-Lang, S.

2016-12-01

This study aimed to identify a set of stable radiomic parameters in CT perfusion (CTP) maps with respect to CTP calculation factors and image discretization, as an input for future prognostic models for local tumor response to chemo-radiotherapy. Pre-treatment CTP images of eleven patients with oropharyngeal carcinoma and eleven patients with non-small cell lung cancer (NSCLC) were analyzed. 315 radiomic parameters were studied per perfusion map (blood volume, blood flow and mean transit time). Radiomics robustness was investigated regarding the potentially standardizable (image discretization method, Hounsfield unit (HU) threshold, voxel size and temporal resolution) and non-standardizable (artery contouring and noise threshold) perfusion calculation factors using the intraclass correlation (ICC). To gain added value for our model radiomic parameters correlated with tumor volume, a well-known predictive factor for local tumor response to chemo-radiotherapy, were excluded from the analysis. The remaining stable radiomic parameters were grouped according to inter-parameter Spearman correlations and for each group the parameter with the highest ICC was included in the final set. The acceptance level was 0.9 and 0.7 for the ICC and correlation, respectively. The image discretization method using fixed number of bins or fixed intervals gave a similar number of stable radiomic parameters (around 40%). The potentially standardizable factors introduced more variability into radiomic parameters than the non-standardizable ones with 56-98% and 43-58% instability rates, respectively. The highest variability was observed for voxel size (instability rate  >97% for both patient cohorts). Without standardization of CTP calculation factors none of the studied radiomic parameters were stable. After standardization with respect to non-standardizable factors ten radiomic parameters were stable for both patient cohorts after correction for inter-parameter correlations. Voxel size, image discretization, HU threshold and temporal resolution have to be standardized to build a reliable predictive model based on CTP radiomics analysis.

Clinical development of CT-P10 and other biosimilar cancer therapeutics.

PubMed

Kim, Won Seog; Coiffier, Bertrand; Kwon, Hyuk-Chan; Kim, SuYeon

2017-05-01

Biosimilars are highly similar versions of approved biologic drugs that may confer equivalent efficacy at a reduced cost. Patents for several biological cancer therapeutics are past or approaching expiry, presenting an opportunity to increase affordability and global accessibility of key drugs through the development of biosimilars. To receive approval, a biosimilar must show no clinically meaningful differences from the reference product in terms of efficacy or safety. The first monoclonal antibody biosimilar cancer therapeutic to gain approval was CT-P10, a biosimilar of rituximab. Here, we review the oncology clinical development program for CT-P10, providing insights into the rationale for, and design of, CT-P10 clinical trials in patients with cancer. Trials of biosimilar cancer therapeutics in development are also discussed.

Assessment of bronchial and pulmonary blood supply in non-small cell lung cancer subtypes using computed tomography perfusion.

PubMed

Nguyen-Kim, Thi Dan Linh; Frauenfelder, Thomas; Strobel, Klaus; Veit-Haibach, Patrick; Huellner, Martin W

2015-03-01

The aim of this study was to investigate the dual blood supply of non-small cell lung cancer (NSCLC) and its association with tumor subtype, size, and stage, using computed tomography perfusion (CTP). A total of 54 patients (median age, 65 years; range, 42-79 years; 15 women, 39 men) with suspected lung cancer underwent a CTP scan of the lung tumor. Pulmonary and bronchial vasculature regions of interest were used to calculate independently CTP parameters (blood flow [BF], blood volume [BV], and mean transit time [MTT]) of the tumor tissue. The mean and maximum pulmonary and bronchial perfusion indexes (PImean and PImax) were calculated. The tumoral volume and the largest tumoral diameter were assessed. Differences in CTP parameters and indexes among NSCLC subtypes, tumor stages and tumor dimensions were analyzed using non-parametric tests. According to biopsy, 37 patients had NSCLC (22 adenocarcinomas [ACs], 8 squamous cell carcinomas [SCCs], 7 large-cell carcinomas [LCC]). The mean bronchial BF/pulmonary BF, bronchial BV/pulmonary BV, and bronchial MTT/pulmonary MTT was 41.2 ± 30.0/36.9 ± 24.2 mL/100 mL/min, 11.4 ± 9.7/10.4 ± 9.4 mL/100 mL, and 11.4 ± 4.3/14.9 ± 4.4 seconds, respectively. In general, higher bronchial BF than pulmonary BF was observed in NSCLC (P = 0.014). Using a tumoral volume cutoff of 3.5 cm, a significant difference in pulmonary PImax was found (P = 0.028). There was a significantly higher mean pulmonary BF in LCCs and SCCs compared with ACs (P = 0.018 and P = 0.044, respectively), whereas the mean bronchial BF was only significantly higher in LCCs compared with ACs (P = 0.024). Correspondingly, the PImax was significantly higher in LCCs and SCCs than in ACs (P = 0.001 for both). Differences between bronchial and pulmonary PImean and PImax among T stages and Union Internationale Contre le Cancer stages were not statistically significant (P values ranging from 0.691 to 0.753). The known dual blood supply of NSCLC, which depends on tumor size and histological subtype, is reflected in CTP parameters, with parameters depending both on tumor size and histological subtype. This has to be accounted for when analyzing NSCLC with CTP.

A Disruption of ctpA Encoding Carboxy-Terminal Protease Attenuates Burkholderia mallei and Induces Partial Protection in CD1 Mice

DTIC Science & Technology

2008-06-03

etiologic agent of glanders in solipeds (horses, mules and donkeys), and incidentally in carnivores and humans. Little is known about the molecular...disintegrated cell envelopes. Furthermore, relative to the wild type, the ctpA mutant displayed slower growth in vitro and less ability to survive in...IgG2a and were partially protected against chal- lenge with wild type B. mallei ATCC 23344. These findings suggest that CtpA regulates in vitro growth

A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study

PubMed Central

Yoo, Dae Hyun; Hrycaj, Pawel; Miranda, Pedro; Ramiterre, Edgar; Piotrowski, Mariusz; Shevchuk, Sergii; Kovalenko, Volodymyr; Prodanovic, Nenad; Abello-Banfi, Mauricio; Gutierrez-Ureña, Sergio; Morales-Olazabal, Luis; Tee, Michael; Jimenez, Renato; Zamani, Omid; Lee, Sang Joon; Kim, HoUng; Park, Won; Müller-Ladner, Ulf

2013-01-01

Objectives To compare the efficacy and safety of innovator infliximab (INX) and CT-P13, an INX biosimilar, in active rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment. Methods Phase III randomised, double-blind, multicentre, multinational, parallel-group study. Patients with active disease despite MTX (12.5–25 mg/week) were randomised to receive 3 mg/kg of CT-P13 (n=302) or INX (n=304) with MTX and folic acid. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 30. Therapeutic equivalence of clinical response according to ACR20 criteria was concluded if the 95% CI for the treatment difference was within ±15%. Secondary endpoints included ACR response criteria, European League Against Rheumatism (EULAR) response criteria, change in Disease Activity Score 28 (DAS28), Medical Outcomes Study Short-Form Health Survey (SF-36), Simplified Disease Activity Index, Clinical Disease Activity Index, as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and immunogenicity. Results At week 30, ACR20 responses were 60.9% for CT-P13 and 58.6% for INX (95% CI −6% to 10%) in the intention-to-treat population. The proportions in CT-P13 and INX groups achieving good or moderate EULAR responses (C reactive protein (CRP)) at week 30 were 85.8% and 87.1%, respectively. Low disease activity or remission according to DAS28–CRP, ACR–EULAR remission rates, ACR50/ACR70 responses and all other PK and PD endpoints were highly similar at week 30. Incidence of drug-related adverse events (35.2% vs 35.9%) and detection of antidrug antibodies (48.4% vs 48.2%) were highly similar for CT-P13 and INX, respectively. Conclusions CT-P13 demonstrated equivalent efficacy to INX at week 30, with a comparable PK profile and immunogenicity. CT-P13 was well tolerated, with a safety profile comparable with that of INX. ClinicalTrials.gov Identifier NCT01217086 PMID:23687260

Assessment of in vitro COPD models for tobacco regulatory science: Workshop proceedings, conclusions and paths forward for in vitro model use.

PubMed

Behrsing, Holger; Raabe, Hans; Manuppello, Joseph; Bombick, Betsy; Curren, Rodger; Sullivan, Kristie; Sethi, Sanjay; Phipps, Richard; Tesfaigzi, Yohannes; Yan, Sherwin; D'Ruiz, Carl; Tarran, Robert; Constant, Samuel; Phillips, Gary; Gaça, Marianna; Hayden, Patrick; Cao, Xuefei; Mathis, Carole; Hoeng, Julia; Braun, Armin; Hill, Erin

2016-05-01

The Family Smoking Prevention and Tobacco Control Act of 2009 established the Food and Drug Administration Center for Tobacco Products (FDA-CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 8-10 December 2014, IIVS organised a workshop conference, entitled Assessment of In Vitro COPD Models for Tobacco Regulatory Science, to bring together stakeholders representing regulatory agencies, academia, industry and animal protection, to address the research priorities articulated by the FDA-CTP. Specific topics were covered to assess the status of current in vitro technologies as they are applied to understanding the adverse pulmonary events resulting from tobacco product exposure, and in particular, the progression of chronic obstructive pulmonary disease (COPD). The four topics covered were: a) Inflammation and Oxidative Stress; b) Ciliary Dysfunction and Ion Transport; c) Goblet Cell Hyperplasia and Mucus Production; and d) Parenchymal/Bronchial Tissue Destruction and Remodelling. The 2.5 day workshop included 18 expert speakers, plus poster sessions, networking and breakout sessions, which identified key findings and provided recommendations to advance the in vitro technologies and assays used to evaluate tobacco-induced disease etiologies. The workshop summary was reported at the 2015 Society of Toxicology Annual Meeting, and the recommendations led to an IIVS-organised technical workshop in June 2015, entitled Goblet Cell Hyperplasia, Mucus Production, and Ciliary Beating Assays, to assess these assays and to conduct a proof-of-principle multi-laboratory exercise to determine their suitability for standardisation. Here, we report on the proceedings, recommendations and outcomes of the December 2014 workshop, including paths forward to continue the development of non-animal methods to evaluate tissue responses that model the disease processes that may lead to COPD, a major cause of mortality worldwide. 2016 FRAME.

California Transportation Plan 2025.

DOT National Transportation Integrated Search

2006-04-01

The California Transportation Plan 2025 (CTP) offers a blueprint for meeting : the States future mobility needs. The CTP is a long-range transportation : policy plan that explores the social, economic, and technological trends : and demographic ch...

A new sampling scheme for developing metamodels with the zeros of Chebyshev polynomials

NASA Astrophysics Data System (ADS)

Wu, Jinglai; Luo, Zhen; Zhang, Nong; Zhang, Yunqing

2015-09-01

The accuracy of metamodelling is determined by both the sampling and approximation. This article proposes a new sampling method based on the zeros of Chebyshev polynomials to capture the sampling information effectively. First, the zeros of one-dimensional Chebyshev polynomials are applied to construct Chebyshev tensor product (CTP) sampling, and the CTP is then used to construct high-order multi-dimensional metamodels using the 'hypercube' polynomials. Secondly, the CTP sampling is further enhanced to develop Chebyshev collocation method (CCM) sampling, to construct the 'simplex' polynomials. The samples of CCM are randomly and directly chosen from the CTP samples. Two widely studied sampling methods, namely the Smolyak sparse grid and Hammersley, are used to demonstrate the effectiveness of the proposed sampling method. Several numerical examples are utilized to validate the approximation accuracy of the proposed metamodel under different dimensions.

Isolation of a euryhaline microalgal strain, Tetraselmis sp. CTP4, as a robust feedstock for biodiesel production

PubMed Central

Pereira, Hugo; Gangadhar, Katkam N.; Schulze, Peter S. C.; Santos, Tamára; de Sousa, Carolina Bruno; Schueler, Lisa M.; Custódio, Luísa; Malcata, F. Xavier; Gouveia, Luísa; Varela, João C. S.; Barreira, Luísa

2016-01-01

Bioprospecting for novel microalgal strains is key to improving the feasibility of microalgae-derived biodiesel production. Tetraselmis sp. CTP4 (Chlorophyta, Chlorodendrophyceae) was isolated using fluorescence activated cell sorting (FACS) in order to screen novel lipid-rich microalgae. CTP4 is a robust, euryhaline strain able to grow in seawater growth medium as well as in non-sterile urban wastewater. Because of its large cell size (9–22 μm), CTP4 settles down after a six-hour sedimentation step. This leads to a medium removal efficiency of 80%, allowing a significant decrease of biomass dewatering costs. Using a two-stage system, a 3-fold increase in lipid content (up to 33% of DW) and a 2-fold enhancement in lipid productivity (up to 52.1 mg L−1 d−1) were observed upon exposure to nutrient depletion for 7 days. The biodiesel synthesized from the lipids of CTP4 contained high levels of oleic acid (25.67% of total fatty acids content) and minor amounts of polyunsaturated fatty acids with ≥4 double bonds (<1%). As a result, this biofuel complies with most of the European (EN14214) and American (ASTM D6751) specifications, which commonly used microalgal feedstocks are usually unable to meet. In conclusion, Tetraselmis sp. CTP4 displays promising features as feedstock with lower downstream processing costs for biomass dewatering and biodiesel refining. PMID:27767051

Mitochondrial and Plasma Membrane Citrate Transporters: Discovery of Selective Inhibitors and Application to Structure/Function Analysis

PubMed Central

Sun, Jiakang; Aluvila, Sreevidya; Kotaria, Rusudan; Mayor, June A.; Walters, D. Eric; Kaplan, Ronald S.

2010-01-01

Cytoplasmic citrate is the prime carbon source for fatty acid, triacylglycerol, and cholesterol biosyntheses, and also regulates glucose metabolism via its allosteric inhibition of phosphofructokinase. It originates either via the efflux of citrate from the mitochondrial matrix on the inner membrane citrate transport protein (CTP) or via the influx of extracellular citrate on the plasma membrane citrate transporter (PMCT). Despite their common substrate, the two transport proteins share little sequence similarity and they transport citrate via fundamentally different mechanisms. We tested the ability of a set of previously identified CTP inhibitors, to inhibit the PMCT. We found that of the top 10 CTP inhibitors only one substantially inhibited the PMCT. Conversely, we identified two other inhibitors that inhibited the PMCT but had little effect on the CTP. All three identified PMCT inhibitors displayed a noncompetitive mechanism. Furthermore, models to explain inhibitor interactions with the CTP are proposed. As part of the present studies a PMCT homology model has been developed based on the crystal structure of the leucine transporter, and a possible citrate binding site has been identified and its composition compared with the two known citrate binding sites present within the CTP. The ability to selectively inhibit the PMCT may prove key to the pharmacologic amelioration of metabolic disorders resulting from the synthesis of excess lipid, cholesterol, and glucose, including human obesity, hyperlipidemia, hyper-cholesterolemia, and Type 2 diabetes. PMID:20686672

Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study.

PubMed

Park, Won; Yoo, Dae Hyun; Jaworski, Janusz; Brzezicki, Jan; Gnylorybov, Andriy; Kadinov, Vladimir; Sariego, Irmgadt Goecke; Abud-Mendoza, Carlos; Escalante, William Jose Otero; Kang, Seong Wook; Andersone, Daina; Blanco, Francisco; Hong, Seung Suh; Lee, Sun Hee; Braun, Jürgen

2016-01-20

CT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®) and is approved in Europe and elsewhere, mostly for the same indications as RP. The aim of this study was to compare the 54-week efficacy, immunogenicity, pharmacokinetics (PK) and safety of CT-P13 with RP in patients with ankylosing spondylitis (AS), with a focus on patient-reported outcomes (PROs). This was a multinational, double-blind, parallel-group study in patients with active AS. Participants were randomized (1:1) to receive CT-P13 (5 mg/kg) or RP (5 mg/kg) at weeks 0, 2, 6 and then every 8 weeks up to week 54. To assess responses, standardized assessment tools were used with an intention-to-treat analysis of observed data. Anti-drug antibodies (ADAs), PK parameters, and safety outcomes were also assessed. Of 250 randomized patients (n = 125 per group), 210 (84.0 %) completed 54 weeks of treatment, with similar completion rates between groups. At week 54, Assessment of Spondylo Arthritis international Society (ASAS)20 response, ASAS40 response and ASAS partial remission were comparable between treatment groups. Changes from baseline in PROs such as mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; CT-P13 -3.1 versus RP -2.8), Bath Ankylosing Spondylitis Functional Index (BASFI; -2.9 versus -2.7), and Short Form Health Survey (SF-36) scores (9.26 versus 10.13 for physical component summary; 7.30 versus 6.54 for mental component summary) were similar between treatment groups. At 54 weeks, 19.5 % and 23.0 % of patients receiving CT-P13 and RP, respectively, had ADAs. All observed PK parameters of CT-P13 and RP, including maximum and minimum serum concentrations, were similar through 54 weeks. The influence of ADAs on PK was similar in the two treatment groups. Most adverse events were mild or moderate in severity. There was no notable difference between treatment groups in the incidence of adverse events, serious adverse events, infections and infusion-related reactions. CT-P13 and RP have highly comparable efficacy (including PROs) and PK up to week 54. Over a 1-year period, CT-P13 was well tolerated and displayed a safety profile comparable to RP; no differences in immunogenicity were observed. ClinicalTrials.gov identifier: NCT01220518 . Registered 4 October 2010.

The P-type ATPase CtpG preferentially transports Cd2+ across the Mycobacterium tuberculosis plasma membrane.

PubMed

López, Marcela; Quitian, Laudy-Viviana; Calderón, Martha-Nancy; Soto, Carlos-Y

2018-04-01

P 1B -type ATPases are involved in heavy metal transport across the plasma membrane. Some Mycobacterium tuberculosis P-type ATPases are induced during infection, suggesting that this type of transporter could play a critical role in mycobacterial survival. To date, the ion specificity of M. tuberculosis heavy metal-transporting P 1B -ATPases is not well understood. In this work, we observed that, although divalent heavy metal cations such as Cu 2+ , Co 2+ , Ni 2+ , Zn 2+ Cd 2+ and Pb 2+ stimulate the ATPase activity of the putative P 1B -type ATPase CtpG in the plasma membrane, whole cells of M. smegmatis expressing CtpG only tolerate high levels of Cd 2+ and Cu 2+ . As indicator of the catalytic constant, Michaelis-Menten kinetics showed that CtpG embedded in the mycobacterial cell membrane has a V max /K m ratio 7.4-fold higher for Cd 2+ than for Cu 2+ ions. Thus, although CtpG can accept different substrates in vitro, this P-type ATPase transports Cd 2+ more efficiently than other heavy metal cations across the mycobacterial plasma membrane.

Prospective assessment of bone turnover and clinical bone diseases after allogeneic hematopoietic stem-cell transplantation.

PubMed

Petropoulou, Anna D; Porcher, Raphael; Herr, Andrée-Laure; Devergie, Agnès; Brentano, Thomas Funck; Ribaud, Patricia; Pinto, Fernando O; Rocha, Vanderson; Peffault de Latour, Régis; Orcel, Philippe; Socié, Gérard; Robin, Marie

2010-06-15

Bone complications after hematopoietic stem-cell transplantation (HSCT) are relatively frequent. Evaluation of biomarkers of bone turnover and dual energy x-ray absorptiometry (DEXA) are not known in this context. We prospectively evaluated bone mineral density, biomarkers of bone turnover, and the cumulative incidence of bone complications after allogeneic HSCT. One hundred forty-six patients were included. Bone mineral density was measured by DEXA 2-month and 1-year post-HSCT. The markers of bone turnover were serum C-telopeptide (C-TP), 5 tartrate-resistant acid phosphatase (bone resorption), and osteocalcin (bone formation) determined pre-HSCT and 2 months and 1 year thereafter. Potential association between osteoporosis at 2 months, osteoporotic fracture or avascular necrosis and, individual patient's characteristics and biologic markers were tested. C-TP was high before and 2 months after transplant. At 2 months, DEXA detected osteoporosis in more than half the patients tested. Male sex, median age less than or equal to 15 years, and abnormal C-TP before HSCT were risk factors significantly associated with osteoporosis. Three-year cumulative incidences of fractures and avascular necrosis were 8% and 11%, respectively. Children were at higher risk of fracture, whereas corticosteroid treatment duration was a significant risk factor for developing a clinical bone complication post-HSCT. Bone complications and osteoporosis are frequent after HSCT. Bone biologic markers and DEXA showed that subclinical bone abnormalities appeared early post-HSCT. The risk factors, age, gender, and C-TP easily available at the time of transplantation were identified. Biphosphonates should probably be given to patients with those risk factors.

Error-prone bypass of O6-methylguanine by DNA polymerase of Pseudomonas aeruginosa phage PaP1.

PubMed

Gu, Shiling; Xiong, Jingyuan; Shi, Ying; You, Jia; Zou, Zhenyu; Liu, Xiaoying; Zhang, Huidong

2017-09-01

O 6 -Methylguanine (O 6 -MeG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, generally leads to G:C to A:T mutagenesis. To study DNA replication encountering O 6 -MeG by the DNA polymerase (gp90) of P. aeruginosa phage PaP1, we analyzed steady-state and pre-steady-state kinetics of nucleotide incorporation opposite O 6 -MeG by gp90 exo - . O 6 -MeG partially inhibited full-length extension by gp90 exo - . O 6 -MeG greatly reduces dNTP incorporation efficiency, resulting in 67-fold preferential error-prone incorporation of dTTP than dCTP. Gp90 exo - extends beyond T:O 6 -MeG 2-fold more efficiently than C:O 6 -MeG. Incorporation of dCTP opposite G and incorporation of dCTP or dTTP opposite O 6 -MeG show fast burst phases. The pre-steady-state incorporation efficiency (k pol /K d,dNTP ) is decreased in the order of dCTP:G>dTTP:O 6 -MeG>dCTP:O 6 -MeG. The presence of O 6 -MeG at template does not affect the binding affinity of polymerase to DNA but it weakened their binding in the presence of dCTP and Mg 2+ . Misincorporation of dTTP opposite O 6 -MeG further weakens the binding affinity of polymerase to DNA. The priority of dTTP incorporation opposite O 6 -MeG is originated from the fact that dTTP can induce a faster conformational change step and a faster chemical step than dCTP. This study reveals that gp90 bypasses O 6 -MeG in an error-prone manner and provides further understanding in DNA replication encountering mutagenic alkylation DNA damage for P. aeruginosa phage PaP1. Copyright © 2017 Elsevier B.V. All rights reserved.

Low dose dynamic myocardial CT perfusion using advanced iterative reconstruction

NASA Astrophysics Data System (ADS)

Eck, Brendan L.; Fahmi, Rachid; Fuqua, Christopher; Vembar, Mani; Dhanantwari, Amar; Bezerra, Hiram G.; Wilson, David L.

2015-03-01

Dynamic myocardial CT perfusion (CTP) can provide quantitative functional information for the assessment of coronary artery disease. However, x-ray dose in dynamic CTP is high, typically from 10mSv to >20mSv. We compared the dose reduction potential of advanced iterative reconstruction, Iterative Model Reconstruction (IMR, Philips Healthcare, Cleveland, Ohio) to hybrid iterative reconstruction (iDose4) and filtered back projection (FBP). Dynamic CTP scans were obtained using a porcine model with balloon-induced ischemia in the left anterior descending coronary artery to prescribed fractional flow reserve values. High dose dynamic CTP scans were acquired at 100kVp/100mAs with effective dose of 23mSv. Low dose scans at 75mAs, 50mAs, and 25mAs were simulated by adding x-ray quantum noise and detector electronic noise to the projection space data. Images were reconstructed with FBP, iDose4, and IMR at each dose level. Image quality in static CTP images was assessed by SNR and CNR. Blood flow was obtained using a dynamic CTP analysis pipeline and blood flow image quality was assessed using flow-SNR and flow-CNR. IMR showed highest static image quality according to SNR and CNR. Blood flow in FBP was increasingly over-estimated at reduced dose. Flow was more consistent for iDose4 from 100mAs to 50mAs, but was over-estimated at 25mAs. IMR was most consistent from 100mAs to 25mAs. Static images and flow maps for 100mAs FBP, 50mAs iDose4, and 25mAs IMR showed comparable, clear ischemia, CNR, and flow-CNR values. These results suggest that IMR can enable dynamic CTP at significantly reduced dose, at 5.8mSv or 25% of the comparable 23mSv FBP protocol.

Frequency and Voltage Dependence of the Dielectrophoretic Trapping of Short Lengths of DNA and dCTP in a Nanopipette

PubMed Central

Ying, Liming; White, Samuel S.; Bruckbauer, Andreas; Meadows, Lisa; Korchev, Yuri E.; Klenerman, David

2004-01-01

The study of the properties of DNA under high electric fields is of both fundamental and practical interest. We have exploited the high electric fields produced locally in the tip of a nanopipette to probe the motion of double- and single-stranded 40-mer DNA, a 1-kb single-stranded DNA, and a single-nucleotide triphosphate (dCTP) just inside and outside the pipette tip at different frequencies and amplitudes of applied voltages. We used dual laser excitation and dual color detection to simultaneously follow two fluorophore-labeled DNA sequences with millisecond time resolution, significantly faster than studies to date. A strong trapping effect was observed during the negative half cycle for all DNA samples and also the dCTP. This effect was maximum below 1 Hz and decreased with higher frequency. We assign this trapping to strong dielectrophoresis due to the high electric field and electric field gradient in the pipette tip. Dielectrophoresis in electrodeless tapered nanostructures has potential applications for controlled mixing and manipulation of short lengths of DNA and other biomolecules, opening new possibilities in miniaturized biological analysis. PMID:14747337

Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis

PubMed Central

Takeuchi, Tsutomu; Yamanaka, Hisashi; Tanaka, Yoshiya; Sakurai, Takeo; Saito, Kazuyoshi; Ohtsubo, Hideo; Lee, Sang Joon; Nambu, Yoshihiro

2015-01-01

Objectives. To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks. Methods. In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6–16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUCτ) (weeks 6–14) and Cmax (week 6) of these drugs, and to compare their efficacy and safety. Results. The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUCτ and Cmax values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24–124.29%) and 104.09% (92.12–117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs. Conclusion. CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety. PMID:25736355

Antibacterial, anti-inflammatory, and bone-regenerative dual-drug-loaded calcium phosphate nanocarriers-in vitro and in vivo studies.

PubMed

Madhumathi, K; Rubaiya, Y; Doble, Mukesh; Venkateswari, R; Sampath Kumar, T S

2018-05-01

A dual local drug delivery system (DDS) composed of calcium phosphate bioceramic nanocarriers aimed at treating the antibacterial, anti-inflammatory, and bone-regenerative aspects of periodontitis has been developed. Calcium-deficient hydroxyapatite (CDHA, Ca/P = 1.61) and tricalcium phosphate (β-TCP) were prepared by microwave-accelerated wet chemical synthesis method. The phase purity of the nanocarriers was confirmed by x-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), while the transmission electron microscopy (TEM) confirmed their nanosized morphology. CDHA was selected as carrier for the antibiotic (tetracycline) while TCP was chosen as the anti-inflammatory drug (ibuprofen) carrier. Combined drug release profile was studied in vitro from CDHA/TCP (CTP) system and compared with a HA/TCP (BCP) biphasic system. The tetracycline and ibuprofen release rate was 71 and 23% from CTP system as compared to 63 and 20% from BCP system. CTP system also showed a more controlled drug release profile compared to BCP system. Modeling of drug release kinetics from CTP system indicated that the release follows Higuchi model with a non-typical Fickian diffusion profile. In vitro biological studies showed the CTP system to be biocompatible with significant antibacterial and anti-inflammatory activity. In vivo implantation studies on rat cranial defects showed greater bone healing and new bone formation in the drug-loaded CTP system compared to control (no carrier) at the end of 12 weeks. The in vitro and in vivo results suggest that the combined drug delivery platform can provide a comprehensive management for all bone infections requiring multi-drug therapy.

The Novel Zinc Finger Protein dASCIZ Regulates Mitosis in Drosophila via an Essential Role in Dynein Light-Chain Expression

PubMed Central

Zaytseva, Olga; Tenis, Nora; Mitchell, Naomi; Kanno, Shin-ichiro; Yasui, Akira; Heierhorst, Jörg; Quinn, Leonie M

2014-01-01

The essential zinc finger protein ASCIZ (also known as ATMIN, ZNF822) plays critical roles during lung organogenesis and B cell development in mice, where it regulates the expression of dynein light chain (DYNLL1/LC8), but its functions in other species including invertebrates are largely unknown. Here we report the identification of the Drosophila ortholog of ASCIZ (dASCIZ) and show that loss of dASCIZ function leads to pronounced mitotic delays with centrosome and spindle positioning defects during development, reminiscent of impaired dynein motor functions. Interestingly, similar mitotic and developmental defects were observed upon knockdown of the DYNLL/LC8-type dynein light chain Cutup (Ctp), and dASCIZ loss-of-function phenotypes could be suppressed by ectopic Ctp expression. Consistent with a genetic function of dASCIZ upstream of Ctp, we show that loss of dASCIZ led to reduced endogenous Ctp mRNA and protein levels and dramatically reduced Ctp–LacZ reporter gene activity in vivo, indicating that dASCIZ regulates development and mitosis as a Ctp transcription factor. We speculate that the more severe mitotic defects in the absence of ASCIZ in flies compared to mice may be due to redundancy with a second, ASCIZ-independent, Dynll2 gene in mammals in contrast to a single Ctp gene in Drosophila. Altogether, our data demonstrate that ASCIZ is an evolutionary highly conserved transcriptional regulator of dynein light-chain levels and a novel regulator of mitosis in flies. PMID:24336747

Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial.

PubMed

Brown, Janet; Rathbone, Emma; Hinsley, Samantha; Gregory, Walter; Gossiel, Fatma; Marshall, Helen; Burkinshaw, Roger; Shulver, Helen; Thandar, Hasina; Bertelli, Gianfilippo; Maccon, Keane; Bowman, Angela; Hanby, Andrew; Bell, Richard; Cameron, David; Coleman, Robert

2018-02-07

Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study. © The Author(s) 2018. Published by Oxford University Press.

Dependence of quantitative accuracy of CT perfusion imaging on system parameters

NASA Astrophysics Data System (ADS)

Li, Ke; Chen, Guang-Hong

2017-03-01

Deconvolution is a popular method to calculate parametric perfusion parameters from four dimensional CT perfusion (CTP) source images. During the deconvolution process, the four dimensional space is squeezed into three-dimensional space by removing the temporal dimension, and a prior knowledge is often used to suppress noise associated with the process. These additional complexities confound the understanding about deconvolution-based CTP imaging system and how its quantitative accuracy depends on parameters and sub-operations involved in the image formation process. Meanwhile, there has been a strong clinical need in answering this question, as physicians often rely heavily on the quantitative values of perfusion parameters to make diagnostic decisions, particularly during an emergent clinical situation (e.g. diagnosis of acute ischemic stroke). The purpose of this work was to develop a theoretical framework that quantitatively relates the quantification accuracy of parametric perfusion parameters with CTP acquisition and post-processing parameters. This goal was achieved with the help of a cascaded systems analysis for deconvolution-based CTP imaging systems. Based on the cascaded systems analysis, the quantitative relationship between regularization strength, source image noise, arterial input function, and the quantification accuracy of perfusion parameters was established. The theory could potentially be used to guide developments of CTP imaging technology for better quantification accuracy and lower radiation dose.

Care to Plan: An Online Tool That Offers Tailored Support to Dementia Caregivers.

PubMed

Gaugler, Joseph E; Reese, Mark; Tanler, Richard

2016-12-01

Even with the advent of evidence-based interventions, an ongoing concern in clinical practice is how to help dementia caregivers determine what type of support is best for them absent a laborious process of trial and error. To help address this practice gap, the present study developed and tested the feasibility of "Care to Plan" (CtP), an online resource for dementia caregivers (e.g., relatives or unpaid nonrelatives) that generates tailored support recommendations. Care to Plan was developed using an iterative prototype and testing process with the assistance of a 29-member Community Advisory Board. A parallel-convergent mixed methods design (quan + QUAL) was used that included a post-CtP survey and a brief semistructured interview to capture in-depth information on the utility and feasibility of CtP. The sample included 30 caregivers of persons with dementia. The integrated qualitative and quantitative data indicated that CtP was simple and easy to understand, the streamlined visual layout facilitated utility, and the individualized recommendations could meet the needs of users. Key barriers to use included the need for additional features (e.g., video introductions of caregiver support types) to further guide dementia caregivers' potential use of tailored support. The multiple data sources underscore the high feasibility and utility of CtP. By describing, identifying, and prioritizing support, CtP could help to improve the care planning process for dementia caregivers. Future dissemination efforts should aim to demonstrate how CtP can be implemented seamlessly within current family caregiver support systems. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Towards robust deconvolution of low-dose perfusion CT: sparse perfusion deconvolution using online dictionary learning.

PubMed

Fang, Ruogu; Chen, Tsuhan; Sanelli, Pina C

2013-05-01

Computed tomography perfusion (CTP) is an important functional imaging modality in the evaluation of cerebrovascular diseases, particularly in acute stroke and vasospasm. However, the post-processed parametric maps of blood flow tend to be noisy, especially in low-dose CTP, due to the noisy contrast enhancement profile and the oscillatory nature of the results generated by the current computational methods. In this paper, we propose a robust sparse perfusion deconvolution method (SPD) to estimate cerebral blood flow in CTP performed at low radiation dose. We first build a dictionary from high-dose perfusion maps using online dictionary learning and then perform deconvolution-based hemodynamic parameters estimation on the low-dose CTP data. Our method is validated on clinical data of patients with normal and pathological CBF maps. The results show that we achieve superior performance than existing methods, and potentially improve the differentiation between normal and ischemic tissue in the brain. Copyright © 2013 Elsevier B.V. All rights reserved.

De-agglomeration and homogenisation of nanoparticles in coal tar pitch-based carbon materials

NASA Astrophysics Data System (ADS)

Gubernat, Maciej; Tomala, Janusz; Frohs, Wilhelm; Fraczek-Szczypta, Aneta; Blazewicz, Stanislaw

2016-03-01

The aim of the work was to characterise coal tar pitch (CTP) modified with selected nanoparticles as a binder precursor for the manufacture of synthetic carbon materials. Different factors influencing the preliminary preparative steps in the preparation of homogenous nanoparticle/CTP composition were studied. Graphene flakes, carbon black and nano-sized silicon carbide were used to modify CTP. Prior to introducing them into liquid CTP, nanoparticles were subjected to sonication. Various dispersants were used to prepare the suspensions, i.e. water, ethanol, dimethylformamide (DMF) and N-methylpyrrolidone (NMP).The results showed that proper dispersant selection is one of the most important factors influencing the de-agglomeration process of nanoparticles. DMF and NMP were found to be effective dispersants for the preparation of homogenous nanoparticle-containing suspensions. The presence of SiC and carbon black nanoparticles in the liquid pitch during heat treatment up to 2000 °C leads to the inhibition of crystallite growth in carbon residue.

Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea.

PubMed

Park, Sang Hyoung; Kim, Young-Ho; Lee, Ji Hyun; Kwon, Hyeok Jin; Lee, Suck-Ho; Park, Dong Il; Kim, Hyung Kil; Cheon, Jae Hee; Im, Jong Pil; Kim, You Sun; Lee, Sung Young; Lee, Sang Joon

2015-01-01

To evaluate the safety and efficacy of CT-P13 (Remsima(®)) in patients with inflammatory bowel disease (IBD) in South Korea. This post-marketing study included patients with active moderate-to-severe Crohn's disease (CD), fistulizing CD (FCD), or moderate-to-severe ulcerative colitis (UC) treated with CT-P13 and followed for 30 weeks. Assessments included treatment-emergent adverse events (TEAEs) and disease-specific clinical response and remission. No unexpected TEAEs were observed in the 173 patients recruited to date. TEAEs occurred in 18.1, 16.7, and 26.9% of CD, FCD, and UC patients, respectively. Treatment-related TEAEs occurred in 10% of patients and were mostly mild-moderate in severity. There were five serious TEAEs (two infusion-related reactions, two infections, one abdominal pain) and no cases of malignancy, pneumonia, or death. Positive outcomes for response/remission were reported regardless of whether patients had received prior infliximab or not. CT-P13 was well tolerated and efficacious in patients with IBD.

Towards robust deconvolution of low-dose perfusion CT: Sparse perfusion deconvolution using online dictionary learning

PubMed Central

Fang, Ruogu; Chen, Tsuhan; Sanelli, Pina C.

2014-01-01

Computed tomography perfusion (CTP) is an important functional imaging modality in the evaluation of cerebrovascular diseases, particularly in acute stroke and vasospasm. However, the post-processed parametric maps of blood flow tend to be noisy, especially in low-dose CTP, due to the noisy contrast enhancement profile and the oscillatory nature of the results generated by the current computational methods. In this paper, we propose a robust sparse perfusion deconvolution method (SPD) to estimate cerebral blood flow in CTP performed at low radiation dose. We first build a dictionary from high-dose perfusion maps using online dictionary learning and then perform deconvolution-based hemodynamic parameters estimation on the low-dose CTP data. Our method is validated on clinical data of patients with normal and pathological CBF maps. The results show that we achieve superior performance than existing methods, and potentially improve the differentiation between normal and ischemic tissue in the brain. PMID:23542422

CT-P13: design, development, and place in therapy

PubMed Central

Gabbani, Tommaso; Deiana, Simona; Annese, Vito

2017-01-01

The introduction of biological agents has revolutionized the management of many life-threatening and debilitating immune-mediated diseases. Because of the high cost of biological drugs and their patent expiration, the market has opened to biosimilar agents, copy versions of the originators, which can lead to reduced health care expenditure and increase treatment access worldwide. CT-P13 is the first biosimilar of infliximab (IFX) and has been approved for the same indications as its originator drug. It obtained regulatory approval by the European Medicines Agency in September 2013 and by the US Food and Drug Administration in April 2016. The Phase I and Phase III clinical trials conducted in ankylosing spondylitis and rheumatoid arthritis have demonstrated pharmacokinetic and efficacy equivalence with comparable safety and immunogenicity to IFX. For these reasons, the use of CT-P13 has been extrapolated also to inflammatory bowel disease. There have been some initial concerns regarding the use of CT-P13 in inflammatory bowel disease patients, because of the lack of randomized controlled trials. However, emerging real-world data have further confirmed the comparability between CT-P13 and its reference product in terms of efficacy, safety, and immunogenicity, in patients naïve to the anti-tumor necrosis factor alpha agents and after switching from IFX, and will be summarized in this review. PMID:28652703

Extraction, purification, characterization and antioxidant activities of polysaccharides from Cistanche tubulosa.

PubMed

Zhang, Wiejie; Huang, Jing; Wang, Wei; Li, Qian; Chen, Yao; Feng, Weiwei; Zheng, Daheng; Zhao, Ting; Mao, Guanghua; Yang, Liuqing; Wu, Xiangyang

2016-12-01

An efficient ultrasonic-cellulase-assisted extraction (UCE) of Cistanche tubulosa polysaccharide (CTP) was established. The response surface methodology based on Box-Behnken Design was employed to further optimize extraction conditions. After quaternary ammonium salt precipitation, the polysaccharide of C. tubulosa was characterized by different techniques. The results showed that a maximum polysaccharide yield of 22.31±0.45% was achieved at a pH of 5.2 for 31.5min at 54.1°C. Compared to hot water extraction, the yield of CTP in UCE and polysaccharide content increased to 44.96% and 70.13±2.19%, respectively. There was no marked difference among polysaccharides extracted using different methods from the infrared spectrum. Ultrasonic-cellulase-assisted extraction polysaccharide showed a fibrous structure from scanning electron microscopy and was composed of rhamnose, mannose, glucose, and galactose in a molar ratio of 2.18:1:28.29:1.43 by gas chromatography. The circular dichroism results indicated that polysaccharides had a maximum positive peak around 210nm with different peak values. The thermogravimetric analysis and differential scanning calorimetry were used to test the thermostability of CTP. Besides, CTP demonstrated appreciable antioxidant potential on antioxidant experiments in vitro. The results suggested that UCE is an effective method for CTP extraction and its polysaccharide showed appreciable antioxidant activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of a cardiac specific protein transduction domain by in vivo biopanning using a M13 phage peptide display library in mice.

PubMed

Zahid, Maliha; Phillips, Brett E; Albers, Sean M; Giannoukakis, Nick; Watkins, Simon C; Robbins, Paul D

2010-08-17

A peptide able to transduce cardiac tissue specifically, delivering cargoes to the heart, would be of significant therapeutic potential for delivery of small molecules, proteins and nucleic acids. In order to identify peptide(s) able to transduce heart tissue, biopanning was performed in cell culture and in vivo with a M13 phage peptide display library. A cardiomyoblast cell line, H9C2, was incubated with a M13 phage 12 amino acid peptide display library. Internalized phage was recovered, amplified and then subjected to a total of three rounds of in vivo biopanning where infectious phage was isolated from cardiac tissue following intravenous injection. After the third round, 60% of sequenced plaques carried the peptide sequence APWHLSSQYSRT, termed cardiac targeting peptide (CTP). We demonstrate that CTP was able to transduce cardiomyocytes functionally in culture in a concentration and cell-type dependent manner. Mice injected with CTP showed significant transduction of heart tissue with minimal uptake by lung and kidney capillaries, and no uptake in liver, skeletal muscle, spleen or brain. The level of heart transduction by CTP also was greater than with a cationic transduction domain. Biopanning using a peptide phage display library identified a peptide able to transduce heart tissue in vivo efficiently and specifically. CTP could be used to deliver therapeutic peptides, proteins and nucleic acid specifically to the heart.

Cannabis for therapeutic purposes: patient characteristics, access, and reasons for use.

PubMed

Walsh, Zach; Callaway, Robert; Belle-Isle, Lynne; Capler, Rielle; Kay, Robert; Lucas, Philippe; Holtzman, Susan

2013-11-01

The authorized and unauthorized use of cannabis for therapeutic purposes (CTP) has increased dramatically in recent years, and physicians have called for further research to better clarify the parameters of effective and appropriate use. We report findings from a large cross-sectional study of the use of CTP in Canada and compare use across medical conditions and across authorized and unauthorized users. We examined cannabis use history, medical conditions and symptoms, patterns of current use of CTP, modes of access and perceived effectiveness among 628 self-selected Canadians consumers of CTP. Participants were recruited from medical cannabis dispensaries and from organizations that assist users of CTP. Patients reported using cannabis to treat multiple symptoms, with sleep, pain, and anxiety being the most common. Cannabis was perceived to provide effective symptoms relief across medical conditions. Patterns of use were also consistent across medical conditions. Notable differences were observed with regard to modes of access. Across medical conditions respondents reported using cannabis to effectively address diverse symptoms. Results indicate a substantial disconnect between the therapeutic use of cannabis and research on the risks and benefits of such use; particularly with regard to the anxiolytic and sedative use of cannabis. Authorized and unauthorized users exhibited few meaningful differences with regard to medical conditions and patterns of use, but faced substantial differences regarding access. Copyright © 2013 Elsevier B.V. All rights reserved.

Crystal Structure of the CTP1L Endolysin Reveals How Its Activity Is Regulated by a Secondary Translation Product*

PubMed Central

Dunne, Matthew; Leicht, Stefan; Krichel, Boris; Thompson, Andrew; Gómez-Torres, Natalia; Garde, Sonia; Narbad, Arjan; Mayer, Melinda J.

2016-01-01

Bacteriophages produce endolysins, which lyse the bacterial host cell to release newly produced virions. The timing of lysis is regulated and is thought to involve the activation of a molecular switch. We present a crystal structure of the activated endolysin CTP1L that targets Clostridium tyrobutyricum, consisting of a complex between the full-length protein and an N-terminally truncated C-terminal cell wall binding domain (CBD). The truncated CBD is produced through an internal translation start site within the endolysin gene. Mutants affecting the internal translation site change the oligomeric state of the endolysin and reduce lytic activity. The activity can be modulated by reconstitution of the full-length endolysin-CBD complex with free CBD. The same oligomerization mechanism applies to the CD27L endolysin that targets Clostridium difficile and the CS74L endolysin that targets Clostridium sporogenes. When the CTP1L endolysin gene is introduced into the commensal bacterium Lactococcus lactis, the truncated CBD is also produced, showing that the alternative start codon can be used in other bacterial species. The identification of a translational switch affecting oligomerization presented here has implications for the design of effective endolysins for the treatment of bacterial infections. PMID:26683375

77 FR 21540 - Notice of Submission for OMB Review; Federal Student Aid; Comprehensive Transition Programs (CTP...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-10

... DEPARTMENT OF EDUCATION Notice of Submission for OMB Review; Federal Student Aid; Comprehensive Transition Programs (CTP) for Students With Intellectual Disabilities Expenditure Report SUMMARY: The Higher Education Opportunity Act, Public Law 110-315, added provisions for the Higher Education Act, as amended in...

In vitro exposure systems and dosimetry assessment tools for inhaled tobacco products: Workshop proceedings, conclusions and paths forward for in vitro model use.

PubMed

Behrsing, Holger; Hill, Erin; Raabe, Hans; Tice, Raymond; Fitzpatrick, Suzanne; Devlin, Robert; Pinkerton, Kent; Oberdörster, Günter; Wright, Chris; Wieczorek, Roman; Aufderheide, Michaela; Steiner, Sandro; Krebs, Tobias; Asgharian, Bahman; Corley, Richard; Oldham, Michael; Adamson, Jason; Li, Xiang; Rahman, Irfan; Grego, Sonia; Chu, Pei-Hsuan; McCullough, Shaun; Curren, Rodger

2017-07-01

In 2009, the passing of the Family Smoking Prevention and Tobacco Control Act facilitated the establishment of the FDA Center for Tobacco Products (CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 4-6 April 2016, the Institute for In Vitro Sciences, Inc. (IIVS) convened a workshop conference entitled, In Vitro Exposure Systems and Dosimetry Assessment Tools for Inhaled Tobacco Products, to bring together stakeholders representing regulatory agencies, academia and industry to address the research priorities articulated by the FDA CTP. Specific topics were covered to assess the status of current in vitro smoke and aerosol/vapour exposure systems, as well as the various approaches and challenges to quantifying the complex exposures in in vitro pulmonary models developed for evaluating adverse pulmonary events resulting from tobacco product exposures. The four core topics covered were: a) Tobacco Smoke and E-Cigarette Aerosols; b) Air-Liquid Interface-In Vitro Exposure Systems; c) Dosimetry Approaches for Particles and Vapours/In Vitro Dosimetry Determinations; and d) Exposure Microenvironment/Physiology of Cells. The 2.5-day workshop included presentations from 20 expert speakers, poster sessions, networking discussions, and breakout sessions which identified key findings and provided recommendations to advance these technologies. Here, we will report on the proceedings, recommendations, and outcome of the April 2016 technical workshop, including paths forward for developing and validating non-animal test methods for tobacco product smoke and next generation tobacco product aerosol/vapour exposures. With the recent FDA publication of the final deeming rule for the governance of tobacco products, there is an unprecedented necessity to evaluate a very large number of tobacco-based products and ingredients. The questionable relevance, high cost, and ethical considerations for the use of in vivo testing methods highlight the necessity of robust in vitro approaches to elucidate tobacco-based exposures and how they may lead to pulmonary diseases that contribute to lung exposure-induced mortality worldwide. 2017 FRAME.

Common Grounds for Modelling Mathematics in Educational Software

ERIC Educational Resources Information Center

Neuper, Walther

2010-01-01

Two kinds of software, CAS and DGS, are starting to work towards mutual integration. This paper envisages common grounds for such integration based on principles of computer theorem proving (CTP). Presently, the CTP community seems to lack awareness as to which of their products' features might serve mathematics education from high-school to…

Attention to Form or Meaning? Error Treatment in the Bangalore Project.

ERIC Educational Resources Information Center

Beretta, Alan

1989-01-01

Reports on an evaluation of the Bangalore/Madras Communicational Teaching Project (CTP), a content-based approach to language learning. Analysis of 21 lesson transcripts revealed a greater incidence of error treatment of content than linguistic error, consonant with the CTP focus on meaning rather than form. (26 references) (Author/CB)

Evaluation of the Bangalore/Madras Communicational Teaching Project.

ERIC Educational Resources Information Center

Beretta, Alan; Davies, Alan

The Bangalore Communicational Teaching Project (CTP) in India operates on the central tenet that in English instruction, form can be acquired through a focus on meaning alone, that a grammatical system can be assimilated unconsciously if the mind is engaged in trying to understand or convey meaning. Linguistic specification is not used in CTP, and…

Genomic Sequence and Characterization of the Virulent Bacteriophage φCTP1 from Clostridium tyrobutyricum and Heterologous Expression of Its Endolysin▿

PubMed Central

Mayer, Melinda J.; Payne, John; Gasson, Michael J.; Narbad, Arjan

2010-01-01

The growth of Clostridium tyrobutyricum in developing cheese leads to spoilage and cheese blowing. Bacteriophages or their specific lytic enzymes may provide a biological control method for eliminating such undesirable organisms without affecting other microflora. We isolated the virulent bacteriophage φCTP1 belonging to the Siphoviridae and have shown that it is effective in causing lysis of sensitive strains. The double-stranded DNA genome of φCTP1 is 59,199 bp, and sequence analysis indicated that it has 86 open reading frames. orf29 was identified as the gene coding for the phage endolysin responsible for cell wall degradation prior to virion release. We cloned and expressed the ctp1l gene in E. coli and demonstrated that the partially purified protein induced lysis of C. tyrobutyricum cells and reduced viable counts both in buffer and in milk. The endolysin was inactive against a range of clostridial species but did show lysis of Clostridium sporogenes, another potential spoilage organism. Removal of the C-terminal portion of the endolysin completely abolished lytic activity. PMID:20581196

La-CTP: Loop-Aware Routing for Energy-Harvesting Wireless Sensor Networks.

PubMed

Sun, Guodong; Shang, Xinna; Zuo, Yan

2018-02-02

In emerging energy-harvesting wireless sensor networks (EH-WSN), the sensor nodes can harvest environmental energy to drive their operation, releasing the user's burden in terms of frequent battery replacement, and even enabling perpetual sensing systems. In EH-WSN applications, usually, the node in energy-harvesting or recharging state has to stop working until it completes the energy replenishment. However, such temporary departures of recharging nodes severely impact the packet routing, and one immediate result is the routing loop problem. Controlling loops in connectivity-intermittent EH-WSN in an efficient way is a big challenge in practice, and so far, users still lack of effective and practicable routing protocols with loop handling. Based on the Collection Tree Protocol (CTP) widely used in traditional wireless sensor networks, this paper proposes a loop-aware routing protocol for real-world EH-WSNs, called La-CTP, which involves a new parent updating metric and a proactive, adaptive beaconing scheme to effectively suppress the occurrence of loops and unlock unavoidable loops, respectively. We constructed a 100-node testbed to evaluate La-CTP, and the experimental results showed its efficacy and efficiency.

Use of MODIS Cloud Top Pressure to Improve Assimilation Yields of AIRS Radiances in GSI

NASA Technical Reports Server (NTRS)

Zavodsky, Bradley; Srikishen, Jayanthi

2014-01-01

Improvements to global and regional numerical weather prediction have been demonstrated through assimilation of data from NASA's Atmospheric Infrared Sounder (AIRS). Current operational data assimilation systems use AIRS radiances, but impact on regional forecasts has been much smaller than for global forecasts. Previously, it has been shown that cloud top designation associated with quality control procedures within the Gridpoint Statistical Interpolation (GSI) system used operationally by a number of Joint Center for Satellite Data Assimilation (JCSDA) partners may not provide the best representation of cloud top pressure (CTP). Because this designated CTP determines which channels are cloud-free and, thus, available for assimilation, ensuring the most accurate representation of this value is imperative to obtaining the greatest impact from satellite radiances. This paper examines the assimilation of hyperspectral sounder data used in operational numerical weather prediction by comparing analysis increments and numerical forecasts generated using operational techniques with a research technique that swaps CTP from the Moderate-resolution Imaging Spectroradiometer (MODIS) for the value of CTP calculated from the radiances within GSI.

Current status of biosimilars in the treatment of inflammatory bowel diseases

PubMed Central

2016-01-01

Introduction of biological therapies have led to dramatic changes in the management of debilitating immune-mediated inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease. However, the long term use of these agents may be very expensive, placing a significant burden on National Healthcare Systems. The development of first biosimilar to infliximab, CT-P13 (Remsima; Celltrion Inc., Incheon, Korea and Inflextra; Hospiral, Lake Forest, Illinois, USA) has become another way to decrease the medical care cost and increase patient treatment option, but, actual equivalence of efficacy and safety of CT-P13 was investigated in rheumatic diseases only. The extrapolation of outcome from rheumatic trials to IBD and the interchangeability of CT-P13 with infliximab have come to be a matter of concern. Two recent retrospective studies reported the similarity of CT-P13 in terms of efficacy and safety. Infliximab biosimilars may be promising new treatment options for IBD patients, however, well-designed, prospective randomized non-inferiority trials should be needed to confidently integrate infliximab biosimilars into IBD treatment. PMID:26884730

Childhood Arthritis and Rheumatology Research Alliance Consensus Clinical Treatment Plans for Juvenile Dermatomyositis with Persistent Skin Rash.

PubMed

Huber, Adam M; Kim, Susan; Reed, Ann M; Carrasco, Ruy; Feldman, Brian M; Hong, Sandy D; Kahn, Philip; Rahimi, Homaira; Robinson, Angela Byun; Vehe, Richard K; Weiss, Jennifer E; Spencer, Charles

2017-01-01

Juvenile dermatomyositis (JDM) is the most common form of idiopathic inflammatory myopathy in children. While outcomes are generally thought to be good, persistence of skin rash is a common problem. The goal of this study was to describe the development of clinical treatment plans (CTP) for children with JDM characterized by persistent skin rash despite complete resolution of muscle involvement. The Childhood Arthritis and Rheumatology Research Alliance, a North American consortium of pediatric rheumatologists and other healthcare providers, used a combination of Delphi surveys and nominal group consensus meetings to develop CTP that reflected consensus on typical treatments for patients with JDM with persistent skin rash. Consensus was reached on patient characteristics and outcome assessment. Patients should have previously received corticosteroids and methotrexate (MTX). Three consensus treatment plans were developed. Plan A added intravenous immunoglobulin (IVIG) if it was not already being used. Plan B added mycophenolate mofetil, while Plan C added cyclosporine. Continuation of previous treatments, including corticosteroids, MTX, and IVIG, was permitted in plans B and C. Three consensus CTP were developed for use in children with JDM and persistent skin rash despite complete resolution of muscle disease. These CTP reflect typical treatment approaches and are not to be considered treatment recommendations or standard of care. Using prospective data collection and statistical methods to account for nonrandom treatment assignment, it is expected that these CTP will be used to allow treatment comparisons, and ultimately determine the best treatment for these patients.

Membrane penetrating peptides greatly enhance baculovirus transduction efficiency into mammalian cells

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

Chen, Hong-Zhang; Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, ROC; Wu, Carol P.

2011-02-11

Research highlights: {yields} Ligation of CTP with GP64 enhances baculovirus transduction into mammalian cells. {yields} Fusion of PTD with VP39 enhances baculovirus transduction into mammalian cells. {yields} CTP and PTD-carrying viruses improve the transduction of co-transduced baculoviruses. {yields} Virus entry and gene expression can be separate events in different cell types. -- Abstract: The baculovirus group of insect viruses is widely used for foreign gene introduction into mammalian cells for gene expression and protein production; however, the efficiency of baculovirus entry into mammalian cells is in general still low. In this study, two recombinant baculoviruses were engineered and their abilitymore » to improve viral entry was examined: (1) cytoplasmic transduction peptide (CTP) was fused with baculovirus envelope protein, GP64, to produce a cytoplasmic membrane penetrating baculovirus (vE-CTP); and (2) the protein transduction domain (PTD) of HIV TAT protein was fused with the baculovirus capsid protein VP39 to form a nuclear membrane penetrating baculovirus (vE-PTD). Transduction experiments showed that both viruses had better transduction efficiency than vE, a control virus that only expresses EGFP in mammalian cells. Interestingly, vE-CTP and vE-PTD were also able to improve the transduction efficiency of a co-transduced baculovirus, resulting in higher levels of gene expression. Our results have described new routes to further enhance the development of baculovirus as a tool for gene delivery into mammalian cells.« less

Assessment of Pre- and Post-Operative Cerebral Perfusion in Anterior Circulation Intracranial Aneurysm Clipping Patients at Hospital Sungai Buloh Using CT Perfusion Scan and Correlations to Fisher, Navarro and WFNS Scores.

PubMed

Ghani, Ailani Ab; Nayan, Saiful Azli Mat; Kandasamy, Regunath; Ghani, Abdul Rahman Izani; Rosman, Azmin Kass

2017-02-01

Intracranial aneurysms may rupture and are typically associated with high morbidity and mortality, commonly due to vasospasm after rupture. Once the aneurysm ruptures, the patient's cerebral blood flow may be disturbed during the acute phase, affecting cerebral circulation and thus cerebral perfusion prior to the onset of vasospasm. Fisher and Navarro scores are used to predict vasospasm, while World Federation of Neurosurgical Societies (WFNS) scores are used to predict patient outcomes. Several score modifications are available to obtain higher sensitivity and specificity for the prediction of vasospasm development, but these scores are still unsuccessful. Alternatively, cerebral CT perfusion scan (CTP) is a non-invasive method for measuring cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) in regions of interests (ROI) to obtain the cerebral perfusion status as well as detecting vasospasm. A total of 30 patients' data with clipped anterior circulation intracranial aneurysms admitted to the hospital between 1 January 2013 and 30 June 2014, were collected from the hospital's electronic database. The data collected included patients' admissions demographic profiles, Fisher, Navarro and WFNS scores; and their immediate pre- and post-operative CTP parameters. This study found a significant increase in post-operative MTT (pre- and post-operative MTT) were 9.75 (SD = 1.31) and 10.44 (SD = 1.56) respectively, ( P < 0.001)) as well as a significant reduction in post-operative CBF (pre- and post-operative mean CBF were 195.29 (SD = 24.92) and 179.49 (SD = 31.17) respectively ( P < 0.001)). There were no significant differences in CBV. There were no significant correlations between the pre- and post-operative CTP parameters and Fisher, Navarro or WFNS scores. Despite the interest in using Fisher, Navarro and WFNS scores to predict vasospasm and patient outcomes for ruptured intracranial aneurysms, this study found no significant correlations between these scores in either pre- or post-operative CTP parameters. These results explain the disagreement in the field regarding the multiple proposed grading systems for vasospasm prediction. CTP measures more than just anatomical structures; therefore, it is more sensitive towards minor changes in cerebral perfusion that would not be detected by WFNS, Fisher or Navarro scores.

Common Readout Unit (CRU) - A new readout architecture for the ALICE experiment

NASA Astrophysics Data System (ADS)

Mitra, J.; Khan, S. A.; Mukherjee, S.; Paul, R.

2016-03-01

The ALICE experiment at the CERN Large Hadron Collider (LHC) is presently going for a major upgrade in order to fully exploit the scientific potential of the upcoming high luminosity run, scheduled to start in the year 2021. The high interaction rate and the large event size will result in an experimental data flow of about 1 TB/s from the detectors, which need to be processed before sending to the online computing system and data storage. This processing is done in a dedicated Common Readout Unit (CRU), proposed for data aggregation, trigger and timing distribution and control moderation. It act as common interface between sub-detector electronic systems, computing system and trigger processors. The interface links include GBT, TTC-PON and PCIe. GBT (Gigabit transceiver) is used for detector data payload transmission and fixed latency path for trigger distribution between CRU and detector readout electronics. TTC-PON (Timing, Trigger and Control via Passive Optical Network) is employed for time multiplex trigger distribution between CRU and Central Trigger Processor (CTP). PCIe (Peripheral Component Interconnect Express) is the high-speed serial computer expansion bus standard for bulk data transport between CRU boards and processors. In this article, we give an overview of CRU architecture in ALICE, discuss the different interfaces, along with the firmware design and implementation of CRU on the LHCb PCIe40 board.

Ischemic Volume and Neurological Deficit: Correlation of Computed Tomography Perfusion with the National Institutes of Health Stroke Scale Score in Acute Ischemic Stroke.

PubMed

Furlanis, Giovanni; Ajčević, Miloš; Stragapede, Lara; Lugnan, Carlo; Ridolfi, Mariana; Caruso, Paola; Naccarato, Marcello; Ukmar, Maja; Manganotti, Paolo

2018-04-30

The National Institutes of Health Stroke Scale (NIHSS) is the most adopted stroke patients' evaluation tool in emergency settings to assess the severity of stroke and to determine the patients' eligibility for specific treatments. Computed tomography perfusion (CTP) is crucial to identify salvageable tissue that can benefit from the reperfusion treatment. The aim of this study is to identify the relation between the NIHSS scores and the hypoperfused volumes evaluated by CTP in patients with hyperacute ischemic stroke. This retrospective study was conducted on 105 patients with ischemic stroke who underwent NIHSS assessment and CTP in the hyperacute phase. Hypoperfused volume was evaluated by CTP maps processed with semi-automatic algorithm. An analysis was conducted to determine the degree of correlation between the NIHSS scores and the ischemic lesion volumes and to investigate the relation between the anterior and the posterior circulation strokes, as well as between the right and the left hemispheric strokes. A significant correlation was found between ischemic volume and NIHSS score at baseline (r = .82; P < .0001) in the entire cohort. A high NIHSS-volume correlation was identified in the anterior circulation stroke (r = .76; P < .0001); whereas, it was nonsignificant in the posterior circulation stroke. NIHSS score and volume correlated for the left and the right hemispheric strokes (r = .83 and .81; P < .0001), showing a slightly higher slope in the left. This study showed a strong correlation between the baseline NIHSS score and the ischemic volume estimated by CTP. We confirmed that NIHSS is a reliable predictor of perfusion deficits in acute ischemic stroke. CTP allows fast imaging assessment in the hyperacute phase. The results highlight the importance of these diagnostic tools in the assessment of stroke severity and in acute decision-making. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Preparation of Chitin-PLA laminated composite for implantable application.

PubMed

Nasrin, Romana; Biswas, Shanta; Rashid, Taslim Ur; Afrin, Sanjida; Jahan, Rumana Akhter; Haque, Papia; Rahman, Mohammed Mizanur

2017-12-01

The present study explores the possibilities of using locally available inexpensive waste prawn shell derived chitin reinforced and bioabsorbable polylactic acid (PLA) laminated composites to develop new materials with excellent mechanical and thermal properties for implantable application such as in bone or dental implant. Chitin at different concentration (1-20% of PLA) reinforced PLA films (CTP) were fabricated by solvent casting process and laminated chitin-PLA composites (LCTP) were prepared by laminating PLA film (obtained by hot press method) with CTP also by hot press method at 160 °C. The effect of variation of chitin concentration on the resulting laminated composite's behavior was investigated. The detailed physico-mechanical, surface morphology and thermal were assessed with different characterization technique such as FT-IR, XRD, SEM and TGA. The FTIR spectra showed the characteristic peaks for chitin and PLA in the composites. SEM images showed an excellent dispersion of chitin in the films and composites. Thermogravimetric analysis (TGA) showed that the complete degradation of chitin, PLA film, 5% chitin reinforced PLA film (CTP2) and LCTP are 98%, 95%, 87% and 98% respectively at temperature of 500 °C. The tensile strength of the LCTP was found 25.09 MPa which is significantly higher than pure PLA film (18.55 MPa) and CTP2 film (8.83 MPa). After lamination of pure PLA and CTP2 film, the composite (LCTP) yielded 0.265-1.061% water absorption from 30 min to 24 h immerse in water that is much lower than PLA and CTP. The increased mechanical properties of the laminated films with the increase of chitin content indicated good dispersion of chitin into PLA and strong interfacial actions between the polymer and chitin. The improvement of mechanical properties and the results of antimicrobial and cytotoxicity of the composites also evaluated and revealed the composite would be a suitable candidate for implant application in biomedical sector.

The influence of early psychosocial intervention on the long-term clinical outcomes of people suffering from schizophrenia.

PubMed

Cechnicki, Andrzej; Bielańska, Anna

2017-02-26

To compare the treatment outcomes of DSM-IV-TR schizophrenia patients in either a Community Treatment Program or an Individual Treatment Program (CTP vs. ITP). The assessment was made after the first hospitalization, and then after three and twelve years. Participants were randomly assigned to CTP (experimental) and ITP (traditional) group, with 40 people in each group. 67 people (84%) participated in all three assessments. The socio-demographic and clinical indicators were the same for both groups. In the first three years only the CTP group participated in day-care treatment, patient and family psychoeducation and community treatment. Later, both groups received this treatment. The following tools were used: Anamnestic and Catamnestic Questionnaire, the GAF scale, the BPRS LA and Lehman's Quality of Life Interview. It was only after twelve years that there was a significant beneficial improvement in the mean GAF score in the CTP group (p = 0.036), which was comparable with the results obtained by Watt and Shepherd for the course of the illness in favorable remission cases (p = 0.038). The difference in the number of relapses was also significantly in favor of the CTP group only after 12 years (p = 0.045), as was the difference in the number of rehospitalizations (p = 0.013). The general severity of symptoms was found to be significantly lower for the CPT group after 3 (p = 0.008) and 12 years (p = 0.030), whereas it was significantly lower in the case of positive syndrome only after 3 years (p = 0.044). 1. A greater number of favorable differences were identified for the CTP group at the twelve-year point than at the conclusion of the experiment. 2. The three-year delay in introducing psycho-social treatment was associated with a poorer long-term outcome for the clinical course of schizophrenia.

Antibodies against a peptide of cholera toxin differing in cross-reactivity with the toxin differ in their specific interactions with the peptide as observed by sup 1 H NMR spectroscopy

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

Anglister, J.; Zilber, B.

1990-01-30

The interactions between the aromatic residues of the monoclonal antibody TE34, and its peptide antigen CTP3, have been studied by 2D TRNOE difference spectroscopy. The sequence of CTP3 corresponds to residues 50-64 of the B subunit of cholera toxin (VEVPGSQHIDSQKKA). Unlike two previously studied anti-CTP3 antibodies (TE32 and TE33), the TE34 antibody does not bind the toxin. The off-rate of CTP3 from TE34 was found to be too slow to measure strong TRNOE cross-peaks between the antibody and the peptide. Much faster off-rates, resulting in a strong TRNOE, were obtained for two peptide analogues: (a) CTP3 with an amide inmore » the C-terminus (VEVPGSQHIDSQKKA-NH{sub 2}) and (b) a truncated version of the peptide (N-acetyl-IDSQKKA). These modifications do not interfere significantly either with the interactions of the unmodified part of the peptide with the antibody or with intramolecular interactions occurring in the epitope recognized by the antibody. The combined use of these peptides allows us to study the interactions between the antibody and the whole peptide. Two tyrosine residues and one or more tryptophan and phenylalanine residues have been found to interact with histidine-8, isoleucine-9, aspartate-10, lysine-13 and/or lysine-14, and alanine-15 of the peptide. The strong interaction of TE34 with the negatively charged C-terminus of CTP3 is one of the main reasons for its lack of cross-reactivity with the native toxin. Similar use of modified peptides may extend the applicability of 2D TRNOE difference spectroscopy to the study of other antibody-peptide complexes involving slow peptide off-rates.« less

Kinetic and Structural Impact of Metal Ions and Genetic Variations on Human DNA Polymerase ι.

PubMed

Choi, Jeong-Yun; Patra, Amritaj; Yeom, Mina; Lee, Young-Sam; Zhang, Qianqian; Egli, Martin; Guengerich, F Peter

2016-09-30

DNA polymerase (pol) ι is a Y-family polymerase involved in translesion synthesis, exhibiting higher catalytic activity with Mn 2+ than Mg 2+ The human germline R96G variant impairs both Mn 2+ -dependent and Mg 2+ -dependent activities of pol ι, whereas the Δ1-25 variant selectively enhances its Mg 2+ -dependent activity. We analyzed pre-steady-state kinetic and structural effects of these two metal ions and genetic variations on pol ι using pol ι core (residues 1-445) proteins. The presence of Mn 2+ (0.15 mm) instead of Mg 2+ (2 mm) caused a 770-fold increase in efficiency (k pol /K d ,dCTP ) of pol ι for dCTP insertion opposite G, mainly due to a 450-fold decrease in K d ,dCTP The R96G and Δ1-25 variants displayed a 53-fold decrease and a 3-fold increase, respectively, in k pol /K d ,dCTP for dCTP insertion opposite G with Mg 2+ when compared with wild type, substantially attenuated by substitution with Mn 2+ Crystal structures of pol ι ternary complexes, including the primer terminus 3'-OH and a non-hydrolyzable dCTP analogue opposite G with the active-site Mg 2+ or Mn 2+ , revealed that Mn 2+ achieves more optimal octahedral coordination geometry than Mg 2+ , with lower values in average coordination distance geometry in the catalytic metal A-site. Crystal structures of R96G revealed the loss of three H-bonds of residues Gly-96 and Tyr-93 with an incoming dNTP, due to the lack of an arginine, as well as a destabilized Tyr-93 side chain secondary to the loss of a cation-π interaction between both side chains. These results provide a mechanistic basis for alteration in pol ι catalytic function with coordinating metals and genetic variation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Kinetic and Structural Impact of Metal Ions and Genetic Variations on Human DNA Polymerase ι*

PubMed Central

Choi, Jeong-Yun; Patra, Amritaj; Yeom, Mina; Lee, Young-Sam; Zhang, Qianqian; Egli, Martin; Guengerich, F. Peter

2016-01-01

DNA polymerase (pol) ι is a Y-family polymerase involved in translesion synthesis, exhibiting higher catalytic activity with Mn2+ than Mg2+. The human germline R96G variant impairs both Mn2+-dependent and Mg2+-dependent activities of pol ι, whereas the Δ1–25 variant selectively enhances its Mg2+-dependent activity. We analyzed pre-steady-state kinetic and structural effects of these two metal ions and genetic variations on pol ι using pol ι core (residues 1–445) proteins. The presence of Mn2+ (0.15 mm) instead of Mg2+ (2 mm) caused a 770-fold increase in efficiency (kpol/Kd,dCTP) of pol ι for dCTP insertion opposite G, mainly due to a 450-fold decrease in Kd,dCTP. The R96G and Δ1–25 variants displayed a 53-fold decrease and a 3-fold increase, respectively, in kpol/Kd,dCTP for dCTP insertion opposite G with Mg2+ when compared with wild type, substantially attenuated by substitution with Mn2+. Crystal structures of pol ι ternary complexes, including the primer terminus 3′-OH and a non-hydrolyzable dCTP analogue opposite G with the active-site Mg2+ or Mn2+, revealed that Mn2+ achieves more optimal octahedral coordination geometry than Mg2+, with lower values in average coordination distance geometry in the catalytic metal A-site. Crystal structures of R96G revealed the loss of three H-bonds of residues Gly-96 and Tyr-93 with an incoming dNTP, due to the lack of an arginine, as well as a destabilized Tyr-93 side chain secondary to the loss of a cation-π interaction between both side chains. These results provide a mechanistic basis for alteration in pol ι catalytic function with coordinating metals and genetic variation. PMID:27555320

Limited reliability of computed tomographic perfusion acute infarct volume measurements compared with diffusion-weighted imaging in anterior circulation stroke.

PubMed

Schaefer, Pamela W; Souza, Leticia; Kamalian, Shervin; Hirsch, Joshua A; Yoo, Albert J; Kamalian, Shahmir; Gonzalez, R Gilberto; Lev, Michael H

2015-02-01

Diffusion-weighted imaging (DWI) can reliably identify critically ischemic tissue shortly after stroke onset. We tested whether thresholded computed tomographic cerebral blood flow (CT-CBF) and CT-cerebral blood volume (CT-CBV) maps are sufficiently accurate to substitute for DWI for estimating the critically ischemic tissue volume. Ischemic volumes of 55 patients with acute anterior circulation stroke were assessed on DWI by visual segmentation and on CT-CBF and CT-CBV with segmentation using 15% and 30% thresholds, respectively. The contrast:noise ratios of ischemic regions on the DWI and CT perfusion (CTP) images were measured. Correlation and Bland-Altman analyses were used to assess the reliability of CTP. Mean contrast:noise ratios for DWI, CT-CBF, and CT-CBV were 4.3, 0.9, and 0.4, respectively. CTP and DWI lesion volumes were highly correlated (R(2)=0.87 for CT-CBF; R(2)=0.83 for CT-CBV; P<0.001). Bland-Altman analyses revealed little systemic bias (-2.6 mL) but high measurement variability (95% confidence interval, ±56.7 mL) between mean CT-CBF and DWI lesion volumes, and systemic bias (-26 mL) and high measurement variability (95% confidence interval, ±64.0 mL) between mean CT-CBV and DWI lesion volumes. A simulated treatment study demonstrated that using CTP-CBF instead of DWI for detecting a statistically significant effect would require at least twice as many patients. The poor contrast:noise ratios of CT-CBV and CT-CBF compared with those of DWI result in large measurement error, making it problematic to substitute CTP for DWI in selecting individual acute stroke patients for treatment. CTP could be used for treatment studies of patient groups, but the number of patients needed to identify a significant effect is much higher than the number needed if DWI is used. © 2014 American Heart Association, Inc.

The USC Adult Twin Cohorts: International Twin Study and California Twin Program.

PubMed

Cozen, Wendy; Hwang, Amie E; Cockburn, Myles G; Hamilton, Ann S; Zadnick, John; Mack, Thomas M

2013-02-01

The study of twin subjects permits the documentation of crude heritability and may promote the identification of specific causal alleles. We believe that at the current time, the chief research advantage of twins as subjects, especially monozygotic twins, is that the commonality of their genetic and cultural identity simplifies the interpretation of biological associations. In order to study genetic and environmental determinants of cancer and chronic diseases, we developed two twin registries, maintained at the University of Southern California: The International Twin Study (ITS) and the California Twin Program (CTP). The ITS is a volunteer registry of twins with cancer and chronic disease consisting of 17,245 twin pairs affected by cancer and chronic disease, respectively, ascertained by advertising in periodicals from 1980-1991. The CTP is a population-based registry of California-born twin pairs ascertained by linking the California birth records to the State Department of Motor Vehicles. Over 51,000 individual California twins representing 36,965 pairs completed and returned 16-page questionnaires. Cancer diagnoses in the California twins are updated by regular linkage to the California Cancer Registry. Over 5,000 cancer patients are represented in the CTP. Twins from both registries have participated extensively in studies of breast cancer, melanoma, lymphoma, multiple sclerosis, systemic lupus erythematosus, diabetes mellitus type 1, mammographic density, smoking, and other traits and conditions.

A novel method for quantification of gemcitabine and its metabolites 2',2'-difluorodeoxyuridine and gemcitabine triphosphate in tumour tissue by LC-MS/MS: comparison with (19)F NMR spectroscopy.

PubMed

Bapiro, Tashinga E; Richards, Frances M; Goldgraben, Mae A; Olive, Kenneth P; Madhu, Basetti; Frese, Kristopher K; Cook, Natalie; Jacobetz, Michael A; Smith, Donna-Michelle; Tuveson, David A; Griffiths, John R; Jodrell, Duncan I

2011-11-01

To develop a sensitive analytical method to quantify gemcitabine (2',2'-difluorodeoxycytidine, dFdC) and its metabolites 2',2'-difluorodeoxyuridine (dFdU) and 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) simultaneously from tumour tissue. Pancreatic ductal adenocarcinoma tumour tissue from genetically engineered mouse models of pancreatic cancer (KP ( FL/FL ) C and KP ( R172H/+) C) was collected after dosing the mice with gemcitabine. (19)F NMR spectroscopy and LC-MS/MS protocols were optimised to detect gemcitabine and its metabolites in homogenates of the tumour tissue. A (19)F NMR protocol was developed, which was capable of distinguishing the three analytes in tumour homogenates. However, it required at least 100 mg of the tissue in question and a long acquisition time per sample, making it impractical for use in large PK/PD studies or clinical trials. The LC-MS/MS protocol was developed using porous graphitic carbon to separate the analytes, enabling simultaneous detection of all three analytes from as little as 10 mg of tissue, with a sensitivity for dFdCTP of 0.2 ng/mg tissue. Multiple pieces of tissue from single tumours were analysed, showing little intra-tumour variation in the concentrations of dFdC or dFdU (both intra- and extra-cellular). Intra-tumoural variation was observed in the concentration of dFdCTP, an intra-cellular metabolite, which may reflect regions of different cellularity within a tumour. We have developed a sensitive LC-MS/MS method capable of quantifying gemcitabine, dFdU and dFdCTP in pancreatic tumour tissue. The requirement for only 10 mg of tissue enables this protocol to be used to analyse multiple areas from a single tumour and to spare tissue for additional pharmacodynamic assays.

A review of the literature analyzing benefits and concerns of infliximab biosimilar CT-P13 for the treatment of rheumatologic diseases: focus on interchangeability

PubMed Central

Becciolini, Andrea; Raimondo, Maria Gabriella; Crotti, Chiara; Agape, Elena; Biggioggero, Martina; Favalli, Ennio Giulio

2017-01-01

The introduction of biological agents drastically changed the treatment paradigm of inflammatory arthritides, ameliorating the natural history of the diseases but concomitantly increasing the drug costs due to the manufacturing process. On this concern, biosimilar drugs may represent a valid option for reducing this elevated cost and increasing the availability of these highly effective treatments. Recently, CT-P13, the first biosimilar of infliximab, has been approved with the same indications established for the reference product (RP), and its daily use is progressively increasing. However, the experience with biosimilar drugs in the field of rheumatology is still limited, raising potential doubts and concerns on their correct management in real-life settings. Comparability analysis between CT-P13 and its RP was evaluated in equivalence randomized controlled trials (RCTs) – PLANETRA and PLANETAS – performed on patients with rheumatoid arthritis and axial spondylitis, respectively. CT-P13 and RP showed similar profile in terms of quality, biological activity, safety, immunogenicity, and efficacy. However, the interchangeability between infliximab RP and its biosimilar still represents the most challenging issue because of a lack of a long-lasting experience. To date, reassuring preliminary data on this topic were reported in open-label extensions of PLANETRA and PLANETAS RCTs and in ongoing real-life observational studies. These findings, taken all together, significantly affect the landscape of biosimilar regulatory pathways and strongly support CT-P13 introduction as a great opportunity for expanding the accessibility to these very effective and high-cost therapies. PMID:28721016

A review of the literature analyzing benefits and concerns of infliximab biosimilar CT-P13 for the treatment of rheumatologic diseases: focus on interchangeability.

PubMed

Becciolini, Andrea; Raimondo, Maria Gabriella; Crotti, Chiara; Agape, Elena; Biggioggero, Martina; Favalli, Ennio Giulio

2017-01-01

The introduction of biological agents drastically changed the treatment paradigm of inflammatory arthritides, ameliorating the natural history of the diseases but concomitantly increasing the drug costs due to the manufacturing process. On this concern, biosimilar drugs may represent a valid option for reducing this elevated cost and increasing the availability of these highly effective treatments. Recently, CT-P13, the first biosimilar of infliximab, has been approved with the same indications established for the reference product (RP), and its daily use is progressively increasing. However, the experience with biosimilar drugs in the field of rheumatology is still limited, raising potential doubts and concerns on their correct management in real-life settings. Comparability analysis between CT-P13 and its RP was evaluated in equivalence randomized controlled trials (RCTs) - PLANETRA and PLANETAS - performed on patients with rheumatoid arthritis and axial spondylitis, respectively. CT-P13 and RP showed similar profile in terms of quality, biological activity, safety, immunogenicity, and efficacy. However, the interchangeability between infliximab RP and its biosimilar still represents the most challenging issue because of a lack of a long-lasting experience. To date, reassuring preliminary data on this topic were reported in open-label extensions of PLANETRA and PLANETAS RCTs and in ongoing real-life observational studies. These findings, taken all together, significantly affect the landscape of biosimilar regulatory pathways and strongly support CT-P13 introduction as a great opportunity for expanding the accessibility to these very effective and high-cost therapies.

Validation of motion correction techniques for liver CT perfusion studies

PubMed Central

Chandler, A; Wei, W; Anderson, E F; Herron, D H; Ye, Z; Ng, C S

2012-01-01

Objectives Motion in images potentially compromises the evaluation of temporally acquired CT perfusion (CTp) data; image registration should mitigate this, but first requires validation. Our objective was to compare the relative performance of manual, rigid and non-rigid registration techniques to correct anatomical misalignment in acquired liver CTp data sets. Methods 17 data sets in patients with liver tumours who had undergone a CTp protocol were evaluated. Each data set consisted of a cine acquisition during a breath-hold (Phase 1), followed by six further sets of cine scans (each containing 11 images) acquired during free breathing (Phase 2). Phase 2 images were registered to a reference image from Phase 1 cine using two semi-automated intensity-based registration techniques (rigid and non-rigid) and a manual technique (the only option available in the relevant vendor CTp software). The performance of each technique to align liver anatomy was assessed by four observers, independently and blindly, on two separate occasions, using a semi-quantitative visual validation study (employing a six-point score). The registration techniques were statistically compared using an ordinal probit regression model. Results 306 registrations (2448 observer scores) were evaluated. The three registration techniques were significantly different from each other (p=0.03). On pairwise comparison, the semi-automated techniques were significantly superior to the manual technique, with non-rigid significantly superior to rigid (p<0.0001), which in turn was significantly superior to manual registration (p=0.04). Conclusion Semi-automated registration techniques achieved superior alignment of liver anatomy compared with the manual technique. We hope this will translate into more reliable CTp analyses. PMID:22374283

Automated prediction of tissue outcome after acute ischemic stroke in computed tomography perfusion images

NASA Astrophysics Data System (ADS)

Vos, Pieter C.; Bennink, Edwin; de Jong, Hugo; Velthuis, Birgitta K.; Viergever, Max A.; Dankbaar, Jan Willem

2015-03-01

Assessment of the extent of cerebral damage on admission in patients with acute ischemic stroke could play an important role in treatment decision making. Computed tomography perfusion (CTP) imaging can be used to determine the extent of damage. However, clinical application is hindered by differences among vendors and used methodology. As a result, threshold based methods and visual assessment of CTP images has not yet shown to be useful in treatment decision making and predicting clinical outcome. Preliminary results in MR studies have shown the benefit of using supervised classifiers for predicting tissue outcome, but this has not been demonstrated for CTP. We present a novel method for the automatic prediction of tissue outcome by combining multi-parametric CTP images into a tissue outcome probability map. A supervised classification scheme was developed to extract absolute and relative perfusion values from processed CTP images that are summarized by a trained classifier into a likelihood of infarction. Training was performed using follow-up CT scans of 20 acute stroke patients with complete recanalization of the vessel that was occluded on admission. Infarcted regions were annotated by expert neuroradiologists. Multiple classifiers were evaluated in a leave-one-patient-out strategy for their discriminating performance using receiver operating characteristic (ROC) statistics. Results showed that a RandomForest classifier performed optimally with an area under the ROC of 0.90 for discriminating infarct tissue. The obtained results are an improvement over existing thresholding methods and are in line with results found in literature where MR perfusion was used.

Computed Tomography Perfusion Improves Diagnostic Accuracy in Acute Posterior Circulation Stroke.

PubMed

Sporns, Peter; Schmidt, Rene; Minnerup, Jens; Dziewas, Rainer; Kemmling, André; Dittrich, Ralf; Zoubi, Tarek; Heermann, Philipp; Cnyrim, Christian; Schwindt, Wolfram; Heindel, Walter; Niederstadt, Thomas; Hanning, Uta

2016-01-01

Computed tomography perfusion (CTP) has a high diagnostic value in the detection of acute ischemic stroke in the anterior circulation. However, the diagnostic value in suspected posterior circulation (PC) stroke is uncertain, and whole brain volume perfusion is not yet in widespread use. We therefore studied the additional value of whole brain volume perfusion to non-contrast CT (NCCT) and CT angiography source images (CTA-SI) for infarct detection in patients with suspected acute ischemic PC stroke. This is a retrospective review of patients with suspected stroke in the PC in a database of our stroke center (n = 3,011) who underwent NCCT, CTA and CTP within 9 h after stroke onset and CT or MRI on follow-up. Images were evaluated for signs and pc-ASPECTS locations of ischemia. Three imaging models - A (NCCT), B (NCCT + CTA-SI) and C (NCCT + CTA-SI + CTP) - were compared with regard to the misclassification rate relative to gold standard (infarction in follow-up imaging) using the McNemar's test. Of 3,011 stroke patients, 267 patients had a suspected stroke in the PC and 188 patients (70.4%) evidenced a PC infarct on follow-up imaging. The sensitivity of Model C (76.6%) was higher compared with that of Model A (21.3%) and Model B (43.6%). CTP detected significantly more ischemic lesions, especially in the cerebellum, posterior cerebral artery territory and thalami. Our findings in a large cohort of consecutive patients show that CTP detects significantly more ischemic strokes in the PC than CTA and NCCT alone. © 2016 S. Karger AG, Basel.

Safe use of proton pump inhibitors in patients with cirrhosis.

PubMed

Weersink, Rianne A; Bouma, Margriet; Burger, David M; Drenth, Joost P H; Froukje Harkes-Idzinga, S; Hunfeld, Nicole G M; Metselaar, Herold J; Monster-Simons, Margje H; van Putten, Sandra A W; Taxis, Katja; Borgsteede, Sander D

2018-04-24

Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in cirrhosis. A systematic literature search identified studies about the safety (i.e. adverse events) and pharmacokinetics of PPIs in cirrhotic patients. This evidence and data from the product information was reviewed by an expert panel who classified drugs as safe; no additional risks known; additional risks known; unsafe; or unknown. Guidance was aimed at the oral use of PPIs and categorized by the severity of cirrhosis, using the Child-Turcotte-Pugh (CTP) classification. A total of 69 studies were included. Esomeprazole, omeprazole and rabeprazole were classified as having 'no additional risks known'. A reduction in maximum dose of omeprazole and rabeprazole is recommended for CTP A and B patients. For patients with CTP C cirrhosis, the only PPI advised is esomeprazole in a maximum dosage of 20 mg per day. Pantoprazole and lansoprazole were classified as unsafe, because of 4- to 8-fold increased exposure. The use of PPIs in cirrhotic patients has been associated with the development of infections and hepatic encephalopathy and should be carefully considered. We suggest using esomeprazole, omeprazole or rabeprazole in patients with CTP A or B cirrhosis and only esomeprazole in patients with CTP C. Pharmacokinetic changes are also important to consider when prescribing PPIs to vulnerable, cirrhotic patients. This article is protected by copyright. All rights reserved.

CTP synthase 1, a smooth muscle-sensitive therapeutic target for effective vascular repair

PubMed Central

Tang, Rui; Cui, Xiao-Bing; Wang, Jia-Ning; Chen, Shi-You

2013-01-01

Objective Vascular remodeling due to smooth muscle cell (SMC) proliferation and neointima formation is a major medical challenge in cardiovascular intervention. However, anti-neointima drugs often indistinguishably block re-endothelialization, an essential step toward successful vascular repair, due to their non-specific effect on endothelial cells (EC). The objective of this study was to identify a therapeutic target that differentially regulates SMC and EC proliferation. Approach and Results By using both rat balloon-injury and mouse wire-injury models, we identified CTP synthase (CTPS) as one of the potential targets that may be used for developing therapeutics for treating neointima-related disorders. CTPS1 was induced in proliferative SMCs in vitro and neointima SMCs in vivo. Blockade of CTPS1 expression by small hairpin RNA or activity by cyclopentenyl cytosine suppressed SMC proliferation and neointima formation. Surprisingly, cyclopentenyl cytosine had much less effect on EC proliferation. Of importance, blockade of CTPS1 in vivo sustained the re-endothelialization due to induction of CTP synthesis salvage pathway enzymes nucleoside diphosphate kinase A and B in ECs. Diphosphate kinase B appeared to preserve EC proliferation via utilization of extracellular cytidine to synthesize CTP. Indeed, blockade of both CTPS1 and diphosphate kinase B suppressed EC proliferation in vitro and the re-endothelization in vivo. Conclusions Our study uncovered a fundamental difference in CTP biosynthesis between SMCs and ECs during vascular remodeling, which provided a novel strategy by using cyclopentenyl cytosine or other CTPS1 inhibitors to selectively block SMC proliferation without disturbing or even promoting re-endothelialization for effective vascular repair following injury. PMID:24008161

Cochlin-tomoprotein (CTP) detection test identified perilymph leakage preoperatively in revision stapes surgery.

PubMed

Kataoka, Yuko; Ikezono, Tetsuo; Fukushima, Kunihiro; Yuen, Koji; Maeda, Yukihide; Sugaya, Akiko; Nishizaki, Kazunori

2013-08-01

Perilymphatic fistula (PLF) is defined as an abnormal leakage between perilymph from the labyrinth to the middle ear. Symptoms include hearing loss, tinnitus, and vertigo. The standard mode of PLF detection is intraoperative visualization of perilymph leakage and fistula, which ostensibly confirms the existence of PLF. Other possible methods of diagnosis include confirmation of pneumolabyrinth via diagnostic imaging. Recently, a cochlin-tomoprotein (CTP) detection test has been developed that allows definitive diagnosis of PLF-related hearing loss. We report the case of a 45-year-old man who presented with right-sided tinnitus, hearing loss, and dizziness 30 years after stapes surgery. Middle ear lavage was performed after myringotomy. A preoperative diagnosis of PLF was reached using the CTP detection test. Intraoperative observations included a necrotic long process of the incus, displaced wire piston, and fibrous tissue in the oval window. Perilymph leakage was not evident. The oval window was closed with fascia, and vertigo disappeared within 2 weeks postoperatively. When PLF is suspected after stapes surgery, the CTP detection test can be a useful, highly sensitive, and less invasive method for preoperative diagnosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

La-CTP: Loop-Aware Routing for Energy-Harvesting Wireless Sensor Networks

PubMed Central

Sun, Guodong; Shang, Xinna; Zuo, Yan

2018-01-01

In emerging energy-harvesting wireless sensor networks (EH-WSN), the sensor nodes can harvest environmental energy to drive their operation, releasing the user’s burden in terms of frequent battery replacement, and even enabling perpetual sensing systems. In EH-WSN applications, usually, the node in energy-harvesting or recharging state has to stop working until it completes the energy replenishment. However, such temporary departures of recharging nodes severely impact the packet routing, and one immediate result is the routing loop problem. Controlling loops in connectivity-intermittent EH-WSN in an efficient way is a big challenge in practice, and so far, users still lack of effective and practicable routing protocols with loop handling. Based on the Collection Tree Protocol (CTP) widely used in traditional wireless sensor networks, this paper proposes a loop-aware routing protocol for real-world EH-WSNs, called La-CTP, which involves a new parent updating metric and a proactive, adaptive beaconing scheme to effectively suppress the occurrence of loops and unlock unavoidable loops, respectively. We constructed a 100-node testbed to evaluate La-CTP, and the experimental results showed its efficacy and efficiency. PMID:29393876

Biosimilar Monoclonal Antibodies for Inflammatory Bowel Disease: Current Comfort and Future Prospects.

PubMed

Gecse, Krisztina B; Lakatos, Péter L

2016-10-01

Biosimilars are biologic medicines that enter the market after a patent for an original reference product expires. The European Medicines Agency (EMA) developed a stringent legislation process for biosimilar monoclonal antibodies, whereby similarity to the reference medicinal product in terms of quality characteristics, biological activity, clinical safety and efficacy must be demonstrated. Biosimilar infliximab CT-P13 was the first biosimilar monoclonal antibody to receive EMA marketing authorization, and further biosimilar molecules are being developed. The phase I and III clinical trials were conducted in ankylosing spondylitis and rheumatoid arthritis, and the use of CT-P13 in inflammatory bowel disease (IBD) was extrapolated on the results of these trials. Medical professionals were initially concerned about the reversed engineering process, the novel legal framework and the lack of clinical data in IBD. Emerging real-world data have confirmed the similarities between CT-P13 and the reference product in terms of efficacy, safety and immunogenicity in IBD. The cost reduction represented by biosimilars promotes industry competition and improves treatment access with sustained quality of care. This article reviews the existing and emerging clinical data for CT-P13 and a future perspective on biosimilar use in IBD.

Kinetic Basis of Nucleotide Selection Employed by a Protein Template-Dependent DNA Polymerase†

PubMed Central

Brown, Jessica A.; Fowler, Jason D.; Suo, Zucai

2010-01-01

Rev1, a Y-family DNA polymerase, contributes to spontaneous and DNA damage-induced mutagenic events. In this paper, we have employed pre-steady state kinetic methodology to establish a kinetic basis for nucleotide selection by human Rev1, a unique nucleotidyl transferase that uses a protein template-directed mechanism to preferentially instruct dCTP incorporation. This work demonstrated that the high incorporation efficiency of dCTP is dependent on both substrates: an incoming dCTP and a templating base dG. The extremely low base substitution fidelity of human Rev1 (100 to 10-5) was due to the preferred misincorporation of dCTP with templating bases dA, dT, and dC over correct dNTPs. Using non-natural nucleotide analogs, we showed that hydrogen bonding interactions between residue R357 of human Rev1 and an incoming dNTP are not essential for DNA synthesis. Lastly, human Rev1 discriminates between ribonucleotides and deoxyribonucleotides mainly by reducing the rate of incorporation, and the sugar selectivity of human Rev1 is sensitive to both the size and orientation of the 2′-substituent of a ribonucleotide. PMID:20518555

CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.

PubMed

Stebbing, Justin; Baranau, Yauheni; Baryash, Valeriy; Manikhas, Alexey; Moiseyenko, Vladimir; Dzagnidze, Giorgi; Zhavrid, Edvard; Boliukh, Dmytro; Stroyakovskii, Daniil; Pikiel, Joanna; Eniu, Alexandru; Komov, Dmitry; Morar-Bolba, Gabriela; Li, Rubi K; Rusyn, Andriy; Lee, Sang Joon; Lee, Sung Young; Esteva, Francisco J

2017-07-01

CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m 2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m 2 ], epirubicin [75 mg/m 2 ], and cyclophosphamide [500 mg/m 2 ]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. Celltrion Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120-catenin with the cytoplasmic tail of MUC1

PubMed Central

Zhang, Lili; Gallup, Marianne; Zlock, Lorna; Basbaum, Carol; Finkbeiner, Walter E.; McNamara, Nancy A.

2014-01-01

Adherens junctions (AJs) containing epithelial cadherin (E-cad) bound to p120-catenin (p120ctn) and β-catenin (β-ctn) play a crucial role in regulating cell–cell adhesion. Cigarette smoke abrogates cell–cell adhesion between epithelial cells by disrupting E-cad, a hallmark of epithelial–mesenchymal transition (EMT), yet the underlying mechanism remains unknown. We used an organotypic culture of primary human bronchial epithelial (HBE) cells treated with smoke-concentrated medium (Smk) to establish an essential role for the interaction between p120ctn and the cytoplasmic tail of MUC1 (MUC1-CT) in regulating E-cad disruption. Within the first 4 h of smoke exposure, apical MUC1-CT repositioned to the basolateral membrane of pseudo-stratified HBE cells, where it interacted with p120ctn. A time-dependent increase in MUC1-CT/p120ctn complexes occurred in conjunction with a time-dependent dissociation of p120ctn/E-cad/β-ctn complexes, as well as the coordinated degradation of p120ctn and E-cad. Interestingly, Smk induced a similar interaction between MUC1-CT and β-ctn, but this occurred 44 h after MUC1-CT’s initial interaction with p120ctn, and well after the AJs were destroyed. Blocking MUC1-CT’s interaction with p120ctn using a MUC1-CT dominant-negative peptide, PMIP, successfully abolished Smk’s disruptive effects on AJs and recovered apical-basolateral polarity of HBE cells. The MUC1-CT/p120ctn interaction was highly dependent on EGFR/Src/Jnk-mediated tyrosine phosphorylation (TyrP) of MUC1-CT. Accordingly, EGFR, Src or Jnk inhibitors (AG1478, PP2, SP600125, respectively) abrogated Smk-induced MUC1-CT-TyrP, MUC1-CT/p120ctn interaction, AJ disruption, and loss of cellular polarity. Our work identified MUC1-CT and p120ctn as important regulators of epithelial polarity and cell-cell adhesion during a smoke-induced EMT-like process. Novel therapeutics designed to inhibit MUC1-CT/p120ctn complex formation may prevent EMT in the smoker’s airway. PMID:22833523

Oral administration of citrus pulp reduces gasrointestinal recovery of orally dosed Escherichia coli F18 in weaned pigs

USDA-ARS?s Scientific Manuscript database

The effects of citrus pulp (CTP), on the immune and cortisol responses to E. coli F18 inoculation and subsequent E. coli recovery were evaluated in newly weaned pigs (23.3 + 1.8 d of age). Barrows were assigned to 1 of 2 treatment groups; with (CTP; n = 15) and without (Control; n = 15) the in-feed ...

Structure-based Mechanism of CMP-2-keto-3-deoxymanno-octulonic Acid Synthetase

PubMed Central

Heyes, Derren J.; Levy, Colin; Lafite, Pierre; Roberts, Ian S.; Goldrick, Marie; Stachulski, Andrew V.; Rossington, Steven B.; Stanford, Deborah; Rigby, Stephen E. J.; Scrutton, Nigel S.; Leys, David

2009-01-01

The enzyme CMP-Kdo synthetase (KdsB) catalyzes the addition of 2-keto-3-deoxymanno-octulonic acid (Kdo) to CTP to form CMP-Kdo, a key reaction in the biosynthesis of lipopolysaccharide. The reaction catalyzed by KdsB and the related CMP-acylneuraminate synthase is unique among the sugar-activating enzymes in that the respective sugars are directly coupled to a cytosine monophosphate. Using inhibition studies, in combination with isothermal calorimetry, we show the substrate analogue 2β-deoxy-Kdo to be a potent competitive inhibitor. The ligand-free Escherichia coli KdsB and ternary complex KdsB-CTP-2β-deoxy-Kdo crystal structures reveal that Kdo binding leads to active site closure and repositioning of the CTP phosphates and associated Mg2+ ion (Mg-B). Both ligands occupy conformations compatible with an Sn2-type attack on the α-phosphate by the Kdo 2-hydroxyl group. Based on strong similarity with DNA/RNA polymerases, both in terms of overall chemistry catalyzed as well as active site configuration, we postulate a second Mg2+ ion (Mg-A) is bound by the catalytically competent KdsB-CTP-Kdo ternary complex. Modeling of this complex reveals the Mg-A coordinated to the conserved Asp100 and Asp235 in addition to the CTP α-phosphate and both the Kdo carboxylic and 2-hydroxyl groups. EPR measurements on the Mn2+-substituted ternary complex support this model. We propose the KdsB/CNS sugar-activating enzymes catalyze the formation of activated sugars, such as the abundant CMP-5-N-acetylneuraminic acid, by recruitment of two Mg2+ to the active site. Although each metal ion assists in correct positioning of the substrates and activation of the α-phosphate, Mg-A is responsible for activation of the sugar-hydroxyl group. PMID:19815542

Transition-state destabilization reveals how human DNA polymerase β proceeds across the chemically unstable lesion N7-methylguanine

PubMed Central

Ouzon-Shubeita, Hala; Lee, Seongmin

2014-01-01

N7-Methyl-2′-deoxyguanosine (m7dG) is the predominant lesion formed by methylating agents. A systematic investigation on the effect of m7dG on DNA replication has been difficult due to the chemical instability of m7dG. To gain insights into the m7dG effect, we employed a 2′-fluorine-mediated transition-state destabilzation strategy. Specifically, we determined kinetic parameters for dCTP insertion opposite a chemically stable m7dG analogue, 2′-fluoro-m7dG (Fm7dG), by human DNA polymerase β (polβ) and solved three X-ray structures of polβ in complex with the templating Fm7dG paired with incoming dCTP or dTTP analogues. The kinetic studies reveal that the templating Fm7dG slows polβ catalysis ∼300-fold, suggesting that m7dG in genomic DNA may impede replication by some DNA polymerases. The structural analysis reveals that Fm7dG forms a canonical Watson–Crick base pair with dCTP, but metal ion coordination is suboptimal for catalysis in the polβ-Fm7dG:dCTP complex, which partially explains the slow insertion of dCTP opposite Fm7dG by polβ. In addition, the polβ-Fm7dG:dTTP structure shows open protein conformations and staggered base pair conformations, indicating that N7-methylation of dG does not promote a promutagenic replication. Overall, the first systematic studies on the effect of m7dG on DNA replication reveal that polβ catalysis across m7dG is slow, yet highly accurate. PMID:24966350

Prediction of Post-operative Mortality in Patients with HCV-related Cirrhosis Undergoing Non-Hepatic Surgeries

PubMed Central

Hemida, Khalid; Shabana, Sherif Sadek; Said, Hani; Ali-Eldin, Fatma

2016-01-01

Introduction Patients with chronic liver diseases are at great risk for both morbidity and mortality during the post-operative period due to the stress of surgery and the effects of general anaesthesia. Aim The main aim of this study was to evaluate the value of Model for End-stage Liver Disease (MELD) score, as compared to Child-Turcotte-Pugh (CTP) score, for prediction of 30- day post-operative mortality in Egyptian patients with liver cirrhosis undergoing non-hepatic surgery under general anaesthesia. Materials and Methods A total of 60 patients with Hepatitis C Virus (HCV) - related liver cirrhosis were included in this study. Sensitivity and specificity of MELD and CTP scores were evaluated for the prediction of post-operative mortality. A total of 20 patients who had no clinical, biochemical or radiological evidence of liver disease were included to serve as a control group. Results The highest sensitivity and specificity for detection of post-operative mortality was detected at a MELD score of 13.5. CTP score had a sensitivity of 75%, a specificity of 96.4%, and an overall accuracy of 95% for prediction of post-operative mortality. On the other side and at a cut-off value of 13.5, MELD score had a sensitivity of 100%, a specificity of 64.0%, and an overall accuracy of 66.6% for prediction of post-operative mortality in patients with HCV- related liver cirrhosis. Conclusion MELD score proved to be more sensitive but less specific than CTP score for prediction of post-operative mortality. CTP and MELD scores may be complementary rather than competitive in predicting post-operative mortality in patients with HCV- related liver cirrhosis. PMID:27891371

Regulation of PRPP and nucleoside tri and tetraphosphate pools in Escherichia coli under conditions of nitrogen starvation.

PubMed Central

Villadsen, I S; Michelsen, O

1977-01-01

The ribonucleoside triphosphate, deoxyribonucleoside triphosphate, 3' -diphosphate guanosine 5' -diphosphate (ppGpp), and 5-phosphoribosyl 1-pyrophosphate (PRPP) pools in Escherichia coli B were determined by thin-layer chromatography during changing conditions to ammonium starvation. The intracellular concentrations of all nucleotides were found to change in a well-defined order several minutes before andy observed change in the optical density of the culture. The levels of purine nucleoside triphosphates (adenosine 5' -triphosphate [CTP], dCTP) and uridine nucleotides (uridine 5' -triphosphate, deoxythymidine 5'-triphosphate). The deoxyribonucleotides thus behaved as the ribonucleotides. The levels of ppGpp increased 11-fold after the decrease in uridine nucleotides, when the accumulation of stable ribonucleic acid (RNA) stopped. The level of the nucleotide pool did not stabilize until 30 min after the change in optical density. The pool of dGTP dropped concomitantly with the pool of CTP. The nucleotide precursor PRPP exhibited a transient increase, wtih maximum value of four times the exponential levels at the onset of starvation. Apparently the cell adjusts early to starvation by reducing either the phosphorylating activity or the nucleotide biosynthetic activity. As in other downshift systems, the accumulation of stable RNA stopped before the break in optical density and before the stop in protein accumulation. Cell divisions were quite insensitive to the control mechanisms operating on RNA and protein accumulation under ammonium starvation, since the cells continued to divide for 21 min without any net accumulation of RNA. Images PMID:323222

Oral administration of citrus pulp reduces gastrointestinal recovery of orally dosed Escherichia coli F18 in weaned pigs

USDA-ARS?s Scientific Manuscript database

The effects of citrus pulp (CTP) on the immune and cortisol responses to E. coli F18 inoculation and subsequent E. coli recovery were evaluated in newly weaned pigs (23.3 + 1.8 d of age). Barrows were assigned to 1 of 2 treatment groups; with (CTP; n = 15) and without (Control; n = 15) the in-feed i...

Serum iron parameters in liver cirrhosis

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Maail, W.

2018-03-01

The liver plays a fundamental role in iron homeostasis. Iron parameters change, especially ferritin, need to be evaluated in patients with liver cirrhosis. Serum ferritin could predict the prognosis of patients with decompensated cirrhosis since it reflects immunemediated and infectious stimuli. Ferritin could express the severity of liver disease and possible subsequent complications. Finally, it might reflect an iron overload condition resulting in significant morbidity and early mortality. 70 patients with decompensated liver cirrhosis divided into three Child-Pugh subgroups. Serum iron parameters include serum iron (SI), total iron binding capacity (TIBC) and ferritin was measured in these groups. From these 70 patients, 30 (42.9%) with HbsAg positive, 26 (37.1%) with anti-HCV positive and 14 (20%) with both HbsAg and anti-HCV positive. Of the 70 patients, 14 (20%) had CTP Class A cirrhosis, 17 (24.3%) had CTP Class B cirrhosis, and 39 (55.7%) had CTP C cirrhosis. The median (range) value of serum iron was 36 (10-345) μg/dl, TIBC was 160 (59-520) μg/dl, Ferritin was 253.5 (8-6078) ng/ml and the transferrin saturation was 22.9 (3.65-216.98) %.We found a significant difference in serum ferritin level with CTP score. Ferritin levels increased as Child-Pugh class progressed (p<0.001).

Detection of Alicyclobacillus species in fruit juice using a random genomic DNA microarray chip.

PubMed

Jang, Jun Hyeong; Kim, Sun-Joong; Yoon, Bo Hyun; Ryu, Jee-Hoon; Gu, Man Bock; Chang, Hyo-Ihl

2011-06-01

This study describes a method using a DNA microarray chip to rapidly and simultaneously detect Alicyclobacillus species in orange juice based on the hybridization of genomic DNA with random probes. Three food spoilage bacteria were used in this study: Alicyclobacillus acidocaldarius, Alicyclobacillus acidoterrestris, and Alicyclobacillus cycloheptanicus. The three Alicyclobacillus species were adjusted to 2 × 10(3) CFU/ml and inoculated into pasteurized 100% pure orange juice. Cy5-dCTP labeling was used for reference signals, and Cy3-dCTP was labeled for target genomic DNA. The molar ratio of 1:1 of Cy3-dCTP and Cy5-dCTP was used. DNA microarray chips were fabricated using randomly fragmented DNA of Alicyclobacillus spp. and were hybridized with genomic DNA extracted from Bacillus spp. Genomic DNA extracted from Alicyclobacillus spp. showed a significantly higher hybridization rate compared with DNA of Bacillus spp., thereby distinguishing Alicyclobacillus spp. from Bacillus spp. The results showed that the microarray DNA chip containing randomly fragmented genomic DNA was specific and clearly identified specific food spoilage bacteria. This microarray system is a good tool for rapid and specific detection of thermophilic spoilage bacteria, mainly Alicyclobacillus spp., and is useful and applicable to the fruit juice industry.

Progress in biosimilar monoclonal antibody development: the infliximab biosimilar CT-P13 in the treatment of rheumatic diseases.

PubMed

Braun, Jürgen; Kudrin, Alex

2015-01-01

Biosimilars are biologic medical products whose active drug substance is made by a living organism or derived from it. The term is used to describe a subsequent version of an innovator biopharmaceutical product aiming at approval following patent expiry on the reference product. Biosimilars of monoclonal need to demonstrate similar but not identical quality of nonclinical and clinical attributes. Not all data of the originator product need to be recapitulated, as large numbers of patient-years of exposure data are already available. Thus, biosimilar development is largely based on the safety profiles of the originator product. The evaluation of biosimilarity includes immunogenicity attributed risks. CT-P13 (Remsima™/Inflectra™, Celltrion/Hospira), a biosimilar of the innovator drug infliximab (INF), was the first approved complex biosimilar monoclonal antibody in the EU, within the framework of WHO, EMA and US FDA biosimilar guidelines. CT-P13 has shown analytical and nonclinical features highly similar to INF including pharmacokinetics, efficacy, safety and immunogenicity profiles in ankylosing spondylitis and rheumatoid arthritis. The objective of this article is to highlight the recent biosimilar development and to review the results from the studies PLANETRA and PLANETAS, which have supported the approval of CT-P13 for several indications.

Identification of CtpL as a chromosomally encoded chemoreceptor for 4-chloroaniline and catechol in Pseudomonas aeruginosa PAO1.

PubMed

Vangnai, Alisa S; Takeuchi, Kazuki; Oku, Shota; Kataoka, Naoya; Nitisakulkan, Tisana; Tajima, Takahisa; Kato, Junichi

2013-12-01

Bacterial chemotaxis influences the ability of bacteria to survive and thrive in most environments, including polluted ones. Despite numerous reports of the phenotypic characterization of chemotactic bacteria, only a few molecular details of chemoreceptors for aromatic pollutants have been described. In this study, the molecular basis of chemotaxis toward an environmentally toxic chlorinated aromatic pollutant, 4-chloroaniline (4CA), was evaluated. Among the three Pseudomonas spp. tested, Pseudomonas aeruginosa PAO1 exhibited positive chemotaxis both to the nonmetabolizable 4CA, where 4-chloroacetanilide was formed as a dead-end transformation product, and to the metabolizable catechol. Molecular analysis of all 26 mutants with a disrupted methyl-accepting chemotaxis gene revealed that CtpL, a chromosomally encoded chemoreceptor, was responsible for the positive chemotactic response toward 4CA. Since CtpL has previously been described to be a major chemoreceptor for inorganic phosphate at low concentrations in PAO1, this report describes a fortuitous ability of CtpL to function toward aromatic pollutants. In addition, its regulation not only was dependent on the presence of the chemoattractant inducer but also was regulated by conditions of phosphate starvation. These results expand the range of known chemotactic transducers and their function in the environmental bacterium PAO1.

Implementation of an anonymisation tool for clinical trials using a clinical trial processor integrated with an existing trial patient data information system.

PubMed

Aryanto, Kadek Y E; Broekema, André; Oudkerk, Matthijs; van Ooijen, Peter M A

2012-01-01

To present an adapted Clinical Trial Processor (CTP) test set-up for receiving, anonymising and saving Digital Imaging and Communications in Medicine (DICOM) data using external input from the original database of an existing clinical study information system to guide the anonymisation process. Two methods are presented for an adapted CTP test set-up. In the first method, images are pushed from the Picture Archiving and Communication System (PACS) using the DICOM protocol through a local network. In the second method, images are transferred through the internet using the HTTPS protocol. In total 25,000 images from 50 patients were moved from the PACS, anonymised and stored within roughly 2 h using the first method. In the second method, an average of 10 images per minute were transferred and processed over a residential connection. In both methods, no duplicated images were stored when previous images were retransferred. The anonymised images are stored in appropriate directories. The CTP can transfer and process DICOM images correctly in a very easy set-up providing a fast, secure and stable environment. The adapted CTP allows easy integration into an environment in which patient data are already included in an existing information system.

An optimized transit peptide for effective targeting of diverse foreign proteins into chloroplasts in rice.

PubMed

Shen, Bo-Ran; Zhu, Cheng-Hua; Yao, Zhen; Cui, Li-Li; Zhang, Jian-Jun; Yang, Cheng-Wei; He, Zheng-Hui; Peng, Xin-Xiang

2017-04-11

Various chloroplast transit peptides (CTP) have been used to successfully target some foreign proteins into chloroplasts, but for other proteins these same CTPs have reduced localization efficiencies or fail completely. The underlying cause of the failures remains an open question, and more effective CTPs are needed. In this study, we initially observed that two E.coli enzymes, EcTSR and EcGCL, failed to be targeted into rice chloroplasts by the commonly-used rice rbcS transit peptide (rCTP) and were subsequently degraded. Further analyses revealed that the N-terminal unfolded region of cargo proteins is critical for their localization capability, and that a length of about 20 amino acids is required to attain the maximum localization efficiency. We considered that the unfolded region may alleviate the steric hindrance produced by the cargo protein, by functioning as a spacer to which cytosolic translocators can bind. Based on this inference, an optimized CTP, named RC2, was constructed. Analyses showed that RC2 can more effectively target diverse proteins, including EcTSR and EcGCL, into rice chloroplasts. Collectively, our results provide further insight into the mechanism of CTP-mediated chloroplastic localization, and more importantly, RC2 can be widely applied in future chloroplastic metabolic engineering, particularly for crop plants.

Gradual plasmon evolution and huge infrared near-field enhancement of metallic bridged nanoparticle dimers.

PubMed

Huang, Yu; Ma, Lingwei; Hou, Mengjing; Xie, Zheng; Zhang, Zhengjun

2016-01-28

By three-dimensional (3D) finite element method (FEM) plasmon mapping, gradual plasmon evolutions of both bonding dipole plasmon (BDP) and charge transfer plasmon (CTP) modes are visualized. In particular, the evolved BDP mode provides a physical insight into the rapid degeneration of electromagnetic hot spots in practical applications, while the rising CTP mode enables a huge near-field enhancement for potential plasmonic devices at infrared wavelengths.

Crystallization and preliminary X-ray analysis of CTP:phosphoethanolamine cytidylyltransferase (ECT) from Saccharomyces cerevisiae

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

Ohtsuka, Jun; Nagata, Koji; Lee, Woo Cheol

2006-10-01

CTP:phosphoethanolamine cytidylyltransferase from S. cerevisiae has been expressed, purified and crystallized. CTP:phosphoethanolamine cytidylyltransferase (ECT) is the enzyme that catalyzes the conversion of phosphoethanolamine to CDP-ethanolamine in the phosphatidylethanolamine-biosynthetic pathway (Kennedy pathway). ECT from Saccharomyces cerevisiae was crystallized by the sitting-drop vapour-diffusion method using PEG 4000 as precipitant. The crystals diffracted X-rays from a synchrotron-radiation source to 1.88 Å resolution. The space group was assigned as primitive tetragonal, P4{sub 1}2{sub 1}2 or P4{sub 3}2{sub 1}2, with unit-cell parameters a = b = 66.3, c = 150.8 Å. The crystals contain one ECT molecule in the asymmetric unit (V{sub M} = 2.2more » Å{sup 3} Da{sup −1}), with a solvent content of 43%.« less

Correction for Delay and Dispersion Results in More Accurate Cerebral Blood Flow Ischemic Core Measurement in Acute Stroke.

PubMed

Lin, Longting; Bivard, Andrew; Kleinig, Timothy; Spratt, Neil J; Levi, Christopher R; Yang, Qing; Parsons, Mark W

2018-04-01

This study aimed to assess how the ischemic core measured by perfusion computed tomography (CTP) was affected by the delay and dispersion effect. Ischemic stroke patients having CTP performed within 6 hours of onset were included. The CTP data were processed twice, generating standard cerebral blood flow (sCBF) and delay- and dispersion-corrected CBF (ddCBF), respectively. Ischemic core measured by the sCBF and ddCBF was then compared at the relative threshold <30% of normal tissue. Two references for ischemic core were used: acute diffusion-weighted imaging or 24-hour diffusion-weighted imaging in patients with complete recanalization. Difference of core volume between CTP and diffusion-weighted imaging was estimated by Mann-Whitney U test and limits of agreement. Patients were also classified into favorable and unfavorable CTP patterns. The imaging pattern classification by sCBF and ddCBF was compared by the χ 2 test; their respective ability to predict good clinical outcome (3-month modified Rankin Scale score) was tested in logistic regression. Fifty-five patients were included in this study. Median sCBF ischemic core volume was 38.5 mL (12.4-61.9 mL), much larger than the median core volume of 17.2 mL measured by ddCBF (interquartile range, 5.5-38.8; P <0.001). Moreover, compared with sCBF <30%, ddCBF <30% measured the ischemic core much closer to diffusion-weighted imaging core references, with the mean volume difference of -0.1 mL (95% limits of agreement, -25.4 to 25.2; P =0.97) and 16.7 mL (95% limits of agreement, -21.7 to 55.2; P <0.001), respectively. Imaging patterns defined by sCBF showed a difference to that defined by ddCBF ( P <0.001), with 12 patients classified as favorable imaging patterns by ddCBF but as unfavorable by sCBF. The favorable imaging pattern classified by ddCBF, compared with sCBF classification, had higher predictive power for good clinical outcome (odds ratio, 7.8 [2-30.5] and 3.1 [0.9-11], respectively). Delay and dispersion correction increases the accuracy of ischemic core measurement on CTP. © 2018 American Heart Association, Inc.

Viewing Human DNA Polymerase β Faithfully and Unfaithfully Bypass an Oxidative Lesion by Time-Dependent Crystallography

DOE PAGES

Vyas, Rajan; Reed, Andrew J.; Tokarsky, E. John; ...

2015-03-31

One common oxidative DNA lesion, 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG), is highly mutagenic in vivo due to its anti-conformation forming a Watson–Crick base pair with correct deoxycytidine 5'-triphosphate (dCTP) and its syn-conformation forming a Hoogsteen base pair with incorrect deoxyadenosine 5'-triphosphate (dATP). Here in this article, we utilized time-resolved X-ray crystallography to follow 8-oxoG bypass by human DNA polymerase β (hPolβ). In the 12 solved structures, both Watson–Crick (anti-8-oxoG:anti-dCTP) and Hoogsteen (syn-8-oxoG:anti-dATP) base pairing were clearly visible and were maintained throughout the chemical reaction. Additionally, a third Mg 2+ appeared during the process of phosphodiester bond formation and was located between the reactingmore » α- and β-phosphates of the dNTP, suggesting its role in stabilizing reaction intermediates. After phosphodiester bond formation, hPolβ reopened its conformation, pyrophosphate was released, and the newly incorporated primer 3'-terminal nucleotide stacked, rather than base paired, with 8-oxoG. These structures provide the first real-time pictures, to our knowledge, of how a polymerase correctly and incorrectly bypasses a DNA lesion.« less

Viewing Human DNA Polymerase β Faithfully and Unfaithfully Bypass an Oxidative Lesion by Time-Dependent Crystallography

PubMed Central

Vyas, Rajan; Reed, Andrew J.; Tokarsky, E. John; Suo, Zucai

2015-01-01

One common oxidative DNA lesion, 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG), is highly mutagenic in vivo due to its anti-conformation forming a Watson–Crick base pair with correct deoxycytidine 5′-triphosphate (dCTP) and its syn-conformation forming a Hoogsteen base pair with incorrect deoxyadenosine 5′-triphosphate (dATP). Here, we utilized time-resolved X-ray crystallography to follow 8-oxoG bypass by human DNA polymerase β (hPolβ). In the 12 solved structures, both Watson–Crick (anti-8-oxoG:anti-dCTP) and Hoogsteen (syn-8-oxoG:anti-dATP) base pairing were clearly visible and were maintained throughout the chemical reaction. Additionally, a third Mg2+ appeared during the process of phosphodiester bond formation and was located between the reacting α- and β-phosphates of the dNTP, suggesting its role in stabilizing reaction intermediates. After phosphodiester bond formation, hPolβ reopened its conformation, pyrophosphate was released, and the newly incorporated primer 3′-terminal nucleotide stacked, rather than base paired, with 8-oxoG. These structures provide the first real-time pictures, to our knowledge, of how a polymerase correctly and incorrectly bypasses a DNA lesion. PMID:25825995

Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 1: Triazoles, triazolopyrimidines, triazinoindoles, quinoline hydrazones and arylpiperazines.

PubMed

Llona-Minguez, Sabin; Häggblad, Maria; Martens, Ulf; Throup, Adam; Loseva, Olga; Jemth, Ann-Sofie; Lundgren, Bo; Scobie, Martin; Helleday, Thomas

2017-08-15

A high-throughput screening campaign using a commercial compound library (ChemBridge DiverSET) revealed diverse chemotypes as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). Triazole, triazolopyrimidine, triazinoindole, quinoline hydrazone and arylpiperazine hits were clustered, confirmed by IC 50 determinations, and their preliminary structure-activity-relationships (SAR) and ligand efficiency scores are discussed in this letter. Copyright © 2017. Published by Elsevier Ltd.

Characterization of a Dopaminergic Stimulatory Factor Derived from Monoclonal Cell Lines of Striatal Origin

DTIC Science & Technology

2006-12-01

other substrates for its biosynthesis would be effective in raising MN9D dopamine content. The pyrimidine, cytidine triphosphate (CTP) reacts with...phosphatidylethanolamine or phosphatidylcholine. MN9D cells were treated for 48 hrs with 2 mM CTP, cytidine diphosphate (CDP) or cytidine monophosphate (CMP), in the...presence or absence of 25 µM ethanolamine or 25 µM phosphoethanolamine. Cytidine alone did not alter the dopaminergic stimulatory effect of

Sugar-modified poly(propylene imine) dendrimers as drug delivery agents for cytarabine to overcome drug resistance.

PubMed

Szulc, Aleksandra; Pulaski, Lukasz; Appelhans, Dietmar; Voit, Brigitte; Klajnert-Maculewicz, Barbara

2016-11-20

Maltose-modified poly(propylene imine) glycodendrimers (PPI-m OS) of the 4th generation provide a promising strategy for leukemia treatment. Anticancer therapy with nucleoside analog drugs such as cytarabine (Ara-C) frequently has limited efficacy due to drug resistance, inefficient uptake and accumulation of the drug inside cancer cells where it has to be transformed into the active triphosphate congener. The cationic nature of PPI dendrimers makes it possible to form complexes with nucleotide Ara-C triphosphate forms (Ara-CTP). The aim of this work was to test the concept of applying PPI glycodendrimers as drug delivery devices in order to facilitate the delivery of activated cytarabine to cancer cells to overcome metabolic limitations of the drug. The study has been carried out using 1301 and HL-60 leukemic cell lines as well as peripheral blood mononuclear cells. The results of cytotoxicity and apoptosis assays showed enhanced activity of Ara-C triphosphate form (Ara-CTP) complexed with PPI-m dendrimers in relation to free Ara-C and Ara-CTP against 1301 leukemic cells. Secondly, enhanced uptake and cytotoxicity of Ara-CTP-dendrimers complexes toward 1301 cells with blocked human equilibrative nucleoside transporter - hENT1 suggested that this combination might be a versatile candidate for chemotherapy against resistant acute lymphoblastic leukemia cells with lower expression of hENT1. Copyright © 2016 Elsevier B.V. All rights reserved.

M-52 spray booth qualification test

NASA Technical Reports Server (NTRS)

1990-01-01

The procedures, performance, and results obtained from the M-52 spray booth qualification test are documented. The test was conducted at Thiokol Corporation, Space Operations, M-52 Inert Parts Preparation facility. The purpose of this testing sequence was to ensure the spray booth would produce flight qualified hardware. The testing sequence was conducted in two series. The first series was conducted under CTP-0142, Revision 1. The second series was conducted in accordance with CTP-0142, Revision 2. The test sequence started with CTP-0142, Revision 1. The series consisted of the contamination removal test and the performance test. The contamination removal test was used to assess the Teflon level in the spray booth. The performance test consisted of painting and Chemloking a forward dome inside the spray booth per flight procedures. During the performance test, two sets of witness panels (case/insulation and steel/epoxy/steel) were prepared and pull tested. The CTP-0142, Revision 2, series of testing consisted of re-testing the steel/epoxy/steel witness panels. The pull tests analysis indicates the results of the tensile tests were comparable to the systems tunnel witness panel database. The exposed panel set and the control panel set average tensile values were above the 1-basis lower limits established on the systems tunnel witness panel database. It is recommended that the M-52 spray booth be qualified for producing flight hardware.

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

Vyas, Rajan; Reed, Andrew J.; Tokarsky, E. John

One common oxidative DNA lesion, 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG), is highly mutagenic in vivo due to its anti-conformation forming a Watson–Crick base pair with correct deoxycytidine 5'-triphosphate (dCTP) and its syn-conformation forming a Hoogsteen base pair with incorrect deoxyadenosine 5'-triphosphate (dATP). Here in this article, we utilized time-resolved X-ray crystallography to follow 8-oxoG bypass by human DNA polymerase β (hPolβ). In the 12 solved structures, both Watson–Crick (anti-8-oxoG:anti-dCTP) and Hoogsteen (syn-8-oxoG:anti-dATP) base pairing were clearly visible and were maintained throughout the chemical reaction. Additionally, a third Mg 2+ appeared during the process of phosphodiester bond formation and was located between the reactingmore » α- and β-phosphates of the dNTP, suggesting its role in stabilizing reaction intermediates. After phosphodiester bond formation, hPolβ reopened its conformation, pyrophosphate was released, and the newly incorporated primer 3'-terminal nucleotide stacked, rather than base paired, with 8-oxoG. These structures provide the first real-time pictures, to our knowledge, of how a polymerase correctly and incorrectly bypasses a DNA lesion.« less

Central Equatorial Pacific Sea Surface Temperatures During the Last Glacial Maximum

NASA Astrophysics Data System (ADS)

Monteagudo, M. M.; Lynch-Stieglitz, J.; Schmidt, M. W.

2017-12-01

The state of the tropical Pacific ocean-atmosphere system during the Last Glacial Maximum (LGM, 19,000-23,000 years BP) remains an area of uncertainty. Spatial patterns of tropical Pacific sea surface temperature (SST) offer insight into atmospheric circulation (i.e. Walker Circulation), however, few records exist for the Central Tropical Pacific (CTP). The few existing glacial CTP SST reconstructions indicate 1-2 °C of warming based on foraminiferal transfer functions (CLIMAP Project Members, 1976). In contrast, evidence from geochemical proxies (Mg/Ca, UK'37, TEX86) show 1-3.5 °C cooling in the eastern and western tropical Pacific (e.g. MARGO Project Members, 2009). In this study we present the first Mg/Ca estimates of glacial CTP SST from a meridional sediment core transect along the Line Islands Ridge (0-7°N, 156-162 °W). We use a time slice approach to establish the magnitude of glacial-interglacial SST change between the LGM (19,000-23,0000 years BP) and the Holocene (0-10,000 years BP) using Mg/Ca in the surface-dwelling foraminifera Globigerinoides ruber. Our results indicate cooling at all latitudes, ranging between 1.2-2.7 °C (Holocene-LGM SST). Northern cores (6.83-2.77 °N) exhibit a smaller glacial-interglacial SST difference than equatorial site 20BB at 1.27 °N. The data generated thus far suggest the glacial meridional SST gradient may have been steeper, possibly as a result of increased zonal winds, equatorial upwelling, or westward expansion of the Eastern Pacific Cold Tongue.

[Etiology and complications of liver cirrhosis: data from a German centre].

PubMed

Sivanathan, V; Kittner, J M; Sprinzl, M F; Weinmann, A; Koch, S; Wiltink, J; Nguyen-Tat, M; Marquardt, J U; Wörns, M A; Zimmermann, T; Lang, H; Galle, P R; Schattenberg, J M

2014-09-01

Liver cirrhosis develops as a terminal complication of chronic liver disease. The clinical course is determined by the underlying etiology and the accompanying risk factors, which are influenced by the geographic and cultural background. A total of 236 patients (159 men, 77 women, median age 57 [22-81] years) were included for retrospective analysis between July 2012 and February 2014 using standardized questionnaires during an outpatient visit at a hepatology clinic. The most common etiologies of liver cirrhosis were related to alcohol consumption (52 %), chronic hepatitis C (28 %) or hepatitis B (14 %) infection and NASH (nonalcoholic steatohepatitis, 6 %). At the time of presentation 55 % patients had compensated cirrhosis corresponding to Child-Turcotte-Pugh (CTP) stage A, while 45 % were in a decompensated stage (30 % CTP B and 15 % CTP C). Subgroups were analyzed for the incidence of complications and the emergence of infections. Most frequently esophageal varices (60 %) and ascites (49 %) were observed, followed by pleural effusion (14 %), hepatic encephalopathy (25 %) or hepatorenal syndrome (18 %). 16 % of patients exhibited infection based on clinical criteria. An infective agent was isolated in 38 % of all cases with infection and of those 50 % were gram positive bacteria. In multivariate analysis only the presence of ascites was an independent risk factor for infection. Despite improved medical therapies for viral hepatitis, these were the most frequent causes of liver cirrhosis, closely followed by alcoholic cirrhosis. The observed complications included bacterial infection and complication related to portal hypertension. © Georg Thieme Verlag KG Stuttgart · New York.

Biochemical Evaluation of the Inhibition Properties of Favipiravir and 2′-C-Methyl-Cytidine Triphosphates against Human and Mouse Norovirus RNA Polymerases

PubMed Central

Tucker, Kathryn; Lin, Xiaoyan; Kao, C. Cheng; Shaw, Ken; Tan, Hua; Symons, Julian; Behera, Ishani; Rajwanshi, Vivek K.; Dyatkina, Natalia; Wang, Guangyi; Beigelman, Leo

2015-01-01

Norovirus (NoV) is a positive-sense single-stranded RNA virus that causes acute gastroenteritis and is responsible for 200,000 deaths per year worldwide. No effective vaccine or treatment is available. Recent studies have shown that the nucleoside analogs favipiravir (T-705) and 2′-C-methyl-cytidine (2CM-C) inhibit NoV replication in vitro and in animal models, but their precise mechanism of action is unknown. We evaluated the molecular interactions between nucleoside triphosphates and NoV RNA-dependent RNA polymerase (NoVpol), the enzyme responsible for replication and transcription of NoV genomic RNA. We found that T-705 ribonucleoside triphosphate (RTP) and 2CM-C triphosphate (2CM-CTP) equally inhibited human and mouse NoVpol activities at concentrations resulting in 50% of maximum inhibition (IC50s) in the low micromolar range. 2CM-CTP inhibited the viral polymerases by competing directly with natural CTP during primer elongation, whereas T-705 RTP competed mostly with ATP and GTP at the initiation and elongation steps. Incorporation of 2CM-CTP into viral RNA blocked subsequent RNA synthesis, whereas T-705 RTP did not cause immediate chain termination of NoVpol. 2CM-CTP and T-705 RTP displayed low levels of enzyme selectivity, as they were both recognized as substrates by human mitochondrial RNA polymerase. The level of discrimination by the human enzyme was increased with a novel analog of T-705 RTP containing a 2′-C-methyl substitution. Collectively, our data suggest that 2CM-C inhibits replication of NoV by acting as a classic chain terminator, while T-705 may inhibit the virus by multiple mechanisms of action. Understanding the precise mechanism of action of anti-NoV compounds could provide a rational basis for optimizing their inhibition potencies and selectivities. PMID:26392512

Structural basis for proficient incorporation of dTTP opposite O6-methylguanine by human DNA polymerase iota.

PubMed

Pence, Matthew G; Choi, Jeong-Yun; Egli, Martin; Guengerich, F Peter

2010-12-24

O(6)-methylguanine (O(6)-methylG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, even physiological ones (e.g. S-adenosylmethionine). The efficiency of a truncated, catalytic DNA polymerase ι core enzyme was determined for nucleoside triphosphate incorporation opposite O(6)-methylG, using steady-state kinetic analyses. The results presented here corroborate previous work from this laboratory using full-length pol ι, which showed that dTTP incorporation occurs with high efficiency opposite O(6)-methylG. Misincorporation of dTTP opposite O(6)-methylG occurred with ∼6-fold higher efficiency than incorporation of dCTP. Crystal structures of the truncated form of pol ι with O(6)-methylG as the template base and incoming dCTP or dTTP were solved and showed that O(6)-methylG is rotated into the syn conformation in the pol ι active site and that dTTP misincorporation by pol ι is the result of Hoogsteen base pairing with the adduct. Both dCTP and dTTP base paired with the Hoogsteen edge of O(6)-methylG. A single, short hydrogen bond formed between the N3 atom of dTTP and the N7 atom of O(6)-methylG. Protonation of the N3 atom of dCTP and bifurcation of the N3 hydrogen between the N7 and O(6) atoms of O(6)-methylG allow base pairing of the lesion with dCTP. We conclude that differences in the Hoogsteen hydrogen bonding between nucleotides is the main factor in the preferential selectivity of dTTP opposite O(6)-methylG by human pol ι, in contrast to the mispairing modes observed previously for O(6)-methylG in the structures of the model DNA polymerases Sulfolobus solfataricus Dpo4 and Bacillus stearothermophilus DNA polymerase I.

Variability of Aerosol and its Impact on Cloud Properties Over Different Cities of Pakistan

NASA Astrophysics Data System (ADS)

Alam, Khan

Interaction between aerosols and clouds is the subject of considerable scientific research, due to the importance of clouds in controlling climate. Aerosols vary in time in space and can lead to variations in cloud microphysics. This paper is a pilot study to examine the temporal and spatial variation of aerosol particles and their impact on different cloud optical properties in the territory of Pakistan using the Moderate resolution Imaging Spectroradiometer (MODIS) on board NASA's Terra satellite data and Multi-angle Imaging Spectroradiometer (MISR) data. We also use Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model for trajectory analysis to obtain origin of air masses in order to understand the spatial and temporal variability of aerosol concentrations. We validate data of MODIS and MISR by using linear correlation and regression analysis, which shows that there is an excellent agreement between data of these instruments. Seasonal study of Aerosol Optical Depth (AOD) shows that maximum value is found in monsoon season (June-August) over all study areas. We analyze the relationships between aerosol optical depth (AOD) and some cloud parameters like water vapor (WV), cloud fraction (CF), cloud top temperature (CTT) and cloud top pressure (CTP). We construct the regional correlation maps and time series plots for aerosol and cloud parameters mandatory for the better understanding of aerosol-cloud interaction. Our analyses show that there is a strong positive correlation between AOD and water vapor in all cities. The correlation between AOD and CF is positive for the cities where the air masses are moist while the correlation is negative for cities where air masses are relatively dry and with lower aerosol abundance. It shows that these correlations depend on meteorological conditions. Similarly as AOD increases Cloud Top Pressure (CTP) is decreasing while Cloud Top Temperature (CTT) is increasing. Key Words: MODIS, MISR, HYSPLIT, AOD, CF, CTP, CTT

How the CCA-Adding Enzyme Selects Adenine over Cytosine at Position 76 of tRNA

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

B Pan; Y Xiong; T Steitz

2011-12-31

CCA-adding enzymes [ATP(CTP):tRNA nucleotidyltransferases] add CCA onto the 3' end of transfer RNA (tRNA) precursors without using a nucleic acid template. Although the mechanism by which cytosine (C) is selected at position 75 of tRNA has been established, the mechanism by which adenine (A) is selected at position 76 remains elusive. Here, we report five cocrystal structures of the enzyme complexed with both a tRNA mimic and nucleoside triphosphates under catalytically active conditions. These structures suggest that adenosine 5'-monophosphate is incorporated onto the A76 position of the tRNA via a carboxylate-assisted, one-metal-ion mechanism with aspartate 110 functioning as a generalmore » base. The discrimination against incorporation of cytidine 5'-triphosphate (CTP) at position 76 arises from improper placement of the {alpha} phosphate of the incoming CTP, which results from the interaction of C with arginine 224 and prevents the nucleophilic attack by the 3' hydroxyl group of cytidine75.« less

Chiral Tricritical Point: A New Universality Class in Dirac Systems

NASA Astrophysics Data System (ADS)

Yin, Shuai; Jian, Shao-Kai; Yao, Hong

2018-05-01

Tricriticality, as a sister of criticality, is a fundamental and absorbing issue in condensed-matter physics. It has been verified that the bosonic Wilson-Fisher universality class can be changed by gapless fermionic modes at criticality. However, the counterpart phenomena at tricriticality have rarely been explored. In this Letter, we study a model in which a tricritical Ising model is coupled to massless Dirac fermions. We find that the massless Dirac fermions result in the emergence of a new tricritical point, which we refer to as the chiral tricritical point (CTP), at the phase boundary between the Dirac semimetal and the charge-density wave insulator. From functional renormalization group analysis of the effective action, we obtain the critical behaviors of the CTP, which are qualitatively distinct from both the tricritical Ising universality and the chiral Ising universality. We further extend the calculations of the chiral tricritical behaviors of Ising spins to the case of Heisenberg spins. The experimental relevance of the CTP in two-dimensional Dirac semimetals is also discussed.

Geographic and demographic variabilities of quantitative parameters in stress myocardial computed tomography perfusion.

PubMed

Park, Jinoh; Kim, Hyun-Sook; Hwang, Hye Jeon; Yang, Dong Hyun; Koo, Hyun Jung; Kang, Joon-Won; Kim, Young-Hak

2017-09-01

To evaluate the geographic and demographic variabilities of the quantitative parameters of computed tomography perfusion (CTP) of the left ventricular (LV) myocardium in patients with normal coronary artery on computed tomography angiography (CTA). From a multicenter CTP registry of stress and static computed tomography, we retrospectively recruited 113 patients (mean age, 60 years; 57 men) without perfusion defect on visual assessment and minimal (< 20% of diameter stenosis) or no coronary artery disease on CTA. Using semiautomatic analysis software, quantitative parameters of the LV myocardium, including the myocardial attenuation in stress and rest phases, transmural perfusion ratio (TPR), and myocardial perfusion reserve index (MPRI), were evaluated in 16 myocardial segments. In the lateral wall of the LV myocardium, all quantitative parameters except for MPRI were significantly higher compared with those in the other walls. The MPRI showed consistent values in all myocardial walls (anterior to lateral wall: range, 25% to 27%; p = 0.401). At the basal level of the myocardium, all quantitative parameters were significantly lower than those at the mid- and apical levels. Compared with men, women had significantly higher values of myocardial attenuation and TPR. Age, body mass index, and Framingham risk score were significantly associated with the difference in myocardial attenuation. Geographic and demographic variabilities of quantitative parameters in stress myocardial CTP exist in healthy subjects without significant coronary artery disease. This information may be helpful when assessing myocardial perfusion defects in CTP.

Dipyridamole stress myocardial perfusion by computed tomography in patients with left bundle branch block.

PubMed

Cabeda, Estêvan Vieira; Falcão, Andréa Maria Gomes; Soares, José; Rochitte, Carlos Eduardo; Nomura, César Higa; Ávila, Luiz Francisco Rodrigues; Parga, José Rodrigues

2015-12-01

Functional tests have limited accuracy for identifying myocardial ischemia in patients with left bundle branch block (LBBB). To assess the diagnostic accuracy of dipyridamole-stress myocardial computed tomography perfusion (CTP) by 320-detector CT in patients with LBBB using invasive quantitative coronary angiography (QCA) (stenosis ≥ 70%) as reference; to investigate the advantage of adding CTP to coronary computed tomography angiography (CTA) and compare the results with those of single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy. Thirty patients with LBBB who had undergone SPECT for the investigation of coronary artery disease were referred for stress tomography. Independent examiners performed per-patient and per-coronary territory assessments. All patients gave written informed consent to participate in the study that was approved by the institution's ethics committee. The patients' mean age was 62 ± 10 years. The mean dose of radiation for the tomography protocol was 9.3 ± 4.6 mSv. With regard to CTP, the per-patient values for sensitivity, specificity, positive and negative predictive values, and accuracy were 86%, 81%, 80%, 87%, and 83%, respectively (p = 0.001). The per-territory values were 63%, 86%, 65%, 84%, and 79%, respectively (p < 0.001). In both analyses, the addition of CTP to CTA achieved higher diagnostic accuracy for detecting myocardial ischemia than SPECT (p < 0.001). The use of the stress tomography protocol is feasible and has good diagnostic accuracy for assessing myocardial ischemia in patients with LBBB.

Variation in primary and culture-expanded cells derived from connective tissue progenitors in human bone marrow space, bone trabecular surface and adipose tissue.

PubMed

Qadan, Maha A; Piuzzi, Nicolas S; Boehm, Cynthia; Bova, Wesley; Moos, Malcolm; Midura, Ronald J; Hascall, Vincent C; Malcuit, Christopher; Muschler, George F

2018-03-01

Connective tissue progenitors (CTPs) embody the heterogeneous stem and progenitor cell populations present in native tissue. CTPs are essential to the formation and remodeling of connective tissue and represent key targets for tissue-engineering and cell-based therapies. To better understand and characterize CTPs, we aimed to compare the (i) concentration and prevalence, (ii) early in vitro biological behavior and (iii) expression of surface-markers and transcription factors among cells derived from marrow space (MS), trabecular surface (TS), and adipose tissues (AT). Cancellous-bone and subcutaneous-adipose tissues were collected from 8 patients. Cells were isolated and cultured. Colony formation was assayed using Colonyze software based on ASTM standards. Cell concentration ([Cell]), CTP concentration ([CTP]) and CTP prevalence (P CTP ) were determined. Attributes of culture-expanded cells were compared based on (i) effective proliferation rate and (ii) expression of surface-markers CD73, CD90, CD105, SSEA-4, SSEA-3, SSEA-1/CD15, Cripto-1, E-Cadherin/CD324, Ep-CAM/CD326, CD146, hyaluronan and transcription factors Oct3/4, Sox-2 and Nanog using flow cytometry. Mean [Cell], [CTP] and P CTP were significantly different between MS and TS samples (P = 0.03, P = 0.008 and P= 0.0003), respectively. AT-derived cells generated the highest mean total cell yield at day 6 of culture-4-fold greater than TS and more than 40-fold greater than MS per million cells plated. TS colonies grew with higher mean density than MS colonies (290 ± 11 versus 150 ± 11 cell per mm 2 ; P = 0.0002). Expression of classical-mesenchymal stromal cell (MSC) markers was consistently recorded (>95%) from all tissue sources, whereas all the other markers were highly variable. The prevalence and biological potential of CTPs are different between patients and tissue sources and lack variation in classical MSC markers. Other markers are more likely to discriminate differences between cell populations in biological performance. Understanding the underlying reasons for variation in the concentration, prevalence, marker expression and biological potential of CTPs between patients and source tissues and determining the means of managing this variation will contribute to the rational development of cell-based clinical diagnostics and targeted cell-based therapies. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Kinetic analysis of bypass of abasic site by the catalytic core of yeast DNA polymerase eta.

PubMed

Yang, Juntang; Wang, Rong; Liu, Binyan; Xue, Qizhen; Zhong, Mengyu; Zeng, Hao; Zhang, Huidong

2015-09-01

Abasic sites (Apurinic/apyrimidinic (AP) sites), produced ∼ 50,000 times/cell/day, are very blocking and miscoding. To better understand miscoding mechanisms of abasic site for yeast DNA polymerase η, pre-steady-state nucleotide incorporation and LC-MS/MS sequence analysis of extension product were studied using pol η(core) (catalytic core, residues 1-513), which can completely eliminate the potential effects of the C-terminal C2H2 motif of pol η on dNTP incorporation. The extension beyond the abasic site was very inefficient. Compared with incorporation of dCTP opposite G, the incorporation efficiencies opposite abasic site were greatly reduced according to the order of dGTP > dATP > dCTP and dTTP. Pol η(core) showed no fast burst phase for any incorporation opposite G or abasic site, suggesting that the catalytic step is not faster than the dissociation of polymerase from DNA. LC-MS/MS sequence analysis of extension products showed that 53% products were dGTP misincorporation, 33% were dATP and 14% were -1 frameshift, indicating that Pol η(core) bypasses abasic site by a combined G-rule, A-rule and -1 frameshift deletions. Compared with full-length pol η, pol η(core) relatively reduced the efficiency of incorporation of dCTP opposite G, increased the efficiencies of dNTP incorporation opposite abasic site and the exclusive incorporation of dGTP opposite abasic site, but inhibited the extension beyond abasic site, and increased the priority in extension of A: abasic site relative to G: abasic site. This study provides further understanding in the mutation mechanism of abasic sites for yeast DNA polymerase η. Copyright © 2015 Elsevier B.V. All rights reserved.

Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease.

PubMed

Li, Jin-Ping; Zhao, De-Li; Jiang, Hui-Jie; Huang, Ya-Hua; Li, Da-Qing; Wan, Yong; Liu, Xin-Ding; Wang, Jin-E

2011-02-01

Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhotic liver disease by this fast imaging method. CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The value of HBF at the tumor rim was significantly higher than that in the controls. HBF, HBV, HAI, HAP and HPP, but not MTT and PS, were significantly higher in the cirrhotic liver parenchyma involved with HCC than those of the controls. Perfusion parameters were not significantly different between the controls and the cirrhotic liver parenchyma not involved with HCC. CTP can clearly distinguish tumor from cirrhotic liver parenchyma and controls and can provide quantitative information about tumor-related angiogenesis, which can be used to assess tumor vascularization in cirrhotic liver disease.

The Dynamic Multi-objective Multi-vehicle Covering Tour Problem

DTIC Science & Technology

2013-06-01

AI Artificial Intelligence AUV Autonomous Underwater Vehicle CLP Clover Leaf Problem CSP Covering Salesman Problem CTP Covering Tour Problem CVRP...introduces a new formalization - the DMOMCTP. Related works from routing problems, Artificial Intelligence ( AI ), and MOPs are discussed briefly. As a...the rest of that framework being replaced. The codebase differs from jMetal 4.2 in that it can handle the time and DM dependent nature of the DMOMCTP

Effects of transcriptional start site sequence and position on nucleotide-sensitive selection of alternative start sites at the pyrC promoter in Escherichia coli.

PubMed Central

Liu, J; Turnbough, C L

1994-01-01

In Escherichia coli, expression of the pyrC gene is regulated primarily by a translational control mechanism based on nucleotide-sensitive selection of transcriptional start sites at the pyrC promoter. When intracellular levels of CTP are high, pyrC transcripts are initiated predominantly with CTP at a site 7 bases downstream of the Pribnow box. These transcripts form a stable hairpin at their 5' ends that blocks ribosome binding. When the CTP level is low and the GTP level is high, conditions found in pyrimidine-limited cells, transcripts are initiated primarily with GTP at a site 9 bases downstream of the Pribnow box. These shorter transcripts are unable to form a hairpin at their 5' ends and are readily translated. In this study, we examined the effects of nucleotide sequence and position on the selection of transcriptional start sites at the pyrC promoter. We characterized promoter mutations that systematically alter the sequence at position 7 or 9 downstream of the Pribnow box or vary the spacing between the Pribnow box and wild-type transcriptional initiation region. The results reveal preferences for particular initiating nucleotides (ATP > or = GTP > UTP >> CTP) and for starting positions downstream of the Pribnow box (7 >> 6 and 8 > 9 > 10). The results indicate that optimal nucleotide-sensitive start site switching at the wild-type pyrC promoter is the result of competition between the preferred start site (position 7) that uses the poorest initiating nucleotide (CTP) and a weak start site (position 9) that uses a good initiating nucleotide (GTP). The sequence of the pyrC promoter also minimizes the synthesis of untranslatable transcripts and provides for maximum stability of the regulatory transcript hairpin. In addition, the results show that the effects of the mutations on pyrC expression and regulation are consistent with the current model for translational control. Possible effects of preferences for initiating nucleotides and start sites on the expression and regulation of other genes are discussed. Images PMID:7910603

Farnesol is utilized for isoprenoid biosynthesis in plant cells via farnesyl pyrophosphate formed by successive monophosphorylation reactions

PubMed Central

Thai, Long; Rush, Jeffrey S.; Maul, Jude E.; Devarenne, Timothy; Rodgers, Dana L.; Chappell, Joseph; Waechter, Charles J.

1999-01-01

The ability of Nicotiana tabacum cell cultures to utilize farnesol (F-OH) for sterol and sesquiterpene biosynthesis was investigated. [3H]F-OH was readily incorporated into sterols by rapidly growing cell cultures. However, the incorporation rate into sterols was reduced by greater than 70% in elicitor-treated cell cultures whereas a substantial proportion of the radioactivity was redirected into capsidiol, an extracellular sesquiterpene phytoalexin. The incorporation of [3H]F-OH into sterols was inhibited by squalestatin 1, suggesting that [3H]F-OH was incorporated via farnesyl pyrophosphate (F-P-P). Consistent with this possibility, N. tabacum proteins were metabolically labeled with [3H]F-OH or [3H]geranylgeraniol ([3H]GG-OH). Kinase activities converting F-OH to farnesyl monophosphate (F-P) and, subsequently, F-P-P were demonstrated directly by in vitro enzymatic studies. [3H]F-P and [3H]F-P-P were synthesized when exogenous [3H]F-OH was incubated with microsomal fractions and CTP. The kinetics of formation suggested a precursor–product relationship between [3H]F-P and [3H]F-P-P. In agreement with this kinetic pattern of labeling, [32P]F-P and [32P]F-P-P were synthesized when microsomal fractions were incubated with F-OH and F-P, respectively, with [γ-32P]CTP serving as the phosphoryl donor. Under similar conditions, the microsomal fractions catalyzed the enzymatic conversion of [3H]GG-OH to [3H]geranylgeranyl monophosphate and [3H]geranylgeranyl pyrophosphate ([3H]GG-P-P) in CTP-dependent reactions. A novel biosynthetic mechanism involving two successive monophosphorylation reactions was supported by the observation that [3H]CTP was formed when microsomes were incubated with [3H]CDP and either F-P-P or GG-P-P, but not F-P. These results document the presence of at least two CTP-mediated kinases that provide a mechanism for the utilization of F-OH and GG-OH for the biosynthesis of isoprenoid lipids and protein isoprenylation. PMID:10557276

Progenitor cells from different zones of human cartilage and their correlation with histopathological osteoarthritis progression.

PubMed

Mantripragada, Venkata P; Bova, Wesley A; Boehm, Cynthia; Piuzzi, Nicolas S; Obuchowski, Nancy A; Midura, Ronald J; Muschler, George F

2018-06-01

Cell-based therapies development for the treatment of osteoarthritis (OA) requires an understanding of the disease progression and attributes of the cells resident in cartilage. This study focused on quantitative assessment of the concentration and biological potential of stem and progenitor cells resident in different zones of cartilage displaying macroscopic Outerbridge grade 1-2 OA, and their correlation with OA progression based on established histologic scoring system. Lateral femoral condyles were collected from 15 patients with idiopathic OA and varus knees undergoing total knee arthroplasty. Superficial(C sp , top ∼ 500 µm) and deep cartilage(C dp ) was separated. Chondrogenic Connective Tissue Progenitors (CTP-C) were assayed by standardized Colony-Forming-Unit assay using automated image analysis (Colonyze TM ) based on ASTM standard F-2944-12. Cell concentration (cells/mg) was significantly greater in C sp (median: 7,000; range: 3,440-17,600) than C dp (median: 5,340; range: 3,393-9,660), p = 0.039. Prevalence (CTPs/million cells) was not different between C sp (median: 1,274; range: 0-3,898) and C dp (median:1,365; range:0-6,330), p = 0.42. In vitro performance of CTP-C progeny varied widely within and between patients, manifest by variation in colony size and morphology. Mean histopathological Mankin score was 4.7 (SD = 1.2), representing mild to moderate OA. Tidemark breach by blood vessels was associated with lower C sp cell concentration (p = 0.02). Matrix degradation was associated with lower C dp cell and CTP-C concentration (p = 0.015 and p = 0.095, respectively), independent of articular surface changes. These findings suggest that the initiation of OA may occur in either superficial or deep zones. The pathological changes affect CTP-Cs in C sp and C dp cartilage zones differently. The heterogeneity among the available CTP-Cs in C sp and C dp suggests performance-based selection to optimize cell-sourcing strategies for therapy. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1728-1738, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Structural Basis for Proficient Incorporation of dTTP Opposite O[superscript 6]-Methylguanine by Human DNA Polymerase [iota

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

Pence, Matthew G.; Choi, Jeong-Yun; Egli, Martin

2012-03-15

O{sup 6}-Methylguanine (O{sup 6}-methylG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, even physiological ones (e.g. S-adenosylmethionine). The efficiency of a truncated, catalytic DNA polymerase L core enzyme was determined for nucleoside triphosphate incorporation opposite O{sup 6}-methylG, using steady-state kinetic analyses. The results presented here corroborate previous work from this laboratory using full-length pol L, which showed that dTTP incorporation occurs with high efficiency opposite O{sup 6}-methylG. Misincorporation of dTTP opposite O{sup 6}-methylG occurred with {approx}6-fold higher efficiency than incorporation of dCTP. Crystal structures of the truncated form of pol L with O{sup 6}-methylG asmore » the template base and incoming dCTP or dTTP were solved and showed that O{sup 6}-methylG is rotated into the syn conformation in the pol L active site and that dTTP misincorporation by pol L is the result of Hoogsteen base pairing with the adduct. Both dCTP and dTTP base paired with the Hoogsteen edge of O{sup 6}-methylG. A single, short hydrogen bond formed between the N3 atom of dTTP and the N7 atom of O{sup 6}-methylG. Protonation of the N3 atom of dCTP and bifurcation of the N3 hydrogen between the N7 and O{sup 6} atoms of O{sup 6}-methylG allow base pairing of the lesion with dCTP. We conclude that differences in the Hoogsteen hydrogen bonding between nucleotides is the main factor in the preferential selectivity of dTTP opposite O{sup 6}-methylG by human pol L, in contrast to the mispairing modes observed previously for O{sup 6}-methylG in the structures of the model DNA polymerases Sulfolobus solfataricus Dpo4 and Bacillus stearothermophilus DNA polymerase I.« less

Farnesol is utilized for isoprenoid biosynthesis in plant cells via farnesyl pyrophosphate formed by successive monophosphorylation reactions.

PubMed

Thai, L; Rush, J S; Maul, J E; Devarenne, T; Rodgers, D L; Chappell, J; Waechter, C J

1999-11-09

The ability of Nicotiana tabacum cell cultures to utilize farnesol (F-OH) for sterol and sesquiterpene biosynthesis was investigated. [(3)H]F-OH was readily incorporated into sterols by rapidly growing cell cultures. However, the incorporation rate into sterols was reduced by greater than 70% in elicitor-treated cell cultures whereas a substantial proportion of the radioactivity was redirected into capsidiol, an extracellular sesquiterpene phytoalexin. The incorporation of [(3)H]F-OH into sterols was inhibited by squalestatin 1, suggesting that [(3)H]F-OH was incorporated via farnesyl pyrophosphate (F-P-P). Consistent with this possibility, N. tabacum proteins were metabolically labeled with [(3)H]F-OH or [(3)H]geranylgeraniol ([(3)H]GG-OH). Kinase activities converting F-OH to farnesyl monophosphate (F-P) and, subsequently, F-P-P were demonstrated directly by in vitro enzymatic studies. [(3)H]F-P and [(3)H]F-P-P were synthesized when exogenous [(3)H]F-OH was incubated with microsomal fractions and CTP. The kinetics of formation suggested a precursor-product relationship between [(3)H]F-P and [(3)H]F-P-P. In agreement with this kinetic pattern of labeling, [(32)P]F-P and [(32)P]F-P-P were synthesized when microsomal fractions were incubated with F-OH and F-P, respectively, with [gamma-(32)P]CTP serving as the phosphoryl donor. Under similar conditions, the microsomal fractions catalyzed the enzymatic conversion of [(3)H]GG-OH to [(3)H]geranylgeranyl monophosphate and [(3)H]geranylgeranyl pyrophosphate ([(3)H]GG-P-P) in CTP-dependent reactions. A novel biosynthetic mechanism involving two successive monophosphorylation reactions was supported by the observation that [(3)H]CTP was formed when microsomes were incubated with [(3)H]CDP and either F-P-P or GG-P-P, but not F-P. These results document the presence of at least two CTP-mediated kinases that provide a mechanism for the utilization of F-OH and GG-OH for the biosynthesis of isoprenoid lipids and protein isoprenylation.

The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β

PubMed Central

Koag, Myong-Chul; Nam, Kwangho; Lee, Seongmin

2014-01-01

To provide molecular-level insights into the spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β (polβ), we report four crystal structures of polβ complexed with dG•dTTP and dA•dCTP mismatches in the presence of Mg2+ or Mn2+. The Mg2+-bound ground-state structures show that the dA•dCTP-Mg2+ complex adopts an ‘intermediate’ protein conformation while the dG•dTTP-Mg2+ complex adopts an open protein conformation. The Mn2+-bound ‘pre-chemistry-state’ structures show that the dA•dCTP-Mn2+ complex is structurally very similar to the dA•dCTP-Mg2+ complex, whereas the dG•dTTP-Mn2+ complex undergoes a large-scale conformational change to adopt a Watson–Crick-like dG•dTTP base pair and a closed protein conformation. These structural differences, together with our molecular dynamics simulation studies, suggest that polβ increases replication fidelity via a two-stage mismatch discrimination mechanism, where one is in the ground state and the other in the closed conformation state. In the closed conformation state, polβ appears to allow only a Watson–Crick-like conformation for purine•pyrimidine base pairs, thereby discriminating the mismatched base pairs based on their ability to form the Watson–Crick-like conformation. Overall, the present studies provide new insights into the spontaneous replication error and the replication fidelity mechanisms of polβ. PMID:25200079

The carboxyl-terminal region is a determinant for the intracellular behavior of the chorionic gonadotropin beta subunit: effects on the processing of the Asn-linked oligosaccharides.

PubMed

Muyan, M; Boime, I

1998-05-01

The placental hormone human CG (hCG) consists of two noncovalently linked alpha- and beta-subunits similar to the other glycoprotein hormones LH, FSH, and TSH. These heterodimers share a common alpha subunit but differ in their structurally distinct beta subunits. The CGbeta subunit is distinguished among the beta subunits by the presence of a C-terminal extension with four serine-linked oligosaccharides (carboxyl terminal peptide or CTP). In previous studies we observed that deleting this sequence decreased assembly of the truncated CGbeta subunit (CGbeta114) with the alpha-subunit and increased the heterogeneity of the secreted forms of the uncombined subunit synthesized in transfected Chinese hamster ovary (CHO) cells. The latter result was attributed to alterations in the processing of the two N-linked oligosaccharides. To examine at what step this heterogeneity occurs, the CGbeta and CGbeta114 genes were transfected into wild-type and mutant CHO cell lines that are defective in the late steps of the N-linked carbohydrate-processing pathway. We show here that removal of the CTP alters the processing of the core mannosyl unit of the subunit to complex forms at both glycosylation sites and that the oligosaccharides contain polylactosamine. Although it has been presumed that there is little intramolecular interaction between the CTP and the proximal domains of the subunit, our data suggest that the CTP sequence participates in the folding of the newly synthesized subunit, which is manifest by the posttranslational changes observed here.

Different CT perfusion algorithms in the detection of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

PubMed

Cremers, Charlotte H P; Dankbaar, Jan Willem; Vergouwen, Mervyn D I; Vos, Pieter C; Bennink, Edwin; Rinkel, Gabriel J E; Velthuis, Birgitta K; van der Schaaf, Irene C

2015-05-01

Tracer delay-sensitive perfusion algorithms in CT perfusion (CTP) result in an overestimation of the extent of ischemia in thromboembolic stroke. In diagnosing delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH), delayed arrival of contrast due to vasospasm may also overestimate the extent of ischemia. We investigated the diagnostic accuracy of tracer delay-sensitive and tracer delay-insensitive algorithms for detecting DCI. From a prospectively collected series of aSAH patients admitted between 2007-2011, we included patients with any clinical deterioration other than rebleeding within 21 days after SAH who underwent NCCT/CTP/CTA imaging. Causes of clinical deterioration were categorized into DCI and no DCI. CTP maps were calculated with tracer delay-sensitive and tracer delay-insensitive algorithms and were visually assessed for the presence of perfusion deficits by two independent observers with different levels of experience. The diagnostic value of both algorithms was calculated for both observers. Seventy-one patients were included. For the experienced observer, the positive predictive values (PPVs) were 0.67 for the delay-sensitive and 0.66 for the delay-insensitive algorithm, and the negative predictive values (NPVs) were 0.73 and 0.74. For the less experienced observer, PPVs were 0.60 for both algorithms, and NPVs were 0.66 for the delay-sensitive and 0.63 for the delay-insensitive algorithm. Test characteristics are comparable for tracer delay-sensitive and tracer delay-insensitive algorithms for the visual assessment of CTP in diagnosing DCI. This indicates that both algorithms can be used for this purpose.

How the CCA-Adding Enzyme Selects Adenine over Cytosine at Position 76 of tRNA

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

Pan, Baocheng; Xiong, Yong; Steitz, Thomas A.

2010-11-22

CCA-adding enzymes [ATP(CTP):tRNA nucleotidyltransferases] add CCA onto the 3{prime} end of transfer RNA (tRNA) precursors without using a nucleic acid template. Although the mechanism by which cytosine (C) is selected at position 75 of tRNA has been established, the mechanism by which adenine (A) is selected at position 76 remains elusive. Here, we report five cocrystal structures of the enzyme complexed with both a tRNA mimic and nucleoside triphosphates under catalytically active conditions. These structures suggest that adenosine 5{prime}-monophosphate is incorporated onto the A76 position of the tRNA via a carboxylate-assisted, one-metal-ion mechanism with aspartate 110 functioning as a generalmore » base. The discrimination against incorporation of cytidine 5{prime}-triphosphate (CTP) at position 76 arises from improper placement of the {alpha} phosphate of the incoming CTP, which results from the interaction of C with arginine 224 and prevents the nucleophilic attack by the 3{prime} hydroxyl group of cytidine75.« less

Computed Tomography Perfusion Imaging for the Diagnosis of Hepatic Alveolar Echinococcosis

PubMed Central

Sade, Recep; Kantarci, Mecit; Genc, Berhan; Ogul, Hayri; Gundogdu, Betul; Yilmaz, Omer

2018-01-01

Objective: Alveolar echinococcosis (AE) is a rare life-threatening parasitic infection. Computed tomography perfusion (CTP) imaging has the potential to provide both quantitative and qualitative information about the tissue perfusion characteristics. The purpose of this study was the examination of the characteristic features and feasibility of CTP in AE liver lesions. Material and Methods: CTP scanning was performed in 25 patients who had a total of 35 lesions identified as AE of the liver. Blood flow (BF), blood volume (BV), portal venous perfusion (PVP), arterial liver perfusion (ALP), and hepatic perfusion indexes (HPI) were computed for background liver parenchyma and each AE lesion. Results: Significant differences were detected between perfusion values of the AE lesions and background liver tissue. The BV, BF, ALP, and PVP values for all components of the AE liver lesions were significantly lower than the normal liver parenchyma (p<0.01). Conclusions: We suggest that perfusion imaging can be used in AE of the liver. Thus, the quantitative knowledge of perfusion parameters are obtained via CT perfusion imaging. PMID:29531482

Modified CLIP with objective liver reserve assessment retains prognosis prediction for patients with advanced hepatocellular carcinoma.

PubMed

Shao, Yu-Yun; Liu, Tsung-Hao; Lee, Ying-Hui; Hsu, Chih-Hung; Cheng, Ann-Lii

2016-07-01

The Cancer of the Liver Italian Program (CLIP) score is a commonly used staging system for hepatocellular carcinoma (HCC) helpful with predicting prognosis of advanced HCC. CLIP uses the Child-Turcotte-Pugh (CTP) score to evaluate liver reserve. A new scoring system, the albumin-bilirubin (ALBI) grade, has been proposed as they objectively evaluate liver reserve. We examined whether the modification of CLIP with ALBI retained its prognosis prediction for patients with advanced HCC. We included patients who received first-line antiangiogenic therapy for advanced HCC. Liver reserve was assessed using CTP and ALBI scores, which were then incorporated into CLIP and ALBI-CLIP, respectively. To assess their efficacies of prognostic prediction, the Cox's proportional hazard model and concordance indexes were used. A total of 142 patients were included; 137 of them were classified CTP A and 5 patients CTP B. Patients could be divided into four or five groups with different prognosis according to CLIP and ALBI-CLIP, respectively. Higher R(2) (0.249 vs 0.216) and lower Akaike information criterion (995.0 vs 1001.1) were observed for ALBI-CLIP than for CLIP in the Cox's model predicting overall survival. ALBI-CLIP remained an independent predictor for overall survival when CLIP and ALBI-CLIP were simultaneously incorporated in Cox's models allowing variable selection with adjustment for hepatitis etiology, treatment, and performance status. The concordance index was also higher for ALBI-CLIP than for CLIP (0.724 vs 0.703). Modification of CLIP scoring with ALBI, which objectively assesses liver reserve, retains and might have improved prognosis prediction for advanced HCC. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Antipyrimidine effects of five different pyrimidine de novo synthesis inhibitors in three head and neck cancer cell lines.

PubMed

Peters, Godefridus J

2018-05-03

The pyrimidine de novo nucleotide synthesis consists of 6 sequential steps. Various inhibitors against these enzymes have been developed and evaluated in the clinic for their potential anticancer activity: acivicin inhibits carbamoyl-phosphate-synthase-II, N-(phosphonacetyl)-L- aspartate (PALA) inhibits aspartate-transcarbamylase, Brequinar sodium and dichloroallyl-lawsone (DCL) inhibit dihydroorotate-dehydrogenase, and pyrazofurin (PF) inhibits orotate-phosphoribosyltransferase. We compared their growth inhibition against 3 cell lines from head-and-neck-cancer (HEP-2, UMSCC-14B and UMSCC-14C) and related the sensitivity to their effects on nucleotide pools. In all cell lines Brequinar and PF were the most active compounds with IC50 (50% growth inhibition) values between 0.06-0.37 µM, Acivicin was as potent (IC50s 0.26-1 µM), but DCL was 20-31-fold less active. PALA was most inactive (24-128 µM). At equitoxic concentrations, all pure antipyrimidine de novo inhibitors depleted UTP and CTP after 24 hr exposure, which was most pronounced for Brequinar (between 6-10% of UTP left, and 12-36% CTP), followed by DCL and PF, which were almost similar (6-16% UTP and 12-27% CTP), while PALA was the least active compound (10-70% UTP and 13-68% CTP). Acivicin is a multi-target inhibitor of more glutamine requiring enzymes (including GMP synthetase) and no decrease of UTP was found, but a pronounced decrease in GTP (31-72% left). In conclusion, these 5 inhibitors of the pyrimidine de novo nucleotide synthesis varied considerably in their efficacy and effect on pyrimidine nucleotide pools. Inhibitors of DHO-DH were most effective suggesting a primary role of this enzyme in controlling pyrimidine nucleotide pools.

Myocardial perfusion 320-row multidetector computed tomography-guided treatment strategy for the clinical management of patients with recent acute-onset chest pain: Design of the CArdiac cT in the treatment of acute CHest pain (CATCH)-2 randomized controlled trial.

PubMed

Sørgaard, Mathias; Linde, Jesper J; Hove, Jens D; Petersen, Jan R; Jørgensen, Tem B S; Abdulla, Jawdat; Heitmann, Merete; Kragelund, Charlotte; Hansen, Thomas Fritz; Udholm, Patricia M; Pihl, Christian; Kühl, J Tobias; Engstrøm, Thomas; Jensen, Jan Skov; Høfsten, Dan E; Kelbæk, Henning; Kofoed, Klaus F

2016-09-01

Patients admitted with chest pain are a diagnostic challenge because the majority does not have coronary artery disease (CAD). Assessment of CAD with coronary computed tomography angiography (CCTA) is safe, cost-effective, and accurate, albeit with a modest specificity. Stress myocardial computed tomography perfusion (CTP) has been shown to increase the specificity when added to CCTA, without lowering the sensitivity. This article describes the design of a randomized controlled trial, CATCH-2, comparing a clinical diagnostic management strategy of CCTA alone against CCTA in combination with CTP. Patients with acute-onset chest pain older than 50 years and with at least one cardiovascular risk factor for CAD are being prospectively enrolled to this study from 6 different clinical sites since October 2013. A total of 600 patients will be included. Patients are randomized 1:1 to clinical management based on CCTA or on CCTA in combination with CTP, determining the need for further testing with invasive coronary angiography including measurement of the fractional flow reserve in vessels with coronary artery lesions. Patients are scanned with a 320-row multidetector computed tomography scanner. Decisions to revascularize the patients are taken by the invasive cardiologist independently of the study allocation. The primary end point is the frequency of revascularization. Secondary end points of clinical outcome are also recorded. The CATCH-2 will determine whether CCTA in combination with CTP is diagnostically superior to CCTA alone in the management of patients with acute-onset chest pain. Copyright © 2015 Elsevier Inc. All rights reserved.

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PubMed

Eisbruch, A; Shewach, D S; Bradford, C R; Littles, J F; Teknos, T N; Chepeha, D B; Marentette, L J; Terrell, J E; Hogikyan, N D; Dawson, L A; Urba, S; Wolf, G T; Lawrence, T S

2001-02-01

To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot.

PubMed

Hiwatashi, Akio; Togao, Osamu; Yamashita, Koji; Kikuchi, Kazufumi; Yoshimoto, Koji; Mizoguchi, Masahiro; Suzuki, Satoshi O; Yoshiura, Takashi; Honda, Hiroshi

2016-07-01

Correction of contrast leakage is recommended when enhancing lesions during perfusion analysis. The purpose of this study was to assess the diagnostic performance of computed tomography perfusion (CTP) with a delay-invariant singular-value decomposition algorithm (SVD+) and a Patlak plot in differentiating glioblastomas from lymphomas. This prospective study included 17 adult patients (12 men and 5 women) with pathologically proven glioblastomas (n=10) and lymphomas (n=7). CTP data were analyzed using SVD+ and a Patlak plot. The relative tumor blood volume and flow compared to contralateral normal-appearing gray matter (rCBV and rCBF derived from SVD+, and rBV and rFlow derived from the Patlak plot) were used to differentiate between glioblastomas and lymphomas. The Mann-Whitney U test and receiver operating characteristic (ROC) analyses were used for statistical analysis. Glioblastomas showed significantly higher rFlow (3.05±0.49, mean±standard deviation) than lymphomas (1.56±0.53; P<0.05). There were no statistically significant differences between glioblastomas and lymphomas in rBV (2.52±1.57 vs. 1.03±0.51; P>0.05), rCBF (1.38±0.41 vs. 1.29±0.47; P>0.05), or rCBV (1.78±0.47 vs. 1.87±0.66; P>0.05). ROC analysis showed the best diagnostic performance with rFlow (Az=0.871), followed by rBV (Az=0.771), rCBF (Az=0.614), and rCBV (Az=0.529). CTP analysis with a Patlak plot was helpful in differentiating between glioblastomas and lymphomas, but CTP analysis with SVD+ was not. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Efficacy and Safety of the Biosimilar Infliximab CT-P13 Treatment in Inflammatory Bowel Diseases: A Prospective, Multicentre, Nationwide Cohort.

PubMed

Gecse, Krisztina B; Lovász, Barbara D; Farkas, Klaudia; Banai, János; Bene, László; Gasztonyi, Beáta; Golovics, Petra Anna; Kristóf, Tünde; Lakatos, László; Csontos, Ágnes Anna; Juhász, Márk; Nagy, Ferenc; Palatka, Károly; Papp, Mária; Patai, Árpád; Lakner, Lilla; Salamon, Ágnes; Szamosi, Tamás; Szepes, Zoltán; Tóth, Gábor T; Vincze, Áron; Szalay, Balázs; Molnár, Tamás; Lakatos, Péter L

2016-02-01

Biosimilar infliximab CT-P13 is approved for all indications of the originator product in Europe. Prospective data on its efficacy, safety, and immunogenicity in inflammatory bowel diseases are lacking. A prospective, nationwide, multicentre, observational cohort was designed to examine the efficacy, safety, and immunogenicity of CT-P13 infliximab biosimilar in the induction treatment of Crohn's disease [CD] and ulcerative colitis [UC]. Demographic data were collected and a harmonised monitoring strategy was applied. Early clinical remission, response, and early biochemical response were evaluated at Week 14, steroid-free clinical remission was evaluated at Week 30. Therapeutic drug level was monitored using a conventional enzyme-linked immunosorbent assay. In all, 210 consecutive inflammatory bowel disease [126 CD and 84 UC] patients were included in the present cohort. At Week 14, 81.4% of CD and 77.6% of UC patients showed clinical response and 53.6% of CD and 58.6% of UC patients were in clinical remission. Clinical remission rates at Week 14 were significantly higher in CD and UC patients who were infliximab naïve, compared with those with previous exposure to the originator compound [p < 0.05]. Until Week 30, adverse events were experienced in 17.1% of all patients. Infusion reactions and infectious adverse events occurred in 6.6% and 5.7% of all patients, respectively. This prospective multicentre cohort shows that CT-P13 is safe and effective in the induction of clinical remission and response in both CD and UC. Patients with previous infliximab exposure exhibited decreased response rates and were more likely to develop allergic reactions. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Feasibility of dual-low scheme combined with iterative reconstruction technique in acute cerebral infarction volume CT whole brain perfusion imaging.

PubMed

Wang, Tao; Gong, Yi; Shi, Yibing; Hua, Rong; Zhang, Qingshan

2017-07-01

The feasibility of application of low-concentration contrast agent and low tube voltage combined with iterative reconstruction in whole brain computed tomography perfusion (CTP) imaging of patients with acute cerebral infarction was investigated. Fifty-nine patients who underwent whole brain CTP examination and diagnosed with acute cerebral infarction from September 2014 to March 2016 were selected. Patients were randomly divided into groups A and B. There were 28 cases in group A [tube voltage, 100 kV; contrast agent, iohexol (350 mg I/ml), reconstructed by filtered back projection] and 31 cases in group B [tube voltage, 80 kV; contrast agent, iodixanol (270 mg I/ml), reconstructed by algebraic reconstruction technique]. The artery CT value, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), dose length product, effective dose (ED) of radiation and brain iodine intake of both groups were measured and statistically analyzed. Two physicians carried out kappa (κ) analysis on the consistency of image quality evaluation. The difference in subjective image quality evaluation between the groups was tested by χ 2 . The differences in CT value, SNR, CNR, CTP and CT angiography subjective image quality evaluation between both groups were not statistically significant (P>0.05); the diagnosis rate of the acute infarcts between the two groups was not significantly different; while the ED and iodine intake in group B (dual low-dose group) were lower than group A. In conclusion, combination of low tube voltage and iterative reconstruction technique, and application of low-concentration contrast agent (270 mg I/ml) in whole brain CTP examination reduced ED and iodine intake without compromising image quality, thereby reducing the risk of contrast-induced nephropathy.

Molecular characterization of the Salmonella typhi StpA protein that is related to both Yersinia YopE cytotoxin and YopH tyrosine phosphatase.

PubMed

Arricau, N; Hermant, D; Waxin, H; Popoff, M Y

1997-01-01

Analysis of the nucleotide sequence of a 4-kb DNA fragment located between the sip and iag loci on Salmonella typhi chromosome revealed three open reading frames, termed sipF, ctpA and stpA. The 82-amino-acid (aa) sipF product showed extensive similarity to the lacP protein from S. typhimurium. The StpA protein (535 aa) exhibited significant similarity to both Yersinia enterocolitica YopE cytotoxin and YopH tyrosine phosphatase. The CtpA polypeptide (130 aa) might be the molecular chaperone of the StpA protein.

Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-ι

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

Jain, Rinku; Choudhury, Jayati Roy; Buku, Angeliki

N1-methyl-deoxyadenosine (1-MeA) is formed by methylation of deoxyadenosine at the N1 atom. 1-MeA presents a block to replicative DNA polymerases due to its inability to participate in Watson-Crick (W-C) base pairing. Here we determine how human DNA polymerase-ι (Polι) promotes error-free replication across 1-MeA. Steady state kinetic analyses indicate that Polι is ~100 fold more efficient in incorporating the correct nucleotide T versus the incorrect nucleotide C opposite 1-MeA. To understand the basis of this selectivity, we determined ternary structures of Polι bound to template 1-MeA and incoming dTTP or dCTP. In both structures, template 1-MeA rotates to the synmore » conformation but pairs differently with dTTP versus dCTP. Thus, whereas dTTP partakes in stable Hoogsteen base pairing with 1-MeA, dCTP fails to gain a “foothold” and is largely disordered. Together, our kinetic and structural studies show how Polι maintains discrimination between correct and incorrect incoming nucleotide opposite 1-MeA in preserving genome integrity.« less

Experimental validation of Critical Temperature-Pressure theory of scuffing

NASA Astrophysics Data System (ADS)

Lee, Si C.; Chen, Huanliang

1995-07-01

A series of experiments was conducted for validating a newly developed theory of scuffing. The Critical temperature-Pressure (CTP) theory is based on the physisorption behavior of lubricants and is capable of predicting the onset of scuffing failures over a wide range of operating conditions, including the contacts operating in the boundary lubrication and in the partial elastohydrodynamic lubrication (EHL) regimes. According to the CTP theory, failures occur when the contact temperature exceeds a certain critical value which is a function of the lubricant pressure generated by the hydrodynamic action of the EHL contact. A special device capable of simulating the ambient conditions of the partial EHL conjunctions (of contact temperature, pressure, and the lubricant pressure) was constructed. A ball-on-flat type wear tester was put inside a pressure vessel, completely immersed in a highly pressurized bath of mineral oil. The temperature on the flat specimen was gradually increased while the ball was slowly traversed. At a certain critical temmperature, the friction force abruptly jumped indicating the incipiency of the lubrication breakdown. This experiment was repeated for several levels of hydrostatic pressure and the corresponding critical temperatures were obtained. The test results showed an excellent correlation with the newly developed CTP theory.

Advances in Behavioral Laboratory Methods that Inform Tobacco Regulatory Science: A TCORS Working Group Special Issue

PubMed Central

Wright, M. Jerry; Valentine, Gerald

2017-01-01

Objective The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) created unprecented enabling conditions for establishing national regulatory policy that reduces the burden of public health and societal problems associated with tobacco product use. The Center for Tobacco Products (CTP), created by the FDA to implement the TCA, developed a first-of-its-kind FDA/National Institutes of Health (NIH) collaborative program to fund Tobacco Centers of Regulatory Science (TCORS). Methods To assist the TCORS with addressing research priorites, working groups (WGs) comprised of FDA-CTP liasions and TCORS investigators were formed. Under the direction of the Center for Evaluation and Coordination of Trainin and Research (CECTR), the TCORS WGs seek to develop tangible work products in their respective areas of focus. Results The focus of the behavioral pharmacology WG evolved from publishing a narrow paper on behavioral methods in electronic cigarette research to a collection of papers on advances in behavioral laboratory methods that may inform tobacco regulatory science. Conclusion This Special Issue contains articles that address all of the CTP research priorities and demonstrates how advances in behavioral laboratory methods made by TCORS investigators can inform FDA efforst to regulate tobacco products. PMID:29152546

Genome-wide re-sequencing of multidrug-resistant Mycobacterium leprae Airaku-3.

PubMed

Singh, P; Benjak, A; Carat, S; Kai, M; Busso, P; Avanzi, C; Paniz-Mondolfi, A; Peter, C; Harshman, K; Rougemont, J; Matsuoka, M; Cole, S T

2014-10-01

Genotyping and molecular characterization of drug resistance mechanisms in Mycobacterium leprae enables disease transmission and drug resistance trends to be monitored. In the present study, we performed genome-wide analysis of Airaku-3, a multidrug-resistant strain with an unknown mechanism of resistance to rifampicin. We identified 12 unique non-synonymous single-nucleotide polymorphisms (SNPs) including two in the transporter-encoding ctpC and ctpI genes. In addition, two SNPs were found that improve the resolution of SNP-based genotyping, particularly for Venezuelan and South East Asian strains of M. leprae. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.

Tunable multiband plasmonic response of indium antimonide touching microrings in the terahertz range.

PubMed

Moridsadat, Maryam; Golmohammadi, Saeed; Baghban, Hamed

2018-06-01

In this paper, we propose a terahertz (THz) plasmonic structure that supports three resonance modes, including the charge transfer plasmon (CTP), the bonding dipole-dipole plasmon, and the antibonding dipole-dipole plasmon, which can be strongly tuned by geometrical parameters, passively, and the temperature, actively. The structure exhibits a considerable thermal sensitivity of more than 0.01 THz/K. The introduced multiband and tunable THz plasmonic structures offer important applications in thermal switches, thermo-optical modulators, broadband filters, design of multifunctional molecules originating from the multiband specification of the proposed structure, and improvement in plasmonic sensor applications stemming from a detailed study of the CTP mode.

Optical Switching Using Transition from Dipolar to Charge Transfer Plasmon Modes in Ge2Sb2Te5 Bridged Metallodielectric Dimers

PubMed Central

Ahmadivand, Arash; Gerislioglu, Burak; Sinha, Raju; Karabiyik, Mustafa; Pala, Nezih

2017-01-01

Capacitive coupling and direct shuttling of charges in nanoscale plasmonic components across a dielectric spacer and through a conductive junction lead to excitation of significantly different dipolar and charge transfer plasmon (CTP) resonances, respectively. Here, we demonstrate the excitation of dipolar and CTP resonant modes in metallic nanodimers bridged by phase-change material (PCM) sections, material and electrical characteristics of which can be controlled by external stimuli. Ultrafast switching (in the range of a few nanoseconds) between amorphous and crystalline phases of the PCM section (here Ge2Sb2Te5 (GST)) allows for designing a tunable plasmonic switch for optical communication applications with significant modulation depth (up to 88%). Judiciously selecting the geometrical parameters and taking advantage of the electrical properties of the amorphous phase of the GST section we adjusted the extinction peak of the dipolar mode at the telecommunication band (λ~1.55 μm), which is considered as the OFF state. Changing the GST phase to crystalline via optical heating allows for direct transfer of charges through the junction between nanodisks and formation of a distinct CTP peak at longer wavelengths (λ~1.85 μm) far from the telecommunication wavelength, which constitutes the ON state. PMID:28205643

Optical Switching Using Transition from Dipolar to Charge Transfer Plasmon Modes in Ge2Sb2Te5 Bridged Metallodielectric Dimers.

PubMed

Ahmadivand, Arash; Gerislioglu, Burak; Sinha, Raju; Karabiyik, Mustafa; Pala, Nezih

2017-02-16

Capacitive coupling and direct shuttling of charges in nanoscale plasmonic components across a dielectric spacer and through a conductive junction lead to excitation of significantly different dipolar and charge transfer plasmon (CTP) resonances, respectively. Here, we demonstrate the excitation of dipolar and CTP resonant modes in metallic nanodimers bridged by phase-change material (PCM) sections, material and electrical characteristics of which can be controlled by external stimuli. Ultrafast switching (in the range of a few nanoseconds) between amorphous and crystalline phases of the PCM section (here Ge 2 Sb 2 Te 5 (GST)) allows for designing a tunable plasmonic switch for optical communication applications with significant modulation depth (up to 88%). Judiciously selecting the geometrical parameters and taking advantage of the electrical properties of the amorphous phase of the GST section we adjusted the extinction peak of the dipolar mode at the telecommunication band (λ~1.55 μm), which is considered as the OFF state. Changing the GST phase to crystalline via optical heating allows for direct transfer of charges through the junction between nanodisks and formation of a distinct CTP peak at longer wavelengths (λ~1.85 μm) far from the telecommunication wavelength, which constitutes the ON state.

An 80-year summer temperature history from the Xiao Dongkemadi ice core in the central Tibetan Plateau and its association with atmospheric circulation

NASA Astrophysics Data System (ADS)

Li, Xiangying; Ding, Yongjian; Yu, Zhongbo; Mika, Sillanpää; Liu, Shiyin; Shangguan, Donghui; Lu, Chengyang

2015-02-01

The climate significance of oxygen isotopes from the central Tibetan Plateau (cTP) ice cores is a debated issue because of large scale atmospheric circulation. A high-resolution δ18O record was recovered from the Xiao Dongkemadi (XD) ice core, which expanded the spatial coverage of δ18O data in this region. Annual average δ18O correlated significantly with nearby MJJAS air temperatures, suggesting the δ18O can be used as a proxy to reconstruct regional climate change. The reconstructed temperature anomaly is related to the regional and global warming trends, and the greater warming amplitude since 1970s is related to the elevation dependency of the warming signal. The close relationship of the warming to variations in glacier mass balances and discharge reveal that recent warming has led to obvious glacier shrinkage and runoff increase. Correlation analysis suggests that monsoon and westerly moisture substantially influence the cTP ice core records, along with an increase in their level of contribution to the XD core accumulation in recent decades, and confirms a teleconnection of regional climate of the cTP ice cores with climate parameters in the Indian and North Atlantic Oceans.

The Effect of Heart Rate on Exposure Window and Best Phase for Stress Perfusion Computed Tomography: Lessons From the CORE320 Study.

PubMed

Steveson, Chloe; Schuijf, Joanne D; Vavere, Andrea L; Mather, Richard T; Caton, Teresa; Mehra, Vishal; Betoko, Aisha; Cox, Christopher; Lima, Joao Ac; George, Richard T

The aim of this study is to evaluate the effect of heart rate on exposure window, best phase, and image quality for stress computed tomography perfusion (CTP) in the CORE320 study. The CTP data sets were analyzed to determine the best phase for perfusion analysis. A predefined exposure window covering 75% to 95% of the R-R cycle was used. Of the 368 patients included in the analysis, 93% received oral β blockade before the rest scan. The median heart rate during the stress acquisition was 69 bpm (interquartile range [IQR], 60-77). The median best phase was 81% (IQR, 76-90), and length of exposure window was 22% (IQR, 19-24). The best phase was significantly later in the cardiac cycle with higher heart rates (P < 0.001), and higher heart rates resulted in a small, but higher number of poor quality scans (6%, P < 0.001). The median effective dose of the stress scan was 5.3 mSv (IQR, 3.8-6.1). Stress myocardial CTP imaging can be performed using prospective electrocardiography triggering, an exposure window of 75% to 95%, and β-blockade resulting in good or excellent image quality in the majority (80%) of patients while maintaining a low effective radiation dose.

Optical Switching Using Transition from Dipolar to Charge Transfer Plasmon Modes in Ge2Sb2Te5 Bridged Metallodielectric Dimers

NASA Astrophysics Data System (ADS)

Ahmadivand, Arash; Gerislioglu, Burak; Sinha, Raju; Karabiyik, Mustafa; Pala, Nezih

2017-02-01

Capacitive coupling and direct shuttling of charges in nanoscale plasmonic components across a dielectric spacer and through a conductive junction lead to excitation of significantly different dipolar and charge transfer plasmon (CTP) resonances, respectively. Here, we demonstrate the excitation of dipolar and CTP resonant modes in metallic nanodimers bridged by phase-change material (PCM) sections, material and electrical characteristics of which can be controlled by external stimuli. Ultrafast switching (in the range of a few nanoseconds) between amorphous and crystalline phases of the PCM section (here Ge2Sb2Te5 (GST)) allows for designing a tunable plasmonic switch for optical communication applications with significant modulation depth (up to 88%). Judiciously selecting the geometrical parameters and taking advantage of the electrical properties of the amorphous phase of the GST section we adjusted the extinction peak of the dipolar mode at the telecommunication band (λ~1.55 μm), which is considered as the OFF state. Changing the GST phase to crystalline via optical heating allows for direct transfer of charges through the junction between nanodisks and formation of a distinct CTP peak at longer wavelengths (λ~1.85 μm) far from the telecommunication wavelength, which constitutes the ON state.

Tobacco regulatory science: research to inform regulatory action at the Food and Drug Administration's Center for Tobacco Products.

PubMed

Ashley, David L; Backinger, Cathy L; van Bemmel, Dana M; Neveleff, Deborah J

2014-08-01

The U.S. Food and Drug Administration (FDA) promotes the development of regulatory science to ensure that a strong evidence base informs all of its regulatory activities related to the manufacture, marketing, and distribution of tobacco products as well as public education about tobacco product constituents and effects. Toward that end, the FDA's Center for Tobacco Products (CTP) provides funding for research studies with scientific aims that fall within its defined regulatory authority. However, given their traditional biomedical focus on basic and applied research, some researchers may not understand the principles of regulatory science or the types of studies CTP funds. The purpose of this paper is (1) to clarify the definition of regulatory science as a distinct scientific discipline, (2) to explore the role of tobacco regulatory science in order to help researchers understand the parameters and types of research that can be funded by CTP, and (3) to describe the types of research efforts that will inform the FDA's public health framework for tobacco product regulation. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Effects of pyrimidines on the guinea-pig coronary vasculature.

PubMed Central

Vials, A. J.; Burnstock, G.

1993-01-01

1. The effects of the pyrimidines, uridine 5'-triphosphate (UTP), thymidine 5'-triphosphate (TTP) and cytidine 5'-triphosphate (CTP), were examined in the guinea-pig coronary bed, by use of a Langendorff technique. Comparisons were made with the actions of the purines adenosine 5'-triphosphate (ATP), inosine 5'-triphosphate (ITP) and guanosine 5'-triphosphate (GTP). The effect of, the nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (L-NAME) and, the prostaglandin synthesis inhibitor, indomethacin on the vasodilator response to these purines and pyrimidines was examined. The effects of these inhibitors were assessed on their ability to inhibit both the amplitude and the area of the vasodilator response. 2. The relative order of potency of the purines and pyrimidines studied was ATP > UTP > ITP >> GTP, TTP, CTP. 3. The maximum amplitude and area of the vasodilator response to the pyrimidines, UTP (5 x 10(-10)-5 x 10(-7) mol), TTP (5 x 10(-8)-5 x 10(-7) mol) and CTP (5 x 10(-7) mol), and purines, ITP (5 x 10(-9)-5 x 10(-7) mol) and GTP (5 x 10(-8)-5 x 10(-7) mol), were significantly reduced by L-NAME (3 x 10(-5) and 10(-4) M).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8298797

Mechanistic Basis for the Bypass of a Bulky DNA Adduct Catalyzed by a Y-Family DNA Polymerase

PubMed Central

Vyas, Rajan; Efthimiopoulos, Georgia; Tokarsky, E. John; Malik, Chanchal K.; Basu, Ashis K.; Suo, Zucai

2015-01-01

1-Nitropyrene (1-NP), an environmental pollutant, induces DNA damage in vivo and is considered to be carcinogenic. The DNA adducts formed by the 1-NP metabolites stall replicative DNA polymerases but are presumably bypassed by error-prone Y-family DNA polymerases at the expense of replication fidelity and efficiency in vivo. Our running start assays confirmed that a site-specifically placed 8-(deoxyguanosin-N2-yl)-1-aminopyrene (dG1,8), one of the DNA adducts derived from 1-NP, can be bypassed by Sulfolobus solfataricus DNA polymerase IV (Dpo4), although this representative Y-family enzyme was paused strongly by the lesion. Pre-steady-state kinetic assays were employed to determine the low nucleotide incorporation fidelity and establish a minimal kinetic mechanism for the dG1,8 bypass by Dpo4. To reveal a structural basis for dCTP incorporation opposite dG1,8, we solved the crystal structures of the complexes of Dpo4 and DNA containing a templating dG1,8 lesion in the absence or presence of dCTP. The Dpo4·DNA-dG1,8 binary structure shows that the aminopyrene moiety of the lesion stacks against the primer/template junction pair, while its dG moiety projected into the cleft between the Finger and Little Finger domains of Dpo4. In the Dpo4·DNA-dG1,8·dCTP ternary structure, the aminopyrene moiety of the dG1,8 lesion, is sandwiched between the nascent and junction base pairs, while its base is present in the major groove. Moreover, dCTP forms a Watson–Crick base pair with dG, two nucleotides upstream from the dG1,8 site, creating a complex for “-2” frameshift mutation. Mechanistically, these crystal structures provide additional insight into the aforementioned minimal kinetic mechanism. PMID:26327169

Inactivation of Lactobacillus leichmannii ribonucleotide reductase by 2',2'-difluoro-2'-deoxycytidine 5'-triphosphate: adenosylcobalamin destruction and formation of a nucleotide-based radical.

PubMed

Lohman, Gregory J S; Gerfen, Gary J; Stubbe, Joanne

2010-02-23

Ribonucleotide reductase (RNR, 76 kDa) from Lactobacillus leichmannii is a class II RNR that requires adenosylcobalamin (AdoCbl) as a cofactor. It catalyzes the conversion of nucleoside triphosphates to deoxynucleotides and is 100% inactivated by 1 equiv of 2',2'-difluoro-2'-deoxycytidine 5'-triphosphate (F(2)CTP) in <2 min. Sephadex G-50 chromatography of the inactivation reaction mixture for 2 min revealed that 0.47 equiv of a sugar moiety is covalently bound to RNR and 0.25 equiv of a cobalt(III) corrin is tightly associated, likely through a covalent interaction with C(419) (Co-S) in the active site of RNR [Lohman, G. J. S., and Stubbe, J. (2010) Biochemistry 49, DOI: 10.1021/bi902132u ]. After 1 h, a similar experiment revealed 0.45 equiv of the Co-S adduct associated with the protein. Thus, at least two pathways are associated with RNR inactivation: one associated with alkylation by the sugar of F(2)CTP and the second with AdoCbl destruction. To determine the fate of [1'-(3)H]F(2)CTP in the latter pathway, the reaction mixture at 2 min was reduced with NaBH(4) (NaB(2)H(4)) and the protein separated from the small molecules using a centrifugation device. The small molecules were dephosphorylated and analyzed by HPLC to reveal 0.25 equiv of a stereoisomer of cytidine, characterized by mass spectrometry and NMR spectroscopy, indicating the trapped nucleotide had lost both of its fluorides and gained an oxygen. High-field ENDOR studies with [1'-(2)H]F(2)CTP from the reaction quenched at 30 s revealed a radical that is nucleotide-based. The relationship between this radical and the trapped cytidine analogue provides insight into the nonalkylative pathway for RNR inactivation relative to the alkylative pathway.

Systematic review with meta-analysis: the efficacy and safety of CT-P13, a biosimilar of anti-tumour necrosis factor-α agent (infliximab), in inflammatory bowel diseases.

PubMed

Komaki, Y; Yamada, A; Komaki, F; Micic, D; Ido, A; Sakuraba, A

2017-04-01

Biosimilars of anti-tumour necrosis factor (TNF)-α agents have now become clinically available for the treatment of inflammatory bowel diseases (IBD). To perform a systematic review and meta-analysis to evaluate the efficacy and safety of biosimilars of anti-TNF-α agents in patients with IBD. Electronic databases were searched. The outcomes were the pooled rates of clinical response or remission, sustained clinical response or remission, and adverse events in patients with IBD induced with or switched to biosimilars of anti-TNF-α agents. Eleven observational studies reporting outcomes in 829 patients treated with biosimilar of infliximab (CT-P13) were identified. The pooled rates of clinical response among Crohn's disease (CD) and ulcerative colitis (UC) at 8-14 weeks were 0.79 (95% confidence interval (CI) = 0.65-0.88) and 0.74 (95% CI = 0.65-0.82), respectively, and at 24-30 weeks were 0.77 (95% CI = 0.63-0.86) and 0.77 (95% CI = 0.67-0.85) respectively. Adverse events were rare (CD, 0.08 (95% CI = 0.02-0.26); UC, 0.08 (95% CI = 0.03-0.17)). The pooled rates of sustained clinical response among CD and UC after switching from infliximab to CT-P13 at 30-32 weeks were 0.85 (95% CI = 0.71-0.93) and 0.96 (95% CI = 0.58-1.00), respectively, and at 48-63 weeks were 0.75 (95% CI = 0.44-0.92) and 0.83 (95% CI = 0.19-0.99) respectively. Adverse events were rare (CD, 0.10, 95% CI = 0.02-0.31; UC, 0.22, 95% CI = 0.04-0.63). CT-P13 was associated with excellent clinical efficacy and safety profile, supporting its use in the treatment of IBD. © 2017 John Wiley & Sons Ltd.

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases*

PubMed Central

Zhao, Linlin; Pence, Matthew G.; Christov, Plamen P.; Wawrzak, Zdzislaw; Choi, Jeong-Yun; Rizzo, Carmelo J.; Egli, Martin; Guengerich, F. Peter

2012-01-01

N2,3-Ethenoguanine (N2,3-ϵG) is one of the exocyclic DNA adducts produced by endogenous processes (e.g. lipid peroxidation) and exposure to bioactivated vinyl monomers such as vinyl chloride, which is a known human carcinogen. Existing studies exploring the miscoding potential of this lesion are quite indirect because of the lability of the glycosidic bond. We utilized a 2′-fluoro isostere approach to stabilize this lesion and synthesized oligonucleotides containing 2′-fluoro-N2,3-ϵ-2′-deoxyarabinoguanosine to investigate the miscoding potential of N2,3-ϵG by Y-family human DNA polymerases (pols). In primer extension assays, pol η and pol κ replicated through N2,3-ϵG, whereas pol ι and REV1 yielded only 1-base incorporation. Steady-state kinetics revealed that dCTP incorporation is preferred opposite N2,3-ϵG with relative efficiencies in the order of pol κ > REV1 > pol η ≈ pol ι, and dTTP misincorporation is the major miscoding event by all four Y-family human DNA pols. Pol ι had the highest dTTP misincorporation frequency (0.71) followed by pol η (0.63). REV1 misincorporated dTTP and dGTP with much lower frequencies. Crystal structures of pol ι with N2,3-ϵG paired to dCTP and dTTP revealed Hoogsteen-like base pairing mechanisms. Two hydrogen bonds were observed in the N2,3-ϵG:dCTP base pair, whereas only one appears to be present in the case of the N2,3-ϵG:dTTP pair. Base pairing mechanisms derived from the crystal structures explain the slightly favored dCTP insertion for pol ι in steady-state kinetic analysis. Taken together, these results provide a basis for the mutagenic potential of N2,3-ϵG. PMID:22910910

Application of silver nanoparticles to the chemiluminescence determination of cefditoren pivoxil using the luminol-ferricyanide system.

PubMed

Alarfaj, Nawal A; Aly, Fatma A; El-Tohamy, Maha F

2015-02-01

A new simple, accurate and sensitive sequential injection analysis chemiluminescence (CL) detection method for the determination of cefditoren pivoxil (CTP) has been developed. The developed method was based on the enhancement effect of silver nanoparticles on the CL signal arising from a luminol-potassium ferricyanide reaction in the presence of CTP. The optimum conditions relevant to the effect of luminol, potassium ferricyanide and silver nanoparticle concentrations were investigated. The proposed method showed linear relationships between relative CL intensity and the investigated drug concentration at the range 0.001-5000 ng/mL, (r = 0.9998, n = 12) with a detection limit of 0.5 pg/mL and quantification limit of 0.001 ng/mL. The relative standard deviation was 1.6%. The proposed method was employed for the determination of CTP in bulk drug, in its pharmaceutical dosage forms and biological fluids such as human serum and urine. The interference of some common additive compounds such as glucose, lactose, starch, talc and magnesium stearate was investigated. In addition, the interference of some related cephalosporins was tested. No interference was recorded. The obtained sequential injection analysis-CL results were statistically compared with those from a reported method and did not show any significant differences. Copyright © 2014 John Wiley & Sons, Ltd.

A potyvirus vector efficiently targets recombinant proteins to chloroplasts, mitochondria and nuclei in plant cells when expressed at the amino terminus of the polyprotein.

PubMed

Majer, Eszter; Navarro, José-Antonio; Daròs, José-Antonio

2015-09-01

Plant virus-based expression systems allow quick and efficient production of recombinant proteins in plant biofactories. Among them, a system derived from tobacco etch virus (TEV; genus potyvirus) permits coexpression of equimolar amounts of several recombinant proteins. This work analyzed how to target recombinant proteins to different subcellular localizations in the plant cell using this system. We constructed TEV clones in which green fluorescent protein (GFP), with a chloroplast transit peptide (cTP), a nuclear localization signal (NLS) or a mitochondrial targeting peptide (mTP) was expressed either as the most amino-terminal product or embedded in the viral polyprotein. Results showed that cTP and mTP mediated efficient translocation of GFP to the corresponding organelle only when present at the amino terminus of the viral polyprotein. In contrast, the NLS worked efficiently at both positions. Viruses expressing GFP in the amino terminus of the viral polyprotein produced milder symptoms. Untagged GFPs and cTP and NLS tagged amino-terminal GFPs accumulated to higher amounts in infected tissues. Finally, viral progeny from clones with internal GFPs maintained the extra gene better. These observations will help in the design of potyvirus-based vectors able to coexpress several proteins while targeting different subcellular localizations, as required in plant metabolic engineering. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and polymerase activity of a fluorescent cytidine TNA triphosphate analogue

PubMed Central

Mei, Hui; Shi, Changhua; Jimenez, Randi M.; Wang, Yajun; Kardouh, Miramar

2017-01-01

Abstract Threose nucleic acid (TNA) is an artificial genetic polymer capable of undergoing Darwinian evolution to produce aptamers with affinity to specific targets. This property, coupled with a backbone structure that is refractory to nuclease digestion, makes TNA an attractive biopolymer system for diagnostic and therapeutic applications. Expanding the chemical diversity of TNA beyond the natural bases would enable the development of functional TNA molecules with enhanced physiochemical properties. Here, we describe the synthesis and polymerase activity of a fluorescent cytidine TNA triphosphate analogue (1,3-diaza-2-oxo-phenothiazine, tCfTP) that maintains Watson-Crick base pairing with guanine. Polymerase-mediated primer-extension assays reveal that tCfTP is efficiently added to the growing end of a TNA primer. Detailed kinetic assays indicate that tCfTP and tCTP have comparable rates for the first nucleotide incorporation step (kobs1). However, addition of the second nucleotide (kobs2) is 700-fold faster for tCfTP than tCTP due the increased effects of base stacking. Last, we found that TNA replication using tCfTP in place of tCTP exhibits 98.4% overall fidelity for the combined process of TNA transcription and reverse transcription. Together, these results expand the chemical diversity of enzymatically generated TNA molecules to include a hydrophobic base analogue with strong fluorescent properties that is compatible with in vitro selection. PMID:28472363

Relative cerebral blood volume is associated with collateral status and infarct growth in stroke patients in SWIFT PRIME.

PubMed

Arenillas, Juan F; Cortijo, Elisa; García-Bermejo, Pablo; Levy, Elad I; Jahan, Reza; Goyal, Mayank; Saver, Jeffrey L; Albers, Gregory W

2017-01-01

We aimed to evaluate how predefined candidate cerebral perfusion parameters correlate with collateral circulation status and to assess their capacity to predict infarct growth in patients with acute ischemic stroke (AIS) eligible for endovascular therapy. Patients enrolled in the SWIFT PRIME trial with baseline computed tomography perfusion (CTP) scans were included. RAPID software was used to calculate mean relative cerebral blood volume (rCBV) in hypoperfused regions, and hypoperfusion index ratio (HIR). Blind assessments of collaterals were performed using CT angiography in the whole sample and cerebral angiogram in the endovascular group. Reperfusion was assessed on 27-h CTP; infarct volume was assessed on 27-h magnetic resonance imaging/CT scans. Logistic and rank linear regression models were conducted. We included 158 patients. High rCBV ( p = 0.03) and low HIR ( p = 0.03) were associated with good collaterals. A positive association was found between rCBV and better collateral grades on cerebral angiography ( p = 0.01). Baseline and 27-h follow-up CTP were available for 115 patients, of whom 74 (64%) achieved successful reperfusion. Lower rCBV predicted a higher infarct growth in successfully reperfused patients ( p = 0.038) and in the endovascular treatment group ( p = 0.049). Finally, rCBV and HIR may serve as markers of collateral circulation in AIS patients prior to endovascular therapy. Unique identifier: NCT0165746.

CTP synthase forms the cytoophidium in human hepatocellular carcinoma.

PubMed

Chang, Chia-Chun; Jeng, Yung-Ming; Peng, Min; Keppeke, Gerson Dierley; Sung, Li-Ying; Liu, Ji-Long

2017-12-15

CTP synthase (CTPS) can aggregate into an intracellular macrostructure, the cytoophidium, in various organisms including human cells. Previous studies have shown that assembly of human CTPS cytoophidia may be correlated with the cellular metabolic status, and is able to promote the activity of CTPS. A correlation between the cytoophidium and cancer metabolism has been proposed but not yet been revealed. In the current study we provide clear evidence of the presence of CTPS cytoophidia in various human cancers and some non-cancerous tissues. Moreover, among 203 tissue samples of hepatocellular carcinoma, 56 (28%) samples exhibited many cytoophidia, whereas no cytoophidia were detected in adjacent non-cancerous hepatocytes for all samples. Our findings suggest that the CTPS cytoophidium may participate in the adaptive metabolism of human hepatocellular carcinoma. Copyright © 2017. Published by Elsevier Inc.

How Y-Family DNA polymerase IV is more accurate than Dpo4 at dCTP insertion opposite an N2-dG adduct of benzo[a]pyrene.

PubMed

Sholder, Gabriel; Creech, Amanda; Loechler, Edward L

2015-11-01

To bypass DNA damage, cells have Y-Family DNA polymerases (DNAPs). One Y-Family-class includes DNAP κ and DNAP IV, which accurately insert dCTP opposite N(2)-dG adducts, including from the carcinogen benzo[a]pyrene (BP). Another class includes DNAP η and DNAP V, which insert accurately opposite UV-damage, but inaccurately opposite BP-N(2)-dG. To investigate structural differences between Y-Family-classes, regions are swapped between DNAP IV (a κ/IV-class-member) and Dpo4 (a η/V-class-member); the kinetic consequences are evaluated via primer-extension studies with a BP-N(2)-dG-containing template. Four key structural elements are revealed. (1) Y-Family DNAPs have discreet non-covalent contacts between their little finger-domain (LF-Domain) and their catalytic core-domain (CC-Domain), which we call "non-covalent bridges" (NCBs). Arg37 and Arg38 in DNAP IV's CC-Domain near the active site form a non-covalent bridge (AS-NCB) by interacting with Glu251 and Asp252, respectively, in DNAP IV's LF-Domain. Without these interactions dATP/dGTP/dTTP misinsertions increase. DNAP IV's AS-NCB suppresses misinsertions better than Dpo4's equivalent AS-NCB. (2) DNAP IV also suppresses dATP/dGTP/dTTP misinsertions via a second non-covalent bridge, which is ∼8Å from the active site (Distal-NCB). Dpo4 has no Distal-NCB, rendering it inferior at dATP/dGTP/dTTP suppression. (3) dCTP insertion is facilitated by the larger minor groove opening near the active site in DNAP IV versus Dpo4, which is sensible given that Watson/Crick-like [dCTP:BP-N(2)-dG] pairing requires the BP-moiety to be in the minor groove. (4) Compared to Dpo4, DNAP IV has a smaller major groove opening, which suppresses dGTP misinsertion, implying BP-N(2)-dG bulk in the major groove during Hoogsteen syn-adduct-dG:dGTP pairing. In summary, DNAP IV has a large minor groove opening to enhance dCTP insertion, a plugged major groove opening to suppress dGTP misinsertion, and two non-covalent bridges (near and distal to the active site) to suppress dATP/dGTP/dTTP misinsertions; collectively these four structural features enhance DNAP IV's dNTP insertion fidelity opposite a BP-N(2)-dG adduct compared to Dpo4. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparison between target magnetic resonance imaging (MRI) in-gantry and cognitively directed transperineal or transrectal-guided prostate biopsies for Prostate Imaging-Reporting and Data System (PI-RADS) 3-5 MRI lesions.

PubMed

Yaxley, Anna J; Yaxley, John W; Thangasamy, Isaac A; Ballard, Emma; Pokorny, Morgan R

2017-11-01

To compare the detection rates of prostate cancer (PCa) in men with Prostate Imaging-Reporting and Data System (PI-RADS) 3-5 abnormalities on 3-Tesla multiparametric (mp) magnetic resonance imaging (MRI) using in-bore MRI-guided biopsy compared with cognitively directed transperineal (cTP) biopsy and transrectal ultrasonography (cTRUS) biopsy. This was a retrospective single-centre study of consecutive men attending the private practice clinic of an experienced urologist performing MRI-guided biopsy and an experienced urologist performing cTP and cTRUS biopsy techniques for PI-RADS 3-5 lesions identified on 3-Tesla mpMRI. There were 595 target mpMRI lesions from 482 men with PI-RADS 3-5 regions of interest during 483 episodes of biopsy. The abnormal mpMRI target lesion was biopsied using the MRI-guided method for 298 biopsies, the cTP method for 248 biopsies and the cTRUS method for 49 biopsies. There were no significant differences in PCa detection among the three biopsy methods in PI-RADS 3 (48.9%, 40.0% and 44.4%, respectively), PI-RADS 4 (73.2%, 81.0% and 85.0%, respectively) or PI-RADS 5 (95.2, 92.0% and 95.0%, respectively) lesions, and there was no significant difference in detection of significant PCa among the biopsy methods in PI-RADS 3 (42.2%, 30.0% and 33.3%, respectively), PI-RADS 4 (66.8%, 66.0% and 80.0%, respectively) or PI-RADS 5 (90.5%, 89.8% and 90.0%, respectively) lesions. There were also no differences in PCa or significant PCa detection based on lesion location or size among the methods. We found no significant difference in the ability to detect PCa or significant PCa using targeted MRI-guided, cTP or cTRUS biopsy methods. Identification of an abnormal area on mpMRI appears to be more important in increasing the detection of PCa than the technique used to biopsy an MRI abnormality. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

Different scoring systems to predict 6-week mortality in cirrhosis patients with acute variceal bleeding: a retrospective analysis of 202 patients.

PubMed

Wang, Fang; Cui, Shu; Wang, Fengmei; Li, Fenghui; Tang, Fei; Zhang, Xu; Gao, Yanying; Lv, Hongmin

2018-06-17

Determine the optimal scoring system for evaluation of 6-week bleeding-related mortality in liver cirrhosis patients with acute variceal bleeding (AVB). Prediction effects of six scoring systems, AIMS65 score, Glasgow-Blatchford (GBS) score, full Rockall (FRS) score, the model for end-stage liver disease (MELD), the MELD-Na model and the Child-Turcotte-Pugh (CTP) score were analyzed in this study. A total of 202 liver cirrhosis patients with AVB were enrolled between 1 January 2014, and 31 December 2014. All subjects were scored according to AIMS65, GBS, FRS, MELD, MELD-Na and CTP scoring systems on the first day of admission. The primary endpoint of the study was 6-week mortality. The prediction effect of these scoring systems for 6-week mortality was compared by ROC curve and the area under the curve (AUC). The scores of nonsurvival group evaluated by the AIMS65, GBS, FRS, MELD, MELD-Na and CTP (2.6 ± 1.1, 12.9 ± 2.7, 6.6 ± 1.8, 26.9 ± 6.5, 31.6 ± 9.3, 9.6 ± 2.2, respectively) were higher than those of the survival group (1.2 ± 1.1, 10.2 ± 3.4, 5.1 ± 1.6, 21.0 ± 6.4, 22.8 ± 8.2, 7.7 ± 2.0, respectively) (p < .01). The values of AUC and Youden index of AIMS65 and MELD-Na scoring systems [(0.808, 0.453) and (0.781, 0.516), respectively] were superior to those of MELD (0.761, 0.454), CTP (0.748, 0.399), FRS (0.738, 0.358) and GBS scoring systems (0.726, 0.370). AIMS65 and MELD-Na scoring systems are recommended for evaluation of 6-week bleeding-related mortality in liver cirrhosis patients with AVB.

Iterative reconstruction for CT perfusion with a prior-image induced hybrid nonlocal means regularization: Phantom studies

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

Li, Bin; Lyu, Qingwen; Ma, Jianhua

2016-04-15

Purpose: In computed tomography perfusion (CTP) imaging, an initial phase CT acquired with a high-dose protocol can be used to improve the image quality of later phase CT acquired with a low-dose protocol. For dynamic regions, signals in the later low-dose CT may not be completely recovered if the initial CT heavily regularizes the iterative reconstruction process. The authors propose a hybrid nonlocal means (hNLM) regularization model for iterative reconstruction of low-dose CTP to overcome the limitation of the conventional prior-image induced penalty. Methods: The hybrid penalty was constructed by combining the NLM of the initial phase high-dose CT inmore » the stationary region and later phase low-dose CT in the dynamic region. The stationary and dynamic regions were determined by the similarity between the initial high-dose scan and later low-dose scan. The similarity was defined as a Gaussian kernel-based distance between the patch-window of the same pixel in the two scans, and its measurement was then used to weigh the influence of the initial high-dose CT. For regions with high similarity (e.g., stationary region), initial high-dose CT played a dominant role for regularizing the solution. For regions with low similarity (e.g., dynamic region), the regularization relied on a low-dose scan itself. This new hNLM penalty was incorporated into the penalized weighted least-squares (PWLS) for CTP reconstruction. Digital and physical phantom studies were performed to evaluate the PWLS-hNLM algorithm. Results: Both phantom studies showed that the PWLS-hNLM algorithm is superior to the conventional prior-image induced penalty term without considering the signal changes within the dynamic region. In the dynamic region of the Catphan phantom, the reconstruction error measured by root mean square error was reduced by 42.9% in PWLS-hNLM reconstructed image. Conclusions: The PWLS-hNLM algorithm can effectively use the initial high-dose CT to reconstruct low-dose CTP in the stationary region while reducing its influence in the dynamic region.« less

SU-E-J-26: Analysis of Image Quality in CBCT QA Using a Treatment Planning System

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

Xu, M

2014-06-01

Purpose: The objective of this study is to propose an alternative QA technique that analyzes imaging quality(IQ) in CBCT-QA processing. Methods: A catphan phantom was used to take CT imaging data set that were imported into a treatment planning system - Eclipse. The image quality was analyzed in terms of in-slice geometry resolution, Hounsfield numbers(HU) accuracy, mean-slice thickness, edge-to-center uniformity, low contrast resolution, and high contrast spatial resolution in Eclipse workstation. The CBCT-QA was also analyzed by OBI-workstation and a commercial software. Comparison was made to evaluation feasibility in a TPS environment. Results: The analysis of IQ was conducted inmore » Eclipse v10.0 TPS. In-slice geometric resolution was measured between 2-rods in section CTP404 and repeated for all 4 rods with the difference between expected and measured values less than +/−0.1 cm. For HU, the difference between expected and measured values in HU was found much less than +/−40. Mean slice thickness measured by a distance on the wire proportional to scanner increment multiplying by a factor of 0.42. After repeating measurements to 4 wires, the average difference between expected and measured values was less +/−0.124 mm in slice thickness. HU uniformity was measured in section CTP486 with the tolerance less than +/−40 HU. Low contrast resolution in section CTP515 and high contrast resolution in section CTP528 were found to be 7 disks in diameter of 4 mm and 6 lp/cm, respectively. Eclipse TPS results indicated a good agreement to those obtained in OBI workstation and ImagePro software for major parameters. Conclusion: An analysis of IQ was proposed as an alternative CBCT QA processing. Based upon measured data assessment, proposed method was accurate and consistent to IQ evaluation and TG142 guideline. The approach was to utilize TPS resource, which can be valuable to re-planning, verification, and delivery in adaptive therapy.« less

“Gate-keeper” Residues and Active-Site Rearrangements in DNA Polymerase μ Help Discriminate Non-cognate Nucleotides

PubMed Central

Li, Yunlang; Schlick, Tamar

2013-01-01

Incorporating the cognate instead of non-cognate substrates is crucial for DNA polymerase function. Here we analyze molecular dynamics simulations of DNA polymerase μ (pol μ) bound to different non-cognate incoming nucleotides including A:dCTP, A:dGTP, A(syn):dGTP, A:dATP, A(syn):dATP, T:dCTP, and T:dGTP to study the structure-function relationships involved with aberrant base pairs in the conformational pathway; while a pol μ complex with the A:dTTP base pair is available, no solved non-cognate structures are available. We observe distinct differences of the non-cognate systems compared to the cognate system. Specifically, the motions of active-site residue His329 and Asp330 distort the active site, and Trp436, Gln440, Glu443 and Arg444 tend to tighten the nucleotide-binding pocket when non-cognate nucleotides are bound; the latter effect may further lead to an altered electrostatic potential within the active site. That most of these “gate-keeper” residues are located farther apart from the upstream primer in pol μ, compared to other X family members, also suggests an interesting relation to pol μ's ability to incorporate nucleotides when the upstream primer is not paired. By examining the correlated motions within pol μ complexes, we also observe different patterns of correlations between non-cognate systems and the cognate system, especially decreased interactions between the incoming nucleotides and the nucleotide-binding pocket. Altered correlated motions in non-cognate systems agree with our recently proposed hybrid conformational selection/induced-fit models. Taken together, our studies propose the following order for difficulty of non-cognate system insertions by pol μ: T:dGTP

Transit management certificate program.

DOT National Transportation Integrated Search

2012-07-01

TTI worked closely with the Landscape Architecture and Urban Planning Department : (LAUP) of Texas A&M University (TAMU) to develop a transit management certificate : focus for the current Graduate Certificate in Transportation Planning (CTP) housed ...

Epileptic negative drop attacks in atypical benign partial epilepsy: a neurophysiological study.

PubMed

Hirano, Yoshiko; Oguni, Hirokazu; Osawa, Makiko

2009-03-01

We conducted a computer-assisted polygraphic analysis of drop attacks in a child with atypical benign partial epilepsy (ABPE) to investigate neurophysiological characteristics. The patient was a six-year two-month-old girl, who had started to have focal motor seizures, later combined with daily epileptic negative myoclonus (ENM) and drop attacks, causing multiple injuries. We studied episodes of ENM and drop attacks using video-polygraphic and computer-assisted back-averaging analysis. A total of 12 ENM episodes, seven involving the left arm (ENMlt) and five involving both arms (ENMbil), and five drop attacks were captured for analysis. All episodes were time-locked to spike-and-wave complexes (SWC) arising from both centro-temporo-parietal (CTP) areas. The latency between the onset of SWC and ENMlt, ENMbil, and drop attacks reached 68 ms, 42 ms, and 8 ms, respectively. The height of the spike as well as the slow-wave component of SWC for drop attacks were significantly larger than that for both ENMlt and ENMbil (p < 0.05). Drop attacks were considered to be epileptic negative myoclonus involving not only upper proximal but also axial muscles, causing the body to fall. Thus, drop attacks in ABPE are considered to be epileptic negative drop attacks arising from bilateral CTP foci and differ from drop attacks of a generalized origin seen in Lennox-Gastaut syndrome and myoclonic-astatic epilepsy.

Cost-effectiveness analysis of ibrutinib in patients with Waldenström macroglobulinemia in Italy.

PubMed

Aiello, Andrea; D'Ausilio, Anna; Lo Muto, Roberta; Randon, Francesca; Laurenti, Luca

2017-01-01

Background and Objective: Ibrutinib has recently been approved in Europe for Waldenström Macroglobulinemia (WM) in symptomatic patients who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy. The aim of the study is to estimate the incremental cost-effectiveness ratio (ICER) of ibrutinib in relapse/refractory WM, compared with the Italian current therapeutic pathways (CTP). Methods: A Markov model was adapted for Italy considering the National Health System perspective. Input data from literature as well as global trials were used. The percentage use of therapies, and healthcare resources consumption were estimated according to expert panel advice. Drugs ex-factory prices and national tariffs were used for estimating costs. The model had a 15-year time horizon, with a 3.0% discount rate for both clinical and economic data. Deterministic and probabilistic sensitivity analyses were performed to test the results strength. Results: Ibrutinib resulted in increased Life Years Gained (LYGs) and increased costs compared to CTP, with an ICER of €52,698/LYG. Sensitivity analyses confirmed the results of the BaseCase. Specifically, in the probabilistic analysis, at a willingness to pay threshold of €60,000/LYG ibrutinib was cost-effective in 84% of simulations. Conclusions: Ibrutinib has demonstrated a positive cost-effectiveness profile in Italy.

Cerebral Hypoperfusion in Posterior Reversible Encephalopathy Syndrome is Different from Transient Ischemic Attack on CT Perfusion.

PubMed

Vanacker, Peter; Matias, Gonçalo; Hagmann, Patric; Michel, Patrik

2015-01-01

PRES is a reversible neurotoxic state presenting with headache, altered mental status, visual loss, and seizures. Delayed diagnosis can be avoided if radiological patterns could distinguish PRES from cerebral ischemia. Clinical and radiological data were collected on all hospitalized patients who had (1) discharge diagnosis of PRES and (2) acute CTP/CTA. Data were compared with 10 TIA patients with proven cytotoxic edema on MRI. Of the four PRES patients found, three were correlated with acute blood pressure and one with chemotherapy. At the radiological level, quantitative analyses of the CTP parameters showed that 2 out of 4 patients had bilaterally reduced CBF-values (23.2-47.1 ml/100g/min) in occipital regions, as seen in the pathological regions of TIA patients (27.3 ± 13.5 ml/100g/min). When compared with TIA patients, the pathological ROI's demonstrated decreased CBV-values (3.4-5.6 ml/100g). Vasogenic edema on MRI FLAIR imaging was seen in only one PRES patient, and cytotoxic edema on DWI-imaging was never found. CT angiography showed in one PRES patient a vasospasm-like unilateral posterior cerebral artery. If confirmed by other groups, CTP and CTA imaging in patients with acute visual loss and confusion may help to distinguish PRES from bi-occipital ischemia. These radiological parameters may identify PRES patients at risk for additional tissue infarction. Copyright © 2014 by the American Society of Neuroimaging.

Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry.

PubMed

Bravery, Christopher A; Carmen, Jessica; Fong, Timothy; Oprea, Wanda; Hoogendoorn, Karin H; Woda, Juliana; Burger, Scott R; Rowley, Jon A; Bonyhadi, Mark L; Van't Hof, Wouter

2013-01-01

The evaluation of potency plays a key role in defining the quality of cellular therapy products (CTPs). Potency can be defined as a quantitative measure of relevant biologic function based on the attributes that are linked to relevant biologic properties. To achieve an adequate assessment of CTP potency, appropriate in vitro or in vivo laboratory assays and properly controlled clinical data need to be created. The primary objective of a potency assay is to provide a mechanism by which the manufacturing process and the final product for batch release are scrutinized for quality, consistency and stability. A potency assay also provides the basis for comparability assessment after process changes, such as scale-up, site transfer and new starting materials (e.g., a new donor). Potency assays should be in place for early clinical development, and validated assays are required for pivotal clinical trials. Potency is based on the individual characteristics of each individual CTP, and the adequacy of potency assays will be evaluated on a case-by-case basis by regulatory agencies. We provide an overview of the expectations and challenges in development of potency assays specific for CTPs; several real-life experiences from the cellular therapy industry are presented as illustrations. The key observation and message is that aggressive early investment in a solid potency evaluation strategy can greatly enhance eventual CTP deployment because it can mitigate the risk of costly product failure in late-stage development. Copyright © 2013. Published by Elsevier Inc.

Effect of oxybuprocaine eye drops on corneal volume and thickness measurements.

PubMed

Rosa, Nicola; De Bernardo, Maddalena; Borrelli, Maria; Filosa, Maria Luisa; Lanza, Michele

2011-05-01

To investigate the effect of oxybuprocaine eye drops on corneal volume (CV) and corneal thickness measurements. Central corneal thickness (CCT), corneal thinnest point (CTP), and CV of 78 eyes of 78 healthy volunteers were measured with Pentacam, before and 5 min after the administration of oxybuprocaine eye drops. The fellow non-anesthetized eyes were used as control. Before topical anesthesia, the mean CCT was 546.76 ± 35.3 μm, after anesthesia, it was 547.76 ± 36.56 μm (p = 0.86). In the fellow eyes, the first mean CCT was 548.82 ± 35.2 μm and the second was 547.55 ± 35.9 μm (p = 0.82). The mean CTP before anesthesia was 543.99 ± 35.23 μm, after it was 544.89 ± 36.3 μm (p = 0.88). In the fellow eyes, the first mean CTP was 544.15 ± 35.35 μm and the second was 542.81 ± 36 μm (p = 0.81). Before topical anesthesia, the mean CV was 60.55 ± 3.84 mm, after it was 60.66 ± 3.97 mm (p = 0.86). In the fellow eyes, the first mean CV was 60.93 ± 3.87 mm and the second was 60.73 ± 4 mm (p = 0.75). Oxybuprocaine eye drops do not appear to induce a significant corneal swelling and do not affect the measurements when comparing CCT measured with optical or ultrasound devices.

Improvement in thin cirrus retrievals using an emissivity-adjusted CO2 slicing algorithm

NASA Astrophysics Data System (ADS)

Zhang, Hong; Menzel, W. Paul

2002-09-01

CO2 slicing has been generally accepted as a useful algorithm for determining cloud top pressure (CTP) and effective cloud amount (ECA) for tropospheric clouds above 600 hPa. To date, the technique has assumed that the surface emissivity is that of a blackbody in the long-wavelength infrared radiances and that the cloud emissivities in spectrally close bands are approximately equal. The modified CO2 slicing algorithm considers adjustments of both surface emissivity and cloud emissivity ratio. Surface emissivity is adjusted according to the surface types. The ratio of cloud emissivities in spectrally close bands is adjusted away from unity according to radiative transfer calculations. The new CO2 slicing algorithm is examined with Moderate Resolution Imaging Spectroradiometer (MODIS) Airborne Simulator (MAS) CO2 band radiance measurements over thin clouds and validated against Cloud Lidar System (CLS) measurements of the same clouds; it is also applied to Geostationary Operational Environmental Satellite (GOES) Sounder data to study the overall impact on cloud property determinations. For high thin clouds an improved product emerges, while for thick and opaque clouds there is little change. For very thin clouds, the CTP increases by about 10-20 hPa and RMS (root mean square bias) difference is approximately 50 hPa; for thin clouds, the CTP increase is about 10 hPa bias and RMS difference is approximately 30 hPa. The new CO2 slicing algorithm places the clouds lower in the troposphere.

Review article: scoring systems for assessing prognosis in critically ill adult cirrhotics.

PubMed

Cholongitas, E; Senzolo, M; Patch, D; Shaw, S; Hui, C; Burroughs, A K

2006-08-01

Cirrhotic patients admitted to intensive care units (ICU) still have poor outcomes. Some current ICU prognostic models [Acute Physiology and Chronic Health Evaluation (APACHE), Organ System Failure (OSF) and Sequential Organ Failure Assessment (SOFA)] were used to stratify cirrhotics into risk categories, but few cirrhotics were included in the original model development. Liver-specific scores [Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD)] could be useful in this setting. To evaluate whether ICU prognostic models perform better compared with liver-disease specific ones in cirrhotics admitted to ICU. We performed a structured literature review identifying clinical studies focusing on prognosis and risk factors for mortality in adult cirrhotics admitted to ICU. We found 21 studies (five solely dealing with gastrointestinal bleeding) published during the last 20 years (54-420 patients in each). APACHE II and III, SOFA and OSF had better discrimination for correctly predicting death compared with the CTP score. The MELD score was evaluated only in one study and had good predictive accuracy [receiver operator characteristic (ROC) curve: 0.81). Organ dysfunction models (OSF, SOFA) were superior compared with APACHE II and III (ROC curve: range 0.83-0.94 vs. 0.66-0.88 respectively). Cardiovascular, liver and renal system dysfunction were more frequently independently associated with mortality. General-ICU models had better performance in cirrhotic populations compared with CTP score; OSF and SOFA had the best predictive ability. Further prospective and validation studies are needed.

Clinical features and predictors of outcome in acute hepatitis A and hepatitis E virus hepatitis on cirrhosis.

PubMed

Radha Krishna, Yellapu; Saraswat, Vivek Anand; Das, Khaunish; Himanshu, Goel; Yachha, Surender Kumar; Aggarwal, Rakesh; Choudhuri, Gour

2009-03-01

Acute hepatitis A and E are recognized triggers of hepatic decompensation in patients with cirrhosis, particularly from the Indian subcontinent. However, the resulting acute-on-chronic liver failure (ACLF) has not been well characterized and no large studies are available. Our study aimed to evaluate the clinical profile and predictors of 3-month mortality in patients with this distinctive form of liver failure. ACLF was diagnosed in patients with acute hepatitis A or E [abrupt rise in serum bilirubin and/or alanine aminotransferase with positive immunoglobulin M anti-hepatitis A virus (HAV)/anti-hepatitis E virus (HEV)] presenting with clinical evidence of liver failure (significant ascites and/or hepatic encephalopathy) and clinical, biochemical, endoscopic (oesophageal varices at least grade II in size), ultrasonographical (presence of nodular irregular liver with porto-systemic collaterals) or histological evidence of cirrhosis. Clinical and laboratory profile were evaluated, predictors of 3-month mortality were determined using univariate and multivariate logistic regression and a prognostic model was constructed. Receiver-operating curves were plotted to measure performance of the present prognostic model, model for end-stage liver disease (MELD) score and Child-Turcotte-Pugh (CTP) score. ACLF occurred in 121 (3.75%) of 3220 patients (mean age 36.3+/-18.0 years; M:F 85:36) with liver cirrhosis admitted from January 2000 to June 2006. It was due to HEV in 80 (61.1%), HAV in 33 (27.2%) and both in 8 (6.1%). The underlying liver cirrhosis was due to HBV (37), alcohol (17), Wilson's disease (8), HCV (5), autoimmune (6), Budd-Chiari syndrome (2), haemochromatosis (2) and was cryptogenic in the rest (42). Common presentations were jaundice (100%), ascites (78%) and hepatic encephalopathy (55%). Mean (SD) CTP score was 11.4+/-1.6 and mean MELD score was 28.6+/-9.06. Three-month mortality was 54 (44.6%). Complications seen were sepsis in 42 (31.8%), renal failure in 45 (34%), spontaneous bacterial peritonitis in 27 (20.5%), UGI bleeding in 15(11%) and hyponatraemia in 50 (41.3%). On univariate analysis, ascites, hepatic encephalopathy, renal failure, GI bleeding, total bilirubin, hyponatraemia and coagulopathy were significant predictors of mortality. Multivariate analysis revealed grades 3 and 4 HE [odds ratio (OR 32.1)], hyponatraemia (OR 9.2) and renal failure (OR 16.8) as significant predictors of 3-month mortality and a prognostic model using these predictors was constructed. Areas under the curve for the present predicted prognostic model, MELD, and CTP were 0.952, 0.941 and 0.636 respectively. ACLF due to hepatitis A or E super infection results in significant short-term mortality. The predictors of ominous outcome include grades 3 and 4 encephalopathy, hyponatraemia and renal failure. Present prognostic model and MELD scoring system were better predictors of 3-month outcome than CTP score in these patients. Early recognition of those with dismal prognosis may permit timely use of liver replacement/supportive therapies.

Noise reduction and functional maps image quality improvement in dynamic CT perfusion using a new k-means clustering guided bilateral filter (KMGB).

PubMed

Pisana, Francesco; Henzler, Thomas; Schönberg, Stefan; Klotz, Ernst; Schmidt, Bernhard; Kachelrieß, Marc

2017-07-01

Dynamic CT perfusion (CTP) consists in repeated acquisitions of the same volume in different time steps, slightly before, during and slightly afterwards the injection of contrast media. Important functional information can be derived for each voxel, which reflect the local hemodynamic properties and hence the metabolism of the tissue. Different approaches are being investigated to exploit data redundancy and prior knowledge for noise reduction of such datasets, ranging from iterative reconstruction schemes to high dimensional filters. We propose a new spatial bilateral filter which makes use of the k-means clustering algorithm and of an optimal calculated guiding image. We named the proposed filter as k-means clustering guided bilateral filter (KMGB). In this study, the KMGB filter is compared with the partial temporal non-local means filter (PATEN), with the time-intensity profile similarity (TIPS) filter, and with a new version derived from it, by introducing the guiding image (GB-TIPS). All the filters were tested on a digital in-house developed brain CTP phantom, were noise was added to simulate 80 kV and 200 mAs (default scanning parameters), 100 mAs and 30 mAs. Moreover, the filters performances were tested on 7 noisy clinical datasets with different pathologies in different body regions. The original contribution of our work is two-fold: first we propose an efficient algorithm to calculate a guiding image to improve the results of the TIPS filter, secondly we propose the introduction of the k-means clustering step and demonstrate how this can potentially replace the TIPS part of the filter obtaining better results at lower computational efforts. As expected, in the GB-TIPS, the introduction of the guiding image limits the over-smoothing of the TIPS filter, improving spatial resolution by more than 50%. Furthermore, replacing the time-intensity profile similarity calculation with a fuzzy k-means clustering strategy (KMGB) allows to control the edge preserving features of the filter, resulting in improved spatial resolution and CNR both for CT images and for functional maps. In the phantom study, the PATEN filter showed overall the poorest results, while the other filters showed comparable performances in terms of perfusion values preservation, with the KMGB filter having overall the best image quality. In conclusion, the KMGB filter leads to superior results for CT images and functional maps quality improvement, in significantly shorter computational times compared to the other filters. Our results suggest that the KMGB filter might be a more robust solution for halved-dose CTP datasets. For all the filters investigated, some artifacts start to appear on the BF maps if one sixth of the dose is simulated, suggesting that no one of the filters investigated in this study might be optimal for such a drastic dose reduction scenario. © 2017 American Association of Physicists in Medicine.

Carotid Artery Stenting and Blood-Brain Barrier Permeability in Subjects with Chronic Carotid Artery Stenosis.

PubMed

Szarmach, Arkadiusz; Halena, Grzegorz; Kaszubowski, Mariusz; Piskunowicz, Maciej; Studniarek, Michal; Lass, Piotr; Szurowska, Edyta; Winklewski, Pawel J

2017-05-08

Failure of the blood-brain barrier (BBB) is a critical event in the development and progression of diseases such as acute ischemic stroke, chronic ischemia or small vessels disease that affect the central nervous system. It is not known whether BBB breakdown in subjects with chronic carotid artery stenosis can be restrained with postoperative recovery of cerebral perfusion. The aim of the study was to assess the short-term effect of internal carotid artery stenting on basic perfusion parameters and permeability surface area-product (PS) in such a population. Forty subjects (23 males) with stenosis of >70% within a single internal carotid artery and neurological symptoms who underwent a carotid artery stenting procedure were investigated. Differences in the following computed tomography perfusion (CTP) parameters were compared before and after surgery: global cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP) and PS. PS acquired by CTP is used to measure the permeability of the BBB to contrast material. In all baseline cases, the CBF and CBV values were low, while MTT and TTP were high on both the ipsi- and contralateral sides compared to reference values. PS was approximately twice the normal value. CBF was higher (+6.14%), while MTT was lower (-9.34%) on the contralateral than on the ipsilateral side. All perfusion parameters improved after stenting on both the ipsilateral (CBF +22.66%; CBV +18.98%; MTT -16.09%, TTP -7.62%) and contralateral (CBF +22.27%, CBV +19.72%, MTT -14.65%, TTP -7.46%) sides. PS decreased by almost half: ipsilateral -48.11%, contralateral -45.19%. The decline in BBB permeability was symmetrical on the ipsi- and contralateral sides to the stenosis. Augmented BBB permeability can be controlled by surgical intervention in humans.

High fructose consumption induces DNA methylation at PPARα and CPT1A promoter regions in the rat liver

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

Ohashi, Koji; Munetsuna, Eiji; Yamada, Hiroya, E-mail: hyamada@fujita-hu.ac.jp

DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR.more » Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARα and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status. - Highlights: • No general consensus has been reached regarding the molecular mechanisms of the pathogenesis of fructose-induced diseases. • Significant increase in hepatic total methylation level was observed after fructose-supplemented feeding. • Fructose feeding significantly decreased mRNA levels for PPARα and CPT1A. • qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. • Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status in rat liver.« less

Evaluation of the Bangalore Project.

ERIC Educational Resources Information Center

Beretta, Alan; Davies, Alan

1985-01-01

Follows up an article by Brumfit on the Bangalore/Madras Communicational Teaching Project (CTP). Discusses the framework, tests, and results of a 1984 evaluation supporting the claim that grammar construction can take place through a focus on meaning alone. (SED)

Direct detection of ligand binding to Sepharose-immobilised protein using saturation transfer double difference (STDD) NMR spectroscopy

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

Haselhorst, Thomas; Muenster-Kuehnel, Anja K.; Oschlies, Melanie

2007-08-10

We report an easy and direct application of 'Saturation Transfer Double Difference' (STDD) NMR spectroscopy to identify ligands that bind to a Sepharose-immobilised target protein. The model protein, cytidine 5'-monophosphate sialic acid (CMP-Sia) synthetase, was expressed as a Strep-Tag II fusion protein and immobilised on Strep-Tactin Sepharose. STD NMR experiments of the protein-enriched Sepharose matrix in the presence of a binding ligand (cytidine 5'-triphosphate, CTP) and a non-binding ligand ({alpha}/{beta}-glucose) clearly show that CTP binds to the immobilised enzyme, whereas glucose has no affinity. This approach has three major advantages: (a) only low quantities of protein are required, (b) nomore » specialised NMR technology or the application of additional data analysis by non-routine methods is required, and (c) easy multiple use of the immobilised protein is available.« less

Dry Sintering Meets Wet Silver-Ion "Soldering": Charge-Transfer Plasmon Engineering of Solution-Assembled Gold Nanodimers From Visible to Near-Infrared I and II Regions.

PubMed

Fang, Lingling; Wang, Yueliang; Liu, Miao; Gong, Ming; Xu, An; Deng, Zhaoxiang

2016-11-07

Achieving highly tunable and localized surface plasmon resonance up to near infrared (NIR) regions is a key target in nanoplasmonics. In particular, a self-assembly process capable of producing highly uniform and solution-processable nanomaterials with tailor-made plasmonic properties is lacking. We herein address this problem through a conjunctive use of wet Ag + soldering and dry thermal sintering to produce nanodimer-derived structures with precisely engineered charge-transfer plasmon (CTP). The sintered dimers are water soluble, featuring gradually shifted CTP spanning an 800 nm wavelength range (up to NIR II). Upon silica removal, the products are grafted by DNA to offer surface functionality. This process is also adaptable to DNA-linked AuNP dimers toward plasmonic meta-materials via DNA-guided soldering and sintering. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Marengo, Barbara; Bottini, Consuelo; La Porta, C.A.M.

Phosphatidylethanolamine N-methyltransferase (PEMT) is the enzyme that converts phosphatidylethanolamine (PE) into phosphatidylcholine. We have previously shown that PEMT suppressed hepatoma growth by triggering apoptosis. We investigate whether PEMT controlled cell death and cell proliferation triggered by fasting/refeeding and whether it is a marker of early preneoplastic lesions. The induction of programmed cell death and suppression of cell proliferation by fasting were associated with enhanced PEMT expression and activity, and with a decrease in CTP:phosphocholine cytidylyltransferase expression. Refeeding returned the liver growth and expression of CTP:phosphocholine cytidylyltransferase to control levels, while the expression of PEMT decreased to below control values. Aftermore » DENA administration, PEMT protein, evaluated by Western blotting, slightly increased, but it remained below control levels. The treatment with 20 mg/kg DENA to refed rats induced the appearance of initiated hepatocytes that were negative for PEMT expression. Present findings indicate that PEMT is a novel tumour marker for early liver preneoplastic lesions.« less

Single and Multi-Pulse Low-Energy Conical Theta Pinch Inductive Pulsed Plasma Thruster Performance

NASA Technical Reports Server (NTRS)

Hallock, Ashley K.; Martin, Adam; Polzin, Kurt; Kimberlin, Adam; Eskridge, Richard

2013-01-01

Fabricated and tested CTP IPPTs at cone angles of 20deg, 38deg, and 60deg, and performed direct single-pulse impulse bit measurements with continuous gas flow. Single pulse performance highest for 38deg angle with impulse bit of approx.1 mN-s for both argon and xenon. Estimated efficiencies low, but not unexpectedly so based on historical data trends and the direction of the force vector in the CTP. Capacitor charging system assembled to provide rapid recharging of capacitor bank, permitting repetition-rate operation. IPPT operated at repetition-rate of 5 Hz, at maximum average power of 2.5 kW, representing to our knowledge the highest average power for a repetitively-pulsed thruster. Average thrust in repetition-rate mode (at 5 kV, 75 sccm argon) was greater than simply multiplying the single-pulse impulse bit and the repetition rate.

Analysis of aerosol effects on warm clouds over the Yangtze River Delta from multi-sensor satellite observations

NASA Astrophysics Data System (ADS)

Liu, Yuqin; de Leeuw, Gerrit; Kerminen, Veli-Matti; Zhang, Jiahua; Zhou, Putian; Nie, Wei; Qi, Ximeng; Hong, Juan; Wang, Yonghong; Ding, Aijun; Guo, Huadong; Krüger, Olaf; Kulmala, Markku; Petäjä, Tuukka

2017-05-01

Aerosol effects on low warm clouds over the Yangtze River Delta (YRD, eastern China) are examined using co-located MODIS, CALIOP and CloudSat observations. By taking the vertical locations of aerosol and cloud layers into account, we use simultaneously observed aerosol and cloud data to investigate relationships between cloud properties and the amount of aerosol particles (using aerosol optical depth, AOD, as a proxy). Also, we investigate the impact of aerosol types on the variation of cloud properties with AOD. Finally, we explore how meteorological conditions affect these relationships using ERA-Interim reanalysis data. This study shows that the relation between cloud properties and AOD depends on the aerosol abundance, with a different behaviour for low and high AOD (i.e. AOD < 0.35 and AOD > 0.35). This applies to cloud droplet effective radius (CDR) and cloud fraction (CF), but not to cloud optical thickness (COT) and cloud top pressure (CTP). COT is found to decrease when AOD increases, which may be due to radiative effects and retrieval artefacts caused by absorbing aerosol. Conversely, CTP tends to increase with elevated AOD, indicating that the aerosol is not always prone to expand the vertical extension. It also shows that the COT-CDR and CWP (cloud liquid water path)-CDR relationships are not unique, but affected by atmospheric aerosol loading. Furthermore, separation of cases with either polluted dust or smoke aerosol shows that aerosol-cloud interaction (ACI) is stronger for clouds mixed with smoke aerosol than for clouds mixed with dust, which is ascribed to the higher absorption efficiency of smoke than dust. The variation of cloud properties with AOD is analysed for various relative humidity and boundary layer thermodynamic and dynamic conditions, showing that high relative humidity favours larger cloud droplet particles and increases cloud formation, irrespective of vertical or horizontal level. Stable atmospheric conditions enhance cloud cover horizontally. However, unstable atmospheric conditions favour thicker and higher clouds. Dynamically, upward motion of air parcels can also facilitate the formation of thicker and higher clouds. Overall, the present study provides an understanding of the impact of aerosols on cloud properties over the YRD. In addition to the amount of aerosol particles (or AOD), evidence is provided that aerosol types and ambient environmental conditions need to be considered to understand the observed relationships between cloud properties and AOD.

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.

PubMed

Schneider, Constanze; Oellerich, Thomas; Baldauf, Hanna-Mari; Schwarz, Sarah-Marie; Thomas, Dominique; Flick, Robert; Bohnenberger, Hanibal; Kaderali, Lars; Stegmann, Lena; Cremer, Anjali; Martin, Margarethe; Lohmeyer, Julian; Michaelis, Martin; Hornung, Veit; Schliemann, Christoph; Berdel, Wolfgang E; Hartmann, Wolfgang; Wardelmann, Eva; Comoglio, Federico; Hansmann, Martin-Leo; Yakunin, Alexander F; Geisslinger, Gerd; Ströbel, Philipp; Ferreirós, Nerea; Serve, Hubert; Keppler, Oliver T; Cinatl, Jindrich

2017-02-01

The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.

SU-G-IeP2-06: Evaluation of Registration Accuracy for Cone-Beam CT Reconstruction Techniques

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

Li, J; Wang, P; Zhang, H

2016-06-15

Purpose: Cone-beam (CB) computed tomography (CT) is used for image guidance during radiotherapy treatment delivery. Conventional Feldkamp and compressed sensing (CS) based CBCT recon-struction techniques are compared for image registration. This study is to evaluate the image registration accuracy of conventional and CS CBCT for head-and-neck (HN) patients. Methods: Ten HN patients with oropharyngeal tumors were retrospectively selected. Each HN patient had one planning CT (CTP) and three CBCTs were acquired during an adaptive radiotherapy proto-col. Each CBCT was reconstructed by both the conventional (CBCTCON) and compressed sens-ing (CBCTCS) methods. Two oncologists manually labeled 23 landmarks of normal tissue andmore » implanted gold markers on both the CTP and CBCTCON. Subsequently, landmarks on CTp were propagated to CBCTs, using a b-spline-based deformable image registration (DIR) and rigid registration (RR). The errors of these registration methods between two CBCT methods were calcu-lated. Results: For DIR, the mean distance between the propagated and the labeled landmarks was 2.8 mm ± 0.52 for CBCTCS, and 3.5 mm ± 0.75 for CBCTCON. For RR, the mean distance between the propagated and the labeled landmarks was 6.8 mm ± 0.92 for CBCTCS, and 8.7 mm ± 0.95 CBCTCON. Conclusion: This study has demonstrated that CS CBCT is more accurate than conventional CBCT in image registration by both rigid and non-rigid methods. It is potentially suggested that CS CBCT is an improved image modality for image guided adaptive applications.« less

ATHENA X-IFU 300 K-50 mK cryochain demonstrator cryostat

NASA Astrophysics Data System (ADS)

Prouvé, T.; Duval, J. M.; Charles, I.; Yamasaki, N. Y.; Mitsuda, K.; Nakagawa, T.; Shinozaki, K.; Tokoku, C.; Yamamoto, R.; Minami, Y.; Le Du, M.; Andre, J.; Daniel, C.; Linder, M.

2018-01-01

In the framework of the ESA X-ray mission ATHENA, scheduled for launch in 2028, an ESA Core Technology Program (CTP) was started in 2016 to build a flight like cryostat demonstrator in parallel with the phase A studies of the ATHENA/X-IFU instrument [1,2]. As part of this CTP, called the Detector Cooling System (DCS), design, manufacturing and test of a cryostat including existing space coolers will be done. In addition to the validation of thermal performance, a Focal Plan Assembly (FPA) demonstrator using Transition Edge Sensors (TES) detector technology will be also integrated and its performance characterized versus the environment provided by the cryostat. This is a unique opportunity to validate many crucial issues of the cryogenic part of such a sensitive instrument. A dedicated activity within this CTP-DCS is the demonstration of the 300 K-50 mK cooling chain in a Ground System Equipment (GSE) cryostat. The studies are focused on the operation of the space coolers, which is made possible by the use of a ground cooler for cooling cryogenic shields and mechanical supports. Thanks to the modularity of the cryostat, several cooling chains could be tested. In the base line configuration described here, the low temperature stage is the CEA hybrid sorption/ADR 50 mK cooler with thermal interfaces at 4 K and 2 K. 4 K cooling is accomplished by a 4 K Joule-Thomson (JT) cryocooler and its Stirling precooler provided by JAXA. Regarding the 2 K stage, at first a 2 K JT from JAXA will be used. Alternatively, a 2 K JT cooler from RAL could replace the JAXA 2 K JT. In both cases new prototype(s) of a 2 K JT will be implemented, precooled by the EM 15 K pule tube cooler from Air Liquide. This test program is also the opportunity to validate the operation of the cryochain with respect to various requirements, such as time constant and temperature stabilities. This would bring us valuable inputs to integrate the cryochain in DCS cryostat or for the X-IFU phase A studies. This cryochain demonstration is also a critical milestone for the SPICA mission [3]. The design of the cryostat and first thermal validations both before and after integration of the JAXA JT coolers are presented in this paper.

Propulsion and Energetics Panel Working Group 23 on Guide to the Measurement of the Transient Performance of Aircraft Turbine Engines and Components (Guide pour la mesure des performances en transitoire des turbomachines Aeronautiques et de leurs composants)

DTIC Science & Technology

1994-03-01

Oft-«) D-mt) Munich 50 Prof. Dring. Wolfgang Braig Universität Stuttgart Institut für Luftfahrtantriebe Pfaffenwaldring 6 D-7000 Stuttgart 80...Symposium, May, 1977. 3.20 MQff»t,R.J., Designing Thermocouples for Response Rate, ASME Paper No. 57-CTP-8. 3.21 Glawe, G.E., Holanda, R., and Krause ...Science and Industry, Vol.3, Part 2, 1962. 4.3.3 Glawe, G.E., Holanda, R., Krause , L.N., Recovery and Radiation Corrections and Time Constants of

Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases.

PubMed

Wassberg, Cecilia; Lubberink, Mark; Sörensen, Jens; Johansson, Silvia

2017-12-01

18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV 50% ). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP. A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV 50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%. Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation.

Ascites and alpha-fetoprotein improve prognostic performance of Barcelona Clinic Liver Cancer staging

PubMed Central

Gomaa, Asmaa I; Al-Khatib, Alzhraa; Abdel-Razek, Wael; Hashim, Mohammed Saad; Waked, Imam

2015-01-01

AIM: To assess how ascites and alpha-fetoprotein (AFP) added to the Barcelona Clinic Liver Cancer (BCLC) staging predict hepatocellular carcinoma survival. METHODS: The presence of underlying cirrhosis, ascites and encephalopathy, Child-Turcotte-Pugh (CTP) score, the number of nodules, and the maximum diameter of the largest nodule were determined at diagnosis for 1060 patients with hepatocellular carcinoma at a tertiary referral center for liver disease in Egypt. Demographic information, etiology of liver disease, and biochemical data (including serum bilirubin, albumin, international normalized ratio, alanine and aspartate aminotransferases, and AFP) were evaluated. Staging of the tumor was determined at the time of diagnosis using the BCLC staging system; 496 patients were stage A and 564 patients were stage B. Patients with mild ascites on initial ultrasound, computed tomography, or clinical examination, and who had a CTP score ≤ 9 were included in this analysis. All patients received therapy according to the recommended treatment based on the BCLC stage, and were monitored from the time of diagnosis to the date of death or date of data collection. The effect of the presence of ascites and AFP level on survival was analyzed. RESULTS: At the time the data were censored, 123/496 (24.8%) and 218/564 (38.6%) patients with BCLC stages A and B, respectively, had died. Overall mean survival of the BCLC A and B patients during a three-year follow-up period was 31 mo [95% confidence interval (95%CI): 29.7-32.3] and 22.7 mo (95%CI: 20.7-24.8), respectively. The presence of ascites, multiple focal lesions, large tumor size, AFP level and CTP score were independent predictors of survival for the included patients on multivariate analysis (P < 0.001). Among stage A patients, 18% had ascites, 33% had AFP ≥ 200 ng/mL, and 8% had both. Their median survival in the presence of ascites was shorter if AFP was ≥ 200 ng/mL (19 mo vs 24 mo), and in the absence of ascites, patients with AFP ≥ 200 ng/mL had a shorter survival (28 mo vs 39 mo). For stage B patients, survival for the corresponding groups was 12, 18, 19 and 22 mo. The one-, two-, and three-year survival rates for stage A patients without ascites and AFP < 200 ng/mL were 94%, 77%, and 71%, respectively, and for patients with ascites and AFP ≥ 200 ng/mL were 83%, 24%, and 22%, respectively (P < 0.001). Adding ascites and AFP ≥ 200 ng/mL improved the discriminatory ability for predicting prognosis (area under the curve, 0.618 vs 0.579 for BCLC, P < 0.001). CONCLUSION: Adding AFP and ascites to the BCLC staging classification can improve prognosis prediction for early and intermediate stages of hepatocellular carcinoma. PMID:25987792

Ascites and alpha-fetoprotein improve prognostic performance of Barcelona Clinic Liver Cancer staging.

PubMed

Gomaa, Asmaa I; Al-Khatib, Alzhraa; Abdel-Razek, Wael; Hashim, Mohammed Saad; Waked, Imam

2015-05-14

To assess how ascites and alpha-fetoprotein (AFP) added to the Barcelona Clinic Liver Cancer (BCLC) staging predict hepatocellular carcinoma survival. The presence of underlying cirrhosis, ascites and encephalopathy, Child-Turcotte-Pugh (CTP) score, the number of nodules, and the maximum diameter of the largest nodule were determined at diagnosis for 1060 patients with hepatocellular carcinoma at a tertiary referral center for liver disease in Egypt. Demographic information, etiology of liver disease, and biochemical data (including serum bilirubin, albumin, international normalized ratio, alanine and aspartate aminotransferases, and AFP) were evaluated. Staging of the tumor was determined at the time of diagnosis using the BCLC staging system; 496 patients were stage A and 564 patients were stage B. Patients with mild ascites on initial ultrasound, computed tomography, or clinical examination, and who had a CTP score ≤ 9 were included in this analysis. All patients received therapy according to the recommended treatment based on the BCLC stage, and were monitored from the time of diagnosis to the date of death or date of data collection. The effect of the presence of ascites and AFP level on survival was analyzed. At the time the data were censored, 123/496 (24.8%) and 218/564 (38.6%) patients with BCLC stages A and B, respectively, had died. Overall mean survival of the BCLC A and B patients during a three-year follow-up period was 31 mo [95% confidence interval (95%CI): 29.7-32.3] and 22.7 mo (95%CI: 20.7-24.8), respectively. The presence of ascites, multiple focal lesions, large tumor size, AFP level and CTP score were independent predictors of survival for the included patients on multivariate analysis (P < 0.001). Among stage A patients, 18% had ascites, 33% had AFP ≥ 200 ng/mL, and 8% had both. Their median survival in the presence of ascites was shorter if AFP was ≥ 200 ng/mL (19 mo vs 24 mo), and in the absence of ascites, patients with AFP ≥ 200 ng/mL had a shorter survival (28 mo vs 39 mo). For stage B patients, survival for the corresponding groups was 12, 18, 19 and 22 mo. The one-, two-, and three-year survival rates for stage A patients without ascites and AFP < 200 ng/mL were 94%, 77%, and 71%, respectively, and for patients with ascites and AFP ≥ 200 ng/mL were 83%, 24%, and 22%, respectively (P < 0.001). Adding ascites and AFP ≥ 200 ng/mL improved the discriminatory ability for predicting prognosis (area under the curve, 0.618 vs 0.579 for BCLC, P < 0.001). Adding AFP and ascites to the BCLC staging classification can improve prognosis prediction for early and intermediate stages of hepatocellular carcinoma.

Cooperation, Technology, and Performance: A Case Study.

ERIC Educational Resources Information Center

Cavanagh, Thomas; Dickenson, Sabrina; Brandt, Suzanne

1999-01-01

Describes the CTP (Cooperation, Technology, and Performance) model and explains how it is used by the Department of Veterans Affairs-Veteran's Benefit Administration (VBA) for training. Discusses task analysis; computer-based training; cooperative-based learning environments; technology-based learning; performance-assessment methods; courseware…

Internal Carotid Artery Stenosis and Collateral Recruitment in Stroke Patients.

PubMed

Dankbaar, Jan W; Kerckhoffs, Kelly G P; Horsch, Alexander D; van der Schaaf, Irene C; Kappelle, L Jaap; Velthuis, Birgitta K

2017-04-24

Leptomeningeal collaterals improve outcome in stroke patients. There is great individual variability in their extent. Internal carotid artery (ICA) stenosis may lead to more extensive recruitment of leptomeningeal collaterals. The purpose of this study was to evaluate the association of pre-existing ICA stenosis with leptomeningeal collateral filling visualized with computed tomography perfusion (CTP). From a prospective acute ischemic stroke cohort, patients were included with an M1 middle cerebral artery (MCA) occlusion and absent ipsilateral, extracranial ICA occlusion. ICA stenosis was determined on admission CT angiography (CTA). Leptomeningeal collaterals were graded as good (>50%) or poor (≤50%) collateral filling in the affected MCA territory on CTP-derived vessel images of the admission scan. The association between ipsilateral ICA stenosis ≥70% and extent of collateral filling was analyzed using logistic regression. In a multivariable analysis the odds ratio (OR) of ICA stenosis ≥70% was adjusted for complete circle of Willis, gender and age. We included 188 patients in our analyses, 50 (26.6%) patients were classified as having poor collateral filling and 138 (73.4%) as good. Of the patients 4 with poor collateral filling had an ICA stenosis ≥70% and 14 with good collateral filling. Unadjusted and adjusted ORs of ICA stenosis ≥70% for good collateral filling were 1.30 (0.41-4.15) and 2.67 (0.81-8.77), respectively. Patients with poor collateral filling had a significantly worse outcome (90-day modified Rankin scale 3-6; 80% versus 52%, p = 0.001). No association was found between pre-existing ICA stenosis and extent of CTP derived collateral filling in patients with an M1 occlusion.

Hypotonic activation of short ClC3 isoform is modulated by direct interaction between its cytosolic C-terminal tail and subcortical actin filaments.

PubMed

McCloskey, Diana T; Doherty, Lynda; Dai, Yan-Ping; Miller, Lisa; Hume, Joseph R; Yamboliev, Ilia A

2007-06-08

Short ClC3 isoform (sClC3) functions as a volume-sensitive outwardly rectifying anion channel (VSOAC) in some cell types. In previous studies, we have shown that the hypotonic activation of sClC3 is linked to cell swelling-mediated remodeling of the actin cytoskeleton. In the present study, we have tested the hypothesis that the cytosolic tails of sClC3 bind to actin directly and that binding modulates the hypotonic activation of the channel. Co-sedimentation assays in vitro demonstrated a strong binding between the glutathione S-transferase-fused cytosolic C terminus of sClC3 (GST-sClC3-CT) to filamentous actin (F-actin) but not to globular monomeric actin (G-actin). The GST-fused N terminus (GST-sClC3-NT) exhibited low binding affinity to both G- and F-actin. Co-sedimentation experiments with progressively truncated GST-sClC3-CT indicated that the F-actin binding region is located between amino acids 690 and 760 of sClC3. Two synthetic peptides mapping basic clusters of the cytosolic sClC3-CT (CTP2, isoleucine 716 to leucine 734; and CTP3, proline 688 to proline 709) prevented binding of GST-sClC3-CT to F-actin in vitro. Dialysis into NIH/3T3 cells of these two peptides (but not of synthetic peptide CTP1 (isoleucine 737 to glutamine 748)) reduced the maximal current density by 60 and 38%, respectively. Based on these results, we have concluded that, by direct interaction with subcortical actin filaments, sClC3 contributes to the hypotonic stress-induced VSOACs in NIH/3T3 cells.

How a low-fidelity DNA polymerase chooses non-Watson-Crick from Watson-Crick incorporation.

PubMed

Wu, Wen-Jin; Su, Mei-I; Wu, Jian-Li; Kumar, Sandeep; Lim, Liang-Hin; Wang, Chun-Wei Eric; Nelissen, Frank H T; Chen, Ming-Chuan Chad; Doreleijers, Jurgen F; Wijmenga, Sybren S; Tsai, Ming-Daw

2014-04-02

A dogma for DNA polymerase catalysis is that the enzyme binds DNA first, followed by MgdNTP. This mechanism contributes to the selection of correct dNTP by Watson-Crick base pairing, but it cannot explain how low-fidelity DNA polymerases overcome Watson-Crick base pairing to catalyze non-Watson-Crick dNTP incorporation. DNA polymerase X from the deadly African swine fever virus (Pol X) is a half-sized repair polymerase that catalyzes efficient dG:dGTP incorporation in addition to correct repair. Here we report the use of solution structures of Pol X in the free, binary (Pol X:MgdGTP), and ternary (Pol X:DNA:MgdGTP with dG:dGTP non-Watson-Crick pairing) forms, along with functional analyses, to show that Pol X uses multiple unprecedented strategies to achieve the mutagenic dG:dGTP incorporation. Unlike high fidelity polymerases, Pol X can prebind purine MgdNTP tightly and undergo a specific conformational change in the absence of DNA. The prebound MgdGTP assumes an unusual syn conformation stabilized by partial ring stacking with His115. Upon binding of a gapped DNA, also with a unique mechanism involving primarily helix αE, the prebound syn-dGTP forms a Hoogsteen base pair with the template anti-dG. Interestingly, while Pol X prebinds MgdCTP weakly, the correct dG:dCTP ternary complex is readily formed in the presence of DNA. H115A mutation disrupted MgdGTP binding and dG:dGTP ternary complex formation but not dG:dCTP ternary complex formation. The results demonstrate the first solution structural view of DNA polymerase catalysis, a unique DNA binding mode, and a novel mechanism for non-Watson-Crick incorporation by a low-fidelity DNA polymerase.

Critical elements in the development of cell therapy potency assays for ischemic conditions.

PubMed

Porat, Yael; Abraham, Eytan; Karnieli, Ohad; Nahum, Sagi; Woda, Juliana; Zylberberg, Claudia

2015-07-01

A successful potency assay for a cell therapy product (CTP) used in the treatment of ischemic conditions should quantitatively measure relevant biological properties that predict therapeutic activity. This is especially challenging because of numerous degrees of complexity stemming from factors that include a multifactorial complex mechanism of action, cell source, inherent cell characteristics, culture method, administration mode and the in vivo conditions to which the cells are exposed. The expected biological function of a CTP encompasses complex interactions that range from a biochemical, metabolic or immunological activity to structural replacement of damaged tissue or organ. Therefore, the requirements for full characterization of the active substance with respect to biological function could be taxing. Moreover, the specific mechanism of action is often difficult to pinpoint to a specific molecular entity; rather, it is more dependent on the functionality of the cellular components acting in a in a multifactorial fashion. In the case of ischemic conditions, the cell therapy mechanism of action can vary from angiogenesis, vasculogenesis and arteriogenesis that may activate different pathways and clinical outcomes. The CTP cellular attributes with relation to the suggested mechanism of action can be used for the development of quantitative and reproducible analytical potency assays. CTPs selected and released on the basis of such potency assays should have the highest probability of providing meaningful clinical benefit for patients. This White Paper will discuss and give examples for key elements in the development of a potency assay for treatment of ischemic disorders treated by the use of CTPs. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

An auto-inhibitory helix in CTP:phosphocholine cytidylyltransferase hijacks the catalytic residue and constrains a pliable, domain-bridging helix pair

PubMed Central

Ramezanpour, Mohsen; Lee, Jaeyong; Taneva, Svetla G.; Tieleman, D. Peter; Cornell, Rosemary B.

2018-01-01

The activity of CTP:phosphocholine cytidylyltransferase (CCT), a key enzyme in phosphatidylcholine synthesis, is regulated by reversible interactions of a lipid-inducible amphipathic helix (domain M) with membrane phospholipids. When dissociated from membranes, a portion of the M domain functions as an auto-inhibitory (AI) element to suppress catalysis. The AI helix from each subunit binds to a pair of α helices (αE) that extend from the base of the catalytic dimer to create a four-helix bundle. The bound AI helices make intimate contact with loop L2, housing a key catalytic residue, Lys122. The impacts of the AI helix on active-site dynamics and positioning of Lys122 are unknown. Extensive MD simulations with and without the AI helix revealed that backbone carbonyl oxygens at the point of contact between the AI helix and loop L2 can entrap the Lys122 side chain, effectively competing with the substrate, CTP. In silico, removal of the AI helices dramatically increased αE dynamics at a predicted break in the middle of these helices, enabling them to splay apart and forge new contacts with loop L2. In vitro cross-linking confirmed the reorganization of the αE element upon membrane binding of the AI helix. Moreover, when αE bending was prevented by disulfide engineering, CCT activation by membrane binding was thwarted. These findings suggest a novel two-part auto-inhibitory mechanism for CCT involving capture of Lys122 and restraint of the pliable αE helices. We propose that membrane binding enables bending of the αE helices, bringing the active site closer to the membrane surface. PMID:29519816

Correlating Computed Tomography Perfusion Changes in the Pharyngeal Constrictor Muscles During Head-and-Neck Radiotherapy to Dysphagia Outcome

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

Truong, Minh Tam, E-mail: mitruong@bu.edu; Department of Radiology, Boston Medical Center and Boston University School of Medicine, Boston, MA; Lee, Richard

2012-02-01

Purpose: To measure changes in perfusion of the pharyngeal constrictor muscles (PCM) using CT perfusion (CTP) imaging during a course of definitive radiotherapy (RT) in head-and-neck cancer (HNC) patients and correlate with dysphagia outcome after RT. Methods and Materials: Fifteen HNC patients underwent CTP imaging of the PCM at baseline and Weeks 2, 4, and 6 during RT and 6 weeks after RT. Blood flow and blood volume were measured in the PCM, and percentage change from baseline scan was determined. A single physician-based assessment of dysphagia was performed every 3 months after RT using the Common Terminology Criteria formore » Adverse Events, version 3.0 grading system. Results: With a median follow-up of 28 months (range, 6-44 months), Grade 3 dysphagia was present in 7 of 15 patients, and 8 patients experienced Grade 0-2 dysphagia. The CTP parameters at Week 2 of RT demonstrated an increase in mean PCM blood flow of 161.9% vs. 12.3% (p = 0.007) and an increase in mean PCM blood volume of 96.6% vs. 8.7% (p = 0.039) in patients with 6-month post-RT Grade 3 dysphagia and Grade 0-2 dysphagia, respectively. On multivariate analysis, when adjusting for smoking history, tumor volume, and baseline dysphagia status, an increase in blood flow in the second week of RT was significant for 3- and 6-month Grade 3 dysphagia (p < 0.05). Conclusions: Perfusion changes in the PCM during Week 2 of RT in the PCM may predict the severity of dysphagia after HNC RT.« less

The ENSO Effects on Tropical Clouds and Top-of-Atmosphere Cloud Radiative Effects in CMIP5 Models

NASA Technical Reports Server (NTRS)

Su, Wenying; Wang, Hailan

2015-01-01

The El Nino-Southern Oscillation (ENSO) effects on tropical clouds and top-of-atmosphere (TOA) cloud radiative effects (CREs) in Coupled Model Intercomparison Project Phase5 (CMIP5) models are evaluated using satellite-based observations and International Satellite Cloud Climatology Project satellite simulator output. Climatologically, most CMIP5 models produce considerably less total cloud amount with higher cloud top and notably larger reflectivity than observations in tropical Indo-Pacific (60 degrees East - 200 degrees East; 10 degrees South - 10 degrees North). During ENSO, most CMIP5 models considerably underestimate TOA CRE and cloud changes over western tropical Pacific. Over central tropical Pacific, while the multi-model mean resembles observations in TOA CRE and cloud amount anomalies, it notably overestimates cloud top pressure (CTP) decreases; there are also substantial inter-model variations. The relative effects of changes in cloud properties, temperature and humidity on TOA CRE anomalies during ENSO in the CMIP5 models are assessed using cloud radiative kernels. The CMIP5 models agree with observations in that their TOA shortwave CRE anomalies are primarily contributed by total cloud amount changes, and their TOA longwave CRE anomalies are mostly contributed by changes in both total cloud amount and CTP. The model biases in TOA CRE anomalies particularly the strong underestimations over western tropical Pacific are, however, mainly explained by model biases in CTP and cloud optical thickness (tau) changes. Despite the distinct model cloud biases particularly in tau regime, the TOA CRE anomalies from cloud amount changes are comparable between the CMIP5 models and observations, because of the strong compensations between model underestimation of TOA CRE anomalies from thin clouds and overestimation from medium and thick clouds.

Nanostructuring effect of multi-walled carbon nanotubes on electrochemical properties of carbon foam as constructive electrode for lead acid battery

NASA Astrophysics Data System (ADS)

Kumar, Rajeev; Kumari, Saroj; Mathur, Rakesh B.; Dhakate, Sanjay R.

2015-01-01

In the present study, nanostructuring effect of multi-walled carbon nanotubes (MWCNTs) on electrochemical properties of coal tar pitch (CTP) based carbon foam (CFoam) was investigated. The different weight fractions of MWCNTs were mixed with CTP and foam was developed from the mixture of CTP and MWCNTs by sacrificial template technique and heat treated at 1,400 and 2,500 °C in inert atmosphere. These foams were characterized by scanning electron microscopy, X-ray diffraction, and potentiostat PARSTAT for cyclic voltammetry. It was observed that, bulk density of CFoam increases with increasing MWCNTs content and decreases after certain amount. The MWCNTs influence the morphology of CFoam and increase the width of ligaments as well as surface area. During the heat treatment, stresses exerting at MWCNTs/carbon interface accelerate ordering of the graphene layer which have positive effect on the electrochemical properties of CFoam. The current density increases from 475 to 675 mA/cm2 of 1,400 °C heat treated and 95 to 210 mA/cm2 of 2,500 °C heat-treated CFoam with 1 wt% MWCNTs. The specific capacitance was decreases with increasing the scan rate from 100 to 1,000 mV/s. In case of 1 % MWCNTs content CFoam the specific capacitance at the scan rate 100 mV/s was increased from 850 to 1,250 μF/cm2 and 48 to 340 μF/cm2 of CFoam heat treated at 1,400 °C and 2,500 °C respectively. Thus, the higher value surface area and current density of MWCNTs-incorporated CFoam heat treated to 1,400 °C can be suitable for lead acid battery electrode with improved charging capability.

Scale-up and large-scale production of Tetraselmis sp. CTP4 (Chlorophyta) for CO2 mitigation: from an agar plate to 100-m3 industrial photobioreactors.

PubMed

Pereira, Hugo; Páramo, Jaime; Silva, Joana; Marques, Ana; Barros, Ana; Maurício, Dinis; Santos, Tamára; Schulze, Peter; Barros, Raúl; Gouveia, Luísa; Barreira, Luísa; Varela, João

2018-03-23

Industrial production of novel microalgal isolates is key to improving the current portfolio of available strains that are able to grow in large-scale production systems for different biotechnological applications, including carbon mitigation. In this context, Tetraselmis sp. CTP4 was successfully scaled up from an agar plate to 35- and 100-m 3 industrial scale tubular photobioreactors (PBR). Growth was performed semi-continuously for 60 days in the autumn-winter season (17 th October - 14 th December). Optimisation of tubular PBR operations showed that improved productivities were obtained at a culture velocity of 0.65-1.35 m s -1 and a pH set-point for CO 2 injection of 8.0. Highest volumetric (0.08 ± 0.01 g L -1 d -1 ) and areal (20.3 ± 3.2 g m -2 d -1 ) biomass productivities were attained in the 100-m 3 PBR compared to those of the 35-m 3 PBR (0.05 ± 0.02 g L -1 d -1 and 13.5 ± 4.3 g m -2 d -1 , respectively). Lipid contents were similar in both PBRs (9-10% of ash free dry weight). CO 2 sequestration was followed in the 100-m 3 PBR, revealing a mean CO 2 mitigation efficiency of 65% and a biomass to carbon ratio of 1.80. Tetraselmis sp. CTP4 is thus a robust candidate for industrial-scale production with promising biomass productivities and photosynthetic efficiencies up to 3.5% of total solar irradiance.

Predictors of hospital re-admissions among Hispanics with hepatitis C-related cirrhosis.

PubMed

Atla, Pradeep R; Sheikh, Muhammad Y; Gill, Firdose; Kundu, Rabindra; Choudhury, Jayanta

2016-01-01

Hospital re-admissions in decompensated cirrhosis are associated with worse patient outcomes. Hispanics have a disproportionately high prevalence of hepatitis C virus (HCV)-related morbidity and mortality. The goal of this study was to evaluate the factors affecting re-admission rates among Hispanics with HCV-related cirrhosis. A total of 292 consecutive HCV-related cirrhosis admissions (Hispanics 189, non-Hispanics 103) from January 2009 to December 2012 were retrospectively reviewed; 132 were cirrhosis-related re-admissions. The statistical analysis was performed using STATA version 11.1. Chi-square/Fisher's exact and Student's t-tests were used to compare categorical and continuous variables, respectively. Multivariate logistic regression analysis was performed to identify predictors for hospital readmissions. Among the 132 cirrhosis-related readmissions, 71% were Hispanics while 29% were non-Hispanics (P=0.035). Hepatic encephalopathy (HE) and esophageal variceal hemorrhage were the most frequent causes of the first and subsequent readmissions. Hispanics with readmissions had a higher Child-Turcotte-Pugh (CTP) class (B and C) and higher model for end-stage liver disease (MELD) scores (≥15), as well as a higher incidence of alcohol use, HE, spontaneous bacterial peritonitis, hepatocellular carcinoma, and varices (P<0.05). The majority of the study patients (81%) had MELD scores <15. Multivariate regression analysis identified alcohol use (OR 2.63; 95%CI 1.1-6.4), HE (OR 5.5; 95%CI 2-15.3), varices (OR 3.2; 95%CI 1.3-8.2), and CTP class (OR 3.3; 95%CI 1.4-8.1) as predictors for readmissions among Hispanics. CTP classes B and C, among other factors, were the major predictors for hospital readmissions in Hispanics with HCV-related cirrhosis. The majority of these readmissions were due to HE and variceal hemorrhage.

Computers in the Schools: State/Provincial Implications.

ERIC Educational Resources Information Center

Thiessen, S. J.

The Alberta goverment has attempted to systematically address educational computing issues through programs of the provincial (K-12) education department (Alberta Education), which have included the development of computer literacy curricula for elementary, junior, and senior high schools; the Computer Technology Project (CTP); evaluation studies;…

21 CFR 1141.12 - Incorporation by reference of required warnings.

Code of Federal Regulations, 2013 CFR

2013-04-01

... SERVICES (CONTINUED) TOBACCO PRODUCTS CIGARETTE PACKAGE AND ADVERTISING WARNINGS Cigarette Package and Advertising Warnings § 1141.12 Incorporation by reference of required warnings. “Cigarette Required Warnings..., ATTN: Cigarette Warning File Requests, 9200 Corporate Blvd., Rockville, MD 20850, 1-877-CTP-1373, or...

Conformation of nanoconfined DNA as a function of ATP, AMP, CTP, Mg2+, and dye binding

NASA Astrophysics Data System (ADS)

Roushan, Maedeh; Riehn, Robert

2014-03-01

DNA molecules stretch in nanochannels with a channel cross-section of 100x100 nm2, thereby allowing analysis by observation of a fluorescent dye. The length and configuration of DNA can be directly observed, and the effect of different DNA-binding proteins on DNA configuration can be studied. Recently, we reported on the ability of T4 ligase to transiently manipulate DNA as a function of ATP and magnesium exposure. In this process we have extensively probed the interactions of dyes and enzyme co-factors with DNA under nanoconfinement. We find negligible effects if DNA is visualized using groove-binding dyes such as DAPI. However, if an intercalating dye (YOYO-1) is used, we find a significant shortening of the DNA in the presence of ATP that we attribute to an interaction of dye and ATP (as well as AMP and CTP). We did not record a noticeable effect due to Mg2+.

Identification of hydrophobic amino acids required for lipid activation of C. elegans CTP:phosphocholine cytidylyltransferase.

PubMed

Braker, Jay D; Hodel, Kevin J; Mullins, David R; Friesen, Jon A

2009-12-01

CTP:phosphocholine cytidylyltransferase (CCT), critical for phosphatidylcholine biosynthesis, is activated by translocation to the membrane surface. The lipid activation region of Caenorhabditis elegans CCT is between residues 246 and 266 of the 347 amino acid polypeptide, a region proposed to form an amphipathic alpha helix. When leucine 246, tryptophan 249, isoleucine 256, isoleucine 257, or phenylalanine 260, on the hydrophobic face of the helix, were changed individually to serine low activity was observed in the absence of lipid vesicles, similar to wild-type CCT, while lipid stimulated activity was reduced compared to wild-type CCT. Mutational analysis of phenylalanine 260 implicated this residue as a contributor to auto-inhibition of CCT while mutation of L246, W249, I256, and I257 simultaneously to serine resulted in significantly higher activity in the absence of lipid vesicles and an enzyme that was not lipid activated. These results support a concerted mechanism of lipid activation that requires multiple residues on the hydrophobic face of the putative amphipathic alpha helix.

Management of Liver Cancer Argon-helium Knife Therapy with Functional Computer Tomography Perfusion Imaging.

PubMed

Wang, Hongbo; Shu, Shengjie; Li, Jinping; Jiang, Huijie

2016-02-01

The objective of this study was to observe the change in blood perfusion of liver cancer following argon-helium knife treatment with functional computer tomography perfusion imaging. Twenty-seven patients with primary liver cancer treated with argon-helium knife and were included in this study. Plain computer tomography (CT) and computer tomography perfusion (CTP) imaging were conducted in all patients before and after treatment. Perfusion parameters including blood flows, blood volume, hepatic artery perfusion fraction, hepatic artery perfusion, and hepatic portal venous perfusion were used for evaluating therapeutic effect. All parameters in liver cancer were significantly decreased after argon-helium knife treatment (p < 0.05 to all). Significant decrease in hepatic artery perfusion was also observed in pericancerous liver tissue, but other parameters kept constant. CT perfusion imaging is able to detect decrease in blood perfusion of liver cancer post-argon-helium knife therapy. Therefore, CTP imaging would play an important role for liver cancer management followed argon-helium knife therapy. © The Author(s) 2014.

76 FR 52994 - Application for a License To Export Heavy Water

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-24

... NUCLEAR REGULATORY COMMISSION Application for a License To Export Heavy Water Pursuant to 10 CFR... (liters). producing an active water). pharmaceutical ingredient known as CTP-499, which incorporates heavy water as the source of deuterium to achieve the hydrogen-deuterium exchange. November 30, 2010 December...

Optimization Review: Bunker Hill Mining and Metallurgical Complex Superfund Site, Central Treatment Plant (CTP), Kellogg, Shoshone County, Idaho

EPA Pesticide Factsheets

The Bunker Hill Mining and Metallurgical Complex Superfund Site includes all areas of the Coeur d’Alene Basin where mining-related contamination occurred and encompasses a 21-square mile “Box” along Interstate 90 surrounding the former smelter complex.

Time optimal paths for high speed maneuvering

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

Reister, D.B.; Lenhart, S.M.

1993-01-01

Recent theoretical results have completely solved the problem of determining the minimum length path for a vehicle with a minimum turning radius moving from an initial configuration to a final configuration. Time optimal paths for a constant speed vehicle are a subset of the minimum length paths. This paper uses the Pontryagin maximum principle to find time optimal paths for a constant speed vehicle. The time optimal paths consist of sequences of axes of circles and straight lines. The maximum principle introduces concepts (dual variables, bang-bang solutions, singular solutions, and transversality conditions) that provide important insight into the nature ofmore » the time optimal paths. We explore the properties of the optimal paths and present some experimental results for a mobile robot following an optimal path.« less

Implementation of a level 1 trigger system using high speed serial (VXS) techniques for the 12GeV high luminosity experimental programs at Thomas Jefferson National Accelerator Facility

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

C. Cuevas, B. Raydo, H. Dong, A. Gupta, F.J. Barbosa, J. Wilson, W.M. Taylor, E. Jastrzembski, D. Abbott

We will demonstrate a hardware and firmware solution for a complete fully pipelined multi-crate trigger system that takes advantage of the elegant high speed VXS serial extensions for VME. This trigger system includes three sections starting with the front end crate trigger processor (CTP), a global Sub-System Processor (SSP) and a Trigger Supervisor that manages the timing, synchronization and front end event readout. Within a front end crate, trigger information is gathered from each 16 Channel, 12 bit Flash ADC module at 4 nS intervals via the VXS backplane, to a Crate Trigger Processor (CTP). Each Crate Trigger Processor receivesmore » these 500 MB/S VXS links from the 16 FADC-250 modules, aligns skewed data inherent of Aurora protocol, and performs real time crate level trigger algorithms. The algorithm results are encoded using a Reed-Solomon technique and transmission of this Level 1 trigger data is sent to the SSP using a multi-fiber link. The multi-fiber link achieves an aggregate trigger data transfer rate to the global trigger at 8 Gb/s. The SSP receives and decodes Reed-Solomon error correcting transmission from each crate, aligns the data, and performs the global level trigger algorithms. The entire trigger system is synchronous and operates at 250 MHz with the Trigger Supervisor managing not only the front end event readout, but also the distribution of the critical timing clocks, synchronization signals, and the global trigger signals to each front end readout crate. These signals are distributed to the front end crates on a separate fiber link and each crate is synchronized using a unique encoding scheme to guarantee that each front end crate is synchronous with a fixed latency, independent of the distance between each crate. The overall trigger signal latency is <3 uS, and the proposed 12GeV experiments at Jefferson Lab require up to 200KHz Level 1 trigger rate.« less

Observer Training Manual for the Changing Teacher Practice Study. Revised Manual.

ERIC Educational Resources Information Center

Barnes, Susan

This observer training manual was developed as a central component of a research effort, Changing Teacher Practice (CTP), which was designed to increase the frequency of effective teaching behaviors and staff development strategies in an ongoing school system. The observations focused on two major aspects of classroom teaching--instruction and…

Evaluation of LEAA Funded Courts Training Programs. Volume I.

ERIC Educational Resources Information Center

McManis Associates, Inc., Washington, DC.

An impact evaluation of eight courts training project (CTP) institutes funded by the Law Enforcement Assistance Administration was conducted. After a literature search and visits to potential evaluation sites in all fifty states, twelve sites were selected from a random stratified sample of court systems. Data were obtained from 1047 respondents…

78 FR 38055 - Building Research Capacity in Global Tobacco Product Regulation Program (U18)

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-25

... Monitoring Database. Examples of Global Tobacco Research Reports/White Papers: [cir] WHO report on the global...] Building Research Capacity in Global Tobacco Product Regulation Program (U18) AGENCY: Food and Drug... availability of grant funds for the support of the Center for Tobacco Product's (CTP's) Building Research...

The Round Table on Computer Performance Metrics for Export Control: Discussions and Results

DTIC Science & Technology

1997-12-01

eligibility, use the CTP parameter to the exclusion of other technical parameters for computers classified under ECCN 4A003.a, .b and .c, except of...parameters specified as Missile Technology (MT) concerns or 4A003.e (equipment performing analog-to-digital conversions exceeding the limits in ECCN

Binding of ATP by pertussis toxin and isolated toxin subunits

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

Hausman, S.Z.; Manclark, C.R.; Burns, D.L.

1990-07-03

The binding of ATP to pertussis toxin and its components, the A subunit and B oligomer, was investigated. Whereas, radiolabeled ATP bound to the B oligomer and pertussis toxin, no binding to the A subunit was observed. The binding of ({sup 3}H)ATP to pertussis toxin and the B oligomer was inhibited by nucleotides. The relative effectiveness of the nucleotides was shown to be ATP > GTP > CTP > TTP for pertussis toxin and ATP > GTP > TTP > CTP for the B oligomer. Phosphate ions inhibited the binding of ({sup 3}H)ATP to pertussis toxin in a competitive manner;more » however, the presence of phosphate ions was essential for binding of ATP to the B oligomer. The toxin substrate, NAD, did not affect the binding of ({sup 3}H)ATP to pertussis toxin, although the glycoprotein fetuin significantly decreased binding. These results suggest that the binding site for ATP is located on the B oligomer and is distinct from the enzymatically active site but may be located near the eukaryotic receptor binding site.« less

Ceramics Technology Project database: September 1991 summary report. [Materials for piston ring-cylinder liner for advanced heat/diesel engines

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

Keyes, B.L.P.

1992-06-01

The piston ring-cylinder liner area of the internal combustion engine must withstand very-high-temperature gradients, highly-corrosive environments, and constant friction. Improving the efficiency in the engine requires ring and cylinder liner materials that can survive this abusive environment and lubricants that resist decomposition at elevated temperatures. Wear and friction tests have been done on many material combinations in environments similar to actual use to find the right materials for the situation. This report covers tribology information produced from 1986 through July 1991 by Battelle columbus Laboratories, Caterpillar Inc., and Cummins Engine Company, Inc. for the Ceramic Technology Project (CTP). All datamore » in this report were taken from the project's semiannual and bimonthly progress reports and cover base materials, coatings, and lubricants. The data, including test rig descriptions and material characterizations, are stored in the CTP database and are available to all project participants on request. Objective of this report is to make available the test results from these studies, but not to draw conclusions from these data.« less

Ceramics Technology Project database: September 1991 summary report

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

Keyes, B.L.P.

1992-06-01

The piston ring-cylinder liner area of the internal combustion engine must withstand very-high-temperature gradients, highly-corrosive environments, and constant friction. Improving the efficiency in the engine requires ring and cylinder liner materials that can survive this abusive environment and lubricants that resist decomposition at elevated temperatures. Wear and friction tests have been done on many material combinations in environments similar to actual use to find the right materials for the situation. This report covers tribology information produced from 1986 through July 1991 by Battelle columbus Laboratories, Caterpillar Inc., and Cummins Engine Company, Inc. for the Ceramic Technology Project (CTP). All datamore » in this report were taken from the project`s semiannual and bimonthly progress reports and cover base materials, coatings, and lubricants. The data, including test rig descriptions and material characterizations, are stored in the CTP database and are available to all project participants on request. Objective of this report is to make available the test results from these studies, but not to draw conclusions from these data.« less

Micromethod for phosphonoformate inhibition assay of hepatitis B viral DNA polymerase.

PubMed

Lin, H J; Wu, P C; Lai, C L; Chak, W

1984-04-01

A micromethod for the specific measurement of hepatitis B viral DNA polymerase in serum is presented, based on the phosphonoformate inhibition assay (J Med Virol 12: 61-70, 1983). In the micromethod, sample volume is reduced to 120 microL and the ultracentrifugation step is eliminated. The method allows good discrimination between serum infected with hepatitis B virus and uninfected serum. The cutoff value for rate of nucleotide incorporation, based on assays of 41 serum specimens negative for hepatitis B serological markers, was about 15 nU/L (90th percentile). Serum containing hepatitis B surface and antigens exhibited rates of phosphonoformate-inhibitive nucleotide incorporation of 150 (SD 150) nU/L, with an upper 90th percentile range of 17 to 667 nU/L (n = 41). The micromethod makes use of commercially available [32P]dCTP (specific activity about 7000 kCi/mol). 125I-labeled dCTP was found to be unsuitable for this assay. Human DNA polymerases in serum are detected by this method but are excluded from the phosphonoformate-inhibitive fraction.

Nucleotide sequence of the gene encoding the nitrogenase iron protein of Thiobacillus ferrooxidans

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

Pretorius, I.M.; Rawlings, D.E.; O'Neill, E.G.

1987-01-01

The DNA sequence was determined for the cloned Thiobacillus ferrooxidans nifH and part of the nifD genes. The DNA chains were radiolabeled with (..cap alpha..-/sup 32/P)dCTP (3000 Ci/mmol) or (..cap alpha..-/sup 35/S)dCTP (400 Ci/mmol). A putative T. ferrooxidans nifH promoter was identified whose sequences showed perfect consensus with those of the Klebsiella pneumoniae nif promoter. Two putative consensus upstream activator sequences were also identified. The amino acid sequence was deduced from the DNA sequence. In a comparison of nifH DNA sequences from T. ferrooxidans and eight other nitrogen-fixing microbes, a Rhizobium sp. isolated from Parasponia andersonii showed the greatest homologymore » (74%) and Clostridium pasteurianum (nifH1) showed the least homology (54%). In the comparison of the amino acid sequences of the Fe proteins, the Rhizobium sp. and Rhizobium japonicum showed the greatest homology (both 86%) and C. pasteurianum (nifH1 gene product) demonstrated the least homology (56%) to the T. ferrooxidans Fe protein.« less

The spatial distribution of cropland carbon transfer in Jilin province during 2014

NASA Astrophysics Data System (ADS)

Cai, Xintong; Meng, Jian; Li, Qiuhui; Gao, Shuang; Zhu, Xianjin

2018-01-01

Cropland carbon transfer (CCT, gC yr-1) is an important component in the carbon budget of terrestrial ecosystems. Analyzing the value of CCT and its spatial variation would provide a data basis for assessing the regional carbon balance. Based on the data from Jilin statistical yearbook 2015, we investigated the spatial variation of CCT in Jilin province during 2014. Results suggest that the CCT of Jilin province was 30.83 TgC, which exhibited a decreasing trend from the centre to the border but the west side was higher than the east. The magnitude of carbon transfer per area (MCT), which showed a similar spatial distribution with CCT, was the dominating component of CCT spatial distribution. The spatial distribution of MCT was jointly affected by that of the ratio of planting area to regional area (RPR) and carbon transfer per planting area (CTP), where RPR and CTP contributed 65.55% and 34.5% of MCT spatial distribution, respectively. Therefore, CCT in Jilin province spatially varied, which made it highly needed to consider the difference in CCT among regions when we assessing the regional carbon budget.

Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

PubMed Central

Mori, Giorgia; Chiarelli, Laurent R.; Esposito, Marta; Makarov, Vadim; Bellinzoni, Marco; Hartkoorn, Ruben C.; Degiacomi, Giulia; Boldrin, Francesca; Ekins, Sean; de Jesus Lopes Ribeiro, Ana Luisa; Marino, Leonardo B.; Centárová, Ivana; Svetlíková, Zuzana; Blaško, Jaroslav; Kazakova, Elena; Lepioshkin, Alexander; Barilone, Nathalie; Zanoni, Giuseppe; Porta, Alessio; Fondi, Marco; Fani, Renato; Baulard, Alain R.; Mikušová, Katarína; Alzari, Pedro M.; Manganelli, Riccardo; de Carvalho, Luiz Pedro S.; Riccardi, Giovanna; Cole, Stewart T.; Pasca, Maria Rosalia

2015-01-01

Summary To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target. PMID:26097035

Cytidine Diphosphoramidate Kinase: An Enzyme Required for the Biosynthesis of the O-Methyl Phosphoramidate Modification in the Capsular Polysaccharides of Campylobacter jejuni.

PubMed

Taylor, Zane W; Raushel, Frank M

2018-04-17

Campylobacter jejuni, a leading cause of gastroenteritis, produces a capsular polysaccharide that is derivatized with a unique O-methyl phosphoramidate (MeOPN) modification. This modification contributes to serum resistance and invasion of epithelial cells. Previously, the first three biosynthetic steps for the formation of MeOPN were elucidated. The first step is catalyzed by a novel glutamine kinase (Cj1418), which catalyzes the adenosine triphosphate (ATP)-dependent phosphorylation of the amide nitrogen of l-glutamine. l-Glutamine phosphate is used by cytidine triphosphate (CTP):phosphoglutamine cytidylyltransferase (Cj1416) to displace pyrophosphate from CTP to generate cytidine diphosphate (CDP)-l-glutamine, which is then hydrolyzed by γ-glutamyl-CDP-amidate hydrolase (Cj1417) to form cytidine diphosphoramidate (CDP-NH 2 ). Here, we show that Cj1415 catalyzes the ATP-dependent phosphorylation of CDP-NH 2 to form 3'-phospho-cytidine-5'-diphosphoramidate. Cj1415 will also catalyze the phosphorylation of adenosine diphosphoramidate (ADP-NH 2 ) and uridine diphosphoramidate (UDP-NH 2 ) but at significantly reduced rates. It is proposed that Cj1415 be named cytidine diphosphoramidate kinase.

Biosynthesis of Nucleoside Diphosphoramidates in Campylobacter jejuni.

PubMed

Taylor, Zane W; Brown, Haley A; Holden, Hazel M; Raushel, Frank M

2017-11-21

Campylobacter jejuni is a pathogenic Gram-negative bacterium and a leading cause of food-borne gastroenteritis. C. jejuni produces a capsular polysaccharide (CPS) that contains a unique O-methyl phosphoramidate modification (MeOPN). Recently, the first step in the biosynthetic pathway for the assembly of the MeOPN modification to the CPS was elucidated. It was shown that the enzyme Cj1418 catalyzes the phosphorylation of the amide nitrogen of l-glutamine to form l-glutamine phosphate. In this investigation, the metabolic fate of l-glutamine phosphate was determined. The enzyme Cj1416 catalyzes the displacement of pyrophosphate from MgCTP by l-glutamine phosphate to form CDP-l-glutamine. The enzyme Cj1417 subsequently catalyzes the hydrolysis of CDP-l-glutamine to generate cytidine diphosphoramidate and l-glutamate. The structures of the two novel intermediates, CDP-l-glutamine and cytidine diphosphoramidate, were confirmed by 31 P nuclear magnetic resonance spectroscopy and mass spectrometry. It is proposed that the enzyme Cj1416 be named CTP:phosphoglutamine cytidylyltransferase and that the enzyme Cj1417 be named γ-glutamyl-CDP-amidate hydrolase.

Mechanism of Error-Free Bypass of the Environmental Carcinogen N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone Adduct by Human DNA Polymerase η.

PubMed

Patra, Amritraj; Politica, Dustin A; Chatterjee, Arindom; Tokarsky, E John; Suo, Zucai; Basu, Ashis K; Stone, Michael P; Egli, Martin

2016-11-03

The environmental pollutant 3-nitrobenzanthrone produces bulky aminobenzanthrone (ABA) DNA adducts with both guanine and adenine nucleobases. A major product occurs at the C8 position of guanine (C8-dG-ABA). These adducts present a strong block to replicative polymerases but, remarkably, can be bypassed in a largely error-free manner by the human Y-family polymerase η (hPol η). Here, we report the crystal structure of a ternary Pol⋅DNA⋅dCTP complex between a C8-dG-ABA-containing template:primer duplex and hPol η. The complex was captured at the insertion stage and provides crucial insight into the mechanism of error-free bypass of this bulky lesion. Specifically, bypass involves accommodation of the ABA moiety inside a hydrophobic cleft to the side of the enzyme active site and formation of an intra-nucleotide hydrogen bond between the phosphate and ABA amino moiety, allowing the adducted guanine to form a standard Watson-Crick pair with the incoming dCTP. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparison of TOF MRA, Contrast-Enhanced MRA and Subtracted CTA from CTP in Residue Evaluation of Treated Intracranial Aneurysms.

PubMed

Dündar, Tolga Turan; Aralaşmak, Ayşe; Özdemir, Hüseyin; Seyithanoğlu, Mehmet Hakan; Uysal, Ömer; Toprak, Hüseyin; Kitiş, Serkan; Özek, Erdinç; Alkan, Alpay

2017-10-18

To compare effectiveness of contrast-enhanced MRA (CE-MRA), 3D-Time-of-flight MRA (3D-TOF-MRA) and subtracted CTA from CTP (sub-CTA) in residue evaluation of intracranial aneurysms treated either with coiling or clipping. Sixteen treated aneurysms, which were evaluated with three methods within two weeks after the operation, were enrolled. The success of each imaging techniques in demonstration of residue aneurysm and nearby vessels was compared by Fisher\\'s Exact Test. The differences among three was evaluated by Cochran\\'s Q test (p ≤ 0.05). Perfusion abnormality was noted in % 81 of clipped and none of coiled patients. Vessel visualization in the vicinity of aneurysm was better in sub-CTA, followed by CE-MRA. In clipped aneurysms, sub-CTA revealed residue aneurysms in % 16,7 of the patients while 3D-TOF-MRA and CE-MRA revealed none. In coiled aneurysms, CE-MRA revealed residue aneurysms in 100 %, and TOF-MRA in 33,3 % while sub-CTA revealed none. Although dramatic differences were noted in the evaluation of residue aneurysm as well as nearby vessel visualization, no statistical significance noted due to very few patients in subcategories Conclusion: This is first study comparing the effectiveness of CE-MRA, 3D-TOF MRA and sub-CTA in residue aneurysms evaluation. Vessel visualization in the vicinity of aneurysm was better in sub-CTA in all regardless of coiling or clipping. Residue aneurysms were more commonly revealed by CE-MRA in coiled patients and more commonly and better shown by sub-CTA in clipped patients in addition of showing perfusion abnormality that's is more common in clipped patients.

Algorithm for prioritization of patients on the waiting list for liver transplantation.

PubMed

Gambato, M; Senzolo, M; Canova, D; Germani, G; Tomat, S; Masier, A; Russo, F P; Perissinotto, E; Zanus, G; Cillo, U; Burra, P

2007-01-01

Prioritization of patients on the waiting list (WL) for OLT is still a critical issue. Numerous models have been developed to predict mortality before and after OLT. The aim of the study was to prospectively evaluate cirrhotics with and without hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT) severity of liver disease on the WL and at transplant, mortality on the WL and after OLT, and their correlations. An algorithm based on seven patient variables (MELD, CTP, UNOS, HCC, BMI, waiting time, age) was created by software dedicated to prioritize patients on the waiting list. We evaluated 118 patients including 75 men and 43 women of age range 19 to 66 years, who underwent OLT from July 2004 to June 2006. Mean CTP and MELD at listing were 8.44 (range 6-12) and 13 (range 2-24), respectively. Overall mortality on the WL at 24 months was 13%, which was significantly higher among patients with MELD > 25 compared to patients with MELD 0 to 15 (P < .0001) or MELD 16 to 25 (P = .0007) at listing. Mean MELD at OLT was 15 (range 7-36), which was significantly lower in patients with than without HCC (MELD 12 vs 16; P = .0003). Six hundred-day patient survival was significantly lower among patients with MELD > 25 compared to patients with MELD < 25 at OLT (P = .017), whereas no difference in survival was observed between patients with and without HCC. The sickest patients are characterized by high mortality both on the waiting list and after liver transplantation. Patients with HCC are transplanted in better condition compared to patients without HCC with the same survival.

Shunt occlusion for portosystemic shunt syndrome related refractory hepatic encephalopathy-A single-center experience in 21 patients from Kerala.

PubMed

Philips, Cyriac Abby; Kumar, Lijesh; Augustine, Philip

2017-09-01

Large spontaneous portosystemic shunts (SPSS) are seen in a subset of patients with liver disease and medically refractory recurrent/persistent hepatic encephalopathy (MRHE). Shunt occlusion has been shown to improve clinical outcomes. We retrospectively analyzed patient characteristics, SPSS attributes, procedural features, baseline clinical and investigational parameters, neurological outcomes, adverse effects (procedure and portal hypertension related), and risk factors predicting outcomes in liver disease patients undergoing shunt occlusion procedure for MRHE. Between October 2016 and July 2017, 21 patients (Child-Pugh score, CTP 6 to 13) with mean model of end-stage liver disease (MELD) and MELD-sodium scores 15.7 and 19.3 respectively with MRHE [3-cirrhotic Parkinsonism (CP)] were diagnosed to have single or multiple large SPSSs. A total of 29 shunts were occluded (1 surgical, 20 non-surgical). Recurrent and persistent HE and CP markedly improved in the short (n=20, 1 to 3 months), intermediate (n=12, 3 to 6 months), and long (n=7, 6 to 9 months) follow up. None had spontaneous or persistent HE at a median follow up 105 (30 to 329) days (p<0.05). Motor, speech, sleep abnormalities, daily activities of living, and liver disease severity scores improved significantly on follow up. Baseline arterial ammonia showed a statistically significant reduction in all time periods of follow up after shunt occlusion (p<0.05). CTP >11 predicted mortality post shunt occlusion (p=0.04). Embolization of large SPSS in liver disease patients with MRHE and modestly preserved liver function is safe and efficacious and associated with improved quality of life and can function as a bridge to liver transplantation in accurately selected patients.

AIRS Subpixel Cloud Characterization Using MODIS Cloud Products.

NASA Astrophysics Data System (ADS)

Li, Jun; Menzel, W. Paul; Sun, Fengying; Schmit, Timothy J.; Gurka, James

2004-08-01

The Moderate Resolution Imaging Spectroradiometer (MODIS) and the Atmospheric Infrared Sounder (AIRS) measurements from the Earth Observing System's (EOS's) Aqua satellite enable improved global monitoring of the distribution of clouds. MODIS is able to provide, at high spatial resolution (1 5 km), a cloud mask, surface and cloud types, cloud phase, cloud-top pressure (CTP), effective cloud amount (ECA), cloud particle size (CPS), and cloud optical thickness (COT). AIRS is able to provide CTP, ECA, CPS, and COT at coarser spatial resolution (13.5 km at nadir) but with much better accuracy using its high-spectral-resolution measurements. The combined MODIS AIRS system offers the opportunity for improved cloud products over those possible from either system alone. The key steps for synergistic use of imager and sounder radiance measurements are 1) collocation in space and time and 2) imager cloud amount, type, and phase determination within the sounder pixel. The MODIS and AIRS measurements from the EOS Aqua satellite provide the opportunity to study the synergistic use of advanced imager and sounder measurements. As the first step, the MODIS classification procedure is applied to identify various surface and cloud types within an AIRS footprint. Cloud-layer information (lower, midlevel, or high clouds) and phase information (water, ice, or mixed-phase clouds) within the AIRS footprint are sorted and characterized using MODIS 1-km-spatial-resolution data. The combined MODIS and AIRS data for various scenes are analyzed to study the utility of the synergistic use of high-spatial-resolution imager products and high-spectral-resolution sounder radiance measurements. There is relevance to the optimal use of data from the Advanced Baseline Imager (ABI) and Hyperspectral Environmental Suite (HES) systems, which are to fly on the Geostationary Operational Environmental Satellite (GOES)-R.

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

Reister, D.B.; Lenhart, S.M.

Recent theoretical results have completely solved the problem of determining the minimum length path for a vehicle with a minimum turning radius moving from an initial configuration to a final configuration. Time optimal paths for a constant speed vehicle are a subset of the minimum length paths. This paper uses the Pontryagin maximum principle to find time optimal paths for a constant speed vehicle. The time optimal paths consist of sequences of axes of circles and straight lines. The maximum principle introduces concepts (dual variables, bang-bang solutions, singular solutions, and transversality conditions) that provide important insight into the nature ofmore » the time optimal paths. We explore the properties of the optimal paths and present some experimental results for a mobile robot following an optimal path.« less

Synergistic Use of MODIS and AIRS in a Variational Retrieval of Cloud Parameters.

NASA Astrophysics Data System (ADS)

Li, Jun; Menzel, W. Paul; Zhang, Wenjian; Sun, Fengying; Schmit, Timothy J.; Gurka, James J.; Weisz, Elisabeth

2004-11-01

The Moderate Resolution Imaging Spectroradiometer (MODIS) and the Atmospheric Infrared Sounder (AIRS) measurements from the Earth Observing System's (EOS's) Aqua satellite enable global monitoring of the distribution of clouds. MODIS is able to provide a cloud mask, surface and cloud types, cloud phase, cloud-top pressure (CTP), effective cloud amount (ECA), cloud particle size, and cloud optical thickness at high spatial resolution (1 5 km). The combined MODIS AIRS system offers the opportunity for improved cloud products, better than from either system alone; this improvement is demonstrated in this paper with both simulated and real radiances. A one-dimensional variational (1DVAR) methodology is used to retrieve the CTP and ECA from AIRS longwave (650 790 cm-1 or 15.38 12.65 μm) cloudy radiance measurements (hereinafter referred to as MODIS AIRS 1DVAR). The MODIS AIRS 1DVAR cloud properties show significant improvement over the MODIS-alone cloud properties and slight improvement over AIRS-alone cloud properties in a simulation study, while MODIS AIRS 1DVAR is much more computationally efficient than the AIRS-alone 1DVAR; comparisons with radiosonde observations show that CTPs improve by 10 40 hPa for MODIS AIRS CTPs over those from MODIS alone. The 1DVAR approach is applied to process the AIRS longwave cloudy radiance measurements; results are compared with MODIS and Geostationary Operational Environmental Satellite sounder cloud products. Data from ground-based instrumentation at the Atmospheric Radiation Measurement Program Cloud and Radiation Test Bed in Oklahoma are used for validation; results show that MODIS AIRS improves the MODIS CTP, especially in low-level clouds. The operational use of a high-spatial-resolution imager, along with information from a high-spectral-resolution sounder will be possible with instruments planned for the next-generation geostationary operational instruments.

Long-term Efficacy, Safety, and Immunogenicity of Biosimilar Infliximab After One Year in a Prospective Nationwide Cohort.

PubMed

Gonczi, Lorant; Gecse, Krisztina B; Vegh, Zsuzsanna; Kurti, Zsuzsanna; Rutka, Mariann; Farkas, Klaudia; Golovics, Petra A; Lovasz, Barbara D; Banai, Janos; Bene, Laszlo; Gasztonyi, Bea; Kristof, Tunde; Lakatos, Laszlo; Miheller, Pal; Nagy, Ferenc; Palatka, Karoly; Papp, Maria; Patai, Arpad; Salamon, Agnes; Szamosi, Tamas; Szepes, Zoltan; Toth, Gabor T; Vincze, Aron; Szalay, Balazs; Molnar, Tamas; Lakatos, Peter L

2017-11-01

It has been previously shown that biosimilar infliximab CT-P13 is effective and safe in inducing remission in inflammatory bowel diseases. We report here the 1-year outcomes from a prospective nationwide inflammatory bowel disease cohort. A prospective, nationwide, multicenter, observational cohort was designed to examine the efficacy and safety of CT-P13 in the induction and maintenance treatment of Crohn's disease (CD) and ulcerative colitis (UC). Demographic data were collected and a harmonized monitoring strategy was applied. Clinical remission, response, and biochemical response were evaluated at weeks 14, 30, and 54, respectively. Safety data were registered. Three hundred fifty-three consecutive inflammatory bowel disease (209 CD and 144 UC) patients were included, of which 229 patients reached the week 54 endpoint at final evaluation. Age at disease onset: 24/28 years (median, interquartile range: 19-34/22-39) in patients with CD/UC. Forty-nine, 53, 48% and 86, 81 and 65% of patients with CD reached clinical remission and response by weeks 14, 30, and 54, respectively. Clinical remission and response rates were 56, 41, 43% and 74, 66, 50% in patients with UC. Clinical efficacy was influenced by previous anti-tumor necrosis factor (TNF) exposure in patients with a drug holiday beyond 1 year. The mean C-reactive protein level decreased significantly in both CD and UC by week 14 and was maintained throughout the 1-year follow-up (both UC/CD: P < 0.001). Thirty-one (8.8%) patients had infusion reactions and 32 (9%) patients had infections. Antidrug antibody positivity rates were significantly higher throughout patients with previous anti-TNF exposure; concomitant azathioprine prevented antidrug antibody formation in anti-TNF-naive patients with CD. Results from this prospective nationwide cohort confirm that CT-P13 is effective and safe in inducing and maintaining long-term remission in both CD and UC. Efficacy was influenced by previous anti-TNF exposure; no new safety signals were detected.

Predictors of hospital re-admissions among Hispanics with hepatitis C-related cirrhosis

PubMed Central

Atla, Pradeep R.; Sheikh, Muhammad Y.; Gill, Firdose; Kundu, Rabindra; Choudhury, Jayanta

2016-01-01

Background Hospital re-admissions in decompensated cirrhosis are associated with worse patient outcomes. Hispanics have a disproportionately high prevalence of hepatitis C virus (HCV)-related morbidity and mortality. The goal of this study was to evaluate the factors affecting re-admission rates among Hispanics with HCV-related cirrhosis. Methods A total of 292 consecutive HCV-related cirrhosis admissions (Hispanics 189, non-Hispanics 103) from January 2009 to December 2012 were retrospectively reviewed; 132 were cirrhosis-related re-admissions. The statistical analysis was performed using STATA version 11.1. Chi-square/Fisher’s exact and Student’s t-tests were used to compare categorical and continuous variables, respectively. Multivariate logistic regression analysis was performed to identify predictors for hospital readmissions. Results Among the 132 cirrhosis-related readmissions, 71% were Hispanics while 29% were non-Hispanics (P=0.035). Hepatic encephalopathy (HE) and esophageal variceal hemorrhage were the most frequent causes of the first and subsequent readmissions. Hispanics with readmissions had a higher Child-Turcotte-Pugh (CTP) class (B and C) and higher model for end-stage liver disease (MELD) scores (≥15), as well as a higher incidence of alcohol use, HE, spontaneous bacterial peritonitis, hepatocellular carcinoma, and varices (P<0.05). The majority of the study patients (81%) had MELD scores <15. Multivariate regression analysis identified alcohol use (OR 2.63; 95%CI 1.1-6.4), HE (OR 5.5; 95%CI 2-15.3), varices (OR 3.2; 95%CI 1.3-8.2), and CTP class (OR 3.3; 95%CI 1.4–8.1) as predictors for readmissions among Hispanics. Conclusion CTP classes B and C, among other factors, were the major predictors for hospital readmissions in Hispanics with HCV-related cirrhosis. The majority of these readmissions were due to HE and variceal hemorrhage. PMID:27708520

Tolbutamide attenuates diazoxide-induced aggravation of hypoxic cell injury.

PubMed

Pissarek, M; Reichelt, C; Krauss, G J; Illes, P

1998-11-23

ATP-dependent potassium (KATP) channels of neurons are closed in the presence of physiological levels of intracellular ATP and open when ATP is depleted during hypoxia or metabolic damage. The present study investigates hypoxic alterations of purine and pyrimidine nucleotide levels supposed to intracellularly modulate KATP channels. In addition, the effects of the KATP channel activator diazoxide and its antagonist tolbutamide were investigated on ATP, GTP, CTP and UTP levels in slices of the parietal cortex. Hypoxia was evoked by saturation of the medium with 95% N2-5% CO2 instead of 95% O2-5% CO2 for 5 min. Nucleotide contents were measured by anion-exchange HPLC in neutralized perchloric acid extracts obtained from slices frozen immediately at the end of incubation. Hypoxia per se decreased purine and pyrimidine nucleoside triphosphate contents. Thus, ATP and GTP contents were reduced to 69.9 and 77.6% of the respective normoxic levels. UTP and CTP contents were even more decreased (to 60.9 and 41.6%),, probably because the salvage pathway of these pyrimidine nucleotides is less effective than that of the purine nucleotides ATP and GTP. While tolbutamide (30 microM) had no effect on the hypoxia-induced decrease of nucleotides, diazoxide at 300, but not 30 microM aggravated the decline of ATP, UTP and CTP to 51.8, 37.5 and 28.5% of the contents observed at normoxia; GTP levels also showed a tendency to decrease after diazoxide application. Tolbutamide (300 microM) antagonized the effects of diazoxide (300 but not 30 microM aggravated the decline of ATP, UTP and CTP to 51.8, 37.5 and 28.5% of the contents observed at normoxia; GTP levels also showed a tendency to decrease after diazoxide application. Tolbutamide (300 microM) antagonized the effects of diazoxide (300 MicroM). Nucleoside diphosphate (ADP, GDP and UDP) levels were uniformly increased by hypoxia. There was no hypoxia-induced increase of ADP contents in the presence of tolbutamide (300 microM). The ATP/ADP, GTP/GDP and UTP/UDP ratios uniformly declined at a low pO2. However, only the ATP/ADP ratio was decreased further by diazoxide (300 microM). The observed alterations in nucleotide contents may be of importance for long- and short-term processes related to acute cerebral hypoxia. Thus, hypoxia-induced alterations of purine and pyrimidine nucleotide levels may influence the open state of KATP-channels during the period of reversible hypoxic cerebral injury. Furthermore, alterations during the irreversible period of cerebral injury may also arise, as a consequence of decreased pyrimidine nucleotide contents affecting cell survival viaprotein and DNA synthesis.

Biochemical and Physical Properties of the Methanococcus jannaschii 20S Proteasome and PAN, a Homolog of the ATPase (Rpt) Subunits of the Eucaryal 26S Proteasome†

PubMed Central

Wilson, Heather L.; Ou, Mark S.; Aldrich, Henry C.; Maupin-Furlow, Julie

2000-01-01

The 20S proteasome is a self-compartmentalized protease which degrades unfolded polypeptides and has been purified from eucaryotes, gram-positive actinomycetes, and archaea. Energy-dependent complexes, such as the 19S cap of the eucaryal 26S proteasome, are assumed to be responsible for the recognition and/or unfolding of substrate proteins which are then translocated into the central chamber of the 20S proteasome and hydrolyzed to polypeptide products of 3 to 30 residues. All archaeal genomes which have been sequenced are predicted to encode proteins with up to ∼50% identity to the six ATPase subunits of the 19S cap. In this study, one of these archaeal homologs which has been named PAN for proteasome-activating nucleotidase was characterized from the hyperthermophile Methanococcus jannaschii. In addition, the M. jannaschii 20S proteasome was purified as a 700-kDa complex by in vitro assembly of the α and β subunits and has an unusually high rate of peptide and unfolded-polypeptide hydrolysis at 100°C. The 550-kDa PAN complex was required for CTP- or ATP-dependent degradation of β-casein by archaeal 20S proteasomes. A 500-kDa complex of PAN(Δ1–73), which has a deletion of residues 1 to 73 of the deduced protein and disrupts the predicted N-terminal coiled-coil, also facilitated this energy-dependent proteolysis. However, this deletion increased the types of nucleotides hydrolyzed to include not only ATP and CTP but also ITP, GTP, TTP, and UTP. The temperature optimum for nucleotide (ATP) hydrolysis was reduced from 80°C for the full-length protein to 65°C for PAN(Δ1–73). Both PAN protein complexes were stable in the absence of ATP and were inhibited by N-ethylmaleimide and p-chloromercuriphenyl-sulfonic acid. Kinetic analysis reveals that the PAN protein has a relatively high Vmax for ATP and CTP hydrolysis of 3.5 and 5.8 μmol of Pi per min per mg of protein as well as a relatively low affinity for CTP and ATP with Km values of 307 and 497 μM compared to other proteins of the AAA family. Based on electron micrographs, PAN and PAN(Δ1–73) apparently associate with the ends of the 20S proteasome cylinder. These results suggest that the M. jannaschii as well as related archaeal 20S proteasomes require a nucleotidase complex such as PAN to mediate the energy-dependent hydrolysis of folded-substrate proteins and that the N-terminal 73 amino acid residues of PAN are not absolutely required for this reaction. PMID:10692374

Transition path time distributions for Lévy flights

NASA Astrophysics Data System (ADS)

Janakiraman, Deepika

2018-07-01

This paper presents a study of transition path time distributions for Lévy noise-induced barrier crossing. Transition paths are short segments of the reactive trajectories and span the barrier region of the potential without spilling into the reactant/product wells. The time taken to traverse this segment is referred to as the transition path time. Since the transition path is devoid of excursions in the minimum, the corresponding time will give the exclusive barrier crossing time, unlike . This work explores the distribution of transition path times for superdiffusive barrier crossing, analytically. This is made possible by approximating the barrier by an inverted parabola. Using this approximation, the distributions are evaluated in both over- and under-damped limits of friction. The short-time behaviour of the distributions, provide analytical evidence for single-step transition events—a feature in Lévy-barrier crossing as observed in prior simulation studies. The average transition path time is calculated as a function of the Lévy index (α), and the optimal value of α leading to minimum average transition path time is discussed, in both the limits of friction. Langevin dynamics simulations corroborating with the analytical results are also presented.

Update of the SEPD position statement on the use of biosimilars for inflammatory bowel disease.

PubMed

Argüelles Arias, Federico; Hinojosa Del Val, Joaquín; Vera Mendoza, Isabel

2018-03-12

In 2013, the European Medicines Agency (EMA) approved the biosimilar infliximab (CT-P13) for the full range of indications of the originator product, based on data from two trials conducted in rheumatoid arthritis and ankylosing spondylitis. The same year, our Society published a position statement that was later reviewed.

Transition path time distributions

NASA Astrophysics Data System (ADS)

Laleman, M.; Carlon, E.; Orland, H.

2017-12-01

Biomolecular folding, at least in simple systems, can be described as a two state transition in a free energy landscape with two deep wells separated by a high barrier. Transition paths are the short part of the trajectories that cross the barrier. Average transition path times and, recently, their full probability distribution have been measured for several biomolecular systems, e.g., in the folding of nucleic acids or proteins. Motivated by these experiments, we have calculated the full transition path time distribution for a single stochastic particle crossing a parabolic barrier, including inertial terms which were neglected in previous studies. These terms influence the short time scale dynamics of a stochastic system and can be of experimental relevance in view of the short duration of transition paths. We derive the full transition path time distribution as well as the average transition path times and discuss the similarities and differences with the high friction limit.

Development and validation of duplex, triplex, and pentaplex real-time PCR screening assays for the detection of genetically modified organisms in food and feed.

PubMed

Huber, Ingrid; Block, Annette; Sebah, Daniela; Debode, Frédéric; Morisset, Dany; Grohmann, Lutz; Berben, Gilbert; Stebih, Dejan; Milavec, Mojca; Zel, Jana; Busch, Ulrich

2013-10-30

Worldwide, qualitative methods based on PCR are most commonly used as screening tools for genetically modified material in food and feed. However, the increasing number and diversity of genetically modified organisms (GMO) require effective methods for simultaneously detecting several genetic elements marking the presence of transgenic events. Herein we describe the development and validation of a pentaplex, as well as complementary triplex and duplex real-time PCR assays, for the detection of the most common screening elements found in commercialized GMOs: P-35S, T-nos, ctp2-cp4-epsps, bar, and pat. The use of these screening assays allows the coverage of many GMO events globally approved for commercialization. Each multiplex real-time PCR assay shows high specificity and sensitivity with an absolute limit of detection below 20 copies for the targeted sequences. We demonstrate by intra- and interlaboratory tests that the assays are robust as well as cost- and time-effective for GMO screening if applied in routine GMO analysis.

PROPOSED PROCEDURE FOR DERIVATION OF REGULATORY VALUES FOR CARCINOGENIC AIRBORNE POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) BASED ON COAL TAR PITCH (CTP) VOLATILES

EPA Science Inventory

A procedure for estimating upper bound lifetime human cancer risk from air levels of 6 common carcinogenic PAHs, termed "PAHs of concern", is proposed. These PAHs are benzo(a)pyrene, benz(a)anathracene, benzo(k)flouranthene, indeno(1,2,3-c,d)pyrene and chrysene. In application,...

46 CFR Table I to Part 150 - Alphabetical List of Cargoes

Code of Federal Regulations, 2014 CFR

2014-10-01

... (C17+) alkanoic acid 34 CUS CFT Corn syrup 43 CSY Cottonseed oil, fatty acid 34 CFY Creosote 21 2 CCT... tar 33 COR OCT Coal tar distillate 33 CDL Coal tar, high temperature 33 CHH Coal tar pitch 33 CTP... MTM Formaldehyde solution 19 2 FMS Formamide 10 FAM Formic acid 4 2 FMA Fructose solution 43 Fumaric...

46 CFR Table I to Part 150 - Alphabetical List of Cargoes

Code of Federal Regulations, 2013 CFR

2013-10-01

... (C17+) alkanoic acid 34 CUS CFT Corn syrup 43 CSY Cottonseed oil, fatty acid 34 CFY Creosote 21 2 CCT... tar 33 COR OCT Coal tar distillate 33 CDL Coal tar, high temperature 33 CHH Coal tar pitch 33 CTP... MTM Formaldehyde solution 19 2 FMS Formamide 10 FAM Formic acid 4 2 FMA Fructose solution 43 Fumaric...

46 CFR Table I to Part 150 - Alphabetical List of Cargoes

Code of Federal Regulations, 2010 CFR

2010-10-01

... (C17+) alkanoic acid 34 CUS CFT Corn syrup 43 CSY Cottonseed oil, fatty acid 34 CFY Creosote 21 2 CCT... tar 33 COR OCT Coal tar distillate 33 CDL Coal tar, high temperature 33 CHH Coal tar pitch 33 CTP... MTM Formaldehyde solution 19 2 FMS Formamide 10 FAM Formic acid 4 2 FMA Fructose solution 43 Fumaric...

46 CFR Table I to Part 150 - Alphabetical List of Cargoes

Code of Federal Regulations, 2011 CFR

2011-10-01

... (C17+) alkanoic acid 34 CUS CFT Corn syrup 43 CSY Cottonseed oil, fatty acid 34 CFY Creosote 21 2 CCT... tar 33 COR OCT Coal tar distillate 33 CDL Coal tar, high temperature 33 CHH Coal tar pitch 33 CTP... MTM Formaldehyde solution 19 2 FMS Formamide 10 FAM Formic acid 4 2 FMA Fructose solution 43 Fumaric...

46 CFR Table I to Part 150 - Alphabetical List of Cargoes

Code of Federal Regulations, 2012 CFR

2012-10-01

... (C17+) alkanoic acid 34 CUS CFT Corn syrup 43 CSY Cottonseed oil, fatty acid 34 CFY Creosote 21 2 CCT... tar 33 COR OCT Coal tar distillate 33 CDL Coal tar, high temperature 33 CHH Coal tar pitch 33 CTP... MTM Formaldehyde solution 19 2 FMS Formamide 10 FAM Formic acid 4 2 FMA Fructose solution 43 Fumaric...

Semi-annual conference review January-June 2000

Treesearch

John K. Borchardt; Marguerite S. Sykes; Mahendra R. Doshi

2000-01-01

Conferences covered in this semiannual review include the TAPPI Recycling Symposium and the 9th PTS/CTP Deinking Symposium. The intent of this feature is to present a synopsis of the significant research results and industry ideas related to paper recycling reported at these conferences. Due to space constraints, we are not able to cover all of the presented papers in...

NREL Collaborates with Trucking Industry to Prioritize R&D Opportunities |

Science.gov Websites

Department drive decision-making and improve efficiency, informing long-term, high-risk research such as the Rosa Using Data to Drive Decision Making NREL's fleet test and evaluation team conducts real-world 21CTP an example of NREL's data evaluation and decision support capabilities. Using data collected in

Effects on Vocal Fold Collision and Phonation Threshold Pressure of Resonance Tube Phonation with Tube End in Water

ERIC Educational Resources Information Center

Enflo, Laura; Sundberg, Johan; Romedahl, Camilla; McAllister, Anita

2013-01-01

Purpose: Resonance tube phonation in water (RTPW) or in air is a voice therapy method successfully used for treatment of several voice pathologies. Its effect on the voice has not been thoroughly studied. This investigation analyzes the effects of RTPW on collision and phonation threshold pressures (CTP and PTP), the lowest subglottal pressure…

Effect of yeast strain and some nutritional factors on tannin composition and potential astringency of model wines.

PubMed

Rinaldi, Alessandra; Blaiotta, Giuseppe; Aponte, Maria; Moio, Luigi

2016-02-01

Nine Saccharomyces cerevisiae cultures, isolated from different sources, were tested for their ability to reduce tannins reactive towards salivary proteins, and potentially responsible for wine astringency. Strains were preliminary genetically characterized and evaluated for physiological features of technological interest. Laboratory-scale fermentations were performed in three synthetic media: CT) containing enological grape tannin; CTP) CT supplemented with organic nitrogen sources; CTPV) CTP supplemented with vitamins. Adsorption of total tannins, tannins reactive towards salivary proteins, yellow pigments, phenolics having antioxidant activity, and total phenols, characterizing the enological tannin, was determined by spectrophotometric methods after fermentation. The presence of vitamins and peptones in musts greatly influenced the adsorption of tannins reactive towards salivary proteins (4.24 g/L gallic acid equivalent), thus promoting the reduction of the potential astringency of model wines. With reference to the different phenolic classes, yeast strains showed different adsorption abilities. From a technological point of view, the yeast choice proved to be crucial in determining changes in gustative and mouthfeel profile of red wines and may assist winemakers to modulate colour and astringency of wine. Copyright © 2015 Elsevier Ltd. All rights reserved.

Head-group specificity for feedback regulation of CTP:phosphocholine cytidylyltransferase.

PubMed Central

Jamil, H; Vance, D E

1990-01-01

The specificity of the phospholipid head-group for feedback regulation of CTP: phosphocholine cytidylyltransferase was examined in rat hepatocytes. In choline-deficient cells there is a 2-fold increase in binding of cytidylyltransferase to cellular membranes, compared with choline-supplemented cells. Supplementation of choline-deficient cells with choline, dimethylethanolamine, monomethylethanolamine or ethanolamine resulted in an increase in the concentration of the corresponding phospholipid. Release of cytidylyltransferase into cytosol was only observed in hepatocytes supplemented with choline or dimethylethanolamine. The apparent EC50 values (concn. giving half of maximal effect) for cytidylyltransferase translocation were similar for choline and dimethylethanolamine (25 and 27 microM respectively). The maximum amount of cytidylyltransferase released into cytosol with choline supplementation (1.13 m-units/mg membrane protein) was twice that (0.62) observed with dimethylethanolamine. Supplementation of choline-deficient hepatocytes with NN'-diethylethanolamine, N-ethylethanolamine or 3-aminopropanol also did not cause release of cytidylyltransferase from cellular membranes. The translocation of cytidylyltransferase appeared to be mediated by the concentration of phosphatidylcholine in the membranes and not the ratio of phosphatidylcholine to phosphatidylethanolamine. The results provide further evidence for feedback regulation of phosphatidylcholine biosynthesis by phosphatidylcholine. PMID:2173550

Oxidative damage in DNA bases revealed by UV resonant Raman spectroscopy.

PubMed

D'Amico, Francesco; Cammisuli, Francesca; Addobbati, Riccardo; Rizzardi, Clara; Gessini, Alessandro; Masciovecchio, Claudio; Rossi, Barbara; Pascolo, Lorella

2015-03-07

We report on the use of the UV Raman technique to monitor the oxidative damage of deoxynucleotide triphosphates (dATP, dGTP, dCTP and dTTP) and DNA (plasmid vector) solutions. Nucleotide and DNA aqueous solutions were exposed to hydrogen peroxide (H2O2) and iron containing carbon nanotubes (CNTs) to produce Fenton's reaction and induce oxidative damage. UV Raman spectroscopy is shown to be maximally efficient to reveal changes in the nitrogenous bases during the oxidative mechanisms occurring on these molecules. The analysis of Raman spectra, supported by numerical computations, revealed that the Fenton's reaction causes an oxidation of the nitrogenous bases in dATP, dGTP and dCTP solutions leading to the production of 2-hydroxyadenine, 8-hydroxyguanine and 5-hydroxycytosine. No thymine change was revealed in the dTTP solution under the same conditions. Compared to single nucleotide solutions, plasmid DNA oxidation has resulted in more radical damage that causes the breaking of the adenine and guanine aromatic rings. Our study demonstrates the advantage of using UV Raman spectroscopy for rapidly monitoring the oxidation changes in DNA aqueous solutions that can be assigned to specific nitrogenous bases.

Regulation of Phosphatidylethanolamine Homeostasis—The Critical Role of CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2)

PubMed Central

Pavlovic, Zvezdan; Bakovic, Marica

2013-01-01

Phosphatidylethanolamine (PE) is the most abundant lipid on the protoplasmatic leaflet of cellular membranes. It has a pivotal role in cellular processes such as membrane fusion, cell cycle regulation, autophagy, and apoptosis. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) is the main regulatory enzyme in de novo biosynthesis of PE from ethanolamine and diacylglycerol by the CDP-ethanolamine Kennedy pathway. The following is a summary of the current state of knowledge on Pcyt2 and how splicing and isoform specific differences could lead to variations in functional properties in this family of enzymes. Results from the most recent studies on Pcyt2 transcriptional regulation, promoter function, autophagy, and cell growth regulation are highlighted. Recent data obtained from Pcyt2 knockout mouse models is also presented, demonstrating the essentiality of this gene in embryonic development as well as the major physiological consequences of deletion of one Pcyt2 allele. Those include development of symptoms of the metabolic syndrome such as elevated lipogenesis and lipoprotein secretion, hypertriglyceridemia, liver steatosis, obesity, and insulin resistance. The objective of this review is to elucidate the nature of Pcyt2 regulation by linking its catalytic function with the regulation of lipid and energy homeostasis. PMID:23354482

Metabolic Recruitment and Directed Evolution of Nucleoside Triphosphate Uptake in Escherichia coli.

PubMed

Pezo, Valérie; Hassan, Camille; Louis, Dominique; Sargueil, Bruno; Herdewijn, Piet; Marlière, Philippe

2018-05-18

We report the design and elaboration of a selection protocol for importing a canonical substrate of DNA polymerase, thymidine triphosphate (dTTP) in Escherichia coli. Bacterial strains whose growth depend on dTTP uptake, through the action of an algal plastid transporter expressed from a synthetic gene inserted in the chromosome, were constructed and shown to withstand the simultaneous loss of thymidylate synthase and thymidine kinase. Such thyA tdk dual deletant strains provide an experimental model of tight nutritional containment for preventing dissemination of microbial GMOs. Our strains transported the four canonical dNTPs, in the following order of preference: dCTP > dATP ≥ dGTP > dTTP. Prolonged cultivation under limitation of exogenous dTTP led to the enhancement of dNTP transport by adaptive evolution. We investigated the uptake of dCTP analogues with altered sugar or nucleobase moieties, which were found to cause a loss of cell viability and an increase of mutant frequency, respectively. E. coli strains equipped with nucleoside triphosphate transporters should be instrumental for evolving organisms whose DNA genome is morphed chemically by fully substituting its canonical nucleotide components.

Biomarkers of Tobacco Exposure: Summary of an FDA-sponsored Public Workshop

PubMed Central

Chang, Cindy M.; Edwards, Selvin H.; Arab, Aarthi; Del Valle-Pinero, Arseima Y.; Yang, Ling; Hatsukami, Dorothy K.

2016-01-01

Since 2009, the United States (U.S.) Food and Drug Administration (FDA) Center for Tobacco Products (CTP) has had the authority to regulate the manufacturing, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers of exposure pertain to actual human exposure to chemicals arising from tobacco use and could play an important role across a number of FDA regulatory activities, including assessing new and modified risk tobacco products and identifying and evaluating potential product standards. On August 3–4, 2015, FDA/CTP hosted a public workshop focused on biomarkers of exposure with participants from government, industry, academia, and other organizations. The workshop was divided into four sessions focused on: 1) approaches to evaluating and selecting biomarkers; 2) biomarkers of exposure and relationship to disease risk; 3) currently-used biomarkers of exposure and biomarkers in development; and 4) biomarkers of exposure and the assessment of smokeless tobacco and electronic nicotine delivery systems (ENDS). This paper synthesizes the main findings from the workshop and highlights research areas that could further strengthen the science around biomarkers of exposure and help determine their application in tobacco product regulation. PMID:28151705

Path Flow Estimation Using Time Varying Coefficient State Space Model

NASA Astrophysics Data System (ADS)

Jou, Yow-Jen; Lan, Chien-Lun

2009-08-01

The dynamic path flow information is very crucial in the field of transportation operation and management, i.e., dynamic traffic assignment, scheduling plan, and signal timing. Time-dependent path information, which is important in many aspects, is nearly impossible to be obtained. Consequently, researchers have been seeking estimation methods for deriving valuable path flow information from less expensive traffic data, primarily link traffic counts of surveillance systems. This investigation considers a path flow estimation problem involving the time varying coefficient state space model, Gibbs sampler, and Kalman filter. Numerical examples with part of a real network of the Taipei Mass Rapid Transit with real O-D matrices is demonstrated to address the accuracy of proposed model. Results of this study show that this time-varying coefficient state space model is very effective in the estimation of path flow compared to time-invariant model.

Petrogenesis and tectonic implications of Triassic mafic complexes with MORB/OIB affinities from the western Garzê-Litang ophiolitic mélange, central Tibetan Plateau

NASA Astrophysics Data System (ADS)

Liu, Bin; Ma, Chang-Qian; Guo, Yu-Heng; Xiong, Fu-Hao; Guo, Pan; Zhang, Xin

2016-09-01

Although numerous Paleo-Tethyan ophiolites with mid-oceanic ridge basalts (MORB) and/or oceanic-island basalt (OIB) affinities have been reported in the central Tibetan Plateau (CTP), the origin and tectonic nature of these ophiolites are not well understood. The petrogenesis, mantle sources and geodynamic setting of the mafic rocks from these ophiolites are unclear, which is the main reason for this uncertainty. In this paper, we present new geochronological, mineralogical and Sr-Nd isotopic data for the Chayong and Xiewu mafic complexes in the western Garzê-Litang suture zone (GLS), a typical Paleo-Tethyan suture crossing the CTP. Zircon LA-ICP-MS U-Pb ages of 234 ± 3 Ma and 236 ± 2 Ma can be interpreted as formation times of the Chayong and Xiewu mafic complexes, respectively. The basalts and gabbros of the Chayong complex exhibit enriched MORB (E-MORB) compositional affinities except for a weak depletion of Nb, Ta and Ti relative to the primitive mantle, whereas the basalts and gabbros of the Xiewu complex display distinct E-MORB and OIB affinities. The geochemical features suggest a probable fractionation of olivine ± clinopyroxene ± plagioclase as well as insignificant crustal contamination. The geochemical and Sr-Nd isotopic data reveal that the Chayong mafic rocks may have been derived from depleted MORB-type mantle metasomatized by crustal components and Xiewu mafic rocks from enriched lithospheric mantle metasomatized by OIB-like components. The ratios of Zn/Fet, La/Yb and Sm/Yb indicate that these mafic melts were produced by the partial melting of garnet + minor spinel-bearing peridotite or spinel ± minor garnet-bearing peridotite. We propose that back-arc basin spreading associated with OIB/seamount recycling had occurred in the western GLS at least since the Middle Triassic times, and the decompression melting of the depleted MORB-type asthenosphere mantle and partial melting of sub-continental lithosphere were metasomatized by plume-related melts, such as OIB s, which led to the generation of the Chayong and Xiewu mafic melts.

Thyrotropic action of human chorionic gonadotropin.

PubMed

Yoshimura, M; Hershman, J M

1995-10-01

Hyperthyroidism or increased thyroid function has been reported in many patients with trophoblastic tumors. In these cases, greatly increased human chorionic gonadotropin (hCG) levels and suppressed TSH levels suggest that hCG has thyrotropic activity. Recent investigations have clarified the structural homology not only in the hCG and TSH molecules but also in their receptors, and this homology suggests the basis for the reactivity of hCG with the TSH receptor. The clinical significance of the thyrotropic action of hCG is now also recognized in normal pregnancy and hyperemesis gravidarum. Highly purified hLH binds to recombinant hTSH receptor and is about 10 times as potent as purified hCG in increasing cAMP. The beta-subunits of hCG and hLH share 85% sequence identity in their first 114 amino acids but differ in the carboxy-terminal peptide because hCG beta contains a 31-amino acid extension (beta-CTP). A recombinant mutant hCG that lacks beta-CTP showed almost identical potency to LH on stimulation of recombinant hTSH receptor. If intact hCG were as potent as hLH in regard to its thyrotropic activity, most pregnant women would become thyrotoxic. One of the roles of the beta-CTP may be to prevent overt hyperthyroidism in the first trimester of pregnancy when a large amount of hCG is produced by the placenta. Nicked hCG preparations, obtained from patients with trophoblastic disease or by enzymatic digestion of intact hCG, showed approximately 1.5- to 2-fold stimulation of recombinant hTSH receptor compared with intact hCG. This suggests that the thyrotropic activity of hCG may be influenced by the metabolism of the hCG molecule itself. Deglycosylation and/or desialylation of hCG enhances its thyrotropic potency. Basic hCG isoforms with lower sialic acid content extracted from hydatidiform moles were more potent in activating adenylate cyclase, and showed high bioactivity/immunoactivity (B/I) ratio in CHO cells expressing human TSH receptors. This is consistent with the finding that the beta-CTP truncated hCG with higher thyrotropic potency is substantially deglycosylated and desialylated in the beta-subunit relative to intact hCG because all four O-linked glycosylation sites occur within the missing C-terminal extension. The desialylated hCG variant also interacts directly with recombinant hTSH receptors transfected into human thyroid cancer cells. There is thyroid-stimulating activity in sera of normal pregnant women, and this correlates with serum hCG levels. The thyroid gland of normal pregnant women may be stimulated by hCG to secrete slightly excessive quantities of T4 and induce a slight suppression of TSH, perhaps being about 1 mU/L less than nongravid levels, but not high enough to induce overt hyperthyroidism. Maternal thyroid glands may secrete more thyroid hormone during early pregnancy in response to the thyrotropic activity of hCG that overrides the normal operation of the hypothalamic-pituitary-thyroid feedback system. Biochemical hyperthyroidism associated with hyperemesis gravidarum has been attributed to hCG. In patients with hyperemesis gravidarum, thyrotropic in serum correlated with hCG immunoreactivity, and the severity of vomiting as indicated by clinical and biochemical parameters correlated with the degree of thyroid stimulation. To understand the thyrotropic action of hCG, it is necessary to know whether hCG activates the same domain of the TSH receptor as does TSH. The identification of the molecular structure of the hCG isoform with the highest thyrotropic potency will resolve the enigma of gestational thyrotoxicosis and the hyperthyroidism associated with trophoblastic disease and hCG-producing tumors.

Pressure Autoregulation Measurement Techniques in Adult Traumatic Brain Injury, Part I: A Scoping Review of Intermittent/Semi-Intermittent Methods.

PubMed

Zeiler, Frederick A; Donnelly, Joseph; Calviello, Leanne; Menon, David K; Smielewski, Peter; Czosnyka, Marek

2017-12-01

The purpose of this study was to perform a systematic, scoping review of commonly described intermittent/semi-intermittent autoregulation measurement techniques in adult traumatic brain injury (TBI). Nine separate systematic reviews were conducted for each intermittent technique: computed tomographic perfusion (CTP)/Xenon-CT (Xe-CT), positron emission tomography (PET), magnetic resonance imaging (MRI), arteriovenous difference in oxygen (AVDO 2 ) technique, thigh cuff deflation technique (TCDT), transient hyperemic response test (THRT), orthostatic hypotension test (OHT), mean flow index (Mx), and transfer function autoregulation index (TF-ARI). MEDLINE ® , BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016), and reference lists of relevant articles were searched. A two tier filter of references was conducted. The total number of articles utilizing each of the nine searched techniques for intermittent/semi-intermittent autoregulation techniques in adult TBI were: CTP/Xe-CT (10), PET (6), MRI (0), AVDO 2 (10), ARI-based TCDT (9), THRT (6), OHT (3), Mx (17), and TF-ARI (6). The premise behind all of the intermittent techniques is manipulation of systemic blood pressure/blood volume via either chemical (such as vasopressors) or mechanical (such as thigh cuffs or carotid compression) means. Exceptionally, Mx and TF-ARI are based on spontaneous fluctuations of cerebral perfusion pressure (CPP) or mean arterial pressure (MAP). The method for assessing the cerebral circulation during these manipulations varies, with both imaging-based techniques and TCD utilized. Despite the limited literature for intermittent/semi-intermittent techniques in adult TBI (minus Mx), it is important to acknowledge the availability of such tests. They have provided fundamental insight into human autoregulatory capacity, leading to the development of continuous and more commonly applied techniques in the intensive care unit (ICU). Numerous methods of intermittent/semi-intermittent pressure autoregulation assessment in adult TBI exist, including: CTP/Xe-CT, PET, AVDO 2 technique, TCDT-based ARI, THRT, OHT, Mx, and TF-ARI. MRI-based techniques in adult TBI are yet to be described, with the main focus of MRI techniques on metabolic-based cerebrovascular reactivity (CVR) and not pressure-based autoregulation.

Proposal for a New Predictive Model of Short-Term Mortality After Living Donor Liver Transplantation due to Acute Liver Failure.

PubMed

Chung, Hyun Sik; Lee, Yu Jung; Jo, Yun Sung

2017-02-21

BACKGROUND Acute liver failure (ALF) is known to be a rapidly progressive and fatal disease. Various models which could help to estimate the post-transplant outcome for ALF have been developed; however, none of them have been proved to be the definitive predictive model of accuracy. We suggest a new predictive model, and investigated which model has the highest predictive accuracy for the short-term outcome in patients who underwent living donor liver transplantation (LDLT) due to ALF. MATERIAL AND METHODS Data from a total 88 patients were collected retrospectively. King's College Hospital criteria (KCH), Child-Turcotte-Pugh (CTP) classification, and model for end-stage liver disease (MELD) score were calculated. Univariate analysis was performed, and then multivariate statistical adjustment for preoperative variables of ALF prognosis was performed. A new predictive model was developed, called the MELD conjugated serum phosphorus model (MELD-p). The individual diagnostic accuracy and cut-off value of models in predicting 3-month post-transplant mortality were evaluated using the area under the receiver operating characteristic curve (AUC). The difference in AUC between MELD-p and the other models was analyzed. The diagnostic improvement in MELD-p was assessed using the net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS The MELD-p and MELD scores had high predictive accuracy (AUC >0.9). KCH and serum phosphorus had an acceptable predictive ability (AUC >0.7). The CTP classification failed to show discriminative accuracy in predicting 3-month post-transplant mortality. The difference in AUC between MELD-p and the other models had statistically significant associations with CTP and KCH. The cut-off value of MELD-p was 3.98 for predicting 3-month post-transplant mortality. The NRI was 9.9% and the IDI was 2.9%. CONCLUSIONS MELD-p score can predict 3-month post-transplant mortality better than other scoring systems after LDLT due to ALF. The recommended cut-off value of MELD-p is 3.98.

3'-Azido-2',3'-dideoxythymidine induced deficiency of thymidine kinases 1, 2 and deoxycytidine kinase in H9 T-lymphoid cells.

PubMed

Gröschel, Bettina; Kaufmann, Andreas; Höver, Gerold; Cinatl, Jaroslav; Doerr, Hans Wilhelm; Noordhuis, Paul; Loves, Willem J P; Peters, Godefridus J; Cinatl, Jindrich

2002-07-15

Continuous cultivation of T-lymphoid H9 cells in the presence of 3'-azido-2',3'-dideoxythymidine (AZT) resulted in a cell variant cross-resistant to both thymidine and deoxycytidine analogs. Cytotoxic effects of AZT, 2',3'-didehydro-3'-deoxythymidine as well as different deoxycytidine analogs such as 2',3'-dideoxycytidine, 2',2'-difluoro-2'-deoxycytidine (dFdC) and 1-ss-D-arabinofuranosylcytosine (Ara-C) were strongly reduced in H9 cells continuously exposed to AZT when compared to parental cells (>8.3-, >6.6-, >9.1-, 5 x 10(4)-, 5 x 10(3)-fold, respectively). Moreover, anti-HIV-1 effects of AZT, d4T, ddC and 2',3'-dideoxy-3'-thiacytidine (3TC) were significantly diminished (>222-, >25-, >400-, >200-fold, respectively) in AZT-resistant H9 cells. Study of cellular mechanisms responsible for cross-resistance to pyrimidine analogs in AZT-resistant H9 cells revealed decreased mRNA levels of thymidine kinase 1 (TK1) and lack of deoxycytidine kinase (dCK) mRNA expression. The loss of dCK gene expression was confirmed by western blot analysis of dCK protein as well as dCK enzyme activity assay. Moreover, enzyme activity of TK1 and TK2 was reduced in AZT-resistant cells. In order to determine whether lack of dCK affected the formation of the active triphosphate of the deoxycytidine analog dFdC, dFdCTP accumulation and retention was measured in H9 parental and AZT-resistant cells after exposure to 1 and 10 microM dFdC. Parental H9 cells accumulated about 30 and 100 pmol dFdCTP/10(6) cells after 4hr, whereas in AZT-resistant cells no dFdCTP accumulation was detected. These results demonstrate that continuous treatment of H9 cells in the presence of AZT selected for a thymidine analog resistant cell variant with cross-resistance to deoxycytidine analogs, due to deficiency in TK1, TK2, and dCK.

Study protocol: cross-national comparative case study of recovery-focused mental health care planning and coordination (COCAPP).

PubMed

Simpson, Alan; Hannigan, Ben; Coffey, Michael; Jones, Aled; Barlow, Sally; Cohen, Rachel; Všetečková, Jitka; Faulkner, Alison; Haddad, Mark

2015-07-03

The collaborative care planning study (COCAPP) is a cross-national comparative study of care planning and coordination in community mental healthcare settings. The context and delivery of mental health care is diverging between the countries of England and Wales whilst retaining points of common interest, hence providing a rich geographical comparison for research. Across England the key vehicle for the provision of recovery-focused, personalised, collaborative mental health care is the care programme approach (CPA). The CPA is a form of case management introduced in England in 1991, then revised in 2008. In Wales the CPA was introduced in 2003 but has now been superseded by The Mental Health (Care Co-ordination and Care and Treatment Planning) (CTP) Regulations (Mental Health Measure), a new statutory framework. In both countries, the CPA/CTP requires providers to: comprehensively assess health/social care needs and risks; develop a written care plan (which may incorporate risk assessments, crisis and contingency plans, advanced directives, relapse prevention plans, etc.) in collaboration with the service user and carer(s); allocate a care coordinator; and regularly review care. The overarching aim of this study is to identify and describe the factors that ensure CPA/CTP care planning and coordination is personalised, recovery-focused and conducted collaboratively. COCAPP will employ a concurrent transformative mixed methods approach with embedded case studies. Phase 1 (Macro-level) will consider the national context through a meta-narrative mapping (MNM) review of national policies and the relevant research literature. Phase 2 (Meso-level and Micro-level) will include in-depth micro-level case studies of everyday 'frontline' practice and experience with detailed qualitative data from interviews and reviews of individual care plans. This will be nested within larger meso-level survey datasets, senior-level interviews and policy reviews in order to provide potential explanations and understanding. COCAPP will help identify the key components that support and hinder the provision of personalised, recovery-focused care planning and provide an informed rationale for a future planned intervention and evaluation.

Use of dry citrus pulp or soybean hulls as a replacement for corn grain in energy and nitrogen partitioning, methane emissions, and milk performance in lactating Murciano-Granadina goats.

PubMed

López, M C; Estellés, F; Moya, V J; Fernández, C

2014-12-01

The aim of this study was to assess the effect of substitution of dietary corn grain by dry citrus pulp or soybean hulls on energy and nitrogen partitioning, substrate oxidation, methane emission, and milk performance in dairy goats during midlactation. Twelve multiparous Murciano-Granadina goats of similar body weight (41.7 ± 2.8 kg) were split in 3 groups in an incomplete crossover design. One group of 4 goats was fed a mixed ration with 605 g/kg of dry matter of corn grain (CRG), another group replaced corn grain with dry citrus pulp (CTP), and the last with soybean hulls (SYH). The goats were allocated to individual metabolism cages. After 14 d of adaptation, feed intake, total fecal and urine output, and milk yield were recorded daily over a 5-d period. Then, gas exchange measurements were recorded by a mobile open-circuit indirect calorimetry system using a head box. Dry matter intake was similar for all 3 groups (1.53 kg/d, on average). Total replacement of the concentrate with fibrous by-products increased fiber apparent digestibility. The metabolizable energy intake was significantly greater for diet CRG than SYH (1,193 vs. 1,079 kJ/kg of BW⁰·⁷⁵, respectively), CTP showed an intermediate value. The heat production was higher for the fiber diet than starchy diet (908 vs. 843 kJ/kg of BW⁰·⁷⁵ for SYH and CRG, respectively). The efficiency of use of metabolizable energy for milk production obtained by regression was 0.59. Goats fed CTP and SYH diets produced similar CH₄ emissions (34.8 g/d, on average), significantly higher compared with goats fed the CRG diet (24.7 g/d). Goats of the 3 treatments were in negative energy balance, so the oxidation of fat was greater than for carbohydrates. No significant differences were observed for milk production (1.72 kg/d), and milk fat was significantly greater for a more fibrous diet compared with a starchy diet (6.57 vs. 4.95% in SYH and CRG, respectively).

Transition path time distribution and the transition path free energy barrier.

PubMed

Pollak, Eli

2016-10-19

The recent experimental measurement of the transition path time distributions of proteins presents several challenges to theory. Firstly, why do the fits of the experimental data to a theoretical expression lead to barrier heights which are much lower than the free energies of activation of the observed transitions? Secondly, there is the theoretical question of determining the transition path time distribution, without invoking the Smoluchowski limit. In this paper, we derive an exact expression for a transition path time distribution which is valid for arbitrary memory friction using the normal mode transformation which underlies Kramers' rate theory. We then recall that for low barriers, there is a noticeable difference between the transition path time distribution obtained with absorbing boundary conditions and free boundary conditions. For the former, the transition times are shorter, since recrossings of the boundaries are disallowed. As a result, if one uses the distribution based on absorbing boundary conditions to fit the experimental data, one will find that the transition path barrier will be larger than the values found based on a theory with free boundary conditions. We then introduce the paradigm of a transition path barrier height, and show that one should always expect it to be much smaller than the activation energy.

Evaluating methods for estimating space-time paths of individuals in calculating long-term personal exposure to air pollution

NASA Astrophysics Data System (ADS)

Schmitz, Oliver; Soenario, Ivan; Vaartjes, Ilonca; Strak, Maciek; Hoek, Gerard; Brunekreef, Bert; Dijst, Martin; Karssenberg, Derek

2016-04-01

Air pollution is one of the major concerns for human health. Associations between air pollution and health are often calculated using long-term (i.e. years to decades) information on personal exposure for each individual in a cohort. Personal exposure is the air pollution aggregated along the space-time path visited by an individual. As air pollution may vary considerably in space and time, for instance due to motorised traffic, the estimation of the spatio-temporal location of a persons' space-time path is important to identify the personal exposure. However, long term exposure is mostly calculated using the air pollution concentration at the x, y location of someone's home which does not consider that individuals are mobile (commuting, recreation, relocation). This assumption is often made as it is a major challenge to estimate space-time paths for all individuals in large cohorts, mostly because limited information on mobility of individuals is available. We address this issue by evaluating multiple approaches for the calculation of space-time paths, thereby estimating the personal exposure along these space-time paths with hyper resolution air pollution maps at national scale. This allows us to evaluate the effect of the space-time path and resulting personal exposure. Air pollution (e.g. NO2, PM10) was mapped for the entire Netherlands at a resolution of 5×5 m2 using the land use regression models developed in the European Study of Cohorts for Air Pollution Effects (ESCAPE, http://escapeproject.eu/) and the open source software PCRaster (http://www.pcraster.eu). The models use predictor variables like population density, land use, and traffic related data sets, and are able to model spatial variation and within-city variability of annual average concentration values. We approximated space-time paths for all individuals in a cohort using various aggregations, including those representing space-time paths as the outline of a persons' home or associated parcel of land, the 4 digit postal code area or neighbourhood of a persons' home, circular areas around the home, and spatial probability distributions of space-time paths during commuting. Personal exposure was estimated by averaging concentrations over these space-time paths, for each individual in a cohort. Preliminary results show considerable differences of a persons' exposure using these various approaches of space-time path aggregation, presumably because air pollution shows large variation over short distances.

A self-interfering clock as a "which path" witness.

PubMed

Margalit, Yair; Zhou, Zhifan; Machluf, Shimon; Rohrlich, Daniel; Japha, Yonathan; Folman, Ron

2015-09-11

In Einstein's general theory of relativity, time depends locally on gravity; in standard quantum theory, time is global-all clocks "tick" uniformly. We demonstrate a new tool for investigating time in the overlap of these two theories: a self-interfering clock, comprising two atomic spin states. We prepare the clock in a spatial superposition of quantum wave packets, which evolve coherently along two paths into a stable interference pattern. If we make the clock wave packets "tick" at different rates, to simulate a gravitational time lag, the clock time along each path yields "which path" information, degrading the pattern's visibility. In contrast, in standard interferometry, time cannot yield "which path" information. This proof-of-principle experiment may have implications for the study of time and general relativity and their impact on fundamental effects such as decoherence and the emergence of a classical world. Copyright © 2015, American Association for the Advancement of Science.

Energy-optimal path planning by stochastic dynamically orthogonal level-set optimization

NASA Astrophysics Data System (ADS)

Subramani, Deepak N.; Lermusiaux, Pierre F. J.

2016-04-01

A stochastic optimization methodology is formulated for computing energy-optimal paths from among time-optimal paths of autonomous vehicles navigating in a dynamic flow field. Based on partial differential equations, the methodology rigorously leverages the level-set equation that governs time-optimal reachability fronts for a given relative vehicle-speed function. To set up the energy optimization, the relative vehicle-speed and headings are considered to be stochastic and new stochastic Dynamically Orthogonal (DO) level-set equations are derived. Their solution provides the distribution of time-optimal reachability fronts and corresponding distribution of time-optimal paths. An optimization is then performed on the vehicle's energy-time joint distribution to select the energy-optimal paths for each arrival time, among all stochastic time-optimal paths for that arrival time. Numerical schemes to solve the reduced stochastic DO level-set equations are obtained, and accuracy and efficiency considerations are discussed. These reduced equations are first shown to be efficient at solving the governing stochastic level-sets, in part by comparisons with direct Monte Carlo simulations. To validate the methodology and illustrate its accuracy, comparisons with semi-analytical energy-optimal path solutions are then completed. In particular, we consider the energy-optimal crossing of a canonical steady front and set up its semi-analytical solution using a energy-time nested nonlinear double-optimization scheme. We then showcase the inner workings and nuances of the energy-optimal path planning, considering different mission scenarios. Finally, we study and discuss results of energy-optimal missions in a wind-driven barotropic quasi-geostrophic double-gyre ocean circulation.

An open-chain imaginary-time path-integral sampling approach to the calculation of approximate symmetrized quantum time correlation functions.

PubMed

Cendagorta, Joseph R; Bačić, Zlatko; Tuckerman, Mark E

2018-03-14

We introduce a scheme for approximating quantum time correlation functions numerically within the Feynman path integral formulation. Starting with the symmetrized version of the correlation function expressed as a discretized path integral, we introduce a change of integration variables often used in the derivation of trajectory-based semiclassical methods. In particular, we transform to sum and difference variables between forward and backward complex-time propagation paths. Once the transformation is performed, the potential energy is expanded in powers of the difference variables, which allows us to perform the integrals over these variables analytically. The manner in which this procedure is carried out results in an open-chain path integral (in the remaining sum variables) with a modified potential that is evaluated using imaginary-time path-integral sampling rather than requiring the generation of a large ensemble of trajectories. Consequently, any number of path integral sampling schemes can be employed to compute the remaining path integral, including Monte Carlo, path-integral molecular dynamics, or enhanced path-integral molecular dynamics. We believe that this approach constitutes a different perspective in semiclassical-type approximations to quantum time correlation functions. Importantly, we argue that our approximation can be systematically improved within a cumulant expansion formalism. We test this approximation on a set of one-dimensional problems that are commonly used to benchmark approximate quantum dynamical schemes. We show that the method is at least as accurate as the popular ring-polymer molecular dynamics technique and linearized semiclassical initial value representation for correlation functions of linear operators in most of these examples and improves the accuracy of correlation functions of nonlinear operators.

An open-chain imaginary-time path-integral sampling approach to the calculation of approximate symmetrized quantum time correlation functions

NASA Astrophysics Data System (ADS)

Cendagorta, Joseph R.; Bačić, Zlatko; Tuckerman, Mark E.

2018-03-01

We introduce a scheme for approximating quantum time correlation functions numerically within the Feynman path integral formulation. Starting with the symmetrized version of the correlation function expressed as a discretized path integral, we introduce a change of integration variables often used in the derivation of trajectory-based semiclassical methods. In particular, we transform to sum and difference variables between forward and backward complex-time propagation paths. Once the transformation is performed, the potential energy is expanded in powers of the difference variables, which allows us to perform the integrals over these variables analytically. The manner in which this procedure is carried out results in an open-chain path integral (in the remaining sum variables) with a modified potential that is evaluated using imaginary-time path-integral sampling rather than requiring the generation of a large ensemble of trajectories. Consequently, any number of path integral sampling schemes can be employed to compute the remaining path integral, including Monte Carlo, path-integral molecular dynamics, or enhanced path-integral molecular dynamics. We believe that this approach constitutes a different perspective in semiclassical-type approximations to quantum time correlation functions. Importantly, we argue that our approximation can be systematically improved within a cumulant expansion formalism. We test this approximation on a set of one-dimensional problems that are commonly used to benchmark approximate quantum dynamical schemes. We show that the method is at least as accurate as the popular ring-polymer molecular dynamics technique and linearized semiclassical initial value representation for correlation functions of linear operators in most of these examples and improves the accuracy of correlation functions of nonlinear operators.

Influence of Glide Path Preparation on the Canal Shaping Times of WaveOne Gold in Curved Mandibular Molar Canals.

PubMed

Vorster, Martin; van der Vyver, Peet J; Paleker, Farzana

2018-05-01

The aim of this study was to compare the glide path preparation times of stainless steel hand files, PathFiles (Dentsply Sirona, Ballaigues, Switzerland), and the WaveOne Gold Glider (Dentsply Sirona). The preparation times for final root canal shaping with the Primary WaveOne Gold instrument in extracted human molar teeth with and without prior glide path preparation were also recorded and compared. Mesiobuccal canals of 60 extracted human mandibular molars (curvature angles between 25° and 35° and radii <10 mm) were selected and randomly divided into 4 groups with 15 canals each. Canals were negotiated to patency with a #8 K-file. Canal preparations were performed by a single operator using precurved #10-15-20 stainless steel manual K-files (the K-file group), a #10 stainless steel manual K-file followed by PathFiles #1-3 (the PathFile group), a #10 stainless steel manual K-file followed by WaveOne Gold Glider (the WaveOne Gold Glider group), or no further glide path preparation. Final canal preparation of all 60 canals was performed with the Primary WaveOne Gold instrument. Glide path and final preparation times were recorded. Glide path enlargement was statistically significantly fastest in the WaveOne Gold Glider group (19.7 ± 5.6 seconds) followed by the PathFile group (41.0 ± 6.8 seconds) and then the K-file group (81.2 ± 26.3 seconds) using analysis of variance (ANOVA) and Kruskal-Wallis tests (P < .0001). No statistically significant difference in the mean final preparation times was found among the WaveOne Gold Glider (23.1 ± 6.0 seconds), PathFile (24.4 ± 4.9 seconds), and K-file groups (27.2 ± 9.5 seconds). All 3 groups were statistically significantly faster than the no glide path preparation group (35.4 ± 10.2 seconds) using ANOVA (P = .0004) and Kruskal-Wallis tests (P = .0010). Preparation time with the Primary WaveOne Gold file was statistically significantly reduced when the file was used in combination with any of the glide path preparation techniques. The WaveOne Gold Glider performed statistically significantly faster in glide path preparation time than the other glide path preparation techniques. Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Path statistics, memory, and coarse-graining of continuous-time random walks on networks

PubMed Central

Kion-Crosby, Willow; Morozov, Alexandre V.

2015-01-01

Continuous-time random walks (CTRWs) on discrete state spaces, ranging from regular lattices to complex networks, are ubiquitous across physics, chemistry, and biology. Models with coarse-grained states (for example, those employed in studies of molecular kinetics) or spatial disorder can give rise to memory and non-exponential distributions of waiting times and first-passage statistics. However, existing methods for analyzing CTRWs on complex energy landscapes do not address these effects. Here we use statistical mechanics of the nonequilibrium path ensemble to characterize first-passage CTRWs on networks with arbitrary connectivity, energy landscape, and waiting time distributions. Our approach can be applied to calculating higher moments (beyond the mean) of path length, time, and action, as well as statistics of any conservative or non-conservative force along a path. For homogeneous networks, we derive exact relations between length and time moments, quantifying the validity of approximating a continuous-time process with its discrete-time projection. For more general models, we obtain recursion relations, reminiscent of transfer matrix and exact enumeration techniques, to efficiently calculate path statistics numerically. We have implemented our algorithm in PathMAN (Path Matrix Algorithm for Networks), a Python script that users can apply to their model of choice. We demonstrate the algorithm on a few representative examples which underscore the importance of non-exponential distributions, memory, and coarse-graining in CTRWs. PMID:26646868

Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances.

PubMed

Ashley, Neil; Adams, Susan; Slama, Abdelhamid; Zeviani, Massimo; Suomalainen, Anu; Andreu, Antonio L; Naviaux, Robert K; Poulton, Joanna

2007-06-15

Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.

Budget impact analysis of biosimilar infliximab (CT-P13) for the treatment of rheumatoid arthritis in six Central and Eastern European countries.

PubMed

Brodszky, Valentin; Baji, Petra; Balogh, Orsolya; Péntek, Márta

2014-05-01

The first biosimilar monoclonal antibody (infliximab, CT-P13) was registered by the European Medicines Agency in 2013 for the treatment of several inflammatory conditions including rheumatoid arthritis (RA). Biosimilar infliximab is first being marketed in the Central and Eastern European countries. This paper presents the estimated budget impact of the introduction of biosimilar infliximab in RA over a 3-year time period in six selected countries, namely Bulgaria, the Czech Republic, Hungary, Poland, Romania and Slovakia. A prevalence-based model was constructed for budget impact analysis. Two scenarios were compared to the reference scenario (RSc) where no biosimilar infliximab is available: biosimilar scenario 1 (BSc1), where interchanging the originator infliximab with biosimilar infliximab is disallowed, and only patients who start new biological therapy are allowed to use biosimilar infliximab; as well as biosimilar scenario 2 (BSc2), where interchanging the originator infliximab with biosimilar infliximab is allowed, and 80% of patients treated with originator infliximab are interchanged to biosimilar infliximab. Compared to the RSc, the net savings are estimated to be €15.3 or €20.8 M in BSc1 and BSc2, respectively, over the 3 years. If budget savings were spent on reimbursement of additional biosimilar infliximab treatment, approximately 1,200 or 1,800 more patients could be treated in the six countries within 3 years in the two biosimilar scenarios, respectively. The actual saving is most sensitive to the assumption of the acquisition cost of the biosimilar drug and to the initial number of patients treated with biological therapy. The study focused on one indication (RA) and demonstrated that the introduction of biosimilar infliximab can lead to substantial budget savings in health care budgets. Further savings are expected for other indications where biosimilar medicines are implemented.

The importance of salivary cortisol in the diagnosis of adrenal insufficiency in cirrhosis.

PubMed

Araz, Filiz; Soydaş, Barış; Özer, Birol; Serin, Ender

2016-05-01

Reports on adrenal insufficiency (AI) are unexpectedly high in cirrhosis, and the diagnosis of this condition remains a challenge. We aimed to define the prevalence rate of AI in stable cirrhotic patients and determine the correlations of free cortisol and salivary cortisol with total cortisol. Between January 2011 and September 2011, 110 consecutive cirrhotic patients without any infection or hemodynamic instability were enrolled. Baseline total and salivary cortisol levels were measured. The free cortisol level was calculated according to the Coolens' formula. Post-stimulation total and salivary cortisol levels were measured, and the free cortisol level was recalculated. The mean age of the patients was 62.1±11.4 years. There were 54 males (49.1%). The mean Child-Turcotte-Pugh (CTP) score was 7.2±2.3. Twenty-two (20%) patients were at the CTP-C level. AI was present in 23 (20.9%) and 17 (15.5%) of all patients according to the total and free cortisol criteria, respectively. For basal and stimulated levels, salivary cortisol rather than total cortisol correlates well with free cortisol. The diagnosis of AI on the basis of total cortisol measurement overestimates the prevalence of AI in cirrhosis. Salivary cortisol, which correlates well with free cortisol, is a promising alternative for the diagnosis of AI in cirrhotic patients.

A web-based institutional DICOM distribution system with the integration of the Clinical Trial Processor (CTP).

PubMed

Aryanto, K Y E; Broekema, A; Langenhuysen, R G A; Oudkerk, M; van Ooijen, P M A

2015-05-01

To develop and test a fast and easy rule-based web-environment with optional de-identification of imaging data to facilitate data distribution within a hospital environment. A web interface was built using Hypertext Preprocessor (PHP), an open source scripting language for web development, and Java with SQL Server to handle the database. The system allows for the selection of patient data and for de-identifying these when necessary. Using the services provided by the RSNA Clinical Trial Processor (CTP), the selected images were pushed to the appropriate services using a protocol based on the module created for the associated task. Five pipelines, each performing a different task, were set up in the server. In a 75 month period, more than 2,000,000 images are transferred and de-identified in a proper manner while 20,000,000 images are moved from one node to another without de-identification. While maintaining a high level of security and stability, the proposed system is easy to setup, it integrate well with our clinical and research practice and it provides a fast and accurate vendor-neutral process of transferring, de-identifying, and storing DICOM images. Its ability to run different de-identification processes in parallel pipelines is a major advantage in both clinical and research setting.

Regulation of CTP Synthase Filament Formation During DNA Endoreplication in Drosophila.

PubMed

Wang, Pei-Yu; Lin, Wei-Cheng; Tsai, Yi-Cheng; Cheng, Mei-Ling; Lin, Yu-Hung; Tseng, Shu-Heng; Chakraborty, Archan; Pai, Li-Mei

2015-12-01

CTP synthase (CTPsyn) plays an essential role in DNA, RNA, and lipid synthesis. Recent studies in bacteria, yeast, and Drosophila all reveal a polymeric CTPsyn structure, which dynamically regulates its enzymatic activity. However, the molecular mechanism underlying the formation of CTPsyn polymers is not completely understood. In this study, we found that reversible ubiquitination regulates the dynamic assembly of the filamentous structures of Drosophila CTPsyn. We further determined that the proto-oncogene Cbl, an E3 ubiquitin ligase, controls CTPsyn filament formation in endocycles. While the E3 ligase activity of Cbl is required for CTPsyn filament formation, Cbl does not affect the protein levels of CTPsyn. It remains unclear whether the regulation of CTPsyn filaments by Cbl is through direct ubiquitination of CTPsyn. In the absence of Cbl or with knockdown of CTPsyn, the progression of the endocycle-associated S phase was impaired. Furthermore, overexpression of wild-type, but not enzymatically inactive CTPsyn, rescued the endocycle defect in Cbl mutant cells. Together, these results suggest that Cbl influences the nucleotide pool balance and controls CTPsyn filament formation in endocycles. This study links Cbl-mediated ubiquitination to the polymerization of a metabolic enzyme and reveals a role for Cbl in endocycles during Drosophila development. Copyright © 2015 by the Genetics Society of America.

Ceramic Technology Project data base: September 1992 summary report

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

Keyes, B.L.P.

Data presented in this report represent an intense effort to improve processing methods, testing methods, and general mechanical properties (rupture modulus, tensile, creep, stress-rupture, dynamic and cyclic fatigue, fracture toughness) of candidate ceramics for use in advanced heat engines. This work was performed by many facilities and represents only a small part of the data generated by the Ceramic Technology Project (CTP) since 1986. Materials discussed include GTE PY6, GN-10, NT-154, NT-164, SN-260, SN-251, SN-252, AY6, silicon nitride combined with rare-earth oxides, Y-TZP, ZTA, NC-433, NT-230, Hexoloy SA, MgO-PSZ-to-MgO-PSZ joints, MgO-PSZ-to-cast iron, and a few whisker/fiber-reinforced ceramics. Information in thismore » report was taken from the project`s semiannual and bimonthly progress reports and from final reports summarizing the results of individual studies. Test results are presented in tabular form and in graphs. All data, including test rig descriptions and material characterizations, are stored in the CTP data base and are available to all project participants on request. The objective of this report is to make available the test results from these studies but not to draw conclusions from those data.« less

In Vitro Exposure Systems and Dosimetry Assessment Tools ...

EPA Pesticide Factsheets

In 2009, the passing of The Family Smoking Prevention and Tobacco Control Act facilitated the establishment of the FDA Center for Tobacco Products (CTP) and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed “modified risk”. On 4-6 April 2016, the Institute for In Vitro Sciences, Inc. (IIVS) convened a workshop conference titled “In Vitro Exposure Systems and Dosimetry Assessment Tools for Inhaled Tobacco Products” to bring together stakeholders representing regulatory agencies, academia, and industry to address the research priorities articulated by the FDA CTP. Specific topics were covered to assess the status of current in vitro smoke and aerosol/vapor exposure systems, as well as the various approaches and challenges to quantifying the complex exposures, in in vitro pulmonary models developed for evaluating adverse pulmonary events resulting from tobacco product exposures. The four core topics covered were, 1) Tobacco Smoke And E-Cigarette Aerosols, 2) Air-Liquid Interface-In Vitro Exposure Systems, 3) Dosimetry Approaches For Particles And Vapors; In Vitro Dosimetry Determinations and 4) Exposure Microenvironment/Physiology Of Cells. The two and a half day workshop included presentations from 20 expert speakers, poster sessions, networking discussions, and breakout sessions which identified key findings and provided recommendations to advance these technologies. Here, we will re

Progress with infliximab biosimilars for inflammatory bowel disease.

PubMed

Kurti, Zsuzsanna; Gonczi, Lorant; Lakatos, Peter L

2018-04-29

Biological therapies have revolutionized the treatment of inflammatory bowel diseases (IBD) in the last two decades. Though biological drugs are effective, their use is associated with high costs and access to biological agents varies among countries. As the patent for the reference products expired, the advent of biosimilar monoclonal antibodies has been expected. Biosimilars represent less expensive alternatives compared to the reference product. Areas covered: In this review, authors will review the literature on the clinical efficacy, safety and immunogenicity of current and future biosimilar infliximabs. Short- and medium-term data from real-life cohorts and from randomized-clinical trials in IBD demonstrated similar outcomes in terms of efficacy, safety and immunogenicity as the reference product for CT-P13. Switch data from the reference to the biosimilar product are also accumulating (including the NOR-SWITCH and the CT-P13 3.4 study). Expert opinion: The use of biosimilar infliximab in IBD is increasing worldwide. Its use may be associated with budget savings leading to better access to biological therapies and consequently improved health outcomes. Switching from the originator to a biosimilar in patients with IBD is acceptable, although scientific and clinical evidence is lacking regarding reverse switching, multiple switching, and cross-switching among biosimilars in IBD patients.

Non-HFE iron overload as a surrogate marker of disease severity in patients of liver cirrhosis.

PubMed

Noor, Mohd Talha; Tiwari, Manish; Kumar, Ravindra

2016-01-01

Decompensated liver cirrhosis is an important cause of mortality worldwide. Various modifiable and non-modifiable factors are involved in the pathogenesis of cirrhosis and its complications. This study was aimed to evaluate the association of iron overload and disease severity in patients of liver cirrhosis and its association with HFE gene mutation. Forty-nine patients with decompensated liver cirrhosis were recruited. Clinical and laboratory parameters were compared in patients with and without iron overload. C282Y and H63D gene mutation analysis was performed in all patients with iron overload. Iron overload was found in 20 (40.82%) patients. A significant positive correlation of transferrin saturation with Child-Turcotte-Pugh (CTP) score (r = 0.705, p < 0.001) and model for end-stage liver disease (MELD) score (r = 0.668, p < 0.001) was found. Transferrin saturation was also independently associated with high CTP and MELD score on multivariate analysis. Mortality over 3 months was significantly more common in iron-overloaded patients (p = 0.028). C282Y homozygosity or C282Y/H63D compound heterozygosity was not found in any of the patients with iron overload. Iron overload was significantly associated with disease severity and reduced survival in patients of decompensated liver cirrhosis.

Radiation dose reduction in computed tomography perfusion using spatial-temporal Bayesian methods

NASA Astrophysics Data System (ADS)

Fang, Ruogu; Raj, Ashish; Chen, Tsuhan; Sanelli, Pina C.

2012-03-01

In current computed tomography (CT) examinations, the associated X-ray radiation dose is of significant concern to patients and operators, especially CT perfusion (CTP) imaging that has higher radiation dose due to its cine scanning technique. A simple and cost-effective means to perform the examinations is to lower the milliampere-seconds (mAs) parameter as low as reasonably achievable in data acquisition. However, lowering the mAs parameter will unavoidably increase data noise and degrade CT perfusion maps greatly if no adequate noise control is applied during image reconstruction. To capture the essential dynamics of CT perfusion, a simple spatial-temporal Bayesian method that uses a piecewise parametric model of the residual function is used, and then the model parameters are estimated from a Bayesian formulation of prior smoothness constraints on perfusion parameters. From the fitted residual function, reliable CTP parameter maps are obtained from low dose CT data. The merit of this scheme exists in the combination of analytical piecewise residual function with Bayesian framework using a simpler prior spatial constrain for CT perfusion application. On a dataset of 22 patients, this dynamic spatial-temporal Bayesian model yielded an increase in signal-tonoise-ratio (SNR) of 78% and a decrease in mean-square-error (MSE) of 40% at low dose radiation of 43mA.

Prevention of neural hypersensitivity after acute upper limb burns: Development and pilot of a cortical training protocol.

PubMed

Edgar, Dale; Zorzi, Lisa M; Wand, Ben M; Brockman, Nathalie; Griggs, Carolyn; Clifford, Matthew; Wood, Fiona

2011-06-01

Acute burn patients suffer pain and secondary hyperalgesia. This alters movement patterns and impairs function. Non-pharmacological methods of treatment are limited and lack rigorous testing and evidence for use. The treatment in this case series was designed to direct conscious attention to, and normalise sensation of, the injured limb in pain free way. The aim of the study was to describe a cortical training programme (CTP) in acute upper limb burn patients and to investigate the efficacy, safety and feasibility of the protocol. The study is a descriptive case series (n=6). Study tasks engaged sensory and motor nerves to influence the perception of the injured area. Visual and tactile inputs to maintain and, or normalise the homuncular map were central to the intervention. One patient, who commenced the study without resting pain, responded negatively. The remaining five patients had reduced pain and fear avoidance behaviours with associated improvement in arm function. The CTP approach is safe and feasible for use with acute burn patients where pain is reported at rest. Comparative studies are required to determine the relative efficacy of the program to usual interventions and the patients who may benefit from the technique. Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.

[DNA microarray reveals changes in gene expression of endothelial cells under shear stress].

PubMed

Cheng, Min; Zhang, Wensheng; Chen, Huaiqing; Wu, Wenchao; Huang, Hua

2004-04-01

cDNA microarray technology is used as a powerful tool for rapid, comprehensive, and quantitative analysis of gene profiles of cultured human umbilical vein endothelial cells(HUVECs) in the normal static group and the shear stressed (4.20 dyne/cm2, 2 h) group. The total RNA from normal static cultured HUVECs was labeled by Cy3-dCTP, and total RNA of HUVECs from the paired shear stressed experiment was labeled by Cy5-dCTP. The expression ratios reported are the average from the two separate experiments. After bioinformatics analysis, we identified a total of 108 genes (approximately 0.026%) revealing differential expression. Of these 53 genes expressions were up-regulated, the most enhanced ones being human homolog of yeast IPP isomerase, human low density lipoprotein receptor gene, Squalene epoxidase gene, 7-dehydrocholesterol reductase, and 55 were down-regulated, the most decreased ones being heat shock 70 kD protein 1, TCB gene encoding cytosolic thyroid hormone-binding protein in HUVECs exposed to low shear stress. These results indicate that the cDNA microarray technique is effective in screening the differentially expressed genes in endothelial cells induced by various experimental conditions and the data may serve as stimuli to further researches.

Identification of cytidine-5-triphosphate synthase1-selective inhibitory peptide from random peptide library displayed on T7 phage.

PubMed

Sakamoto, Kotaro; Ishibashi, Yoshihiro; Adachi, Ryutaro; Matsumoto, Shin-Ichi; Oki, Hideyuki; Kamada, Yusuke; Sogabe, Satoshi; Zama, Yumi; Sakamoto, Jun-Ichi; Tani, Akiyoshi

2017-08-01

Cytidine triphosphate synthase 1 (CTPS1) is an enzyme expressed in activated lymphocytes that catalyzes the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP) with ATP-dependent amination, using either L-glutamine or ammonia as the nitrogen source. Since CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialyation, CTPS1-inhibition is expected to control lymphocyte proliferation and size expansion in inflammatory diseases. In contrast, CTPS2, an isozyme of CTPS1 possessing 74% amino acid sequence homology, is expressed in normal lymphocytes. Thus, CTPS1-selective inhibition is important to avoid undesirable side effects. Here, we report the discovery of CTpep-3: Ac-FRLGLLKAFRRLF-OH from random peptide libraries displayed on T7 phage, which exhibited CTPS1-selective binding with a K D value of 210nM in SPR analysis and CTPS1-selective inhibition with an IC 50 value of 110nM in the enzyme assay. Furthermore, two fundamentally different approaches, enzyme inhibition assay and HDX-MS, provided the same conclusion that CTpep-3 acts by binding to the amidoligase (ALase) domain on CTPS1. To our knowledge, CTpep-3 is the first CTPS1-selective inhibitor. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Reister, D.B.

This paper uses the Pontryagin maximum principle to find time optimal paths for a constant speed unicycle. The time optimal paths consist of sequences of arcs of circles and straight lines. The maximum principle introduced concepts (dual variables, bang-bang solutions, singular solutions, and transversality conditions) that provide important insight into the nature of the time optimal paths. 10 refs., 6 figs.

An optically passive method that doubles the rate of 2-Ghz timing fiducials

NASA Astrophysics Data System (ADS)

Boni, R.; Kendrick, J.; Sorce, C.

2017-08-01

Solid-state optical comb-pulse generators provide a convenient and accurate method to include timing fiducials in a streak camera image for time base correction. Commercially available vertical-cavity surface-emitting lasers (VCSEL's) emitting in the visible currently in use can be modulated up to 2 GHz. An optically passive method is presented to interleave a time-delayed path of the 2-GHz comb with itself, producing a 4-GHz comb. This technique can be applied to VCSEL's with higher modulation rates. A fiber-delivered, randomly polarized 2-GHz VCSEL comb is polarization split into s-polarization and p-polarization paths. One path is time delayed relative to the other by twice the 2-GHz rate with +/-1-ps accuracy; the two paths then recombine at the fiber-coupled output. High throughput (>=90%) is achieved by carefully using polarization beam-splitting cubes, a total internal reflection beam-path-steering prism, and antireflection coatings. The glass path-length delay block and turning prism are optically contacted together. The beam polarizer cubes that split and recombine the paths are precision aligned and permanently cemented into place. We expect the palm-sized, inline fiber-coupled, comb-rate-doubling device to maintain its internal alignment indefinitely.

Job resumption status, hindering factors, and interpersonal relationship within post-heart transplant 1 to 4 years as perceived by heart transplant recipients in Taiwan: a between-method triangulation study.

PubMed

Tseng, P H; Wang, S S; Chang, C L; Shih, F J

2010-12-01

This project examined heart transplant (HT) recipients' perspectives of (a) the changes in their working competence (WC), status for job resumption and related factors at 1- to 2-year, 2- to 3-year, and 3- to 4-year stages; and (b) impacts of HT on interpersonal relationships (IPR). We used a between-method triangulation (including qualitative and quantitative data) design. Quantitative data were collected using the Vertical Visual Analogue Scale and Taiwan's version of the World Health Organization Health-Related Quality-of-Life (HRQoL) questionnaire. Six qualitative semistructured questions were further applied to explore social and environmental domains. The Fifty subjects (86% males and 14% females) had an age range from 20 to 70 years old (mean, 47.68 years). Their post-HT time ranged from 1 to 4.1 years with 42%, 42%, and 16% at 1- to 2-, 2- to 3-, or 3- to 4-years post-HT, respectively. Within 6 months, 10% of administration or restaurant staff, and police resumed their jobs. At 6 to 12 months, 8% of administration, quality control, and design and planning staff resumed their jobs. At 12 months, 14% of educators, insurance personnel, managers, informatics engineers, and ironworkers resumed their jobs. Hindering factors to returning to work included (a) physical (ie, lack of energy, second heart attack, recurrence of rejection, physical discomforts of dizziness, memory lapses/lack of concentration or bone pain from osteoporosis); (b) psychological (ie, lack of confidence, worries about discrimination, being different, maladaptation); and (c) environmental (inadequate job opportunities due to poor socioeconomic conditions). Additionally, 34% reported worse IPR after HT due to diet limitations, slower pacing, less contacts with friends, and changes in personality. Reflections on both the meaning and value of life caused 10% to report better IPR with a better personality and positive mindset. By the end of the first postoperative year, the mean score of HRQoL in the preoperative extracorporeal membrane oxygenation (ECMO) group was similar to the non-preoperative ECMO group; the mean scores of WC and physical functions for the preoperative ECMO group were even higher than the non-preoperative ECMO group. Meanwhile, the mean scores of HRQoL and WC were higher in the Clinical Trail Plan (CTP) group than non-CTP groups across the three stages. As such, the use of preoperative ECMO and CTP groups are suggested to be both clinically and significantly associated with HTs recovery in heath status, positive HRQoL, and job resumption in the society. Finally, HRQoL and related domains of physical, psychological, social, and environmental health were stable at 12 months post-HT, with no significant change between 1- to 2-, 2- to 3-, and 3- to 4-years post-HT. Copyright © 2010 Elsevier Inc. All rights reserved.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

PubMed

Romano, Antonietta; Angeli, Paolo; Piovesan, Sara; Noventa, Franco; Anastassopoulos, Georgios; Chemello, Liliana; Cavalletto, Luisa; Gambato, Martina; Russo, Francesco Paolo; Burra, Patrizia; Vincenzi, Valter; Scotton, Pier Giorgio; Panese, Sandro; Tempesta, Diego; Bertin, Tosca; Carrara, Maurizio; Carlotto, Antonio; Capra, Franco; Carolo, Giada; Scroccaro, Giovanna; Alberti, Alfredo

2018-03-16

Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days. Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure. Copyright © 2018. Published by Elsevier B.V.

Statistical Analysis of the First Passage Path Ensemble of Jump Processes

NASA Astrophysics Data System (ADS)

von Kleist, Max; Schütte, Christof; Zhang, Wei

2018-02-01

The transition mechanism of jump processes between two different subsets in state space reveals important dynamical information of the processes and therefore has attracted considerable attention in the past years. In this paper, we study the first passage path ensemble of both discrete-time and continuous-time jump processes on a finite state space. The main approach is to divide each first passage path into nonreactive and reactive segments and to study them separately. The analysis can be applied to jump processes which are non-ergodic, as well as continuous-time jump processes where the waiting time distributions are non-exponential. In the particular case that the jump processes are both Markovian and ergodic, our analysis elucidates the relations between the study of the first passage paths and the study of the transition paths in transition path theory. We provide algorithms to numerically compute statistics of the first passage path ensemble. The computational complexity of these algorithms scales with the complexity of solving a linear system, for which efficient methods are available. Several examples demonstrate the wide applicability of the derived results across research areas.

Sunrise effects on VLF signals propagating over a long north-south path

NASA Astrophysics Data System (ADS)

Clilverd, Mark A.; Thomson, Neil R.; Rodger, Craig J.

1999-07-01

We present a detailed study of the times of amplitude minima observed on the 12-Mm path from NAA (24 kHz, 1 MW, Cutler, Maine) to Faraday, Antarctica, during the period 1990-1995. (NAA is a naval transmitter call sign.) This study represents the first account of the effect of the sunrise terminator when it is parallel to a propagation path at some times of the year. Since the NAA-Faraday path is within 3° of the north-south meridian, parallel orientation happens close to the equinoxes, while the maximum angle of incidence occurs during the solstices. During the solstices the terminator takes a significant length of time to cross the entire propagation path, so modal conversion effects are observed over a range of hours. During the equinoxes, however, the leading edge of the night-day transition region crosses the whole propagation path within 20 min. The interpretation of the timing of minima is consistent with modal conversion taking place as the sunrise terminator crosses the NAA-Faraday transmission path at specific, consistent locations. The timing of minima is remarkably consistent from year to year. Long wave propagation modeling is used to show that the location of nightside minima at an altitude of 45-75 km in the subionospheric waveguide represents the location of the sunrise terminator on the great circle path when dayside minima occur.

Energy Optimal Path Planning: Integrating Coastal Ocean Modelling with Optimal Control

NASA Astrophysics Data System (ADS)

Subramani, D. N.; Haley, P. J., Jr.; Lermusiaux, P. F. J.

2016-02-01

A stochastic optimization methodology is formulated for computing energy-optimal paths from among time-optimal paths of autonomous vehicles navigating in a dynamic flow field. To set up the energy optimization, the relative vehicle speed and headings are considered to be stochastic, and new stochastic Dynamically Orthogonal (DO) level-set equations that govern their stochastic time-optimal reachability fronts are derived. Their solution provides the distribution of time-optimal reachability fronts and corresponding distribution of time-optimal paths. An optimization is then performed on the vehicle's energy-time joint distribution to select the energy-optimal paths for each arrival time, among all stochastic time-optimal paths for that arrival time. The accuracy and efficiency of the DO level-set equations for solving the governing stochastic level-set reachability fronts are quantitatively assessed, including comparisons with independent semi-analytical solutions. Energy-optimal missions are studied in wind-driven barotropic quasi-geostrophic double-gyre circulations, and in realistic data-assimilative re-analyses of multiscale coastal ocean flows. The latter re-analyses are obtained from multi-resolution 2-way nested primitive-equation simulations of tidal-to-mesoscale dynamics in the Middle Atlantic Bight and Shelbreak Front region. The effects of tidal currents, strong wind events, coastal jets, and shelfbreak fronts on the energy-optimal paths are illustrated and quantified. Results showcase the opportunities for longer-duration missions that intelligently utilize the ocean environment to save energy, rigorously integrating ocean forecasting with optimal control of autonomous vehicles.

Scan path entropy and arrow plots: capturing scanning behavior of multiple observers

PubMed Central

Hooge, Ignace; Camps, Guido

2013-01-01

Designers of visual communication material want their material to attract and retain attention. In marketing research, heat maps, dwell time, and time to AOI first hit are often used as evaluation parameters. Here we present two additional measures (1) “scan path entropy” to quantify gaze guidance and (2) the “arrow plot” to visualize the average scan path. Both are based on string representations of scan paths. The latter also incorporates transition matrices and time required for 50% of the observers to first hit AOIs (T50). The new measures were tested in an eye tracking study (48 observers, 39 advertisements). Scan path entropy is a sensible measure for gaze guidance and the new visualization method reveals aspects of the average scan path and gives a better indication in what order global scanning takes place. PMID:24399993

Short-Path Statistics and the Diffusion Approximation

NASA Astrophysics Data System (ADS)

Blanco, Stéphane; Fournier, Richard

2006-12-01

In the field of first return time statistics in bounded domains, short paths may be defined as those paths for which the diffusion approximation is inappropriate. This is at the origin of numerous open questions concerning the characterization of residence time distributions. We show here how general integral constraints can be derived that make it possible to address short-path statistics indirectly by application of the diffusion approximation to long paths. Application to the moments of the distribution at the low-Knudsen limit leads to simple practical results and novel physical pictures.

Method and apparatus for timing of laser beams in a multiple laser beam fusion system

DOEpatents

Eastman, Jay M.; Miller, Theodore L.

1981-01-01

The optical path lengths of a plurality of comparison laser beams directed to impinge upon a common target from different directions are compared to that of a master laser beam by using an optical heterodyne interferometric detection technique. The technique consists of frequency shifting the master laser beam and combining the master beam with a first one of the comparison laser beams to produce a time-varying heterodyne interference pattern which is detected by a photo-detector to produce an AC electrical signal indicative of the difference in the optical path lengths of the two beams which were combined. The optical path length of this first comparison laser beam is adjusted to compensate for the detected difference in the optical path lengths of the two beams. The optical path lengths of all of the comparison laser beams are made equal to the optical path length of the master laser beam by repeating the optical path length adjustment process for each of the comparison laser beams. In this manner, the comparison laser beams are synchronized or timed to arrive at the target within .+-.1.times.10.sup.-12 second of each other.

Optimal impulsive time-fixed orbital rendezvous and interception with path constraints

NASA Technical Reports Server (NTRS)

Taur, D.-R.; Prussing, J. E.; Coverstone-Carroll, V.

1990-01-01

Minimum-fuel, impulsive, time-fixed solutions are obtained for the problem of orbital rendezvous and interception with interior path constraints. Transfers between coplanar circular orbits in an inverse-square gravitational field are considered, subject to a circular path constraint representing a minimum or maximum permissible orbital radius. Primer vector theory is extended to incorporate path constraints. The optimal number of impulses, their times and positions, and the presence of initial or final coasting arcs are determined. The existence of constraint boundary arcs and boundary points is investigated as well as the optimality of a class of singular arc solutions. To illustrate the complexities introduced by path constraints, an analysis is made of optimal rendezvous in field-free space subject to a minimum radius constraint.

Nucleotide and bivalent cation specificity of the insulin-granule proton translocase.

PubMed Central

Hutton, J C; Peshavaria, M

1983-01-01

1. The nucleotide and bivalent cation specificity of the proton translocase activity of insulin secretory granules was investigated by assessing the inhibitor-sensitive rates of nucleotide hydrolysis by these organelles in relation to their chemiosmotic properties. 2. The relative rates of nucleotide hydrolysis by freeze/thawed granule preparations were: Mg2+ATP (100%) greater than Mg2+GTP (55%) greater than Mg2+UTP (48%) greater than Mg2+ITP (44%) greater than Mg2+CTP (23%) greater than Mg2+TTP (20%), and by intact granules were: Mg2+ATP (100%) greater than Mg2+ITP (74%) greater than Mg2+GTP (60%) greater than Mg2+CTP (35%). Mg2+ATP, Mg2+GTP and Mg2+ITP hydrolyses were inhibited by tributyltin and stimulated, in intact granules, by the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone; Mg2+CTP hydrolysis was not markedly affected by these compounds. Correspondingly, only Mg2+ATP, Mg2+GTP and Mg2+ITP produced large changes in the delta psi and delta mu H+ across the granule membrane. 3. The relative rates of maximal ATPase activity stimulated by bivalent cations in freeze/thawed granule preparations were: Mg2+ (100%) greater than Mn2+ (82%) greater than Ca2+ (40%) greater than Co2+ (36%) greater than Zn2+ (0%), and in intact granules were: Mg2+ (100%) greater than Mn2+ (85%) greater than Co2+ (61%) greater than Ca2+ (42%). Tributyltin and carbonyl cyanide p-trifluoromethoxyphenylhydrazone affected Mg2+-, Mn2+- and Co2+-activated, but not Ca2+-activated, ATP hydrolysis. Correspondingly, only Mg2+, Mn2+ and Co2+ supported the generation of a delta psi and delta mu H+ across granule membranes in the presence of ATP. 4. The results were consistent with a single proton translocase that had its catalytic site exposed on the external face of the granule membrane. The indicated specificity (Mg2+ATP = Mn2+ATP greater than Co2+ATP greater than Mg2+GTP greater than Mg2+ITP) was similar to that of enzymes described in membrane fractions prepared from adenohypophyseal tissue, adrenal chromaffin granules and yeast vacuoles. The insulin-granule activity thus appears to be a type of proton translocase, which is characteristic of intracellular storage vesicles in eukaryotic cells. PMID:6303313

Formal language constrained path problems

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

Barrett, C.; Jacob, R.; Marathe, M.

1997-07-08

In many path finding problems arising in practice, certain patterns of edge/vertex labels in the labeled graph being traversed are allowed/preferred, while others are disallowed. Motivated by such applications as intermodal transportation planning, the authors investigate the complexity of finding feasible paths in a labeled network, where the mode choice for each traveler is specified by a formal language. The main contributions of this paper include the following: (1) the authors show that the problem of finding a shortest path between a source and destination for a traveler whose mode choice is specified as a context free language is solvablemore » efficiently in polynomial time, when the mode choice is specified as a regular language they provide algorithms with improved space and time bounds; (2) in contrast, they show that the problem of finding simple paths between a source and a given destination is NP-hard, even when restricted to very simple regular expressions and/or very simple graphs; (3) for the class of treewidth bounded graphs, they show that (i) the problem of finding a regular language constrained simple path between source and a destination is solvable in polynomial time and (ii) the extension to finding context free language constrained simple paths is NP-complete. Several extensions of these results are presented in the context of finding shortest paths with additional constraints. These results significantly extend the results in [MW95]. As a corollary of the results, they obtain a polynomial time algorithm for the BEST k-SIMILAR PATH problem studied in [SJB97]. The previous best algorithm was given by [SJB97] and takes exponential time in the worst case.« less

Path integrals, supersymmetric quantum mechanics, and the Atiyah-Singer index theorem for twisted Dirac

NASA Astrophysics Data System (ADS)

Fine, Dana S.; Sawin, Stephen

2017-01-01

Feynman's time-slicing construction approximates the path integral by a product, determined by a partition of a finite time interval, of approximate propagators. This paper formulates general conditions to impose on a short-time approximation to the propagator in a general class of imaginary-time quantum mechanics on a Riemannian manifold which ensure that these products converge. The limit defines a path integral which agrees pointwise with the heat kernel for a generalized Laplacian. The result is a rigorous construction of the propagator for supersymmetric quantum mechanics, with potential, as a path integral. Further, the class of Laplacians includes the square of the twisted Dirac operator, which corresponds to an extension of N = 1/2 supersymmetric quantum mechanics. General results on the rate of convergence of the approximate path integrals suffice in this case to derive the local version of the Atiyah-Singer index theorem.

Comparison Between Path Lengths Traveled by Solar Electrons and Ions in Ground-Level Enhancement Events

NASA Technical Reports Server (NTRS)

Tan, Lun C.; Malandraki, Olga E.; Reames, Donald; NG, Chee K.; Wang, Linghua; Patsou, Ioanna; Papaioannou, Athanasios

2013-01-01

We have examined the Wind/3DP/SST electron and Wind/EPACT/LEMT ion data to investigate the path length difference between solar electrons and ions in the ground-level enhancement (GLE) events in solar cycle 23. Assuming that the onset time of metric type II or decameter-hectometric (DH) type III radio bursts is the solar release time of non-relativistic electrons, we have found that within an error range of plus or minus 10% the deduced path length of low-energy (approximately 27 keV) electrons from their release site near the Sun to the 1 AU observer is consistent with the ion path length deduced by Reames from the onset time analysis. In addition, the solar longitude distribution and IMF topology of the GLE events examined are in favor of the coronal mass ejection-driven shock acceleration origin of observed non-relativistic electrons.We have also found an increase of electron path lengths with increasing electron energies. The increasing rate of path lengths is correlated with the pitch angle distribution (PAD) of peak electron intensities locally measured, with a higher rate corresponding to a broader PAD. The correlation indicates that the path length enhancement is due to the interplanetary scattering experienced by first arriving electrons. The observed path length consistency implies that the maximum stable time of magnetic flux tubes, along which particles transport, could reach 4.8 hr.

On computing the global time-optimal motions of robotic manipulators in the presence of obstacles

NASA Technical Reports Server (NTRS)

Shiller, Zvi; Dubowsky, Steven

1991-01-01

A method for computing the time-optimal motions of robotic manipulators is presented that considers the nonlinear manipulator dynamics, actuator constraints, joint limits, and obstacles. The optimization problem is reduced to a search for the time-optimal path in the n-dimensional position space. A small set of near-optimal paths is first efficiently selected from a grid, using a branch and bound search and a series of lower bound estimates on the traveling time along a given path. These paths are further optimized with a local path optimization to yield the global optimal solution. Obstacles are considered by eliminating the collision points from the tessellated space and by adding a penalty function to the motion time in the local optimization. The computational efficiency of the method stems from the reduced dimensionality of the searched spaced and from combining the grid search with a local optimization. The method is demonstrated in several examples for two- and six-degree-of-freedom manipulators with obstacles.

Warrior Transition Leader: Medical Rehabilitation Handbook

DTIC Science & Technology

2011-01-01

serve. rE f E r E n c E S 1. http://www.army.mil/warriorcarenews/. Accessed January 24, 2011. 2. Warrior Transition Command Web site. http...www.wtc.army.mil/about_us/ ctp.html. Accessed January 24, 2011. 3. Leipold JD. Warrior Transition Command stands up at Pentagon. US Army Web site. Army...January 24, 2011. 4. Warrior Transition Command Web site. http://wtc.armylive.dodlive.mil/ about-wtu/. Accessed January 24, 2011. 5. Leipold JD

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

Khinkis, Mark J.; Kozlov, Aleksandr P.

A radiant, non-catalytic recuperative reformer has a flue gas flow path for conducting hot exhaust gas from a thermal process and a reforming mixture flow path for conducting a reforming mixture. At least a portion of the reforming mixture flow path is positioned adjacent to the flue gas flow path to permit heat transfer from the hot exhaust gas to the reforming mixture. The reforming mixture flow path contains substantially no material commonly used as a catalyst for reforming hydrocarbon fuel (e.g., nickel oxide, platinum group elements or rhenium), but instead the reforming mixture is reformed into a higher calorificmore » fuel via reactions due to the heat transfer and residence time. In a preferred embodiment, a portion of the reforming mixture flow path is positioned outside of flue gas flow path for a relatively large residence time.« less

Path generation algorithm for UML graphic modeling of aerospace test software

NASA Astrophysics Data System (ADS)

Qu, MingCheng; Wu, XiangHu; Tao, YongChao; Chen, Chao

2018-03-01

Aerospace traditional software testing engineers are based on their own work experience and communication with software development personnel to complete the description of the test software, manual writing test cases, time-consuming, inefficient, loopholes and more. Using the high reliability MBT tools developed by our company, the one-time modeling can automatically generate test case documents, which is efficient and accurate. UML model to describe the process accurately express the need to rely on the path is reached, the existing path generation algorithm are too simple, cannot be combined into a path and branch path with loop, or too cumbersome, too complicated arrangement generates a path is meaningless, for aerospace software testing is superfluous, I rely on our experience of ten load space, tailor developed a description of aerospace software UML graphics path generation algorithm.

Replication of a carcinogenic nitropyrene DNA lesion by human Y-family DNA polymerase

PubMed Central

Kirouac, Kevin N.; Basu, Ashis K.; Ling, Hong

2013-01-01

Nitrated polycyclic aromatic hydrocarbons are common environmental pollutants, of which many are mutagenic and carcinogenic. 1-Nitropyrene is the most abundant nitrated polycyclic aromatic hydrocarbon, which causes DNA damage and is carcinogenic in experimental animals. Error-prone translesion synthesis of 1-nitropyrene–derived DNA lesions generates mutations that likely play a role in the etiology of cancer. Here, we report two crystal structures of the human Y-family DNA polymerase iota complexed with the major 1-nitropyrene DNA lesion at the insertion stage, incorporating either dCTP or dATP nucleotide opposite the lesion. Polι maintains the adduct in its active site in two distinct conformations. dCTP forms a Watson–Crick base pair with the adducted guanine and excludes the pyrene ring from the helical DNA, which inhibits replication beyond the lesion. By contrast, the mismatched dATP stacks above the pyrene ring that is intercalated in the helix and achieves a productive conformation for misincorporation. The intra-helical bulky pyrene mimics a base pair in the active site and facilitates adenine misincorporation. By structure-based mutagenesis, we show that the restrictive active site of human polη prevents the intra-helical conformation and A-base misinsertions. This work provides one of the molecular mechanisms for G to T transversions, a signature mutation in human lung cancer. PMID:23268450

Infliximab Biosimilar (CT-P13; Infliximab-dyyb): A Review in Autoimmune Inflammatory Diseases.

PubMed

Blair, Hannah A; Deeks, Emma D

2016-10-01

Infliximab biosimilar (CT-P13/infliximab-dyyb; Remsima ® , Inflectra ® ) is approved in several countries for use in all indications for which reference infliximab (Remicade ® ) is approved, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn's disease, and ulcerative colitis. Clinical data contributing to the EU approval of infliximab biosimilar were obtained from two pivotal double-blind clinical trials in patients with AS (PLANETAS) or RA (PLANETRA). Infliximab biosimilar demonstrated equivalence to reference infliximab in terms of its pharmacokinetic profile in patients with AS, patients with RA, and in healthy volunteers, and in terms of its efficacy in patients with RA. Clinical response rates in patients with RA or AS were maintained over the longer term (up to 102 weeks). In addition, the efficacy of infliximab biosimilar in patients with RA or Crohn's disease and ulcerative colitis [i.e. inflammatory bowel disease (IBD)] has been demonstrated in the real-world setting. Infliximab biosimilar was generally well tolerated, with a tolerability profile similar to that of reference infliximab. Switching from reference infliximab to infliximab biosimilar had no detrimental effect on efficacy, safety, or immunogenicity compared with continuous infliximab biosimilar therapy, according to the extensions of PLANETAS and PLANETRA, and real-world data in IBD. Current evidence therefore suggests that infliximab biosimilar is a useful alternative to reference infliximab in patients with autoimmune inflammatory diseases.

CyDNA: Synthesis and Replication of Highly Cy-Dye Substituted DNA by an Evolved Polymerase

PubMed Central

2010-01-01

DNA not only transmits genetic information but can also serve as a versatile supramolecular scaffold. Here we describe a strategy for the synthesis and replication of DNA displaying hundreds of substituents using directed evolution of polymerase function by short-patch compartmentalized self-replication (spCSR) and the widely used fluorescent dye labeled deoxinucleotide triphosphates Cy3-dCTP and Cy5-dCTP as substrates. In just two rounds of spCSR selection, we have isolated a polymerase that allows the PCR amplification of double stranded DNA fragments up to 1kb, in which all dC bases are substituted by its fluorescent dye-labeled equivalent Cy3- or Cy5-dC. The resulting “CyDNA” displays hundreds of aromatic heterocycles on the outside of the DNA helix and is brightly colored and highly fluorescent. CyDNA also exhibits significantly altered physicochemical properties compared to standard B-form DNA, including loss of silica and intercalating dye binding, resistance to cleavage by some endonucleases, an up to 40% increased apparent diameter as judged by atomic force microscopy and organic phase partitioning during phenol extraction. CyDNA also displays very bright fluorescence enabling significant signal gains in microarray and microfluidic applications. CyDNA represents a step toward a long-term goal of the encoded synthesis of DNA-based polymers of programmable and evolvable sequence and properties. PMID:20235594

CyDNA: synthesis and replication of highly Cy-dye substituted DNA by an evolved polymerase.

PubMed

Ramsay, Nicola; Jemth, Ann-Sofie; Brown, Anthony; Crampton, Neal; Dear, Paul; Holliger, Philipp

2010-04-14

DNA not only transmits genetic information but can also serve as a versatile supramolecular scaffold. Here we describe a strategy for the synthesis and replication of DNA displaying hundreds of substituents using directed evolution of polymerase function by short-patch compartmentalized self-replication (spCSR) and the widely used fluorescent dye labeled deoxinucleotide triphosphates Cy3-dCTP and Cy5-dCTP as substrates. In just two rounds of spCSR selection, we have isolated a polymerase that allows the PCR amplification of double stranded DNA fragments up to 1kb, in which all dC bases are substituted by its fluorescent dye-labeled equivalent Cy3- or Cy5-dC. The resulting "CyDNA" displays hundreds of aromatic heterocycles on the outside of the DNA helix and is brightly colored and highly fluorescent. CyDNA also exhibits significantly altered physicochemical properties compared to standard B-form DNA, including loss of silica and intercalating dye binding, resistance to cleavage by some endonucleases, an up to 40% increased apparent diameter as judged by atomic force microscopy and organic phase partitioning during phenol extraction. CyDNA also displays very bright fluorescence enabling significant signal gains in microarray and microfluidic applications. CyDNA represents a step toward a long-term goal of the encoded synthesis of DNA-based polymers of programmable and evolvable sequence and properties.

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

Liu, Shengqiang; Li, Jie; Yu, Junsheng, E-mail: jsyu@uestc.edu.cn

A color tuning index (I{sub CT}) parameter for evaluating the color change capability of color-tunable organic light-emitting diodes (CT-OLEDs) was proposed and formulated. And a series of CT-OLEDs, consisting of five different carrier/exciton adjusting interlayers (C/EALs) inserted between two complementary emitting layers, were fabricated and applied to disclose the relationship between I{sub CT} and C/EALs. The result showed that the trend of electroluminescence spectra behavior in CT-OLEDs has good accordance with I{sub CT} values, indicating that the I{sub CT} parameter is feasible for the evaluation of color variation. Meanwhile, by changing energy level and C/EAL thickness, the optimized device withmore » the widest color tuning range was based on N,N′-dicarbazolyl-3,5-benzene C/EAL, exhibiting the highest I{sub CT} value of 41.2%. Based on carrier quadratic hopping theory and exciton transfer model, two fitting I{sub CT} formulas derived from the highest occupied molecular orbital (HOMO) energy level and triplet energy level were simulated. Finally, a color tuning prediction (CTP) model was developed to deduce the I{sub CT} via C/EAL HOMO and triplet energy levels, and verified by the fabricated OLEDs with five different C/EALs. We believe that the CTP model assisted with I{sub CT} parameter will be helpful for fabricating high performance CT-OLEDs with a broad range of color tuning.« less

Alternative Constraint Handling Technique for Four-Bar Linkage Path Generation

NASA Astrophysics Data System (ADS)

Sleesongsom, S.; Bureerat, S.

2018-03-01

This paper proposes an extension of a new concept for path generation from our previous work by adding a new constraint handling technique. The propose technique was initially designed for problems without prescribed timing by avoiding the timing constraint, while remain constraints are solving with a new constraint handling technique. The technique is one kind of penalty technique. The comparative study is optimisation of path generation problems are solved using self-adaptive population size teaching-learning based optimization (SAP-TLBO) and original TLBO. In this study, two traditional path generation test problem are used to test the proposed technique. The results show that the new technique can be applied with the path generation problem without prescribed timing and gives better results than the previous technique. Furthermore, SAP-TLBO outperforms the original one.

An exact formulation of the time-ordered exponential using path-sums

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

Giscard, P.-L., E-mail: p.giscard1@physics.ox.ac.uk; Lui, K.; Thwaite, S. J.

2015-05-15

We present the path-sum formulation for the time-ordered exponential of a time-dependent matrix. The path-sum formulation gives the time-ordered exponential as a branched continued fraction of finite depth and breadth. The terms of the path-sum have an elementary interpretation as self-avoiding walks and self-avoiding polygons on a graph. Our result is based on a representation of the time-ordered exponential as the inverse of an operator, the mapping of this inverse to sums of walks on a graphs, and the algebraic structure of sets of walks. We give examples demonstrating our approach. We establish a super-exponential decay bound for the magnitudemore » of the entries of the time-ordered exponential of sparse matrices. We give explicit results for matrices with commonly encountered sparse structures.« less

Transition paths in single-molecule force spectroscopy

NASA Astrophysics Data System (ADS)

Cossio, Pilar; Hummer, Gerhard; Szabo, Attila

2018-03-01

In a typical single-molecule force spectroscopy experiment, the ends of the molecule of interest are connected by long polymer linkers to a pair of mesoscopic beads trapped in the focus of two laser beams. At constant force load, the total extension, i.e., the end-to-end distance of the molecule plus linkers, is measured as a function of time. In the simplest systems, the measured extension fluctuates about two values characteristic of folded and unfolded states, with occasional transitions between them. We have recently shown that molecular (un)folding rates can be recovered from such trajectories, with a small linker correction, as long as the characteristic time of the bead fluctuations is shorter than the residence time in the unfolded (folded) state. Here, we show that accurate measurements of the molecular transition path times require an even faster apparatus response. Transition paths, the trajectory segments in which the molecule (un)folds, are properly resolved only if the beads fluctuate more rapidly than the end-to-end distance of the molecule. Therefore, over a wide regime, the measured rates may be meaningful but not the transition path times. Analytic expressions for the measured mean transition path times are obtained for systems diffusing anisotropically on a two-dimensional free energy surface. The transition path times depend on the properties both of the molecule and of the pulling device.

Time optimized path-choice in the termite hunting ant Megaponera analis.

PubMed

Frank, Erik T; Hönle, Philipp O; Linsenmair, K Eduard

2018-05-10

Trail network systems among ants have received a lot of scientific attention due to their various applications in problem solving of networks. Recent studies have shown that ants select the fastest available path when facing different velocities on different substrates, rather than the shortest distance. The progress of decision-making by these ants is determined by pheromone-based maintenance of paths, which is a collective decision. However, path optimization through individual decision-making remains mostly unexplored. Here we present the first study of time-optimized path selection via individual decision-making by scout ants. Megaponera analis scouts search for termite foraging sites and lead highly organized raid columns to them. The path of the scout determines the path of the column. Through installation of artificial roads around M. analis nests we were able to influence the pathway choice of the raids. After road installation 59% of all recorded raids took place completely or partly on the road, instead of the direct, i.e. distance-optimized, path through grass from the nest to the termites. The raid velocity on the road was more than double the grass velocity, the detour thus saved 34.77±23.01% of the travel time compared to a hypothetical direct path. The pathway choice of the ants was similar to a mathematical model of least time allowing us to hypothesize the underlying mechanisms regulating the behavior. Our results highlight the importance of individual decision-making in the foraging behavior of ants and show a new procedure of pathway optimization. © 2018. Published by The Company of Biologists Ltd.

Automated flight path planning for virtual endoscopy.

PubMed

Paik, D S; Beaulieu, C F; Jeffrey, R B; Rubin, G D; Napel, S

1998-05-01

In this paper, a novel technique for rapid and automatic computation of flight paths for guiding virtual endoscopic exploration of three-dimensional medical images is described. While manually planning flight paths is a tedious and time consuming task, our algorithm is automated and fast. Our method for positioning the virtual camera is based on the medial axis transform but is much more computationally efficient. By iteratively correcting a path toward the medial axis, the necessity of evaluating simple point criteria during morphological thinning is eliminated. The virtual camera is also oriented in a stable viewing direction, avoiding sudden twists and turns. We tested our algorithm on volumetric data sets of eight colons, one aorta and one bronchial tree. The algorithm computed the flight paths in several minutes per volume on an inexpensive workstation with minimal computation time added for multiple paths through branching structures (10%-13% per extra path). The results of our algorithm are smooth, centralized paths that aid in the task of navigation in virtual endoscopic exploration of three-dimensional medical images.

A 2-dimensional optical architecture for solving Hamiltonian path problem based on micro ring resonators

NASA Astrophysics Data System (ADS)

Shakeri, Nadim; Jalili, Saeed; Ahmadi, Vahid; Rasoulzadeh Zali, Aref; Goliaei, Sama

2015-01-01

The problem of finding the Hamiltonian path in a graph, or deciding whether a graph has a Hamiltonian path or not, is an NP-complete problem. No exact solution has been found yet, to solve this problem using polynomial amount of time and space. In this paper, we propose a two dimensional (2-D) optical architecture based on optical electronic devices such as micro ring resonators, optical circulators and MEMS based mirror (MEMS-M) to solve the Hamiltonian Path Problem, for undirected graphs in linear time. It uses a heuristic algorithm and employs n+1 different wavelengths of a light ray, to check whether a Hamiltonian path exists or not on a graph with n vertices. Then if a Hamiltonian path exists, it reports the path. The device complexity of the proposed architecture is O(n2).

Congestion patterns of electric vehicles with limited battery capacity.

PubMed

Jing, Wentao; Ramezani, Mohsen; An, Kun; Kim, Inhi

2018-01-01

The path choice behavior of battery electric vehicle (BEV) drivers is influenced by the lack of public charging stations, limited battery capacity, range anxiety and long battery charging time. This paper investigates the congestion/flow pattern captured by stochastic user equilibrium (SUE) traffic assignment problem in transportation networks with BEVs, where the BEV paths are restricted by their battery capacities. The BEV energy consumption is assumed to be a linear function of path length and path travel time, which addresses both path distance limit problem and road congestion effect. A mathematical programming model is proposed for the path-based SUE traffic assignment where the path cost is the sum of the corresponding link costs and a path specific out-of-energy penalty. We then apply the convergent Lagrangian dual method to transform the original problem into a concave maximization problem and develop a customized gradient projection algorithm to solve it. A column generation procedure is incorporated to generate the path set. Finally, two numerical examples are presented to demonstrate the applicability of the proposed model and the solution algorithm.

Congestion patterns of electric vehicles with limited battery capacity

PubMed Central

2018-01-01

The path choice behavior of battery electric vehicle (BEV) drivers is influenced by the lack of public charging stations, limited battery capacity, range anxiety and long battery charging time. This paper investigates the congestion/flow pattern captured by stochastic user equilibrium (SUE) traffic assignment problem in transportation networks with BEVs, where the BEV paths are restricted by their battery capacities. The BEV energy consumption is assumed to be a linear function of path length and path travel time, which addresses both path distance limit problem and road congestion effect. A mathematical programming model is proposed for the path-based SUE traffic assignment where the path cost is the sum of the corresponding link costs and a path specific out-of-energy penalty. We then apply the convergent Lagrangian dual method to transform the original problem into a concave maximization problem and develop a customized gradient projection algorithm to solve it. A column generation procedure is incorporated to generate the path set. Finally, two numerical examples are presented to demonstrate the applicability of the proposed model and the solution algorithm. PMID:29543875

Quantum circuit dynamics via path integrals: Is there a classical action for discrete-time paths?

NASA Astrophysics Data System (ADS)

Penney, Mark D.; Enshan Koh, Dax; Spekkens, Robert W.

2017-07-01

It is straightforward to compute the transition amplitudes of a quantum circuit using the sum-over-paths methodology when the gates in the circuit are balanced, where a balanced gate is one for which all non-zero transition amplitudes are of equal magnitude. Here we consider the question of whether, for such circuits, the relative phases of different discrete-time paths through the configuration space can be defined in terms of a classical action, as they are for continuous-time paths. We show how to do so for certain kinds of quantum circuits, namely, Clifford circuits where the elementary systems are continuous-variable systems or discrete systems of odd-prime dimension. These types of circuit are distinguished by having phase-space representations that serve to define their classical counterparts. For discrete systems, the phase-space coordinates are also discrete variables. We show that for each gate in the generating set, one can associate a symplectomorphism on the phase-space and to each of these one can associate a generating function, defined on two copies of the configuration space. For discrete systems, the latter association is achieved using tools from algebraic geometry. Finally, we show that if the action functional for a discrete-time path through a sequence of gates is defined using the sum of the corresponding generating functions, then it yields the correct relative phases for the path-sum expression. These results are likely to be relevant for quantizing physical theories where time is fundamentally discrete, characterizing the classical limit of discrete-time quantum dynamics, and proving complexity results for quantum circuits.

Heterogeneous Data Fusion Method to Estimate Travel Time Distributions in Congested Road Networks

PubMed Central

Lam, William H. K.; Li, Qingquan

2017-01-01

Travel times in congested urban road networks are highly stochastic. Provision of travel time distribution information, including both mean and variance, can be very useful for travelers to make reliable path choice decisions to ensure higher probability of on-time arrival. To this end, a heterogeneous data fusion method is proposed to estimate travel time distributions by fusing heterogeneous data from point and interval detectors. In the proposed method, link travel time distributions are first estimated from point detector observations. The travel time distributions of links without point detectors are imputed based on their spatial correlations with links that have point detectors. The estimated link travel time distributions are then fused with path travel time distributions obtained from the interval detectors using Dempster-Shafer evidence theory. Based on fused path travel time distribution, an optimization technique is further introduced to update link travel time distributions and their spatial correlations. A case study was performed using real-world data from Hong Kong and showed that the proposed method obtained accurate and robust estimations of link and path travel time distributions in congested road networks. PMID:29210978

Heterogeneous Data Fusion Method to Estimate Travel Time Distributions in Congested Road Networks.

PubMed

Shi, Chaoyang; Chen, Bi Yu; Lam, William H K; Li, Qingquan

2017-12-06

Travel times in congested urban road networks are highly stochastic. Provision of travel time distribution information, including both mean and variance, can be very useful for travelers to make reliable path choice decisions to ensure higher probability of on-time arrival. To this end, a heterogeneous data fusion method is proposed to estimate travel time distributions by fusing heterogeneous data from point and interval detectors. In the proposed method, link travel time distributions are first estimated from point detector observations. The travel time distributions of links without point detectors are imputed based on their spatial correlations with links that have point detectors. The estimated link travel time distributions are then fused with path travel time distributions obtained from the interval detectors using Dempster-Shafer evidence theory. Based on fused path travel time distribution, an optimization technique is further introduced to update link travel time distributions and their spatial correlations. A case study was performed using real-world data from Hong Kong and showed that the proposed method obtained accurate and robust estimations of link and path travel time distributions in congested road networks.

SALSA3D: A Tomographic Model of Compressional Wave Slowness in the Earth’s Mantle for Improved Travel-Time Prediction and Travel-Time Prediction Uncertainty

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

Ballard, Sanford; Hipp, James R.; Begnaud, Michael L.

The task of monitoring the Earth for nuclear explosions relies heavily on seismic data to detect, locate, and characterize suspected nuclear tests. In this study, motivated by the need to locate suspected explosions as accurately and precisely as possible, we developed a tomographic model of the compressional wave slowness in the Earth’s mantle with primary focus on the accuracy and precision of travel-time predictions for P and Pn ray paths through the model. Path-dependent travel-time prediction uncertainties are obtained by computing the full 3D model covariance matrix and then integrating slowness variance and covariance along ray paths from source tomore » receiver. Path-dependent travel-time prediction uncertainties reflect the amount of seismic data that was used in tomography with very low values for paths represented by abundant data in the tomographic data set and very high values for paths through portions of the model that were poorly sampled by the tomography data set. The pattern of travel-time prediction uncertainty is a direct result of the off-diagonal terms of the model covariance matrix and underscores the importance of incorporating the full model covariance matrix in the determination of travel-time prediction uncertainty. In addition, the computed pattern of uncertainty differs significantly from that of 1D distance-dependent travel-time uncertainties computed using traditional methods, which are only appropriate for use with travel times computed through 1D velocity models.« less

SALSA3D: A Tomographic Model of Compressional Wave Slowness in the Earth’s Mantle for Improved Travel-Time Prediction and Travel-Time Prediction Uncertainty

DOE PAGES

Ballard, Sanford; Hipp, James R.; Begnaud, Michael L.; ...

2016-10-11

The task of monitoring the Earth for nuclear explosions relies heavily on seismic data to detect, locate, and characterize suspected nuclear tests. In this study, motivated by the need to locate suspected explosions as accurately and precisely as possible, we developed a tomographic model of the compressional wave slowness in the Earth’s mantle with primary focus on the accuracy and precision of travel-time predictions for P and Pn ray paths through the model. Path-dependent travel-time prediction uncertainties are obtained by computing the full 3D model covariance matrix and then integrating slowness variance and covariance along ray paths from source tomore » receiver. Path-dependent travel-time prediction uncertainties reflect the amount of seismic data that was used in tomography with very low values for paths represented by abundant data in the tomographic data set and very high values for paths through portions of the model that were poorly sampled by the tomography data set. The pattern of travel-time prediction uncertainty is a direct result of the off-diagonal terms of the model covariance matrix and underscores the importance of incorporating the full model covariance matrix in the determination of travel-time prediction uncertainty. In addition, the computed pattern of uncertainty differs significantly from that of 1D distance-dependent travel-time uncertainties computed using traditional methods, which are only appropriate for use with travel times computed through 1D velocity models.« less

Real-time Feynman path integral with Picard–Lefschetz theory and its applications to quantum tunneling

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

Tanizaki, Yuya, E-mail: yuya.tanizaki@riken.jp; Theoretical Research Division, Nishina Center, RIKEN, Wako 351-0198; Koike, Takayuki, E-mail: tkoike@ms.u-tokyo.ac.jp

Picard–Lefschetz theory is applied to path integrals of quantum mechanics, in order to compute real-time dynamics directly. After discussing basic properties of real-time path integrals on Lefschetz thimbles, we demonstrate its computational method in a concrete way by solving three simple examples of quantum mechanics. It is applied to quantum mechanics of a double-well potential, and quantum tunneling is discussed. We identify all of the complex saddle points of the classical action, and their properties are discussed in detail. However a big theoretical difficulty turns out to appear in rewriting the original path integral into a sum of path integralsmore » on Lefschetz thimbles. We discuss generality of that problem and mention its importance. Real-time tunneling processes are shown to be described by those complex saddle points, and thus semi-classical description of real-time quantum tunneling becomes possible on solid ground if we could solve that problem. - Highlights: • Real-time path integral is studied based on Picard–Lefschetz theory. • Lucid demonstration is given through simple examples of quantum mechanics. • This technique is applied to quantum mechanics of the double-well potential. • Difficulty for practical applications is revealed, and we discuss its generality. • Quantum tunneling is shown to be closely related to complex classical solutions.« less

Architectural constraints are a major factor reducing path integration accuracy in the rat head direction cell system.

PubMed

Page, Hector J I; Walters, Daniel; Stringer, Simon M

2015-01-01

Head direction cells fire to signal the direction in which an animal's head is pointing. They are able to track head direction using only internally-derived information (path integration)In this simulation study we investigate the factors that affect path integration accuracy. Specifically, two major limiting factors are identified: rise time, the time after stimulation it takes for a neuron to start firing, and the presence of symmetric non-offset within-layer recurrent collateral connectivity. On the basis of the latter, the important prediction is made that head direction cell regions directly involved in path integration will not contain this type of connectivity; giving a theoretical explanation for architectural observations. Increased neuronal rise time is found to slow path integration, and the slowing effect for a given rise time is found to be more severe in the context of short conduction delays. Further work is suggested on the basis of our findings, which represent a valuable contribution to understanding of the head direction cell system.

Cloning and Characterization of the Mouse Hepatitis Virus Receptor

DTIC Science & Technology

1991-02-11

reactivity, but they are readily distinguishable by their host specificity and clinical syndromes . Analysis of murine coronaviruses indicates that...express the HE glycoprotein. The HE gene 23 of MHV-A59 lacks an initiator methionine , and cells infected with MHV-A59 do not make an RNA which would...hepatitis virus. MATERIALS AND METHODS Materials : All radioactive compounds used, a [32p] UTP, a (32P] dCTP, y [32P] ATP, [35S] - methionine and a [35S

Modulation of Ionic Channel Function by Protein Phosphorylation

DTIC Science & Technology

1992-11-12

were prepared from the cloned cDNAs using the SP6 RNA promoter/polymerase system (32) with capping accomplished by priming with cap analogues (33...triphosphate (ATP), cytidine triphosphate (CTP) and uridine triphosphate (UTP) [ct-32p]UTP at 80 Cilmmol; 0.1 mM GTP; 0.5 mM diguanosinetriphosphate; 200 g.g/ml...state NMR spectroscopy . J. Biomol. NMR 1:167-173. (1991). Tomich, J.M., A. Grove, T. Iwamoto, S. Marrer, M.S. Montal and M. Montal. Design principles

Blip decomposition of the path integral: exponential acceleration of real-time calculations on quantum dissipative systems.

PubMed

Makri, Nancy

2014-10-07

The real-time path integral representation of the reduced density matrix for a discrete system in contact with a dissipative medium is rewritten in terms of the number of blips, i.e., elementary time intervals over which the forward and backward paths are not identical. For a given set of blips, it is shown that the path sum with respect to the coordinates of all remaining time points is isomorphic to that for the wavefunction of a system subject to an external driving term and thus can be summed by an inexpensive iterative procedure. This exact decomposition reduces the number of terms by a factor that increases exponentially with propagation time. Further, under conditions (moderately high temperature and/or dissipation strength) that lead primarily to incoherent dynamics, the "fully incoherent limit" zero-blip term of the series provides a reasonable approximation to the dynamics, and the blip series converges rapidly to the exact result. Retention of only the blips required for satisfactory convergence leads to speedup of full-memory path integral calculations by many orders of magnitude.

Path integration of head direction: updating a packet of neural activity at the correct speed using neuronal time constants.

PubMed

Walters, D M; Stringer, S M

2010-07-01

A key question in understanding the neural basis of path integration is how individual, spatially responsive, neurons may self-organize into networks that can, through learning, integrate velocity signals to update a continuous representation of location within an environment. It is of vital importance that this internal representation of position is updated at the correct speed, and in real time, to accurately reflect the motion of the animal. In this article, we present a biologically plausible model of velocity path integration of head direction that can solve this problem using neuronal time constants to effect natural time delays, over which associations can be learned through associative Hebbian learning rules. The model comprises a linked continuous attractor network and competitive network. In simulation, we show that the same model is able to learn two different speeds of rotation when implemented with two different values for the time constant, and without the need to alter any other model parameters. The proposed model could be extended to path integration of place in the environment, and path integration of spatial view.

Project Scheduling Based on Risk of Gas Transmission Pipe

NASA Astrophysics Data System (ADS)

Silvianita; Nurbaity, A.; Mulyadi, Y.; Suntoyo; Chamelia, D. M.

2018-03-01

The planning of a project has a time limit on which must be completed before or right at a predetermined time. Thus, in a project planning, it is necessary to have scheduling management that is useful for completing a project to achieve maximum results by considering the constraints that will exists. Scheduling management is undertaken to deal with uncertainties and negative impacts of time and cost in project completion. This paper explains about scheduling management in gas transmission pipeline project Gresik-Semarang to find out which scheduling plan is most effectively used in accordance with its risk value. Scheduling management in this paper is assissted by Microsoft Project software to find the critical path of existing project scheduling planning data. Critical path is the longest scheduling path with the fastest completion time. The result is found a critical path on project scheduling with completion time is 152 days. Furthermore, the calculation of risk is done by using House of Risk (HOR) method and it is found that the critical path has a share of 40.98 percent of all causes of the occurence of risk events that will be experienced.

Calculating Path-Dependent Travel Time Prediction Variance and Covariance fro a Global Tomographic P-Velocity Model

NASA Astrophysics Data System (ADS)

Ballard, S.; Hipp, J. R.; Encarnacao, A.; Young, C. J.; Begnaud, M. L.; Phillips, W. S.

2012-12-01

Seismic event locations can be made more accurate and precise by computing predictions of seismic travel time through high fidelity 3D models of the wave speed in the Earth's interior. Given the variable data quality and uneven data sampling associated with this type of model, it is essential that there be a means to calculate high-quality estimates of the path-dependent variance and covariance associated with the predicted travel times of ray paths through the model. In this paper, we describe a methodology for accomplishing this by exploiting the full model covariance matrix and show examples of path-dependent travel time prediction uncertainty computed from SALSA3D, our global, seamless 3D tomographic P-velocity model. Typical global 3D models have on the order of 1/2 million nodes, so the challenge in calculating the covariance matrix is formidable: 0.9 TB storage for 1/2 of a symmetric matrix, necessitating an Out-Of-Core (OOC) blocked matrix solution technique. With our approach the tomography matrix (G which includes Tikhonov regularization terms) is multiplied by its transpose (GTG) and written in a blocked sub-matrix fashion. We employ a distributed parallel solution paradigm that solves for (GTG)-1 by assigning blocks to individual processing nodes for matrix decomposition update and scaling operations. We first find the Cholesky decomposition of GTG which is subsequently inverted. Next, we employ OOC matrix multiplication methods to calculate the model covariance matrix from (GTG)-1 and an assumed data covariance matrix. Given the model covariance matrix, we solve for the travel-time covariance associated with arbitrary ray-paths by summing the model covariance along both ray paths. Setting the paths equal and taking the square root yields the travel prediction uncertainty for the single path.

Robotic path-finding in inverse treatment planning for stereotactic radiosurgery with continuous dose delivery

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

Vandewouw, Marlee M., E-mail: marleev@mie.utoronto

Purpose: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife® Perfexion™ that continuously delivers dose along a path in the target. Methods: The authors’ method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, aremore » used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry. Results: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and-shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution. Conclusions: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and-shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies.« less

Coupled long term simulation of reach scale water and heat fluxes across the river groundwater interface and hyporheic temperature dynamics

NASA Astrophysics Data System (ADS)

Munz, Matthias; Oswald, Sascha E.; Schmidt, Christian

2017-04-01

Flow pattern and seasonal as well as diurnal temperature variations control ecological and biogeochemical conditions in hyporheic sediments. In particular, hyporheic temperatures have a great impact on many microbial processes. In this study we used 3-D coupled water flow and heat transport simulations applying the HydroGeoSphere code in combination with high frequent observations of hydraulic heads and temperatures for quantifying reach scale water and heat flux across the river groundwater interface and hyporheic temperature dynamics of a lowland gravel-bed river. The magnitude and dynamics of simulated temperatures matched the observed with an average mean absolute error of 0.7 °C and an average Nash Sutcliffe Efficiency of 0.87. Our results highlight that the average temperature in the hyporheic zone follows the temperature in the river which is characterized by distinct seasonal and daily temperature cycles. Individual hyporheic flow path temperature substantially varies around the average hyporheic temperature. Hyporheic flow path temperature was found to strongly depend on the flow path residence time and the temperature gradient between river and groundwater; that is, in winter the average flow path temperature of long flow paths is potentially higher compared to short flow paths. Based on the simulation results we derived a general empirical relationship, estimating the influence of hyporheic flow path residence time on hyporheic flow path temperature. Furthermore we used an empirical temperature relationship between effective temperature and respiration rate to estimate the influence of hyporheic flow path residence time and temperature on hyporheic oxygen consumption. This study highlights the relation between complex hyporheic temperature patterns, hyporheic residence times and their implications on temperature sensitive biogeochemical processes.

Terrain classification in navigation of an autonomous mobile robot

NASA Astrophysics Data System (ADS)

Dodds, David R.

1991-03-01

In this paper we describe a method of path planning that integrates terrain classification (by means of fractals) the certainty grid method of spatial representation Kehtarnavaz Griswold collision-zones Dubois Prade fuzzy temporal and spatial knowledge and non-point sized qualitative navigational planning. An initially planned (" end-to-end" ) path is piece-wise modified to accommodate known and inferred moving obstacles and includes attention to time-varying multiple subgoals which may influence a section of path at a time after the robot has begun traversing that planned path.

Time signal distribution in communication networks based on synchronous digital hierarchy

NASA Technical Reports Server (NTRS)

Imaoka, Atsushi; Kihara, Masami

1993-01-01

A new method that uses round-trip paths to accurately measure transmission delay for time synchronization is proposed. The performance of the method in Synchronous Digital Hierarchy networks is discussed. The feature of this method is that it separately measures the initial round trip path delay and the variations in round-trip path delay. The delay generated in SDH equipment is determined by measuring the initial round-trip path delay. In an experiment with actual SDH equipment, the error of initial delay measurement was suppressed to 30ns.

High frequency modulation circuits based on photoconductive wide bandgap switches

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

Sampayan, Stephen

Methods, systems, and devices for high voltage and/or high frequency modulation. In one aspect, an optoelectronic modulation system includes an array of two or more photoconductive switch units each including a wide bandgap photoconductive material coupled between a first electrode and a second electrode, a light source optically coupled to the WBGP material of each photoconductive switch unit via a light path, in which the light path splits into multiple light paths to optically interface with each WBGP material, such that a time delay of emitted light exists along each subsequent split light path, and in which the WBGP materialmore » conducts an electrical signal when a light signal is transmitted to the WBGP material, and an output to transmit the electrical signal conducted by each photoconductive switch unit. The time delay of the photons emitted through the light path is substantially equivalent to the time delay of the electrical signal.« less

From waste to resource: a systems-based approach to sustainable community development through equitable enterprise and agriculturally-derived polymeric composites

NASA Astrophysics Data System (ADS)

Teipel, Elisa

Rural communities in developing countries are most vulnerable to the plight of requiring repeated infusions of charitable aid over time. Micro-business opportunities that effectively break the cycle of poverty in resource-rich countries in the developing world are limited. However, a strong model for global commerce can break the cycle of donor-based economic supplements and limited local economic growth. Sustainable economic development can materialize when a robust framework combines engineering with the generous investment of profits back into the community. This research presents a novel, systems-based approach to sustainable community development in which a waste-to-resource methodology catalyzes the disruption of rural poverty. The framework developed in this thesis was applied to the rural communities of Cagmanaba and Badian, Philippines. An initial assessment of these communities showed that community members are extremely poor, but they possess an abundant natural resource: coconuts. The various parts of the coconut offer excellent potential value in global commerce. Today the sale of coconut water is on the rise, and coconut oil is an established $3 billion market annually that is also growing rapidly. Since these current industries harvest only two parts of the coconut (meat and water), the 50 billion coconuts that grow annually leave behind approximately 100 billion pounds of coconut shell and husk as agricultural waste. Coconuts thus provide an opportunity to create and test a waste-to-resource model. Intensive materials analysis, research, development, and optimization proved that coconut shell, currently burned as a fuel or discarded as agricultural waste, can be manufactured into high-grade coconut shell powder (CSP), which can be a viable filler in polymeric composites. This framework was modeled and tested as a case study in a manufacturing facility known as a Community Transformation Plant (CTP) in Cagmanaba, Philippines. The CTP enables local creation of globally viable products from agricultural waste. This researcher seeks to encourage the propagation of CTPs throughout developing communities worldwide, each profiting from its own waste-to-resource value.

SU-F-R-51: Radiomics in CT Perfusion Maps of Head and Neck Cancer

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

Nesteruk, M; Riesterer, O; Veit-Haibach, P

2016-06-15

Purpose: The aim of this study was to test the predictive value of radiomics features of CT perfusion (CTP) for tumor control, based on a preselection of radiomics features in a robustness study. Methods: 11 patients with head and neck cancer (HNC) and 11 patients with lung cancer were included in the robustness study to preselect stable radiomics parameters. Data from 36 HNC patients treated with definitive radiochemotherapy (median follow-up 30 months) was used to build a predictive model based on these parameters. All patients underwent pre-treatment CTP. 315 texture parameters were computed for three perfusion maps: blood volume, bloodmore » flow and mean transit time. The variability of texture parameters was tested with respect to non-standardizable perfusion computation factors (noise level and artery contouring) using intraclass correlation coefficients (ICC). The parameter with the highest ICC in the correlated group of parameters (inter-parameter Spearman correlations) was tested for its predictive value. The final model to predict tumor control was built using multivariate Cox regression analysis with backward selection of the variables. For comparison, a predictive model based on tumor volume was created. Results: Ten parameters were found to be stable in both HNC and lung cancer regarding potentially non-standardizable factors after the correction for inter-parameter correlations. In the multivariate backward selection of the variables, blood flow entropy showed a highly significant impact on tumor control (p=0.03) with concordance index (CI) of 0.76. Blood flow entropy was significantly lower in the patient group with controlled tumors at 18 months (p<0.1). The new model showed a higher concordance index compared to the tumor volume model (CI=0.68). Conclusion: The preselection of variables in the robustness study allowed building a predictive radiomics-based model of tumor control in HNC despite a small patient cohort. This model was found to be superior to the volume-based model. The project was supported by the KFSP Tumor Oxygenation of the University of Zurich, by a grant of the Center for Clinical Research, University and University Hospital Zurich and by a research grant from Merck (Schweiz) AG.« less

Understanding and applying open-path optical sensing data

NASA Astrophysics Data System (ADS)

Virag, Peter; Kricks, Robert J.

1999-02-01

During the last 10 years, open-path air monitors have evolved to yield reliable and effective measurements of single and multiple compounds on a real-time basis. To many individuals within the optical remote sensing community, the attributes of open-path and its the potential uses seem unlimited. Then why has the market has been stagnant for the last few years? The reason may center on how open-path information is applied and how well the end user understands that information. We constantly try to compare open-path data to risk/health or safety levels that are based for use at a single point and for a specific averaging period often far longer than a typical open-path data point. Often this approach is perceived as putting a square peg in a round hole. This perception may be well founded, as open-path data at times may need to go through extensive data manipulation and assumptions before it can be applied. This paper will review pervious open-path monitoring programs and their success in applying the data collected. We will also look at how open-path data is being currently used, some previous pitfalls in data use, alternate methods of data interpretation, and how open-path data can be best practically applied to fit current needs.

Curvature and torsion in growing actin networks

NASA Astrophysics Data System (ADS)

Shaevitz, Joshua W.; Fletcher, Daniel A.

2008-06-01

Intracellular pathogens such as Listeria monocytogenes and Rickettsia rickettsii move within a host cell by polymerizing a comet-tail of actin fibers that ultimately pushes the cell forward. This dense network of cross-linked actin polymers typically exhibits a striking curvature that causes bacteria to move in gently looping paths. Theoretically, tail curvature has been linked to details of motility by considering force and torque balances from a finite number of polymerizing filaments. Here we track beads coated with a prokaryotic activator of actin polymerization in three dimensions to directly quantify the curvature and torsion of bead motility paths. We find that bead paths are more likely to have low rather than high curvature at any given time. Furthermore, path curvature changes very slowly in time, with an autocorrelation decay time of 200 s. Paths with a small radius of curvature, therefore, remain so for an extended period resulting in loops when confined to two dimensions. When allowed to explore a three-dimensional (3D) space, path loops are less evident. Finally, we quantify the torsion in the bead paths and show that beads do not exhibit a significant left- or right-handed bias to their motion in 3D. These results suggest that paths of actin-propelled objects may be attributed to slow changes in curvature, possibly associated with filament debranching, rather than a fixed torque.

An improved global dynamic routing strategy for scale-free network with tunable clustering

NASA Astrophysics Data System (ADS)

Sun, Lina; Huang, Ning; Zhang, Yue; Bai, Yannan

2016-08-01

An efficient routing strategy can deliver packets quickly to improve the network capacity. Node congestion and transmission path length are inevitable real-time factors for a good routing strategy. Existing dynamic global routing strategies only consider the congestion of neighbor nodes and the shortest path, which ignores other key nodes’ congestion on the path. With the development of detection methods and techniques, global traffic information is readily available and important for the routing choice. Reasonable use of this information can effectively improve the network routing. So, an improved global dynamic routing strategy is proposed, which considers the congestion of all nodes on the shortest path and incorporates the waiting time of the most congested node into the path. We investigate the effectiveness of the proposed routing for scale-free network with different clustering coefficients. The shortest path routing strategy and the traffic awareness routing strategy only considering the waiting time of neighbor node are analyzed comparatively. Simulation results show that network capacity is greatly enhanced compared with the shortest path; congestion state increase is relatively slow compared with the traffic awareness routing strategy. Clustering coefficient increase will not only reduce the network throughput, but also result in transmission average path length increase for scale-free network with tunable clustering. The proposed routing is favorable to ease network congestion and network routing strategy design.

Path Complexity in Virtual Water Maze Navigation: Differential Associations with Age, Sex, and Regional Brain Volume.

PubMed

Daugherty, Ana M; Yuan, Peng; Dahle, Cheryl L; Bender, Andrew R; Yang, Yiqin; Raz, Naftali

2015-09-01

Studies of human navigation in virtual maze environments have consistently linked advanced age with greater distance traveled between the start and the goal and longer duration of the search. Observations of search path geometry suggest that routes taken by older adults may be unnecessarily complex and that excessive path complexity may be an indicator of cognitive difficulties experienced by older navigators. In a sample of healthy adults, we quantify search path complexity in a virtual Morris water maze with a novel method based on fractal dimensionality. In a two-level hierarchical linear model, we estimated improvement in navigation performance across trials by a decline in route length, shortening of search time, and reduction in fractal dimensionality of the path. While replicating commonly reported age and sex differences in time and distance indices, a reduction in fractal dimension of the path accounted for improvement across trials, independent of age or sex. The volumes of brain regions associated with the establishment of cognitive maps (parahippocampal gyrus and hippocampus) were related to path dimensionality, but not to the total distance and time. Thus, fractal dimensionality of a navigational path may present a useful complementary method of quantifying performance in navigation. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A two-stage path planning approach for multiple car-like robots based on PH curves and a modified harmony search algorithm

NASA Astrophysics Data System (ADS)

Zeng, Wenhui; Yi, Jin; Rao, Xiao; Zheng, Yun

2017-11-01

In this article, collision-avoidance path planning for multiple car-like robots with variable motion is formulated as a two-stage objective optimization problem minimizing both the total length of all paths and the task's completion time. Accordingly, a new approach based on Pythagorean Hodograph (PH) curves and Modified Harmony Search algorithm is proposed to solve the two-stage path-planning problem subject to kinematic constraints such as velocity, acceleration, and minimum turning radius. First, a method of path planning based on PH curves for a single robot is proposed. Second, a mathematical model of the two-stage path-planning problem for multiple car-like robots with variable motion subject to kinematic constraints is constructed that the first-stage minimizes the total length of all paths and the second-stage minimizes the task's completion time. Finally, a modified harmony search algorithm is applied to solve the two-stage optimization problem. A set of experiments demonstrate the effectiveness of the proposed approach.

Multifold paths of neutrons in the three-beam interferometer detected by a tiny energy kick

NASA Astrophysics Data System (ADS)

Geppert-Kleinrath, Hermann; Denkmayr, Tobias; Sponar, Stephan; Lemmel, Hartmut; Jenke, Tobias; Hasegawa, Yuji

2018-05-01

A neutron optical experiment is presented to investigate the paths taken by neutrons in a three-beam interferometer. In various beam paths of the interferometer, the energy of the neutrons is partially shifted so that the faint traces are left along the beam path. By ascertaining an operational meaning to "the particle's path," which-path information is extracted from these faint traces with minimal perturbations. Theory is derived by simply following the time evolution of the wave function of the neutrons, which clarifies the observation in the framework of standard quantum mechanics. Which-way information is derived from the intensity, sinusoidally oscillating in time at different frequencies, which is considered to result from the interfering cross terms between stationary main component and the energy-shifted which-way signals. Final results give experimental evidence that the (partial) wave functions of the neutrons in each beam path are superimposed and present in multiple locations in the interferometer.

Energy consumption of ProTaper Next X1 after glide path with PathFiles and ProGlider.

PubMed

Berutti, Elio; Alovisi, Mario; Pastorelli, Michele Angelo; Chiandussi, Giorgio; Scotti, Nicola; Pasqualini, Damiano

2014-12-01

Instrument failure caused by excessive torsional stress can be controlled by creating a manual or mechanical glide path. The ProGlider single-file system (Dentsply Maillefer, Ballaigues, Switzerland) was recently introduced to perform a mechanical glide path. This study was designed to compare the effect of a glide path performed with PathFiles (Dentsply Maillefer) and ProGlider on torque, time, and pecking motion required for ProTaper Next X1 (Dentsply Maillefer) to reach the full working length in simulated root canals. Forty Endo Training Blocks (Dentsply Maillefer) were used. Twenty were prepared with a mechanical glide path using PathFiles 1 and 2 (the PathFile group), and 20 were prepared with a mechanical glide path using a ProGlider single file (the ProGlider group). All samples were shaped with ProTaper Next X1 driven by an endodontic motor connected to a digital wattmeter. The required torque for root canal instrumentation was analyzed by evaluating the electrical power consumption of the endodontic engine. Electric power consumption (mW/h), elapsed time (seconds), and number of pecking motions required to reach the full working length with ProTaper Next X1 were calculated. Differences among groups were analyzed with the parametric Student t test for independent data (P < .05). Elapsed time and electric power consumption were significantly different between groups (P = .0001 for both). ProGlider appears to perform more efficiently than PathFiles in decreasing electric power consumption of ProTaper Next X1 to reach the full working length. This study confirmed the ability of ProGlider to reduce stress in ProTaper Next X1 during shaping through a glide path and preliminary middle and coronal preflaring. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Path integration of the time-dependent forced oscillator with a two-time quadratic action

NASA Astrophysics Data System (ADS)

Zhang, Tian Rong; Cheng, Bin Kang

1986-03-01

Using the prodistribution theory proposed by DeWitt-Morette [C. DeWitt-Morette, Commun. Math. Phys. 28, 47 (1972); C. DeWitt-Morette, A. Maheshwari, and B. Nelson, Phys. Rep. 50, 257 (1979)], the path integration of a time-dependent forced harmonic oscillator with a two-time quadratic action has been given in terms of the solutions of some integrodifferential equations. We then evaluate explicitly both the classical path and the propagator for the specific kernel introduced by Feynman in the polaron problem. Our results include the previous known results as special cases.

Fast exploration of an optimal path on the multidimensional free energy surface

PubMed Central

Chen, Changjun

2017-01-01

In a reaction, determination of an optimal path with a high reaction rate (or a low free energy barrier) is important for the study of the reaction mechanism. This is a complicated problem that involves lots of degrees of freedom. For simple models, one can build an initial path in the collective variable space by the interpolation method first and then update the whole path constantly in the optimization. However, such interpolation method could be risky in the high dimensional space for large molecules. On the path, steric clashes between neighboring atoms could cause extremely high energy barriers and thus fail the optimization. Moreover, performing simulations for all the snapshots on the path is also time-consuming. In this paper, we build and optimize the path by a growing method on the free energy surface. The method grows a path from the reactant and extends its length in the collective variable space step by step. The growing direction is determined by both the free energy gradient at the end of the path and the direction vector pointing at the product. With fewer snapshots on the path, this strategy can let the path avoid the high energy states in the growing process and save the precious simulation time at each iteration step. Applications show that the presented method is efficient enough to produce optimal paths on either the two-dimensional or the twelve-dimensional free energy surfaces of different small molecules. PMID:28542475

Methodology for Augmenting Existing Paths with Additional Parallel Transects

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

Wilson, John E.

2013-09-30

Visual Sample Plan (VSP) is sample planning software that is used, among other purposes, to plan transect sampling paths to detect areas that were potentially used for munition training. This module was developed for application on a large site where existing roads and trails were to be used as primary sampling paths. Gap areas between these primary paths needed to found and covered with parallel transect paths. These gap areas represent areas on the site that are more than a specified distance from a primary path. These added parallel paths needed to optionally be connected together into a single path—themore » shortest path possible. The paths also needed to optionally be attached to existing primary paths, again with the shortest possible path. Finally, the process must be repeatable and predictable so that the same inputs (primary paths, specified distance, and path options) will result in the same set of new paths every time. This methodology was developed to meet those specifications.« less

Objectively-measured outdoor time and physical and psychological function among older adults.

PubMed

Harada, Kazuhiro; Lee, Sangyoon; Lee, Sungchul; Bae, Seongryu; Harada, Kenji; Suzuki, Takao; Shimada, Hiroyuki

2017-10-01

Objective measurements of outdoor time are essential to establishing evidence about the health benefits of going outdoors among older adults. To better understanding the health benefits of going outdoors, clarification of potential mediators to connect going outdoors with health benefits is necessary. The present study aimed to investigate associations of objectively-measured outdoor time with older adults' physical and psychological function, and examine the mediating role of physical activity on these associations. Baseline data from a randomized control trial of physical activity among older adults with global cognitive impairment was used. Data from 192 participants were analyzed. Measures included steps-per-day, objectively-measured outdoor time per day using global positioning systems, physical function (cardiorespiratory fitness, lower-extremity strength), psychological function (depression, well-being) and basic factors. Path analysis showed that outdoor time was significantly associated with steps-per-day (path coefficient = 0.23) and depression (path coefficient = -0.16). Outdoor time was not directly associated with cardiorespiratory fitness, lower-extremity strength and well-being. However, steps-per-day was associated with cardiorespiratory fitness (path coefficient = 0.18), lower-extremity strength (path coefficient = -0.22) and well-being (path coefficient = 0.14). We found that objectively-measured outdoor time was indirectly associated with physical function, and both directly and indirectly with psychological function through physical activity among older adults. This finding indicates that going outdoors influences older adults' health outcomes, and is mainly mediated by physical activity. Geriatr Gerontol Int 2017; 17: 1455-1462. © 2016 Japan Geriatrics Society.

The Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans: Toward Comparative Effectiveness in the Pediatric Rheumatic Diseases.

PubMed

Ringold, Sarah; Nigrovic, Peter A; Feldman, Brian M; Tomlinson, George A; von Scheven, Emily; Wallace, Carol A; Huber, Adam M; Schanberg, Laura E; Li, Suzanne C; Weiss, Pamela F; Fuhlbrigge, Robert C; Morgan, Esi M; Kimura, Yukiko

2018-05-01

The pediatric rheumatic diseases are a heterogeneous group of rare diseases, posing a number of challenges for the use of traditional clinical and translational research methods. Innovative comparative effectiveness approaches are needed to efficiently study treatment strategies and disease outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed the consensus treatment plan (CTP) approach as a comparative effectiveness tool for research in pediatric rheumatology. CTPs are treatment strategies, developed by consensus methods among CARRA members, intended to reduce variation in treatment approaches, standardize outcome measurements, and allow for comparison of the effectiveness of different approaches with the goal of improving disease outcomes. To date, CTPs have been published for 8 different diseases and disease manifestations. The approach has been successfully piloted for juvenile localized scleroderma, systemic juvenile idiopathic arthritis (JIA), polyarticular JIA, dermatomyositis, and lupus nephritis. Large-scale studies are underway for systemic JIA and polyarticular JIA, with the CARRA patient registry serving as the data collection platform. These studies have been designed with stakeholder involvement, including active input from CARRA providers, patients, and parents, with the goal of increasing feasibility and ensuring the relevance of the outcomes. These studies include ancillary biologic specimen collection intended to support additional translational and mechanistic studies. Data from these ongoing CTP studies will provide more information on the ability of this approach to identify effective treatment strategies and improve outcomes in the pediatric rheumatic diseases. © 2018, American College of Rheumatology.

Personal protective equipment for the Ebola virus disease: A comparison of 2 training programs.

PubMed

Casalino, Enrique; Astocondor, Eugenio; Sanchez, Juan Carlos; Díaz-Santana, David Enrique; Del Aguila, Carlos; Carrillo, Juan Pablo

2015-12-01

Personal protective equipment (PPE) for preventing Ebola virus disease (EVD) includes basic PPE (B-PPE) and enhanced PPE (E-PPE). Our aim was to compare conventional training programs (CTPs) and reinforced training programs (RTPs) on the use of B-PPE and E-PPE. Four groups were created, designated CTP-B, CTP-E, RTP-B, and RTP-E. All groups received the same theoretical training, followed by 3 practical training sessions. A total of 120 students were included (30 per group). In all 4 groups, the frequency and number of total errors and critical errors decreased significantly over the course of the training sessions (P < .01). The RTP was associated with a greater reduction in the number of total errors and critical errors (P < .0001). During the third training session, we noted an error frequency of 7%-43%, a critical error frequency of 3%-40%, 0.3-1.5 total errors, and 0.1-0.8 critical errors per student. The B-PPE groups had the fewest errors and critical errors (P < .0001). Our results indicate that both training methods improved the student's proficiency, that B-PPE appears to be easier to use than E-PPE, that the RTP achieved better proficiency for both PPE types, and that a number of students are still potentially at risk for EVD contamination despite the improvements observed during the training. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Pharmacology of biosimilar candidate drugs in rheumatology: a literature review.

PubMed

Araújo, F; Cordeiro, I; Teixeira, F; Gonçalves, J; Fonseca, J E

2014-01-01

To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis.

Expression of phosphatidylcholine biosynthetic enzymes during early embryogenesis in the amphibian Bufo arenarum.

PubMed

Fernández-Bussy, Rodrigo; Mouguelar, Valeria; Banchio, Claudia; Coux, Gabriela

2015-04-01

In the principal route of phosphatidylcholine (PC) synthesis the regulatory steps are catalysed by CTP:phosphocholine cytidylyltransferase (CCT) and choline kinase (CK). Knock-out mice in Pcyt1a (CCT gene) and Chka1 (CK gene) resulted in preimplantation embryonic lethality, demonstrating the essential role of this pathway. However, there is still a lack of detailed CCT and CK expression analysis during development. The aim of the current work was to study the expression during early development of both enzymes in the external-fertilization vertebrate Bufo arenarum. Reverse transcription polymerase chain reaction (RT-PCR) and western blot confirmed their presence in unfertilized eggs. Analysis performed in total extracts from staged embryos showed constant protein levels of both enzymes until the 32-cell stage: then they decreased, reaching a minimum in the gastrula before starting to recover. CTP:phosphocholine cytidylyltransferase is an amphitropic enzyme that inter-converts between cytosolic inactive and membrane-bound active forms. Immunoblot analysis demonstrated that the cytosolic:total CCT protein ratio does not change throughout embryogenesis, suggesting a progressive decline of CCT activity in early development. However, PC (and phosphatidylethanolamine) content per egg/embryo remained constant throughout the stages analysed. In conclusion, the current data for B. arenarum suggest that net synthesis of PC mediated by CCT and CK is not required in early development and that supplies for membrane biosynthesis are fulfilled by lipids already present in the egg/embryo reservoirs.

Production data in media systems and press front ends: capture, formats and database methods

NASA Astrophysics Data System (ADS)

Karttunen, Simo

1997-02-01

The nature, purpose and data presentation features of media jobs are analyzed in relation to the content, document, process and resource management in media production. Formats are the natural way of presenting, collecting and storing information, contents, document components and final documents. The state of the art and the trends in the media formats and production data are reviewed. The types and the amount of production data are listed, e.g. events, schedules, product descriptions, reports, visual support, quality, process states and color data. The data exchange must be vendor-neutral. Adequate infrastructure and system architecture are defined for production and media data. The roles of open servers and intranets are evaluated and their potential roles as future solutions are anticipated. The press frontend is the part of print media production where large files dominate. The new output alternatives, i.e. film recorders, direct plate output (CTP and CTP-on-press) and digital, plateless printing lines need new workflow tools and very efficient file and format management. The paper analyzes the capture, formatting and storing of job files and respective production data, such as the event logs of the processes. Intranet, browsers, Java applets and open web severs will be used to capture production data, especially where intranets are used anyhow, or where several companies are networked to plan, design and use documents and printed products. The user aspects of installing intranets is stressed since there are numerous more traditional and more dedicated networking solutions on the market.

Predictor laws for pictorial flight displays

NASA Technical Reports Server (NTRS)

Grunwald, A. J.

1985-01-01

Two predictor laws are formulated and analyzed: (1) a circular path law based on constant accelerations perpendicular to the path and (2) a predictor law based on state transition matrix computations. It is shown that for both methods the predictor provides the essential lead zeros for the path-following task. However, in contrast to the circular path law, the state transition matrix law furnishes the system with additional zeros that entirely cancel out the higher-frequency poles of the vehicle dynamics. On the other hand, the circular path law yields a zero steady-state error in following a curved trajectory with a constant radius. A combined predictor law is suggested that utilizes the advantages of both methods. A simple analysis shows that the optimal prediction time mainly depends on the level of precision required in the path-following task, and guidelines for determining the optimal prediction time are given.

Analysis of water flow paths: methodology and example calculations for a potential geological repository in Sweden.

PubMed

Werner, Kent; Bosson, Emma; Berglund, Sten

2006-12-01

Safety assessment related to the siting of a geological repository for spent nuclear fuel deep in the bedrock requires identification of potential flow paths and the associated travel times for radionuclides originating at repository depth. Using the Laxemar candidate site in Sweden as a case study, this paper describes modeling methodology, data integration, and the resulting water flow models, focusing on the Quaternary deposits and the upper 150 m of the bedrock. Example simulations identify flow paths to groundwater discharge areas and flow paths in the surface system. The majority of the simulated groundwater flow paths end up in the main surface waters and along the coastline, even though the particles used to trace the flow paths are introduced with a uniform spatial distribution at a relatively shallow depth. The calculated groundwater travel time, determining the time available for decay and retention of radionuclides, is on average longer to the coastal bays than to other biosphere objects at the site. Further, it is demonstrated how GIS-based modeling can be used to limit the number of surface flow paths that need to be characterized for safety assessment. Based on the results, the paper discusses an approach for coupling the present models to a model for groundwater flow in the deep bedrock.

Surface Navigation Using Optimized Waypoints and Particle Swarm Optimization

NASA Technical Reports Server (NTRS)

Birge, Brian

2013-01-01

The design priority for manned space exploration missions is almost always placed on human safety. Proposed manned surface exploration tasks (lunar, asteroid sample returns, Mars) have the possibility of astronauts traveling several kilometers away from a home base. Deviations from preplanned paths are expected while exploring. In a time-critical emergency situation, there is a need to develop an optimal home base return path. The return path may or may not be similar to the outbound path, and what defines optimal may change with, and even within, each mission. A novel path planning algorithm and prototype program was developed using biologically inspired particle swarm optimization (PSO) that generates an optimal path of traversal while avoiding obstacles. Applications include emergency path planning on lunar, Martian, and/or asteroid surfaces, generating multiple scenarios for outbound missions, Earth-based search and rescue, as well as human manual traversal and/or path integration into robotic control systems. The strategy allows for a changing environment, and can be re-tasked at will and run in real-time situations. Given a random extraterrestrial planetary or small body surface position, the goal was to find the fastest (or shortest) path to an arbitrary position such as a safe zone or geographic objective, subject to possibly varying constraints. The problem requires a workable solution 100% of the time, though it does not require the absolute theoretical optimum. Obstacles should be avoided, but if they cannot be, then the algorithm needs to be smart enough to recognize this and deal with it. With some modifications, it works with non-stationary error topologies as well.

Time-Critical Cooperative Path Following of Multiple UAVs: Case Studies

DTIC Science & Technology

2012-10-30

control algorithm for UAVs in 3D space. Section IV derives a strategy for time-critical cooperative path following of multiple UAVs that relies on the...UAVs in 3D space, in which a fleet of UAVs is tasked to converge to and follow a set of desired feasible paths so as to meet spatial and temporal...cooperative trajectory generation is not addressed in this paper. In fact, it is assumed that a set of desired 3D time trajectories pd,i(td) : R → R3

Quantitative assessment of local perfusion change in acute intracerebral hemorrhage areas with and without "dynamic spot sign" using CT perfusion imaging.

PubMed

Fu, Fan; Sui, Binbin; Liu, Liping; Su, Yaping; Sun, Shengjun; Li, Yingying

2018-01-01

Background Positive "dynamic spot sign" has been proven to be a potential risk factor for acute intracerebral hemorrhage (ICH) expansion, but local perfusion change has not been quantitatively investigated. Purpose To quantitatively evaluate perfusion changes at the ICH area using computed tomography perfusion (CTP) imaging. Material and Methods Fifty-three patients with spontaneous ICH were recruited. Unenhanced computed tomography (NCCT), CTP within 6 h, and follow-up NCCT were performed for 21 patients in the "spot sign"-positive group and 32 patients in the control group. Cerebral perfusion change was quantitatively measured on regional cerebral blood flow/regional cerebral blood volume (rCBF/rCBV) maps. Regions of interest (ROIs) were set at the "spot-sign" region and the whole hematoma area for "spot-sign"-positive cases, and at one of the highest values of three interested areas and the whole hematoma area for the control group. Hematoma expansion was determined by follow-up NCCT. Results For the "spot-sign"-positive group, the average rCBF (rCBV) values at the "spot-sign" region and the whole hematoma area were 21.34 ± 15.24 mL/min/100 g (21.64 ± 21.48 mL/100g) and 5.78 ± 6.32 mL/min/100 g (6.07 ± 5.45 mL/100g); for the control group, the average rCBF (rCBV) values at the interested area and whole hematoma area were 2.50 ± 1.83 mL/min/100 g (3.13 ± 1.96 mL/100g) and 3.02 ± 1.80 mL/min/100 g (3.40 ± 1.44 mL/100g), respectively. Average rCBF and rCBV values of the "spot-sign" region were significantly different from other regions ( P < 0.001; P = 0.004). The average volumes of hematoma expansion in the "spot-sign"-positive and control groups were 25.24 ± 19.38 mL and -0.41 ± 1.34 mL, respectively. Conclusion The higher perfusion change at ICH on CTP images may reflect the contrast extravasation and be associated with the hematoma expansion.

The REFANI-S study protocol: a non-randomised cluster controlled trial to assess the role of an unconditional cash transfer, a non-food item kit, and free piped water in reducing the risk of acute malnutrition among children aged 6-59 months living in camps for internally displaced persons in the Afgooye corridor, Somalia.

PubMed

Jelle, Mohamed; Grijalva-Eternod, Carlos S; Haghparast-Bidgoli, Hassan; King, Sarah; Cox, Cassy L; Skordis-Worrall, Jolene; Morrison, Joanna; Colbourn, Timothy; Fottrell, Edward; Seal, Andrew J

2017-07-06

The prevalence of acute malnutrition is often high in emergency-affected populations and is associated with elevated mortality risk and long-term health consequences. Increasingly, cash transfer programmes (CTP) are used instead of direct food aid as a nutritional intervention, but there is sparse evidence on their nutritional impact. We aim to understand whether CTP reduces acute malnutrition and its known risk factors. A non-randomised, cluster-controlled trial will assess the impact of an unconditional cash transfer of US$84 per month for 5 months, a single non-food items kit, and free piped water on the risk of acute malnutrition in children, aged 6-59 months. The study will take place in camps for internally displaced persons (IDP) in peri-urban Mogadishu, Somalia. A cluster will consist of one IDP camp and 10 camps will be allocated to receive the intervention based on vulnerability targeting criteria. The control camps will then be selected from the same geographical area. Needs assessment data indicates small differences in vulnerability between camps. In each trial arm, 120 households will be randomly sampled and two detailed household surveys will be implemented at baseline and 3 months after the initiation of the cash transfer. The survey questionnaire will cover risk factors for malnutrition including household expenditure, assets, food security, diet diversity, coping strategies, morbidity, WASH, and access to health care. A community surveillance system will collect monthly mid-upper arm circumference measurements from all children aged 6-59 months in the study clusters to assess the incidence of acute malnutrition over the duration of the intervention. Process evaluation data will be compiled from routine quantitative programme data and primary qualitative data collected using key informant interviews and focus group discussions. The UK Department for International Development will provide funding for this study. The European Civil Protection and Humanitarian Aid Operations will fund the intervention. Concern Worldwide will implement the intervention as part of their humanitarian programming. This non-randomised cluster controlled trial will provide needed evidence on the role of unconditional CTP in reducing the risk of acute malnutrition among IDP in this context. ISRCTN29521514 . Registered 19 January 2016.

Hormonal regulation of phosphatidylcholine synthesis by reversible modulation of cytidylyltransferase.

PubMed Central

Kelly, K L; Gutierrez, G; Martin, A

1988-01-01

The effect of both lipolytic and antilipolytic hormones on the turnover of phosphatidylcholine in freshly isolated rat adipocytes was investigated. Treatment of adipocytes with agonists such as glucagon or isoprenaline that stimulate lipolysis through a cyclic AMP-dependent mechanism caused an increase in the incorporation of [Me-3H]choline into phosphatidylcholine. Pulse-chase studies indicated that the stimulation was due to an increase in the conversion of choline into phosphatidylcholine, which was both time- and dose-dependent. The stimulatory effect of isoprenaline was inhibited in a dose-dependent manner by oxytocin or insulin. Oxytocin inhibited the incorporation of [Me-3H]choline into phosphatidylcholine in both the presence and the absence of isoprenaline, whereas in the absence of isoprenaline insulin increased the incorporation of [Me-3H]choline into phosphatidylcholine. The effects of isoprenaline, oxytocin and insulin on the incorporation of [3H]choline into phosphatidylcholine were paralleled by changes in the activity of CTP:phosphocholine cytidylyltransferase. PMID:2849424

A path planning method used in fluid jet polishing eliminating lightweight mirror imprinting effect

NASA Astrophysics Data System (ADS)

Li, Wenzong; Fan, Bin; Shi, Chunyan; Wang, Jia; Zhuo, Bin

2014-08-01

With the development of space technology, the design of optical system tends to large aperture lightweight mirror with high dimension-thickness ratio. However, when the lightweight mirror PV value is less than λ/10 , the surface will show wavy imprinting effect obviously. Imprinting effect introduced by head-tool pressure has become a technological barrier in high-precision lightweight mirror manufacturing. Fluid jet polishing can exclude outside pressure. Presently, machining tracks often used are grating type path, screw type path and pseudo-random path. On the edge of imprinting error, the speed of adjacent path points changes too fast, which causes the machine hard to reflect quickly, brings about new path error, and increases the polishing time due to superfluous path. This paper presents a new planning path method to eliminate imprinting effect. Simulation results show that the path of the improved grating path can better eliminate imprinting effect compared to the general path.

Pseudo-random tool paths for CNC sub-aperture polishing and other applications.

PubMed

Dunn, Christina R; Walker, David D

2008-11-10

In this paper we first contrast classical and CNC polishing techniques in regard to the repetitiveness of the machine motions. We then present a pseudo-random tool path for use with CNC sub-aperture polishing techniques and report polishing results from equivalent random and raster tool-paths. The random tool-path used - the unicursal random tool-path - employs a random seed to generate a pattern which never crosses itself. Because of this property, this tool-path is directly compatible with dwell time maps for corrective polishing. The tool-path can be used to polish any continuous area of any boundary shape, including surfaces with interior perforations.

Extended charge banking model of dual path shocks for implantable cardioverter defibrillators

PubMed Central

Dosdall, Derek J; Sweeney, James D

2008-01-01

Background Single path defibrillation shock methods have been improved through the use of the Charge Banking Model of defibrillation, which predicts the response of the heart to shocks as a simple resistor-capacitor (RC) circuit. While dual path defibrillation configurations have significantly reduced defibrillation thresholds, improvements to dual path defibrillation techniques have been limited to experimental observations without a practical model to aid in improving dual path defibrillation techniques. Methods The Charge Banking Model has been extended into a new Extended Charge Banking Model of defibrillation that represents small sections of the heart as separate RC circuits, uses a weighting factor based on published defibrillation shock field gradient measures, and implements a critical mass criteria to predict the relative efficacy of single and dual path defibrillation shocks. Results The new model reproduced the results from several published experimental protocols that demonstrated the relative efficacy of dual path defibrillation shocks. The model predicts that time between phases or pulses of dual path defibrillation shock configurations should be minimized to maximize shock efficacy. Discussion Through this approach the Extended Charge Banking Model predictions may be used to improve dual path and multi-pulse defibrillation techniques, which have been shown experimentally to lower defibrillation thresholds substantially. The new model may be a useful tool to help in further improving dual path and multiple pulse defibrillation techniques by predicting optimal pulse durations and shock timing parameters. PMID:18673561

MO-F-CAMPUS-T-05: SQL Database Queries to Determine Treatment Planning Resource Usage

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

Fox, C; Gladstone, D

2015-06-15

Purpose: A radiation oncology clinic’s treatment capacity is traditionally thought to be limited by the number of machines in the clinic. As the number of fractions per course decrease and the number of adaptive plans increase, the question of how many treatment plans a clinic can plan becomes increasingly important. This work seeks to lay the ground work for assessing treatment planning resource usage. Methods: Care path templates were created using the Aria 11 care path interface. Care path tasks included key steps in the treatment planning process from the completion of CT simulation through the first radiation treatment. SQLmore » Server Management Studio was used to run SQL queries to extract task completion time stamps along with care path template information and diagnosis codes from the Aria database. 6 months of planning cycles were evaluated. Elapsed time was evaluated in terms of work hours within Monday – Friday, 7am to 5pm. Results: For the 195 validated treatment planning cycles, the average time for planning and MD review was 22.8 hours. Of those cases 33 were categorized as urgent. The average planning time for urgent plans was 5 hours. A strong correlation between diagnosis code and range of elapsed planning time was as well as between elapsed time and select diagnosis codes was observed. It was also observed that tasks were more likely to be completed on the date due than the time that they were due. Follow-up confirmed that most users did not look at the due time. Conclusion: Evaluation of elapsed planning time and other tasks suggest that care paths should be adjusted to allow for different contouring and planning times for certain diagnosis codes and urgent cases. Additional clinic training around task due times vs dates or a structuring of care paths around due dates is also needed.« less

Path integration of head direction: updating a packet of neural activity at the correct speed using axonal conduction delays.

PubMed

Walters, Daniel; Stringer, Simon; Rolls, Edmund

2013-01-01

The head direction cell system is capable of accurately updating its current representation of head direction in the absence of visual input. This is known as the path integration of head direction. An important question is how the head direction cell system learns to perform accurate path integration of head direction. In this paper we propose a model of velocity path integration of head direction in which the natural time delay of axonal transmission between a linked continuous attractor network and competitive network acts as a timing mechanism to facilitate the correct speed of path integration. The model effectively learns a "look-up" table for the correct speed of path integration. In simulation, we show that the model is able to successfully learn two different speeds of path integration across two different axonal conduction delays, and without the need to alter any other model parameters. An implication of this model is that, by learning look-up tables for each speed of path integration, the model should exhibit a degree of robustness to damage. In simulations, we show that the speed of path integration is not significantly affected by degrading the network through removing a proportion of the cells that signal rotational velocity.

Path Integration of Head Direction: Updating a Packet of Neural Activity at the Correct Speed Using Axonal Conduction Delays

PubMed Central

Walters, Daniel; Stringer, Simon; Rolls, Edmund

2013-01-01

The head direction cell system is capable of accurately updating its current representation of head direction in the absence of visual input. This is known as the path integration of head direction. An important question is how the head direction cell system learns to perform accurate path integration of head direction. In this paper we propose a model of velocity path integration of head direction in which the natural time delay of axonal transmission between a linked continuous attractor network and competitive network acts as a timing mechanism to facilitate the correct speed of path integration. The model effectively learns a “look-up” table for the correct speed of path integration. In simulation, we show that the model is able to successfully learn two different speeds of path integration across two different axonal conduction delays, and without the need to alter any other model parameters. An implication of this model is that, by learning look-up tables for each speed of path integration, the model should exhibit a degree of robustness to damage. In simulations, we show that the speed of path integration is not significantly affected by degrading the network through removing a proportion of the cells that signal rotational velocity. PMID:23526976

Reasoning on the Self-Organizing Incremental Associative Memory for Online Robot Path Planning

NASA Astrophysics Data System (ADS)

Kawewong, Aram; Honda, Yutaro; Tsuboyama, Manabu; Hasegawa, Osamu

Robot path-planning is one of the important issues in robotic navigation. This paper presents a novel robot path-planning approach based on the associative memory using Self-Organizing Incremental Neural Networks (SOINN). By the proposed method, an environment is first autonomously divided into a set of path-fragments by junctions. Each fragment is represented by a sequence of preliminarily generated common patterns (CPs). In an online manner, a robot regards the current path as the associative path-fragments, each connected by junctions. The reasoning technique is additionally proposed for decision making at each junction to speed up the exploration time. Distinct from other methods, our method does not ignore the important information about the regions between junctions (path-fragments). The resultant number of path-fragments is also less than other method. Evaluation is done via Webots physical 3D-simulated and real robot experiments, where only distance sensors are available. Results show that our method can represent the environment effectively; it enables the robot to solve the goal-oriented navigation problem in only one episode, which is actually less than that necessary for most of the Reinforcement Learning (RL) based methods. The running time is proved finite and scales well with the environment. The resultant number of path-fragments matches well to the environment.

HAI, a new airborne, absolute, twin dual-channel, multi-phase TDLAS-hygrometer: background, design, setup, and first flight data

NASA Astrophysics Data System (ADS)

Buchholz, Bernhard; Afchine, Armin; Klein, Alexander; Schiller, Cornelius; Krämer, Martina; Ebert, Volker

2017-01-01

The novel Hygrometer for Atmospheric Investigation (HAI) realizes a unique concept for simultaneous gas-phase and total (gas-phase + evaporated cloud particles) water measurements. It has been developed and successfully deployed for the first time on the German HALO research aircraft. This new instrument combines direct tunable diode laser absorption spectroscopy (dTDLAS) with a first-principle evaluation method to allow absolute water vapor measurements without any initial or repetitive sensor calibration using a reference gas or a reference humidity generator. HAI contains two completely independent dual-channel (closed-path, open-path) spectrometers, one at 1.4 and one at 2.6 µm, which together allow us to cover the entire atmospheric H2O range from 1 to 40 000 ppmv with a single instrument. Both spectrometers each comprise a separate, wavelength-individual extractive, closed-path cell for total water (ice and gas-phase) measurements. Additionally, both spectrometers couple light into a common open-path cell outside of the aircraft fuselage for a direct, sampling-free, and contactless determination of the gas-phase water content. This novel twin dual-channel setup allows for the first time multiple self-validation functions, in particular a reliable, direct, in-flight validation of the open-path channels. During the first field campaigns, the in-flight deviations between the independent and calibration-free channels (i.e., closed-path to closed-path and open-path to closed-path) were on average in the 2 % range. Further, the fully autonomous HAI hygrometer allows measurements up to 240 Hz with a minimal integration time of 1.4 ms. The best precision is achieved by the 1.4 µm closed-path cell at 3.8 Hz (0.18 ppmv) and by the 2.6 µm closed-path cell at 13 Hz (0.055 ppmv). The requirements, design, operation principle, and first in-flight performance of the hygrometer are described and discussed in this work.

Effects of Glide Path on the Centering Ability and Preparation Time of Two Reciprocating Instruments

PubMed Central

Coelho, Marcelo Santos; Fontana, Carlos Eduardo; Kato, Augusto Shoji; de Martin, Alexandre Sigrist; da Silveira Bueno, Carlos Eduardo

2016-01-01

Introduction: The aim of this in vitro study was to evaluate the effects of establishing glide path on the centering ability and preparation time of two single-file reciprocating systems in mesial root canals of mandibular molars. Methods and Materials: Sixty extracted mandibular molars with curvatures of 25-39 degrees and separate foramina for the mesiobuccal and mesiolingual canals, were divided into four groups (n=15); WaveOne+glide path; WaveOne; Reciproc+glide path and Reciproc. Non-patent canals were excluded and only one canal in each tooth was instrumented. A manual glide path was established in first and third groups with #10, 15 and 20 hand K-files. Preparation was performed with reciprocating in-and-out motion, with a 3-4 mm amplitude and slight apical pressure. Initial and final radiographs were taken to analyze the amount of dentin removed in the instrumented canals. The radiographs were superimposed with an image editing software and examined to assess discrepancies at 3-, 6- and 9-mm distances from the apex. The Kruskal-Wallis test was used for statistical analysis. The level of significance was set at 0.05. Results: Preparation in groups without glide paths was swifter than the other groups (P=0.001). However, no difference was observed regarding centering ability. Conclusion: Establishing a glide path increased the total instrumentation time for preparing curved canals with WaveOne and Reciproc instruments. Glide path had no influence on the centering ability of these systems. PMID:26843875

Optimal Paths in Gliding Flight

NASA Astrophysics Data System (ADS)

Wolek, Artur

Underwater gliders are robust and long endurance ocean sampling platforms that are increasingly being deployed in coastal regions. This new environment is characterized by shallow waters and significant currents that can challenge the mobility of these efficient (but traditionally slow moving) vehicles. This dissertation aims to improve the performance of shallow water underwater gliders through path planning. The path planning problem is formulated for a dynamic particle (or "kinematic car") model. The objective is to identify the path which satisfies specified boundary conditions and minimizes a particular cost. Several cost functions are considered. The problem is addressed using optimal control theory. The length scales of interest for path planning are within a few turn radii. First, an approach is developed for planning minimum-time paths, for a fixed speed glider, that are sub-optimal but are guaranteed to be feasible in the presence of unknown time-varying currents. Next the minimum-time problem for a glider with speed controls, that may vary between the stall speed and the maximum speed, is solved. Last, optimal paths that minimize change in depth (equivalently, maximize range) are investigated. Recognizing that path planning alone cannot overcome all of the challenges associated with significant currents and shallow waters, the design of a novel underwater glider with improved capabilities is explored. A glider with a pneumatic buoyancy engine (allowing large, rapid buoyancy changes) and a cylindrical moving mass mechanism (generating large pitch and roll moments) is designed, manufactured, and tested to demonstrate potential improvements in speed and maneuverability.

Path-Dependent Travel Time Prediction Variance and Covariance for a Global Tomographic P- and S-Velocity Model

NASA Astrophysics Data System (ADS)

Hipp, J. R.; Ballard, S.; Begnaud, M. L.; Encarnacao, A. V.; Young, C. J.; Phillips, W. S.

2015-12-01

Recently our combined SNL-LANL research team has succeeded in developing a global, seamless 3D tomographic P- and S-velocity model (SALSA3D) that provides superior first P and first S travel time predictions at both regional and teleseismic distances. However, given the variable data quality and uneven data sampling associated with this type of model, it is essential that there be a means to calculate high-quality estimates of the path-dependent variance and covariance associated with the predicted travel times of ray paths through the model. In this paper, we describe a methodology for accomplishing this by exploiting the full model covariance matrix and show examples of path-dependent travel time prediction uncertainty computed from our latest tomographic model. Typical global 3D SALSA3D models have on the order of 1/2 million nodes, so the challenge in calculating the covariance matrix is formidable: 0.9 TB storage for 1/2 of a symmetric matrix, necessitating an Out-Of-Core (OOC) blocked matrix solution technique. With our approach the tomography matrix (G which includes a prior model covariance constraint) is multiplied by its transpose (GTG) and written in a blocked sub-matrix fashion. We employ a distributed parallel solution paradigm that solves for (GTG)-1 by assigning blocks to individual processing nodes for matrix decomposition update and scaling operations. We first find the Cholesky decomposition of GTG which is subsequently inverted. Next, we employ OOC matrix multiplication methods to calculate the model covariance matrix from (GTG)-1 and an assumed data covariance matrix. Given the model covariance matrix, we solve for the travel-time covariance associated with arbitrary ray-paths by summing the model covariance along both ray paths. Setting the paths equal and taking the square root yields the travel prediction uncertainty for the single path.

Fade Analysis of ORCA DATA Beam at NTTR and Pax River

DTIC Science & Technology

2010-08-01

bit-error-rate (BER) of the data beam on the downlink path. 15 Start Time-PST (Duration) Range Scin Index 1 Rx=5.1cm... Scin Index 2 Rx=13.7cm Scin Index 3 Rx=27.2cm Path Ave Cn2 (m-2/3) Path Ave Inner Scale Path Ave Outer Scale Flight 2 May 16

A Note on the Stochastic Nature of Feynman Quantum Paths

NASA Astrophysics Data System (ADS)

Botelho, Luiz C. L.

2016-11-01

We propose a Fresnel stochastic white noise framework to analyze the stochastic nature of the Feynman paths entering on the Feynman Path Integral expression for the Feynman Propagator of a particle quantum mechanically moving under a time-independent potential.

Crossing fitness canyons by a finite population

NASA Astrophysics Data System (ADS)

Saakian, David B.; Bratus, Alexander S.; Hu, Chin-Kun

2017-06-01

We consider the Wright-Fisher model of the finite population evolution on a fitness landscape defined in the sequence space by a path of nearly neutral mutations. We study a specific structure of the fitness landscape: One of the intermediate mutations on the mutation path results in either a large fitness value (climbing up a fitness hill) or a low fitness value (crossing a fitness canyon), the rest of the mutations besides the last one are neutral, and the last sequence has much higher fitness than any intermediate sequence. We derive analytical formulas for the first arrival time of the mutant with two point mutations. For the first arrival problem for the further mutants in the case of canyon crossing, we analytically deduce how the mean first arrival time scales with the population size and fitness difference. The location of the canyon on the path of sequences has a crucial role. If the canyon is at the beginning of the path, then it significantly prolongs the first arrival time; otherwise it just slightly changes it. Furthermore, the fitness hill at the beginning of the path strongly prolongs the arrival time period; however, the hill located near the end of the path shortens it. We optimize the first arrival time by applying a nonzero selection to the intermediate sequences. We extend our results and provide a scaling for the valley crossing time via the depth of the canyon and population size in the case of a fitness canyon at the first position. Our approach is useful for understanding some complex evolution systems, e.g., the evolution of cancer.

Energy-optimal path planning in the coastal ocean

NASA Astrophysics Data System (ADS)

Subramani, Deepak N.; Haley, Patrick J.; Lermusiaux, Pierre F. J.

2017-05-01

We integrate data-driven ocean modeling with the stochastic Dynamically Orthogonal (DO) level-set optimization methodology to compute and study energy-optimal paths, speeds, and headings for ocean vehicles in the Middle-Atlantic Bight (MAB) region. We hindcast the energy-optimal paths from among exact time-optimal paths for the period 28 August 2006 to 9 September 2006. To do so, we first obtain a data-assimilative multiscale reanalysis, combining ocean observations with implicit two-way nested multiresolution primitive-equation simulations of the tidal-to-mesoscale dynamics in the region. Second, we solve the reduced-order stochastic DO level-set partial differential equations (PDEs) to compute the joint probability of minimum arrival time, vehicle-speed time series, and total energy utilized. Third, for each arrival time, we select the vehicle-speed time series that minimize the total energy utilization from the marginal probability of vehicle-speed and total energy. The corresponding energy-optimal path and headings are obtained through the exact particle-backtracking equation. Theoretically, the present methodology is PDE-based and provides fundamental energy-optimal predictions without heuristics. Computationally, it is 3-4 orders of magnitude faster than direct Monte Carlo methods. For the missions considered, we analyze the effects of the regional tidal currents, strong wind events, coastal jets, shelfbreak front, and other local circulations on the energy-optimal paths. Results showcase the opportunities for vehicles that intelligently utilize the ocean environment to minimize energy usage, rigorously integrating ocean forecasting with optimal control of autonomous vehicles.

A Framework for Simulation of Aircraft Flyover Noise Through a Non-Standard Atmosphere

NASA Technical Reports Server (NTRS)

Arntzen, Michael; Rizzi, Stephen A.; Visser, Hendrikus G.; Simons, Dick G.

2012-01-01

This paper describes a new framework for the simulation of aircraft flyover noise through a non-standard atmosphere. Central to the framework is a ray-tracing algorithm which defines multiple curved propagation paths, if the atmosphere allows, between the moving source and listener. Because each path has a different emission angle, synthesis of the sound at the source must be performed independently for each path. The time delay, spreading loss and absorption (ground and atmosphere) are integrated along each path, and applied to each synthesized aircraft noise source to simulate a flyover. A final step assigns each resulting signal to its corresponding receiver angle for the simulation of a flyover in a virtual reality environment. Spectrograms of the results from a straight path and a curved path modeling assumption are shown. When the aircraft is at close range, the straight path results are valid. Differences appear especially when the source is relatively far away at shallow elevation angles. These differences, however, are not significant in common sound metrics. While the framework used in this work performs off-line processing, it is conducive to real-time implementation.

Finding Out Critical Points For Real-Time Path Planning

NASA Astrophysics Data System (ADS)

Chen, Wei

1989-03-01

Path planning for a mobile robot is a classic topic, but the path planning under real-time environment is a different issue. The system sources including sampling time, processing time, processes communicating time, and memory space are very limited for this type of application. This paper presents a method which abstracts the world representation from the sensory data and makes the decision as to which point will be a potentially critical point to span the world map by using incomplete knowledge about physical world and heuristic rule. Without any previous knowledge or map of the workspace, the robot will determine the world map by roving through the workspace. The computational complexity for building and searching such a map is not more than O( n2 ) The find-path problem is well-known in robotics. Given an object with an initial location and orientation, a goal location and orientation, and a set of obstacles located in space, the problem is to find a continuous path for the object from the initial position to the goal position which avoids collisions with obstacles along the way. There are a lot of methods to find a collision-free path in given environment. Techniques for solving this problem can be classified into three approaches: 1) the configuration space approach [1],[2],[3] which represents the polygonal obstacles by vertices in a graph. The idea is to determine those parts of the free space which a reference point of the moving object can occupy without colliding with any obstacles. A path is then found for the reference point through this truly free space. Dealing with rotations turns out to be a major difficulty with the approach, requiring complex geometric algorithms which are computationally expensive. 2) the direct representation of the free space using basic shape primitives such as convex polygons [4] and overlapping generalized cones [5]. 3) the combination of technique 1 and 2 [6] by which the space is divided into the primary convex region, overlap region and obstacle region, then obstacle boundaries with attribute values are represented by the vertices of the hypergraph. The primary convex region and overlap region are represented by hyperedges, the centroids of overlap form the critical points. The difficulty is generating segment graph and estimating of minimum path width. The all techniques mentioned above need previous knowledge about the world to make path planning and the computational cost is not low. They are not available in an unknow and uncertain environment. Due to limited system resources such as CPU time, memory size and knowledge about the special application in an intelligent system (such as mobile robot), it is necessary to use algorithms that provide the good decision which is feasible with the available resources in real time rather than the best answer that could be achieved in unlimited time with unlimited resources. A real-time path planner should meet following requirements: - Quickly abstract the representation of the world from the sensory data without any previous knowledge about the robot environment. - Easily update the world model to spell out the global-path map and to reflect changes in the robot environment. - Must make a decision of where the robot must go and which direction the range sensor should point to in real time with limited resources. The method presented here assumes that the data from range sensors has been processed by signal process unite. The path planner will guide the scan of range sensor, find critical points, make decision where the robot should go and which point is poten- tial critical point, generate the path map and monitor the robot moves to the given point. The program runs recursively until the goal is reached or the whole workspace is roved through.

Technical Evaluation Motor No. 10 (TEM-10)

NASA Technical Reports Server (NTRS)

1993-01-01

Technical Evaluation Motor No. 10 (TEM-10) was static fired on 27 Apr. 1993 at the Thiokol Corporation full-scale motor static test bay, T-24. This final test report documents the procedures, performance, and results of the static test firing of TEM-10. All observations, discussions, conclusions, and recommendations contained are final. Included is a presentation and discussion of TEM-10 performance, anomalies, and test results in concurrence with the objectives outlined in CTP-0110, Revision D, Space Shuttle Technical Evaluation Motor No. 10 (TEM-10) Static Fire Test Plan.

An Assay of RNA Synthesis in Hepatic Nuclei from Control and Streptococcus pneumoniae-Infected Rats

DTIC Science & Technology

1982-02-22

26) as modified by pended in 2.0 ml of 1.0 N KOH and incu- McNamara et al. (27). Nuclei (about 0.25 mg bated for 20 hr at 370 to hydrolyze RNA (28...containing hydrolyzed RNA was ml yeast RNA, 18 units pyruvate kinase, I counted in Scintisol. The pellet was solubi- mM cytidine triphosphate (CTP), I mM...WC. Lecithin biosynthesis in liver mi- 16. Blobel G, Potter VR. Nuclei from rat liver, isolation tochondrial fractions. Biochem Biophys Res Coin

A Note on Feynman Path Integral for Electromagnetic External Fields

NASA Astrophysics Data System (ADS)

Botelho, Luiz C. L.

2017-08-01

We propose a Fresnel stochastic white noise framework to analyze the nature of the Feynman paths entering on the Feynman Path Integral expression for the Feynman Propagator of a particle quantum mechanically moving under an external electromagnetic time-independent potential.

Self-organization and solution of shortest-path optimization problems with memristive networks

NASA Astrophysics Data System (ADS)

Pershin, Yuriy V.; Di Ventra, Massimiliano

2013-07-01

We show that memristive networks, namely networks of resistors with memory, can efficiently solve shortest-path optimization problems. Indeed, the presence of memory (time nonlocality) promotes self organization of the network into the shortest possible path(s). We introduce a network entropy function to characterize the self-organized evolution, show the solution of the shortest-path problem and demonstrate the healing property of the solution path. Finally, we provide an algorithm to solve the traveling salesman problem. Similar considerations apply to networks of memcapacitors and meminductors, and networks with memory in various dimensions.

Experimental and numerical study of the relation between flow paths and fate of a pesticide in a riparian wetland

NASA Astrophysics Data System (ADS)

Kidmose, Jacob; Dahl, Mette; Engesgaard, Peter; Nilsson, Bertel; Christensen, Britt S. B.; Andersen, Stine; Hoffmann, Carl Christian

2010-05-01

SummaryA field-scale pulse-injection experiment with the herbicide Isoproturon was conducted in a Danish riparian wetland. A non-reactive tracer (bromide) experiment was also carried out to characterize the physical transport system. Groundwater flow and reactive transport modelling was used to simulate flow paths, residence times, as well as bromide and Isoproturon distributions. The wetland can be characterized by two distinct riparian flow paths; one flow path discharges 2/3 of the incoming groundwater directly to the free water surface of the wetland near the foot of the hillslope with an average residence time of 205 days, and another flow path diffusively discharging the remaining 1/3 of the incoming groundwater to the stream with an average residence time of 425 days. The reactive transport simulations reveal that Isoproturon is retarded by a factor of 2-4, which is explained by the high organic content in the peat layer of the wetland. Isoproturon was found to be aerobically degraded with a half-life in the order of 12-80 days. Based on the quantification of flow paths, residence times and half-lives it is estimated that about 2/3 of the injected Isoproturon is removed in the wetland. Thus, close to 1/3 may find its way to the stream through overland flow. It is also possible that high concentrations of metabolites will reach the stream.

Realization of a multipath ultrasonic gas flowmeter based on transit-time technique.

PubMed

Chen, Qiang; Li, Weihua; Wu, Jiangtao

2014-01-01

A microcomputer-based ultrasonic gas flowmeter with transit-time method is presented. Modules of the flowmeter are designed systematically, including the acoustic path arrangement, ultrasound emission and reception module, transit-time measurement module, the software and so on. Four 200 kHz transducers forming two acoustic paths are used to send and receive ultrasound simultaneously. The synchronization of the transducers can eliminate the influence caused by the inherent switch time in simple chord flowmeter. The distribution of the acoustic paths on the mechanical apparatus follows the Tailored integration, which could reduce the inherent error by 2-3% compared with the Gaussian integration commonly used in the ultrasonic flowmeter now. This work also develops timing modules to determine the flight time of the acoustic signal. The timing mechanism is different from the traditional method. The timing circuit here adopts high capability chip TDC-GP2, with the typical resolution of 50 ps. The software of Labview is used to receive data from the circuit and calculate the gas flow value. Finally, the two paths flowmeter has been calibrated and validated on the test facilities for air flow in Shaanxi Institute of Measurement & Testing. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigating the source of anomalous PKP travel-times on south-Sandwich to Alaska paths

NASA Astrophysics Data System (ADS)

Frost, D. A.; Romanowicz, B. A.

2017-12-01

Inner core anisotropy was proposed thirty years ago to explain differences in travel times of inner core phases (PKIKP) on polar and equatorial paths (Morelli et al., 1986). Over time, models of inner core anisotropy have become very complex, with evidence for depth dependence, hemispherical variations, and other localised features. Some models propose the strength of anisotropy to be in excess of 4% in the western hemisphere of the inner core. This is difficult to reconcile with predictions from mineral physics and dynamical models of inner core growth. The strong anisotropy is confined to anomalous paths between earthquakes in the south Sandwich Islands and stations in Alaska. In contrast, the strength of inner core anisotropy obtained from measurements of PKPPKP travel times on polar paths does not exceed 1-2% (Bréger et al., 2000; Frost and Romanowicz, 2017). We re-examine the trends of PKIKP travel times on polar paths, in order to reconcile the different measurements and to determine whether discrepancies can be explained by structure in the mantle, the outer core, or localized strong anisotropy in the inner core. For this, we combine existing and new measurements, taking advantage of recent deployments of broadband arrays in Alaska and Antarctica.

Compensation of high order harmonic long quantum-path attosecond chirp

NASA Astrophysics Data System (ADS)

Guichard, R.; Caillat, J.; Lévêque, C.; Risoud, F.; Maquet, A.; Taïeb, R.; Zaïr, A.

2017-12-01

We propose a method to compensate for the extreme ultra violet (XUV) attosecond chirp associated with the long quantum-path in the high harmonic generation process. Our method employs an isolated attosecond pulse (IAP) issued from the short trajectory contribution in a primary target to assist the infrared driving field to produce high harmonics from the long trajectory in a secondary target. In our simulations based on the resolution of the time-dependent Schrödinger equation, the resulting high harmornics present a clear phase compensation of the long quantum-path contribution, near to Fourier transform limited attosecond XUV pulse. Employing time-frequency analysis of the high harmonic dipole, we found that the compensation is not a simple far-field photonic interference between the IAP and the long-path harmonic emission, but a coherent phase transfer from the weak IAP to the long quantum-path electronic wavepacket. Our approach opens the route to utilizing the long quantum-path for the production and applications of attosecond pulses.

Real-time path planning and autonomous control for helicopter autorotation

NASA Astrophysics Data System (ADS)

Yomchinda, Thanan

Autorotation is a descending maneuver that can be used to recover helicopters in the event of total loss of engine power; however it is an extremely difficult and complex maneuver. The objective of this work is to develop a real-time system which provides full autonomous control for autorotation landing of helicopters. The work includes the development of an autorotation path planning method and integration of the path planner with a primary flight control system. The trajectory is divided into three parts: entry, descent and flare. Three different optimization algorithms are used to generate trajectories for each of these segments. The primary flight control is designed using a linear dynamic inversion control scheme, and a path following control law is developed to track the autorotation trajectories. Details of the path planning algorithm, trajectory following control law, and autonomous autorotation system implementation are presented. The integrated system is demonstrated in real-time high fidelity simulations. Results indicate feasibility of the capability of the algorithms to operate in real-time and of the integrated systems ability to provide safe autorotation landings. Preliminary simulations of autonomous autorotation on a small UAV are presented which will lead to a final hardware demonstration of the algorithms.

PathVisio 3: an extendable pathway analysis toolbox.

PubMed

Kutmon, Martina; van Iersel, Martijn P; Bohler, Anwesha; Kelder, Thomas; Nunes, Nuno; Pico, Alexander R; Evelo, Chris T

2015-02-01

PathVisio is a commonly used pathway editor, visualization and analysis software. Biological pathways have been used by biologists for many years to describe the detailed steps in biological processes. Those powerful, visual representations help researchers to better understand, share and discuss knowledge. Since the first publication of PathVisio in 2008, the original paper was cited more than 170 times and PathVisio was used in many different biological studies. As an online editor PathVisio is also integrated in the community curated pathway database WikiPathways. Here we present the third version of PathVisio with the newest additions and improvements of the application. The core features of PathVisio are pathway drawing, advanced data visualization and pathway statistics. Additionally, PathVisio 3 introduces a new powerful extension systems that allows other developers to contribute additional functionality in form of plugins without changing the core application. PathVisio can be downloaded from http://www.pathvisio.org and in 2014 PathVisio 3 has been downloaded over 5,500 times. There are already more than 15 plugins available in the central plugin repository. PathVisio is a freely available, open-source tool published under the Apache 2.0 license (http://www.apache.org/licenses/LICENSE-2.0). It is implemented in Java and thus runs on all major operating systems. The code repository is available at http://svn.bigcat.unimaas.nl/pathvisio. The support mailing list for users is available on https://groups.google.com/forum/#!forum/wikipathways-discuss and for developers on https://groups.google.com/forum/#!forum/wikipathways-devel.

Immunochemical mapping of gonadotropins.

PubMed

Berger, P; Bidart, J M; Delves, P S; Dirnhofer, S; Hoermann, R; Isaacs, N; Jackson, A; Klonisch, T; Lapthorn, A; Lund, T; Mann, K; Roitt, I; Schwarz, S; Wick, G

1996-12-20

As a glycoprotein hormone, human chorionic gonadotropic (hCG) is not a single molecular entity but this term rather comprises an array of molecular variants such as hCG, hCG beta, hCGn, hCG beta n, hCG beta cf, -CTPhCG, hCG beta CTP, deglyhCG, asialohCG, hCGav and the closely related molecules hLH, hLH beta and hLH beta ef. The advent of monoclonal antibodies (MCA), the availability of ultrasensitive detection systems and the recent determination of the crystal structure of hCG, made it possible to design special purpose diagnostic and clinical research immunoassays for hCG-like molecules. For more than a decade we and others have tried to refine epitope maps for hCG and related molecules by means of a large panel of MCA, naturally occurring metabolic variants of hCG (hCGn, hCG beta, hCG alpha, hCG beta cf, hCG beta CTP), homologous hormones and subunits of various species (e.g. hLH, hLH beta, hFSH, hTSH, oLH, rLH beta), chemically modified molecules (deglyhCG, asialohCG, tryptic and chymotryptic hCG beta and hCG alpha fragments) and synthetic peptides (octapeptides and longer). It appeared that all epitopes on molecular hCG-variants recognized by our MCA are determined by the protein backbone. Except for the two major epitopes on hCG beta CTP and parts of two antigenic domains on hCG alpha, epitopes on hCG-derived molecules are determined by the tertiary and quarternary structure. Operationally useful descriptive epitope maps were designed including information on assay suitability of antigenic determinants. On this basis we established ultrasensitive time-resolved fluoroimmuno-assays for hCG, hCG and hCGn, hCG beta and hCG beta n and hCG beta cf, hCG alpha and additional assays recognizing different spectra of hCG-variants. Such assay have been applied by us and others to the detection of pregnancy, early pregnancy loss, choriocarcinoma, testicular cancer, other cancers and prenatal diagnosis. However, as the molecular structure of many epitopes utilized in immunoassays of different laboratories was not resolved, comparability of results was not satisfactory. Consequently, attempts were made to compare schematic epitope maps from different research institutions. The situation has been much improved by solving the three-dimensional (3D) structure of hCG. It has been shown that hCG is a member of the structural superfamily of cystine knot growth factors like NGF, PDGF-B and TGF-beta. Each of its subunits is stabilized in its topology by three disulfide bonds forming a cystine knot. Moreover, it turned out that the disulfide bridges in their majority have previously been wrongly assigned. Computer molecular modeling of crystallographic coordinates of hCG and subsequent selective combined--PCR-based and immunological--mutational analyses of hCG beta expressed via the transmembrane region of a MHC molecule made it possible to more precisely localize epitopes on hCG-derived molecules. Although the entire surface of hCG has to be regarded as potentially immunogenic there seems to be hot spots where epitopes are clustered in antigenic domains. These are located on the first and third loops protuding from the cystine knots of both subunits and are possibly centered around the knot itself. Ultimate answers on epitope localizations will be given by the crystal structure determination of hCG complexed with different Fabs.

Remote Sensing of Cloud Top Height from SEVIRI: Analysis of Eleven Current Retrieval Algorithms

NASA Technical Reports Server (NTRS)

Hamann, U.; Walther, A.; Baum, B.; Bennartz, R.; Bugliaro, L.; Derrien, M.; Francis, P. N.; Heidinger, A.; Joro, S.; Kniffka, A.;

Modified dwell time optimization model and its applications in subaperture polishing.

PubMed

Dong, Zhichao; Cheng, Haobo; Tam, Hon-Yuen

2014-05-20

The optimization of dwell time is an important procedure in deterministic subaperture polishing. We present a modified optimization model of dwell time by iterative and numerical method, assisted by extended surface forms and tool paths for suppressing the edge effect. Compared with discrete convolution and linear equation models, the proposed model has essential compatibility with arbitrary tool paths, multiple tool influence functions (TIFs) in one optimization, and asymmetric TIFs. The emulational fabrication of a Φ200  mm workpiece by the proposed model yields a smooth, continuous, and non-negative dwell time map with a root-mean-square (RMS) convergence rate of 99.6%, and the optimization costs much less time. By the proposed model, influences of TIF size and path interval to convergence rate and polishing time are optimized, respectively, for typical low and middle spatial-frequency errors. Results show that (1) the TIF size is nonlinear inversely proportional to convergence rate and polishing time. A TIF size of ~1/7 workpiece size is preferred; (2) the polishing time is less sensitive to path interval, but increasing the interval markedly reduces the convergence rate. A path interval of ~1/8-1/10 of the TIF size is deemed to be appropriate. The proposed model is deployed on a JR-1800 and MRF-180 machine. Figuring results of Φ920  mm Zerodur paraboloid and Φ100  mm Zerodur plane by them yield RMS of 0.016λ and 0.013λ (λ=632.8  nm), respectively, and thereby validate the feasibility of proposed dwell time model used for subaperture polishing.

On the Path Integral in Non-Commutative (nc) Qft

NASA Astrophysics Data System (ADS)

Dehne, Christoph

2008-09-01

As is generally known, different quantization schemes applied to field theory on NC spacetime lead to Feynman rules with different physical properties, if time does not commute with space. In particular, the Feynman rules that are derived from the path integral corresponding to the T*-product (the so-called naïve Feynman rules) violate the causal time ordering property. Within the Hamiltonian approach to quantum field theory, we show that we can (formally) modify the time ordering encoded in the above path integral. The resulting Feynman rules are identical to those obtained in the canonical approach via the Gell-Mann-Low formula (with T-ordering). They preserve thus unitarity and causal time ordering.

Motion detection, novelty filtering, and target tracking using an interferometric technique with GaAs phase conjugate mirror

NASA Technical Reports Server (NTRS)

Cheng, Li-Jen (Inventor); Liu, Tsuen-Hsi (Inventor)

1991-01-01

A method and apparatus for detecting and tracking moving objects in a noise environment cluttered with fast- and slow-moving objects and other time-varying background. A pair of phase conjugate light beams carrying the same spatial information commonly cancel each other out through an image subtraction process in a phase conjugate interferometer, wherein gratings are formed in a fast photorefractive phase conjugate mirror material. In the steady state, there is no output. When the optical path of one of the two phase conjugate beams is suddenly changed, the return beam loses its phase conjugate nature and the interferometer is out of balance, resulting in an observable output. The observable output lasts until the phase conjugate nature of the beam has recovered. The observable time of the output signal is roughly equal to the formation time of the grating. If the optical path changing time is slower than the formation time, the change of optical path becomes unobservable, because the index grating can follow the change. Thus, objects traveling at speeds which result in a path changing time which is slower than the formation time are not observable and do not clutter the output image view.

Receiver-Based Ad Hoc On Demand Multipath Routing Protocol for Mobile Ad Hoc Networks

PubMed Central

Al-Nahari, Abdulaziz; Mohamad, Mohd Murtadha

2016-01-01

Decreasing the route rediscovery time process in reactive routing protocols is challenging in mobile ad hoc networks. Links between nodes are continuously established and broken because of the characteristics of the network. Finding multiple routes to increase the reliability is also important but requires a fast update, especially in high traffic load and high mobility where paths can be broken as well. The sender node keeps re-establishing path discovery to find new paths, which makes for long time delay. In this paper we propose an improved multipath routing protocol, called Receiver-based ad hoc on demand multipath routing protocol (RB-AOMDV), which takes advantage of the reliability of the state of the art ad hoc on demand multipath distance vector (AOMDV) protocol with less re-established discovery time. The receiver node assumes the role of discovering paths when finding data packets that have not been received after a period of time. Simulation results show the delay and delivery ratio performances are improved compared with AOMDV. PMID:27258013

Grey-Theory-Based Optimization Model of Emergency Logistics Considering Time Uncertainty.

PubMed

Qiu, Bao-Jian; Zhang, Jiang-Hua; Qi, Yuan-Tao; Liu, Yang

2015-01-01

Natural disasters occur frequently in recent years, causing huge casualties and property losses. Nowadays, people pay more and more attention to the emergency logistics problems. This paper studies the emergency logistics problem with multi-center, multi-commodity, and single-affected-point. Considering that the path near the disaster point may be damaged, the information of the state of the paths is not complete, and the travel time is uncertainty, we establish the nonlinear programming model that objective function is the maximization of time-satisfaction degree. To overcome these drawbacks: the incomplete information and uncertain time, this paper firstly evaluates the multiple roads of transportation network based on grey theory and selects the reliable and optimal path. Then simplify the original model under the scenario that the vehicle only follows the optimal path from the emergency logistics center to the affected point, and use Lingo software to solve it. The numerical experiments are presented to show the feasibility and effectiveness of the proposed method.

Grey-Theory-Based Optimization Model of Emergency Logistics Considering Time Uncertainty

PubMed Central

Qiu, Bao-Jian; Zhang, Jiang-Hua; Qi, Yuan-Tao; Liu, Yang

2015-01-01

Natural disasters occur frequently in recent years, causing huge casualties and property losses. Nowadays, people pay more and more attention to the emergency logistics problems. This paper studies the emergency logistics problem with multi-center, multi-commodity, and single-affected-point. Considering that the path near the disaster point may be damaged, the information of the state of the paths is not complete, and the travel time is uncertainty, we establish the nonlinear programming model that objective function is the maximization of time-satisfaction degree. To overcome these drawbacks: the incomplete information and uncertain time, this paper firstly evaluates the multiple roads of transportation network based on grey theory and selects the reliable and optimal path. Then simplify the original model under the scenario that the vehicle only follows the optimal path from the emergency logistics center to the affected point, and use Lingo software to solve it. The numerical experiments are presented to show the feasibility and effectiveness of the proposed method. PMID:26417946

Receiver-Based Ad Hoc On Demand Multipath Routing Protocol for Mobile Ad Hoc Networks.

PubMed

Al-Nahari, Abdulaziz; Mohamad, Mohd Murtadha

2016-01-01

Decreasing the route rediscovery time process in reactive routing protocols is challenging in mobile ad hoc networks. Links between nodes are continuously established and broken because of the characteristics of the network. Finding multiple routes to increase the reliability is also important but requires a fast update, especially in high traffic load and high mobility where paths can be broken as well. The sender node keeps re-establishing path discovery to find new paths, which makes for long time delay. In this paper we propose an improved multipath routing protocol, called Receiver-based ad hoc on demand multipath routing protocol (RB-AOMDV), which takes advantage of the reliability of the state of the art ad hoc on demand multipath distance vector (AOMDV) protocol with less re-established discovery time. The receiver node assumes the role of discovering paths when finding data packets that have not been received after a period of time. Simulation results show the delay and delivery ratio performances are improved compared with AOMDV.

Two Meter Flight Path - Time of Flight Positron Annihilation Induced Auger Electron Spectrometer

NASA Astrophysics Data System (ADS)

Mukherjee, S.; Shastry, K.; Maddox, W.; Weiss, A. H.

2008-03-01

Details of the design and construction of a new time of flight positron annihilation induced Auger electron (TOF-PAES) spectrometer are presented. The new spectrometer will be equipped with a 2 meter long ``TOF'' tube that can be biased at a potential different from that of the sample in order to increase or decrease the kinetic energy of the electrons traveling through the tube. The time of flight will be determined from timing signals obtained from the detection of the annihilation gamma (signaling the start of the flight) and detection of the annihilation induced Auger electron at the end of the 2 meter flight path (signaling the end of the flight). The 2 meter long flight path is a factor of two longer than used in previous TOF-PAES systems. The longer flight path can be expected to result in a fractional energy width: delta E/ E that is .5ex1 -.1em/ -.15em.25ex2 as large as the current UTA lab based TOF-PAES spectrometer.

CTP:phosphocholine cytidylyltransferase binds anionic phospholipid vesicles in a cross-bridging mode.

PubMed

Taneva, Svetla G; Patty, Philipus J; Frisken, Barbara J; Cornell, Rosemary B

2005-07-05

CTP:phosphocholine cytidylyltransferase (CCT) catalyzes the rate-limiting step in phosphatidylcholine (PC) synthesis, and its activity is regulated by reversible association with membranes, mediated by an amphipathic helical domain M. Here we describe a new feature of the CCTalpha isoform, vesicle tethering. We show, using dynamic light scattering and transmission electron microscopy, that dimers of CCTalpha can cross-bridge separate vesicles to promote vesicle aggregation. The vesicles contained either class I activators (anionic phospholipids) or the less potent class II activators, which favor nonlamellar phase formation. CCT increased the apparent hydrodynamic radius and polydispersity of anionic phospholipid vesicles even at low CCT concentrations corresponding to only one or two dimers per vesicle. Electron micrographs of negatively stained phosphatidylglycerol (PG) vesicles confirmed CCT-mediated vesicle aggregation. CCT conjugated to colloidal gold accumulated on the vesicle surfaces and in areas of vesicle-vesicle contact. PG vesicle aggregation required both the membrane-binding domain and the intact CCT dimer, suggesting binding of CCT to apposed membranes via the two M domains situated on opposite sides of the dimerization domain. In contrast to the effects on anionic phospholipid vesicles, CCT did not induce aggregation of PC vesicles containing the class II lipids, oleic acid, diacylglycerol, or phosphatidylethanolamine. The different behavior of the two lipid classes reflected differences in measured binding affinity, with only strongly binding phospholipid vesicles being susceptible to CCT-induced aggregation. Our findings suggest a new model for CCTalpha domain organization and membrane interaction, and a potential involvement of the enzyme in cellular events that implicate close apposition of membranes.

Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.

PubMed Central

Gao, W Y; Shirasaka, T; Johns, D G; Broder, S; Mitsuya, H

1993-01-01

The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM. The mean drug concentration which yielded 50% p24 Gag negative cultures were substantially different: 0.06, 0.2, and 6 microM for AZT, ddC, and ddI, respectively. We found that AZT was preferentially phosphorylated to its triphosphate (TP) form in PHA-PBM rather than unstimulated, resting PBM (R-PBM), producing 10- to 17-fold higher ratios of AZTTP/dTTP in PHA-PBM than in R-PBM. The phosphorylation of ddC and ddI to their TP forms was, however, much less efficient in PHA-PBM, resulting in approximately 5-fold and approximately 15-fold lower ratios of ddCTP/dCTP and ddATP/dATP, respectively, in PHA-PBM than in R-PBM. The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase. We conclude that AZT, ddC, and ddI exert disproportionate antiviral effects depending on the activation state of the target cells, i.e., ddI and ddC exert antiviral activity more favorably in resting cells than in activated cells, while AZT preferentially protects activated cells against HIV infection. Considering that HIV-1 proviral DNA synthesis in resting lymphocytes is reportedly initiated at levels comparable with those of activated lymphocytes, the current data should have practical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy. PMID:8387546

Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils.

PubMed

Cansev, Mehmet; Watkins, Carol J; van der Beek, Eline M; Wurtman, Richard J

2005-10-05

We examined the biochemical pathways whereby oral uridine-5'-monophosphate (UMP) increases membrane phosphatide synthesis in brains of gerbils. We previously showed that supplementing PC12 cells with uridine caused concentration-related increases in CDP-choline levels, and that this effect was mediated by elevations in intracellular uridine triphosphate (UTP) and cytidine triphosphate (CTP). In the present study, adult gerbils received UMP (1 mmol/kg), a constituent of human breast milk and infant formulas, by gavage, and plasma samples and brains were collected for assay between 5 min and 8 h thereafter. Thirty minutes after gavage, plasma uridine levels were increased from 6.6 +/- 0.58 to 32.7 +/- 1.85 microM (P < 0.001), and brain uridine from 22.6 +/- 2.9 to 89.1 +/- 8.82 pmol/mg tissue (P < 0.001). UMP also significantly increased plasma and brain cytidine levels; however, both basally and following UMP, these levels were much lower than those of uridine. Brain UTP, CTP, and CDP-choline were all elevated 15 min after UMP (from 254 +/- 31.9 to 417 +/- 50.2, [P < 0.05]; 56.8 +/- 1.8 to 71.7 +/- 1.8, [P < 0.001]; and 11.3 +/- 0.5 to 16.4 +/- 1, [P < 0.001] pmol/mg tissue, respectively), returning to basal levels after 20 and 30 min. The smallest UMP dose that significantly increased brain CDP-choline was 0.05 mmol/kg. These results show that oral UMP, a uridine source, enhances the synthesis of CDP-choline, the immediate precursor of PC, in gerbil brain.

GPS Metric Tracking Unit

NASA Technical Reports Server (NTRS)

2008-01-01

As Global Positioning Satellite (GPS) applications become more prevalent for land- and air-based vehicles, GPS applications for space vehicles will also increase. The Applied Technology Directorate of Kennedy Space Center (KSC) has developed a lightweight, low-cost GPS Metric Tracking Unit (GMTU), the first of two steps in developing a lightweight, low-cost Space-Based Tracking and Command Subsystem (STACS) designed to meet Range Safety's link margin and latency requirements for vehicle command and telemetry data. The goals of STACS are to improve Range Safety operations and expand tracking capabilities for space vehicles. STACS will track the vehicle, receive commands, and send telemetry data through the space-based asset, which will dramatically reduce dependence on ground-based assets. The other step was the Low-Cost Tracking and Data Relay Satellite System (TDRSS) Transceiver (LCT2), developed by the Wallops Flight Facility (WFF), which allows the vehicle to communicate with a geosynchronous relay satellite. Although the GMTU and LCT2 were independently implemented and tested, the design collaboration of KSC and WFF engineers allowed GMTU and LCT2 to be integrated into one enclosure, leading to the final STACS. In operation, GMTU needs only a radio frequency (RF) input from a GPS antenna and outputs position and velocity data to the vehicle through a serial or pulse code modulation (PCM) interface. GMTU includes one commercial GPS receiver board and a custom board, the Command and Telemetry Processor (CTP) developed by KSC. The CTP design is based on a field-programmable gate array (FPGA) with embedded processors to support GPS functions.

A non-linear regression method for CT brain perfusion analysis

NASA Astrophysics Data System (ADS)

Bennink, E.; Oosterbroek, J.; Viergever, M. A.; Velthuis, B. K.; de Jong, H. W. A. M.

2015-03-01

CT perfusion (CTP) imaging allows for rapid diagnosis of ischemic stroke. Generation of perfusion maps from CTP data usually involves deconvolution algorithms providing estimates for the impulse response function in the tissue. We propose the use of a fast non-linear regression (NLR) method that we postulate has similar performance to the current academic state-of-art method (bSVD), but that has some important advantages, including the estimation of vascular permeability, improved robustness to tracer-delay, and very few tuning parameters, that are all important in stroke assessment. The aim of this study is to evaluate the fast NLR method against bSVD and a commercial clinical state-of-art method. The three methods were tested against a published digital perfusion phantom earlier used to illustrate the superiority of bSVD. In addition, the NLR and clinical methods were also tested against bSVD on 20 clinical scans. Pearson correlation coefficients were calculated for each of the tested methods. All three methods showed high correlation coefficients (>0.9) with the ground truth in the phantom. With respect to the clinical scans, the NLR perfusion maps showed higher correlation with bSVD than the perfusion maps from the clinical method. Furthermore, the perfusion maps showed that the fast NLR estimates are robust to tracer-delay. In conclusion, the proposed fast NLR method provides a simple and flexible way of estimating perfusion parameters from CT perfusion scans, with high correlation coefficients. This suggests that it could be a better alternative to the current clinical and academic state-of-art methods.

Acute-On-Chronic Liver Failure: Causes, Clinical Characteristics and Predictors of Mortality.

PubMed

Tasneem, Abbas Ali; Luck, Nasir Hassan

2017-01-01

To determine the causes, characteristics and predictors of mortality in patients with acute-on-chronic liver failure (ACLF). Cross-sectional study. Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, from July 2014 to June 2016. All patients with acute-on-chronic liver disease (ACLD) with ages > 12 were included. Patients with ACLF, as defined by the Asian Pacific Association for the Study of Liver (APASL, 2014) were identified. Predictors of mortality were identified using chi-square or Fisher's exact test. Included in the study were 72 patients with mean age of 36.71 years, 46 (63.9%) being males. Among them, 61 developed ACLF. Commonest causes of chronic liver disease (CLD) were chronic viral hepatitis (37, 51.4%) and autoimmune hepatitis (14, 19.4%). Commonest causes of acute liver injury (ALI) were acute viral hepatitis (24, 33.3%) and drug induced liver injury (DILI) (17, 23.6%). Among those with ACLF, 24 (39.3%) patients died with median survival of 17.1 ±13.5 days. Mortality was significantly associated with Child Turcotte Pugh (CTP) score ≥13 (p=0.010), model for end-stage liver disease (MELD) score ≥30 (p=0.001), age >40 years (p=0.036), organ failures (OF) ≥3 (p <0.0001), portosystemic encephalopathy (PSE) (p <0.0001), renal failure (p <0.0001) and urosepsis (p <0.0001). Acute viral hepatitis and DILI are commonest causes of ACLF. Mortality is high in ACLF patients having OF ≥3, CTP ≥13, MELD ≥30, age >40 years, PSE, renal failure and urosepsis.

Lung cancer perfusion: can we measure pulmonary and bronchial circulation simultaneously?

PubMed

Yuan, Xiaodong; Zhang, Jing; Ao, Guokun; Quan, Changbin; Tian, Yuan; Li, Hong

2012-08-01

To describe a new CT perfusion technique for assessing the dual blood supply in lung cancer and present the initial results. This study was approved by the institutional review board. A CT protocol was developed, and a dual-input CT perfusion (DI-CTP) analysis model was applied and evaluated regarding the blood flow fractions in lung tumours. The pulmonary trunk and the descending aorta were selected as the input arteries for the pulmonary circulation and the bronchial circulation respectively. Pulmonary flow (PF), bronchial flow (BF), and a perfusion index (PI, = PF/ (PF + BF)) were calculated using the maximum slope method. After written informed consent was obtained, 13 consecutive subjects with primary lung cancer underwent DI-CTP. Perfusion results are as follows: PF, 13.45 ± 10.97 ml/min/100 ml; BF, 48.67 ± 28.87 ml/min/100 ml; PI, 21 % ± 11 %. BF is significantly larger than PF, P < 0.001. There is a negative correlation between the tumour volume and perfusion index (r = 0.671, P = 0.012). The dual-input CT perfusion analysis method can be applied successfully to lung tumours. Initial results demonstrate a dual blood supply in primary lung cancer, in which the systemic circulation is dominant, and that the proportion of the two circulation systems is moderately dependent on tumour size. A new CT perfusion technique can assess lung cancer's dual blood supply. A dual blood supply was confirmed with dominant bronchial circulation in lung cancer. The proportion of the two circulations is moderately dependent on tumour size. This new technique may benefit the management of lung cancer.

Elucidation of Kinetic Mechanisms of Human Translesion DNA Polymerase κ Using Tryptophan Mutants

PubMed Central

Zhao, Linlin; Pence, Matthew G.; Eoff, Robert L.; Yuan, Shuai; Fercu, Catinca A.; Guengerich, F. Peter

2014-01-01

In order to investigate the conformational dynamics of human DNA polymerase κ (hpol κ), we generated two mutants, Y50W (N-clasp region) and Y408W (linker between the thumb and little finger domains), using a Trp-null mutant (W214Y/W392H) of the hpol κ catalytic core enzyme. These mutants retained catalytic activity and similar patterns of selectivity for bypassing the DNA adduct 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG), as judged by the results of steady-state and pre-steady-state kinetic experiments. Stopped-flow kinetic assays with hpol κ Y50W and T408W revealed a decrease in Trp fluorescence with the template G:dCTP pair but not for any mispairs. This decrease in fluorescence was not rate-limiting and is considered to be related to a conformational change necessary for correct nucleotidyl transfer. When a free 3′-hydroxyl was present on the primer, the Trp fluorescence returned to the baseline level at a rate similar to the observed kcat, suggesting that this change occurs during or after nucleotidyl transfer. However, polymerization rates (kpol) of extended-product formation were fast, indicating that the slow fluorescence step follows phosphodiester bond formation and is rate-limiting. Pyrophosphate formation and release were fast and are likely to precede the slower relaxation step. The available kinetic data were used to fit a simplified minimal model. The extracted rate constants confirmed that the conformational change after phosphodiester formation was rate-limiting for hpol κ catalysis with the template G:dCTP pair. PMID:25065501

Location of the redox-active thiols of ribonucleotide reductase: sequences similarity between the Escherichia coli and Lactobacillus leichmannii enzymes

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

Lin, A.N.I.; Ashley, G.W.; Stubbe, J.

1987-11-03

The redox-active thiols of Escherichia coli ribonucleoside diphosphate reductase and of Lactobacillus leichmannii ribonucleoside triphosphate reductase have been located by a procedure involving (1) prereduction of enzyme with dithiothreitol, (2) specific oxidation of the redox-active thiols by treatment with substrate in the absence of exogenous reductant, (3) alkylation of other thiols with iodoacetamide, and (4) reduction of the disulfides with dithiothreitol and alkylation with (1-/sup 14/C)iodoacetamide. The dithiothreitol-reduce E. coli B1 subunit is able to convert 3 equiv of CDP to dCDP and is labeled with 5.4 equiv of /sup 14/C. Sequencing of tryptic peptides shows that 2.8 equiv ofmore » /sup 14/C is on cysteines-752 and -757 at the C-terminus of B1, while 1.0-1.5 equiv of /sup 14/C is on cysteines-222 and -227. It thus appears that two sets of redox-active dithiols are involved in substrate reduction. The L. leichmannii reductase is able to convert 1.1 equiv of CTP to dCTP and is labeled with 2.1 equiv of /sup 14/C. Sequencing of tryptic peptides shows that 1.4 equiv of /sup 14/C is located on the two cysteines of C-E-G-G-A-C-P-I-K. This peptide shows remarkable and unexpected similarity to the thiol-containing region of the C-terminal peptide of E. coli B1, C-E-S-G-A-C-K-I.« less

Cyclopentenyl cytosine increases gemcitabine radiosensitisation in human pancreatic cancer cells

PubMed Central

van Bree, C; Rodermond, H M; Leen, R; Medema, J P; van Kuilenburg, A B P

2008-01-01

The deoxycytidine analogue 2′,2′-difluoro-2′-deoxycytidine (dFdC, gemcitabine) is a potent radiosensitiser, but has limited efficacy in combination with radiotherapy in patients with pancreatic cancer due to acute toxicity. We investigated whether cyclopentenyl cytosine (CPEC), targetting the ‘de novo' biosynthesis of cytidine triphosphate (CTP), could increase dFdC cytotoxicity alone or in combination with irradiation in a panel of human pancreatic cancer cells (Panc-1, Miapaca-2, BxPC-3). To investigate the role of deoxycytidine kinase (dCK), the rate-limiting enzyme in the activation of dFdC, human lung cancer cells without (dFdC-resistant SWg) and with an intact dCK gene (dFdC-sensitive SWp) were included. We found that CPEC (100–1000 nmol l−1) specifically reduced CTP levels in a dose-dependent manner that lasted up to 72 h in all cell lines. Preincubation with CPEC resulted in a dose-dependent increase in dFdC incorporated into the DNA only in dFdC-sensitive cells. Consequently, CPEC increased the effectiveness of dFdC (300 nmol l−1 for 4 h) only in dFdC-sensitive cells, which was accompanied by an increase in apoptosis. We also found that CPEC enhanced the radiosensitivity of cells treated with dFdC (30–300 nmol l−1 for 4 h). These results indicate that CPEC enhances the cytotoxicity of dFdC alone and in combination with irradiation in several human tumour cell lines with an intact dCK gene. PMID:18349845

Effects of Cloud Properties on PM2.5 Levels in the Southeastern United States

NASA Astrophysics Data System (ADS)

Yu, C.; Zhang, X.; Liu, Y.

2012-12-01

The spatial and temporal characteristics of fine particulate matter (PM2.5) are increasingly being derived from satellite aerosol remote sensing data. A major concern of satellite-derived PM2.5 information is cloud cover, i.e., PM2.5 mass concentrations cannot be estimated from satellite observations under cloudy conditions. There has been little research on the effects of cloud properties on PM2.5 levels. In this study, we performed a statistical analysis of relationships between various cloud parameters and PM2.5 concentrations. We used 2005-2010 PM2.5 observations from 8 sites in the Southeastern Aerosol Research and Characterization (SEARCH) Network, and cloud parameters from MODIS cloud product retrievals from Terra and Aqua satellites. We find that cloud fraction (CF) is generally negatively correlated with the mean value of PM2.5 mass concentration. However, the largest mean value occurs when the cloud fraction is between 10% and 30% instead of lower cloud cover (CF < 10%). The mean value of PM2.5 decreased from 14.3μg/m3 during 10%~30% cloud fraction to 9.3μg/m3 in cloudy days (CF=100%), and the negative correlation is more significant during the summer and fall than spring and winter. In addition, Cloud top pressure (CTP) and cloud optical thickness (COT) also influence PM2.5 mass concentration, with CTP being positively correlated with PM2.5 while COT being negatively correlated. These results suggest that cloud parameters may be used as predictor variables in satellite models of PM2.5.

Variceal bleeding in cirrhotic patients: What is the best prognostic score?

PubMed

Mohammad, Asmaa N; Morsy, Khairy H; Ali, Moustafa A

2016-09-01

To find the most accurate, suitable, and applicable scoring system for the prediction of outcome in cirrhotic patients with bleeding varices. A prospective study was conducted comprising 120 cirrhotic patients with acute variceal bleeding who were admitted to Tropical Medicine and Gastroenterology Department in Sohag University Hospital, over a 1-year period (1/2015 to 1/2016). The clinical, laboratory, and endoscopic parameters were studied. Child-Turcotte-Pugh (CTP) classification score, Model for end-stage liver disease (MELD) score, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, and AIMS65 score were calculated for all patients. Univariate and multivariate analyses were performed for all the measured parameters and scores. Of the 120 patients (92 male) admitted during the study period, eight patients (6.67%) died in the hospital. Advanced age, the presence of encephalopathy, rebleeding, and higher serum bilirubin were independent factors associated with higher hospital mortality. The largest area under the receiver operator curve (AUROC) was obtained for the AIMS65 score and SOFA score, followed by the MELD score and APACHEII score, then CTP score, all of which achieved very good performance (AUROC>0.8). AIMS65 score showed the best sensitivity, specificity, and negative and positive predictive values. Although the AIMS65 score was not significantly different from the MELD, SOFA, and APACHEII scores, it was the optimum among them in terms of the prediction of mortality. AIMS65 score is the best simple and applicable scoring system for independently predicting mortality in cirrhotic patients with acute variceal bleeding.

Sikorsky Aircraft Advanced Rotorcraft Transmission (ART) program

NASA Technical Reports Server (NTRS)

Kish, Jules G.

1993-01-01

The objectives of the Advanced Rotorcraft Transmission program were to achieve a 25 percent weight reduction, a 10 dB noise reduction, and a 5,000 hour mean time between removals (MTBR). A three engine Army Cargo Aircraft (ACA) of 85,000 pounds gross weight was used as the baseline. Preliminary designs were conducted of split path and split torque transmissions to evaluate weight, reliability, and noise. A split path gearbox was determined to be 23 percent lighter, greater than 10 dB quieter, and almost four times more reliable than the baseline two stage planetary design. Detail design studies were conducted of the chosen split path configuration, and drawings were produced of a 1/2 size gearbox consisting of a single engine path of the split path section. Fabrication and testing was then conducted on the 1/2 size gearbox. The 1/2 size gearbox testing proved that the concept of the split path gearbox with high reduction ratio double helical output gear was sound. The improvements were attributed to extensive use of composites, spring clutches, advanced high hot hardness gear steels, the split path configuration itself, high reduction ratio, double helical gearing on the output stage, elastomeric load sharing devices, and elimination of accessory drives.

Equipartition terms in transition path ensemble: Insights from molecular dynamics simulations of alanine dipeptide.

PubMed

Li, Wenjin

2018-02-28

Transition path ensemble consists of reactive trajectories and possesses all the information necessary for the understanding of the mechanism and dynamics of important condensed phase processes. However, quantitative description of the properties of the transition path ensemble is far from being established. Here, with numerical calculations on a model system, the equipartition terms defined in thermal equilibrium were for the first time estimated in the transition path ensemble. It was not surprising to observe that the energy was not equally distributed among all the coordinates. However, the energies distributed on a pair of conjugated coordinates remained equal. Higher energies were observed to be distributed on several coordinates, which are highly coupled to the reaction coordinate, while the rest were almost equally distributed. In addition, the ensemble-averaged energy on each coordinate as a function of time was also quantified. These quantitative analyses on energy distributions provided new insights into the transition path ensemble.

Variations of Solar Non-axisymmetric Activity

NASA Astrophysics Data System (ADS)

Gyenge, N.; Baranyi, T.; Ludmány, A.

The temporal behaviour of solar active longitudes has been examined by using two sunspot catalogues, the Greenwich Photoheliographic Results (GPR) and the Debrecen Photoheliographic Data (DPD). The time-longitude diagrams of the activity distribution reveal the preferred longitudinal zones and their migration with respect to the Carrington frame. The migration paths outline a set of patterns in which the activity zone has alternating prograde/retrograde angular velocities with respect to the Carrington rotation rate. The time profiles of these variations can be described by a set of successive parabolae. Two similar migration paths have been selected from these datasets, one northern path during cycles 21 - 22 and one southern path during cycles 13 - 14, for closer examination and comparison of their dynamical behaviours. The rates of sunspot emergence exhibited in both migration paths similar periodicities, close to 1.3 years. This behaviour may imply that the active longitude is connected to the bottom of convection zone.

On Channel-Discontinuity-Constraint Routing in Wireless Networks☆

PubMed Central

Sankararaman, Swaminathan; Efrat, Alon; Ramasubramanian, Srinivasan; Agarwal, Pankaj K.

2011-01-01

Multi-channel wireless networks are increasingly deployed as infrastructure networks, e.g. in metro areas. Network nodes frequently employ directional antennas to improve spatial throughput. In such networks, between two nodes, it is of interest to compute a path with a channel assignment for the links such that the path and link bandwidths are the same. This is achieved when any two consecutive links are assigned different channels, termed as “Channel-Discontinuity-Constraint” (CDC). CDC-paths are also useful in TDMA systems, where, preferably, consecutive links are assigned different time-slots. In the first part of this paper, we develop a t-spanner for CDC-paths using spatial properties; a sub-network containing O(n/θ) links, for any θ > 0, such that CDC-paths increase in cost by at most a factor t = (1−2 sin (θ/2))−2. We propose a novel distributed algorithm to compute the spanner using an expected number of O(n log n) fixed-size messages. In the second part, we present a distributed algorithm to find minimum-cost CDC-paths between two nodes using O(n2) fixed-size messages, by developing an extension of Edmonds’ algorithm for minimum-cost perfect matching. In a centralized implementation, our algorithm runs in O(n2) time improving the previous best algorithm which requires O(n3) running time. Moreover, this running time improves to O(n/θ) when used in conjunction with the spanner developed. PMID:24443646

The Study of Intelligent Vehicle Navigation Path Based on Behavior Coordination of Particle Swarm.

PubMed

Han, Gaining; Fu, Weiping; Wang, Wen

2016-01-01

In the behavior dynamics model, behavior competition leads to the shock problem of the intelligent vehicle navigation path, because of the simultaneous occurrence of the time-variant target behavior and obstacle avoidance behavior. Considering the safety and real-time of intelligent vehicle, the particle swarm optimization (PSO) algorithm is proposed to solve these problems for the optimization of weight coefficients of the heading angle and the path velocity. Firstly, according to the behavior dynamics model, the fitness function is defined concerning the intelligent vehicle driving characteristics, the distance between intelligent vehicle and obstacle, and distance of intelligent vehicle and target. Secondly, behavior coordination parameters that minimize the fitness function are obtained by particle swarm optimization algorithms. Finally, the simulation results show that the optimization method and its fitness function can improve the perturbations of the vehicle planning path and real-time and reliability.

The Study of Intelligent Vehicle Navigation Path Based on Behavior Coordination of Particle Swarm

PubMed Central

Han, Gaining; Fu, Weiping; Wang, Wen

2016-01-01

In the behavior dynamics model, behavior competition leads to the shock problem of the intelligent vehicle navigation path, because of the simultaneous occurrence of the time-variant target behavior and obstacle avoidance behavior. Considering the safety and real-time of intelligent vehicle, the particle swarm optimization (PSO) algorithm is proposed to solve these problems for the optimization of weight coefficients of the heading angle and the path velocity. Firstly, according to the behavior dynamics model, the fitness function is defined concerning the intelligent vehicle driving characteristics, the distance between intelligent vehicle and obstacle, and distance of intelligent vehicle and target. Secondly, behavior coordination parameters that minimize the fitness function are obtained by particle swarm optimization algorithms. Finally, the simulation results show that the optimization method and its fitness function can improve the perturbations of the vehicle planning path and real-time and reliability. PMID:26880881

Aircraft path planning for optimal imaging using dynamic cost functions

NASA Astrophysics Data System (ADS)

Christie, Gordon; Chaudhry, Haseeb; Kochersberger, Kevin

2015-05-01

Unmanned aircraft development has accelerated with recent technological improvements in sensing and communications, which has resulted in an "applications lag" for how these aircraft can best be utilized. The aircraft are becoming smaller, more maneuverable and have longer endurance to perform sensing and sampling missions, but operating them aggressively to exploit these capabilities has not been a primary focus in unmanned systems development. This paper addresses a means of aerial vehicle path planning to provide a realistic optimal path in acquiring imagery for structure from motion (SfM) reconstructions and performing radiation surveys. This method will allow SfM reconstructions to occur accurately and with minimal flight time so that the reconstructions can be executed efficiently. An assumption is made that we have 3D point cloud data available prior to the flight. A discrete set of scan lines are proposed for the given area that are scored based on visibility of the scene. Our approach finds a time-efficient path and calculates trajectories between scan lines and over obstacles encountered along those scan lines. Aircraft dynamics are incorporated into the path planning algorithm as dynamic cost functions to create optimal imaging paths in minimum time. Simulations of the path planning algorithm are shown for an urban environment. We also present our approach for image-based terrain mapping, which is able to efficiently perform a 3D reconstruction of a large area without the use of GPS data.

Real-time Collision Avoidance and Path Optimizer for Semi-autonomous UAVs.

NASA Astrophysics Data System (ADS)

Hawary, A. F.; Razak, N. A.

2018-05-01

Whilst UAV offers a potentially cheaper and more localized observation platform than current satellite or land-based approaches, it requires an advance path planner to reveal its true potential, particularly in real-time missions. Manual control by human will have limited line-of-sights and prone to errors due to careless and fatigue. A good alternative solution is to equip the UAV with semi-autonomous capabilities that able to navigate via a pre-planned route in real-time fashion. In this paper, we propose an easy-and-practical path optimizer based on the classical Travelling Salesman Problem and adopts a brute force search method to re-optimize the route in the event of collisions using range finder sensor. The former utilizes a Simple Genetic Algorithm and the latter uses Nearest Neighbour algorithm. Both algorithms are combined to optimize the route and avoid collision at once. Although many researchers proposed various path planning algorithms, we find that it is difficult to integrate on a basic UAV model and often lacks of real-time collision detection optimizer. Therefore, we explore a practical benefit from this approach using on-board Arduino and Ardupilot controllers by manually emulating the motion of an actual UAV model prior to test on the flying site. The result showed that the range finder sensor provides a real-time data to the algorithm to find a collision-free path and eventually optimized the route successfully.

Time-of-flight dependency on transducer separation distance in a reflective-path guided-wave ultrasonic flow meter at zero flow conditions.

PubMed

Aanes, Magne; Kippersund, Remi Andre; Lohne, Kjetil Daae; Frøysa, Kjell-Eivind; Lunde, Per

2017-08-01

Transit-time flow meters based on guided ultrasonic wave propagation in the pipe spool have several advantages compared to traditional inline ultrasonic flow metering. The extended interrogation field, obtained by continuous leakage from guided waves traveling in the pipe wall, increases robustness toward entrained particles or gas in the flow. In reflective-path guided-wave ultrasonic flow meters (GW-UFMs), the flow equations are derived from signals propagating solely in the pipe wall and from signals passing twice through the fluid. In addition to the time-of-flight (TOF) through the fluid, the fluid path experiences an additional time delay upon reflection at the opposite pipe wall due to specular and non-specular reflections. The present work investigates the influence of these reflections on the TOF in a reflective-path GW-UFM as a function of transducer separation distance at zero flow conditions. Two models are used to describe the signal propagation through the system: (i) a transient full-wave finite element model, and (ii) a combined plane-wave and ray-tracing model. The study shows that a range-dependent time delay is associated with the reflection of the fluid path, introducing transmitter-receiver distance dependence. Based on these results, the applicability of the flow equations derived using model (ii) is discussed.

Nonintrusive performance measurement of a gas turbine engine in real time

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

DeSilva, Upul P.; Claussen, Heiko

Performance of a gas turbine engine is monitored by computing a mass flow rate through the engine. Acoustic time-of-flight measurements are taken between acoustic transmitters and receivers in the flow path of the engine. The measurements are processed to determine average speeds of sound and gas flow velocities along those lines-of-sound. A volumetric flow rate in the flow path is computed using the gas flow velocities together with a representation of the flow path geometry. A gas density in the flow path is computed using the speeds of sound and a measured static pressure. The mass flow rate is calculatedmore » from the gas density and the volumetric flow rate.« less