A novel mechanism of E2F1 regulation via nucleocytoplasmic shuttling: determinants of nuclear import and export.

PubMed

Ivanova, Iordanka A; Vespa, Alisa; Dagnino, Lina

2007-09-01

E2F1 is a transcription factor central for cell survival, proliferation, and repair following genomic insult. Depending on the cell type and conditions, E2F1 can induce apoptosis in transformed cells, behaving as a tumour suppressor, or impart growth advantages favouring tumour formation. The pleiotropic functions of E2F1 are a likely consequence of its ability to transcriptionally control a wide variety of target genes, and require tight regulation of its activity at multiple levels. Although sequestration of proteins to particular cellular compartments is a well-established regulatory mechanism, virtually nothing is known about its contribution to modulation of E2F1 target gene expression. We have examined the subcellular trafficking of E2F1 and, contrary to the widely held notion that this factor is constitutively nuclear, we now demonstrate that it is subjected to continuous nucleocytoplasmic shuttling. We have also defined two nuclear localization domains and a nuclear export region, which mediates CRM1-dependent transit out of the nucleus. The predominant subcellular location of E2F1 is likely determined by the balance between the activity of nuclear import and export domains, and can be modulated by differentiation stimuli in epidermal cells. Thus, we have identified a hitherto unrecognized mechanism to control E2F1 function through modulation of its subcellular localization.

Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.

PubMed

Chang, Wing Y; Andrews, Joseph; Carter, David E; Dagnino, Lina

2006-08-01

E2F transcription factors are central to epidermal morphogenesis and regeneration after injury. The precise nature of E2F target genes involved in epidermal formation and repair has yet to be determined. Identification of these genes is essential to understand how E2F proteins regulate fundamental aspects of epidermal homeostasis and transformation. We have conducted a genome-wide screen using CpG island microarray analysis to identify novel promoters bound by E2F3 and E2F5 in human keratinocytes. We further characterized several of these genes, and determined that multiple E2F and retinoblastoma (pRb) family proteins associate with them in exponentially proliferating cells. We also assessed the effect on E2F and pRb binding to those genes in response to differentiation induced by bone morphogenetic protein-6 (BMP-6), or to activation of repair mechanisms induced by transforming growth factor-beta (TGF-beta). These studies demonstrate promoter- and cytokine-specific changes in binding profiles of E2F and/or pRb family proteins. For example, E2F1, 3, 4 and p107 were recruited to the N-myc promoter in cells treated with BMP-6, whereas E2F1, 3, 4, 5, p107 and p130 were bound to this promoter in the presence of TGF-beta. Functionally, these different interactions resulted in transcriptional repression by BMP-6 and TGF-beta of the N-myc gene, via mechanisms that involved E2F binding to the promoter and association with pRb-family proteins. Thus, multiple combinations of E2F and pRb family proteins may associate with and transcriptionally regulate a given target promoter in response to differentiation and injury-repair stimuli in epidermal keratinocytes.

PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy

PubMed Central

Brodin, N P; Björk-Eriksson, T; Birk Christensen, C; Kiil-Berthelsen, A; Aznar, M C; Hollensen, C; Markova, E; Munck af Rosenschöld, P

2015-01-01

Objective: To investigate the impact of including fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). Methods: Target volumes were first delineated without and subsequently re-delineated with access to 18F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). Results: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. Conclusion: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. Advances in knowledge: 18F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT. PMID:25494657

Specificity of the Human Frequency Following Response for Carrier and Modulation Frequency Assessed Using Adaptation.

PubMed

Gockel, Hedwig E; Krugliak, Alexandra; Plack, Christopher J; Carlyon, Robert P

2015-12-01

The frequency following response (FFR) is a scalp-recorded measure of phase-locked brainstem activity to stimulus-related periodicities. Three experiments investigated the specificity of the FFR for carrier and modulation frequency using adaptation. FFR waveforms evoked by alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. The first experiment investigated peristimulus adaptation of the FFR for pure and complex tones as a function of stimulus frequency and fundamental frequency (F0). It showed more adaptation of the FFR in response to sounds with higher frequencies or F0s than to sounds with lower frequency or F0s. The second experiment investigated tuning to modulation rate in the FFR. The FFR to a complex tone with a modulation rate of 213 Hz was not reduced more by an adaptor that had the same modulation rate than by an adaptor with a different modulation rate (90 or 504 Hz), thus providing no evidence that the FFR originates mainly from neurons that respond selectively to the modulation rate of the stimulus. The third experiment investigated tuning to audio frequency in the FFR using pure tones. An adaptor that had the same frequency as the target (213 or 504 Hz) did not generally reduce the FFR to the target more than an adaptor that differed in frequency (by 1.24 octaves). Thus, there was no evidence that the FFR originated mainly from neurons tuned to the frequency of the target. Instead, the results are consistent with the suggestion that the FFR for low-frequency pure tones at medium to high levels mainly originates from neurons tuned to higher frequencies. Implications for the use and interpretation of the FFR are discussed.

Mechanism of Fusion Triggering by Human Parainfluenza Virus Type III

PubMed Central

Porotto, Matteo; Palmer, Samantha G.; Palermo, Laura M.; Moscona, Anne

2012-01-01

Parainfluenza viruses enter host cells by fusing the viral and target cell membranes via concerted action of their two envelope glycoproteins: the hemagglutinin-neuraminidase (HN) and the fusion protein (F). Receptor-bound HN triggers F to undergo conformational changes that render it fusion-competent. To address the role of receptor engagement and to elucidate how HN and F interact during the fusion process, we used bimolecular fluorescence complementation to follow the dynamics of human parainfluenza virus type 3 (HPIV3) HN/F pairs in living cells. We show that HN and F associate before receptor engagement. HN drives the formation of HN-F clusters at the site of fusion, and alterations in HN-F interaction determine the fusogenicity of the glycoprotein pair. An interactive site, at the HN dimer interface modulates HN fusion activation property, which is critical for infection of the natural host. This first evidence for the sequence of initial events that lead to viral entry may indicate a new paradigm for understanding Paramyxovirus infection. PMID:22110138

Breast Tumors with Elevated Expression of 1q Candidate Genes Confer Poor Clinical Outcome and Sensitivity to Ras/PI3K Inhibition

PubMed Central

Viveka Thangaraj, Soundara; Periasamy, Jayaprakash; Bhaskar Rao, Divya; Barnabas, Georgina D.; Raghavan, Swetha; Ganesan, Kumaresan

2013-01-01

Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA–drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors. PMID:24147022

Task-discriminative space-by-time factorization of muscle activity

PubMed Central

Delis, Ioannis; Panzeri, Stefano; Pozzo, Thierry; Berret, Bastien

2015-01-01

Movement generation has been hypothesized to rely on a modular organization of muscle activity. Crucial to this hypothesis is the ability to perform reliably a variety of motor tasks by recruiting a limited set of modules and combining them in a task-dependent manner. Thus far, existing algorithms that extract putative modules of muscle activations, such as Non-negative Matrix Factorization (NMF), identify modular decompositions that maximize the reconstruction of the recorded EMG data. Typically, the functional role of the decompositions, i.e., task accomplishment, is only assessed a posteriori. However, as motor actions are defined in task space, we suggest that motor modules should be computed in task space too. In this study, we propose a new module extraction algorithm, named DsNM3F, that uses task information during the module identification process. DsNM3F extends our previous space-by-time decomposition method (the so-called sNM3F algorithm, which could assess task performance only after having computed modules) to identify modules gauging between two complementary objectives: reconstruction of the original data and reliable discrimination of the performed tasks. We show that DsNM3F recovers the task dependence of module activations more accurately than sNM3F. We also apply it to electromyographic signals recorded during performance of a variety of arm pointing tasks and identify spatial and temporal modules of muscle activity that are highly consistent with previous studies. DsNM3F achieves perfect task categorization without significant loss in data approximation when task information is available and generalizes as well as sNM3F when applied to new data. These findings suggest that the space-by-time decomposition of muscle activity finds robust task-discriminating modular representations of muscle activity and that the insertion of task discrimination objectives is useful for describing the task modulation of module recruitment. PMID:26217213

Task-discriminative space-by-time factorization of muscle activity.

PubMed

Delis, Ioannis; Panzeri, Stefano; Pozzo, Thierry; Berret, Bastien

2015-01-01

Movement generation has been hypothesized to rely on a modular organization of muscle activity. Crucial to this hypothesis is the ability to perform reliably a variety of motor tasks by recruiting a limited set of modules and combining them in a task-dependent manner. Thus far, existing algorithms that extract putative modules of muscle activations, such as Non-negative Matrix Factorization (NMF), identify modular decompositions that maximize the reconstruction of the recorded EMG data. Typically, the functional role of the decompositions, i.e., task accomplishment, is only assessed a posteriori. However, as motor actions are defined in task space, we suggest that motor modules should be computed in task space too. In this study, we propose a new module extraction algorithm, named DsNM3F, that uses task information during the module identification process. DsNM3F extends our previous space-by-time decomposition method (the so-called sNM3F algorithm, which could assess task performance only after having computed modules) to identify modules gauging between two complementary objectives: reconstruction of the original data and reliable discrimination of the performed tasks. We show that DsNM3F recovers the task dependence of module activations more accurately than sNM3F. We also apply it to electromyographic signals recorded during performance of a variety of arm pointing tasks and identify spatial and temporal modules of muscle activity that are highly consistent with previous studies. DsNM3F achieves perfect task categorization without significant loss in data approximation when task information is available and generalizes as well as sNM3F when applied to new data. These findings suggest that the space-by-time decomposition of muscle activity finds robust task-discriminating modular representations of muscle activity and that the insertion of task discrimination objectives is useful for describing the task modulation of module recruitment.

Possible role of cochlear nonlinearity in the detection of mistuning of a harmonic component in a harmonic complex

NASA Astrophysics Data System (ADS)

Stoelinga, Christophe; Heo, Inseok; Long, Glenis; Lee, Jungmee; Lutfi, Robert; Chang, An-Chieh

2015-12-01

The human auditory system has a remarkable ability to "hear out" a wanted sound (target) in the background of unwanted sounds. One important property of sound which helps us hear-out the target is inharmonicity. When a single harmonic component of a harmonic complex is slightly mistuned, that component is heard to separate from the rest. At high harmonic numbers, where components are unresolved, the harmonic segregation effect is thought to result from detection of modulation of the time envelope (roughness cue) resulting from the mistuning. Neurophysiological research provides evidence that such envelope modulations are represented early in the auditory system, at the level of the auditory nerve. When the mistuned harmonic is a low harmonic, where components are resolved, the harmonic segregation is attributed to more centrally-located auditory processes, leading harmonic components to form a perceptual group heard separately from the mistuned component. Here we consider an alternative explanation that attributes the harmonic segregation to detection of modulation when both high and low harmonic numbers are mistuned. Specifically, we evaluate the possibility that distortion products in the cochlea generated by the mistuned component introduce detectable beating patterns for both high and low harmonic numbers. Distortion product otoacoustic emissions (DPOAEs) were measured using 3, 7, or 12-tone harmonic complexes with a fundamental frequency (F0) of 200 or 400 Hz. One of two harmonic components was mistuned at each F0: one when harmonics are expected to be resulted and the other from unresolved harmonics. Many non-harmonic DPOAEs are present whenever a harmonic component is mistuned. These non-harmonic DPOAEs are often separated by the amount of the mistuning (ΔF). This small frequency difference will generate a slow beating pattern at ΔF, because this beating is only present when a harmonic component is mistuned, it could provide a cue for behavioral detection of harmonic complex mistuning and may also be associated with the modulation of auditory nerve responses.

SU-F-T-184: 3D Range-Modulator for Scanned Particle Therapy: Development, Monte Carlo Simulations and Measurements

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

Simeonov, Y; Penchev, P; Ringbaek, T Printz

2016-06-15

Purpose: Active raster scanning in particle therapy results in highly conformal dose distributions. Treatment time, however, is relatively high due to the large number of different iso-energy layers used. By using only one energy and the so called 3D range-modulator irradiation times of a few seconds only can be achieved, thus making delivery of homogeneous dose to moving targets (e.g. lung cancer) more reliable. Methods: A 3D range-modulator consisting of many pins with base area of 2.25 mm2 and different lengths was developed and manufactured with rapid prototyping technique. The form of the 3D range-modulator was optimised for a sphericalmore » target volume with 5 cm diameter placed at 25 cm in a water phantom. Monte Carlo simulations using the FLUKA package were carried out to evaluate the modulating effect of the 3D range-modulator and simulate the resulting dose distribution. The fine and complicated contour form of the 3D range-modulator was taken into account by a specially programmed user routine. Additionally FLUKA was extended with the capability of intensity modulated scanning. To verify the simulation results dose measurements were carried out at the Heidelberg Ion Therapy Center (HIT) with a 400.41 MeV 12C beam. Results: The high resolution measurements show that the 3D range-modulator is capable of producing homogeneous 3D conformal dose distributions, simultaneously reducing significantly irradiation time. Measured dose is in very good agreement with the previously conducted FLUKA simulations, where slight differences were traced back to minor manufacturing deviations from the perfect optimised form. Conclusion: Combined with the advantages of very short treatment time the 3D range-modulator could be an alternative to treat small to medium sized tumours (e.g. lung metastasis) with the same conformity as full raster-scanning treatment. Further simulations and measurements of more complex cases will be conducted to investigate the full potential of the 3D range-modulator.« less

Prospective feasibility trial of radiotherapy target definition for head and neck cancer using 3-dimensional PET and CT imaging.

PubMed

Scarfone, Christopher; Lavely, William C; Cmelak, Anthony J; Delbeke, Dominique; Martin, William H; Billheimer, Dean; Hallahan, Dennis E

2004-04-01

The aim of this investigation was to evaluate the influence and accuracy of (18)F-FDG PET in target volume definition as a complementary modality to CT for patients with head and neck cancer (HNC) using dedicated PET and CT scanners. Six HNC patients were custom fitted with head and neck and upper body immobilization devices, and conventional radiotherapy CT simulation was performed together with (18)F-FDG PET imaging. Gross target volume (GTV) and pathologic nodal volumes were first defined in the conventional manner based on CT. A segmentation and surface-rendering registration technique was then used to coregister the (18)F-FDG PET and CT planning image datasets. (18)F-FDG PET GTVs were determined and displayed simultaneously with the CT contours. CT GTVs were then modified based on the PET data to form final PET/CT treatment volumes. Five-field intensity-modulated radiation therapy (IMRT) was then used to demonstrate dose targeting to the CT GTV or the PET/CT GTV. One patient was PET-negative after induction chemotherapy. The CT GTV was modified in all remaining patients based on (18)F-FDG PET data. The resulting PET/CT GTV was larger than the original CT volume by an average of 15%. In 5 cases, (18)F-FDG PET identified active lymph nodes that corresponded to lymph nodes contoured on CT. The pathologically enlarged CT lymph nodes were modified to create final lymph node volumes in 3 of 5 cases. In 1 of 6 patients, (18)F-FDG-avid lymph nodes were not identified as pathologic on CT. In 2 of 6 patients, registration of the independently acquired PET and CT data using segmentation and surface rendering resulted in a suboptimal alignment and, therefore, had to be repeated. Radiotherapy planning using IMRT demonstrated the capability of this technique to target anatomic or anatomic/physiologic target volumes. In this manner, metabolically active sites can be intensified to greater daily doses. Inclusion of (18)F-FDG PET data resulted in modified target volumes in radiotherapy planning for HNC. PET and CT data acquired on separate, dedicated scanners may be coregistered for therapy planning; however, dual-acquisition PET/CT systems may be considered to reduce the need for reregistrations. It is possible to use IMRT to target dose to metabolically active sites based on coregistered PET/CT data.

PIM1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

DTIC Science & Technology

2008-10-31

2007) C«t Pr. T«K:J1 r. 587-605 CaUtr«M, F. I . |200S> Oil . te- Tx\\u< 35.443-582 I ..-:tiatr.-ir, C.Iixo;, X. Cfitniti t,B<nor V..Dcrtgovsu, V,Chat...control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. I . REPORT DATE (DD-MM-YYYY) 31-10-2008 2. REPORT TYPE Annual 3. DATES COVERED...reporting period a number of studies were undertaken to characterize Fig. 4. Modulation of docetaxel cell kill by enforced expression of pim-1 cDNAs. 1 i

Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for {sup 18}F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study

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

Teoh, May, E-mail: m.teoh@nhs.net; Beveridge, Sabeena; Wood, Katie

2013-04-01

Fluorine-18-fluorodeoxyglucose-positron emission tomography ({sup 18}F-FDG-PET)–guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to {sup 18}F-FDG-PET–positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gymore » in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI{sub Paddick}) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI{sub Paddick} scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8–49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). {sup 18}F-FDG-PET–guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.« less

Modulation of empathy in the left ventrolateral prefrontal cortex facilitates altruistic behavior: An fNIRS study.

PubMed

Himichi, Toshiyuki; Nomura, Michio

2015-06-01

Previous studies suggest that the ventrolateral prefrontal cortex (VLPFC) is involved in modulating empathy. However, it is unclear whether VLPFC activation while an individual empathizes with others is related to subsequent altruistic behavior. In the present study, participants observed two people playing a card game while empathizing with one of them (target person); PFC activation during the task was measured using functional near-infrared spectroscopy (fNIRS). After this task, participants distributed money to the target person. Results showed that activation in the left VLPFC during empathizing with the target person, who lost a small amount of money, was positively correlated with the amount of money distributed; this activation mediated a relationship between norm of restitution toward helping and the amount of distributed money. These results suggest that activation in the left VLPFC during empathizing with others experiencing negative circumstances is associated with altruistic behavior.

MO-F-CAMPUS-T-02: Optimizing Orientations of Hundreds of Intensity-Modulated Beams to Treat Multiple Brain Targets

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

Ma, L; Dong, P; Larson, D

Purpose: To investigate a new modulated beam orientation optimization (MBOO) approach maximizing treatment planning quality for the state-of-the-art flattening filter free (FFF) beam that has enabled rapid treatments of multiple brain targets. Methods: MBOO selects and optimizes a large number of intensity-modulated beams (400 or more) from all accessible beam angles surrounding a patient’s skull. The optimization algorithm was implemented on a standalone system that interfaced with the 3D Dicom images and structure sets. A standard published data set that consisted of 1 to 12 metastatic brain tumor combinations was selected for MBOO planning. The planning results from various coplanarmore » and non-coplanar configurations via MBOO were then compared with the results obtained from a clinical volume modulated arc therapy (VMAT) delivery system (Truebeam RapidArc, Varian Oncology). Results: When planning a few number of targets (n<4), MBOO produced results equivalent to non-coplanar multi-arc VMAT planning in terms of target volume coverage and normal tissue sparing. For example, the 12-Gy and 4-Gy normal brain volumes for the 3-target plans differed by less than 1 mL ( 3.0 mLvs 3.8 mL; and 35.2 mL vs 36.3 mL, respectively) for MBOO versus VMAT. However, when planning a larger number of targets (n≥4), MBOO significantly reduced the dose to the normal brain as compared to VMAT, though the target volume coverage was equivalent. For example, the 12-Gy and 4-Gy normal brain volumes for the 12-target plans were 10.8 mL vs. 18.0 mL and 217.9 mL vs. 390.0 mL, respectively for the non-coplanar MBOO versus the non-coplanar VMAT treatment plans, yielding a reduction in volume of more than 60% for the case. Conclusion: MBOO is a unique approach for maximizing normal tissue sparing when treating a large number (n≥4) of brain tumors with FFF linear accelerators. Dr Ma and Dr Sahgal are currently on the board of international society of stereotactic radiosurgery. Dr Sahgal has received support for educational presentations from Elekta company.« less

TL and OSL dose response of LiF:Mg,Ti and Al2O3:C dosimeters using a PMMA phantom for IMRT technique quality assurance.

PubMed

Matsushima, Luciana C; Veneziani, Glauco R; Sakuraba, Roberto K; Cruz, José C; Campos, Letícia L

2015-06-01

The principle of IMRT is to treat a patient from a number of different directions (or continuous arcs) with beams of nonuniform fluences, which have been optimized to deliver a high dose to the target volume and an acceptably low dose to the surrounding normal structures (Khan, 2010). This study intends to provide information to the physicist regarding the application of different dosimeters type, phantoms and analysis technique for Intensity Modulated Radiation Therapy (IMRT) dose distributions evaluation. The measures were performed using dosimeters of LiF:Mg,Ti and Al2O3:C evaluated by techniques of thermoluminescent (TL) and Optically Stimulated Luminescence (OSL). A polymethylmethacrylate (PMMA) phantom with five cavities, two principal target volumes considered like tumours to be treated and other three cavities to measure the scattered radiation dose was developed to carried out the measures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge

PubMed Central

Wolf, Daniel H.; Satterthwaite, Theodore D.; Loughead, James; Pinkham, Amy; Overton, Eve; Elliott, Mark A.; Dent, Gersham W.; Smith, Mark A.; Gur, Ruben C.; Gur, Raquel E.

2014-01-01

Rationale Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation. Objectives We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis. Methods An oral 1mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory. Results Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task. Conclusions GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia. PMID:21603892

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

PubMed Central

Figueira, T. N.; Palermo, L. M.; Veiga, A. S.; Huey, D.; Alabi, C. A.; Santos, N. C.; Welsch, J. C.; Mathieu, C.; Niewiesk, S.; Moscona, A.

2016-01-01

ABSTRACT Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo. We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides. PMID:27733647

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence.

PubMed

Figueira, T N; Palermo, L M; Veiga, A S; Huey, D; Alabi, C A; Santos, N C; Welsch, J C; Mathieu, C; Horvat, B; Niewiesk, S; Moscona, A; Castanho, M A R B; Porotto, M

2017-01-01

Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides. Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides. Copyright © 2016 American Society for Microbiology.

Parametric fMRI of paced motor responses uncovers novel whole-brain imaging biomarkers in spinocerebellar ataxia type 3.

PubMed

Duarte, João Valente; Faustino, Ricardo; Lobo, Mercês; Cunha, Gil; Nunes, César; Ferreira, Carlos; Januário, Cristina; Castelo-Branco, Miguel

2016-10-01

Machado-Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole-brain functional biomarkers, based on parametric performance-level-dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel-based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio-paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance-level-based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency-dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate-dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger-tapping task significantly often reached >80% sensitivity and specificity in single regions-of-interest.Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia. Hum Brain Mapp 37:3656-3668, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The spatio-temporal dynamics of deviance and target detection in the passive and active auditory oddball paradigm: a sLORETA study.

PubMed

Justen, Christoph; Herbert, Cornelia

2018-04-19

Numerous studies have investigated the neural underpinnings of passive and active deviance and target detection in the well-known auditory oddball paradigm by means of event-related potentials (ERPs) or functional magnetic resonance imaging (fMRI). The present auditory oddball study investigates the spatio-temporal dynamics of passive versus active deviance and target detection by analyzing amplitude modulations of early and late ERPs while at the same time exploring the neural sources underling this modulation with standardized low-resolution brain electromagnetic tomography (sLORETA) . A 64-channel EEG was recorded from twelve healthy right-handed participants while listening to 'standards' and 'deviants' (500 vs. 1000 Hz pure tones) during a passive (block 1) and an active (block 2) listening condition. During passive listening, participants had to simply listen to the tones. During active listening they had to attend and press a key in response to the deviant tones. Passive and active listening elicited an N1 component, a mismatch negativity (MMN) as difference potential (whose amplitudes were temporally overlapping with the N1) and a P3 component. N1/MMN and P3 amplitudes were significantly more pronounced for deviants as compared to standards during both listening conditions. Active listening augmented P3 modulation to deviants significantly compared to passive listening, whereas deviance detection as indexed by N1/MMN modulation was unaffected by the task. During passive listening, sLORETA contrasts (deviants > standards) revealed significant activations in the right superior temporal gyrus (STG) and the lingual gyri bilaterally (N1/MMN) as well as in the left and right insulae (P3). During active listening, significant activations were found for the N1/MMN in the right inferior parietal lobule (IPL) and for the P3 in multiple cortical regions (e.g., precuneus). The results provide evidence for the hypothesis that passive as well as active deviance and target detection elicit cortical activations in spatially distributed brain regions and neural networks including the ventral attention network (VAN), dorsal attention network (DAN) and salience network (SN). Based on the temporal activation of the neural sources underlying ERP modulations, a neurophysiological model of passive and active deviance and target detection is proposed which can be tested in future studies.

Lateral and medial prefrontal contributions to emotion generation by semantic elaboration during episodic encoding.

PubMed

Kaneda, Takumi; Shigemune, Yayoi; Tsukiura, Takashi

2017-02-01

Memories for emotion-laden stimuli are remembered more accurately than those for neutral stimuli. Although this enhancement reflects stimulus-driven modulation of memory by emotions, functional neuroimaging evidence of the interacting mechanisms between emotions generated by intentional processes, such as semantic elaboration, and memory is scarce. The present fMRI study investigated how encoding-related activation is modulated by emotions generated during the process of semantic elaboration. During encoding with fMRI, healthy young adults viewed neutral (target) pictures either passively or with semantic elaboration. In semantic elaboration, participants imagined background stories related to the pictures. Encoding trials with semantic elaboration were subdivided into conditions in which participants imagined negative, positive, or neutral stories. One week later, memories for target pictures were tested. In behavioral results, memories for target pictures were significantly enhanced by semantic elaboration, compared to passive viewing, and the memory enhancement was more remarkable when negative or positive stories were imagined. fMRI results demonstrated that activations in the left inferior frontal gyrus and dorsal medial prefrontal cortex (dmPFC) were greater during the encoding of target pictures with semantic elaboration than those with passive viewing, and that these activations further increased during encoding with semantic elaboration of emotional stories than of neutral stories. Functional connectivity between the left inferior frontal gyrus and dmPFC/hippocampus during encoding significantly predicted retrieval accuracies of memories encoded with self-generated emotional stories. These findings suggest that networks including the left inferior frontal region, dmPFC, and hippocampus could contribute to the modulation of memories encoded with the emotion generation.

An improved radiosynthesis of [18F]AV-133: a PET imaging agent for vesicular monoamine transporter 2.

PubMed

Zhu, Lin; Liu, Yajing; Plössl, Karl; Lieberman, Brian; Liu, Jingying; Kung, Hank F

2010-02-01

Recently, a PET tracer, 9-[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133), targeting vesicular monoamine transporter 2 (VMAT2) in the central nervous system has been reported. It is currently under Phase II clinical trials to establish its usefulness in the diagnosis of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. The radiolabeling of [(18)F]AV-133, nucleophilic fluorination reaction and potential effects of pseudo-carrier were evaluated by in vivo biodistribution. The preparation of [(18)F]AV-133 was evaluated under different conditions, specifically by employing different precursors (-OTs or -Br as the leaving group at the 9-propoxy position), reagents (K222/K(2)CO(3) vs. tributylammonium bicarbonate) and solvents (acetonitrile vs. DMSO), reaction temperature and reaction time. With optimized conditions from these experiments, radiosynthesis and purification with solid-phase extraction (SPE) of [(18)F]AV-133 were performed by an automated nucleophilic [(18)F]fluorination module. In vivo biodistribution in mice on [(18)F]AV-133 purified by either HPLC (no-carrier-added) or the SPE method (containing a pseudo-carrier) was performed and the results compared. Under a mild fluorination condition (heating at 115 degrees C for 5 min in dimethyl sulfoxide), [(18)F]AV-133 was obtained in a high yield using either -OTs or -Br as the leaving group. However, the -OTs precursor gave better radiochemical yields (>70%, thin layer chromatography analysis) compared to those of the -Br precursor. The optimized reaction conditions were successfully implemented to an automated nucleophilic fluorination module. Labeling and purification of [(18)F]AV133 were readily achieved via this automatic module in good radiochemical yield of 21-41% (n=10) in 40 min. The radiochemical purity was larger than 95%. Biodistribution of SPE-purified product (containing a pseudo-carrier) in mice showed a high striatum/cerebellum ratio (4.18+/-0.51), which was comparable to that of HPLC-purified [(18)F]AV-133 (4.51+/-0.10). The formation of [(18)F]AV-133 was evaluated under different labeling conditions. These improved labeling conditions and SPE purification were successfully implemented into an automated synthesis module. This offers a short preparation time (about 40 min), simplicity in operation and ready applicability for routine clinical operation. (c) 2010 Elsevier Inc. All rights reserved.

Ppbv-Level Ethane Detection Using Quartz-Enhanced Photoacoustic Spectroscopy with a Continuous-Wave, Room Temperature Interband Cascade Laser

PubMed Central

Li, Chunguang; Dong, Lei; Zheng, Chuantao; Lin, Jun; Wang, Yiding

2018-01-01

A ppbv-level quartz-enhanced photoacoustic spectroscopy (QEPAS)-based ethane (C2H6) sensor was demonstrated by using a 3.3 μm continuous-wave (CW), distributed feedback (DFB) interband cascade laser (ICL). The ICL was employed for targeting a strong C2H6 absorption line located at 2996.88 cm−1 in its fundamental absorption band. Wavelength modulation spectroscopy (WMS) combined with the second harmonic (2f) detection technique was utilized to increase the signal-to-noise ratio (SNR) and simplify data acquisition and processing. Gas pressure and laser frequency modulation depth were optimized to be 100 Torr and 0.106 cm−1, respectively, for maximizing the 2f signal amplitude. Performance of the QEPAS sensor was evaluated using specially prepared C2H6 samples. A detection limit of 11 parts per billion in volume (ppbv) was obtained with a 1-s integration time based on an Allan-Werle variance analysis, and the detection precision can be further improved to ~1.5 ppbv by increasing the integration time up to 230 s. PMID:29495610

19 F(α,n) thick target yield from 3.5 to 10.0 MeV

DOE PAGES

Norman, E.B.; Chupp, T.E.; Lesko, K.T.; ...

2015-09-01

Using a target of PbF2, the thick-target yield from the 19F(α,n) reaction was measured from Eα=3.5–10 MeV. From these results, we infer the thick-target neutron yields from targets of F2 and UF6 over this same alpha-particle energy range.

Modulation of the Phosphate-Deficient Responses by MicroRNA156 and its Targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 in Arabidopsis.

PubMed

Lei, Kai-Jian; Lin, Ya-Ming; Ren, Jing; Bai, Ling; Miao, Yu-Chen; An, Guo-Yong; Song, Chun-Peng

2016-01-01

The microRNA156 (miR156)-modulated SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) is involved in diverse biological processes that include growth, development and metabolism. Here, we report that the Arabidopsis miR156 and SPL3 as regulators play important roles in phosphate (Pi) deficiency response. MiR156 was induced during Pi starvation whereas SPL3 expression was repressed. Phenotypes of reduced rhizosphere acidification and decreased anthocyanin accumulation were observed in 35S:MIM156 (via target mimicry) transgenic plants under Pi deficiency. The content and uptake of Pi in 35S:MIM156 Arabidopsis plants were increased compared with wild-type (Col-0 ecotype) plants. 35S:rSPL3 seedlings showed similar anthocyanin accumulation and Pi content phenotypes to those of 35S:MIM156 plants. Chromatin immunoprecipitation and an electrophoretic mobility shift assay indicated that the SPL3 protein directly bound to GTAC motifs in the PLDZ2, Pht1;5 and miR399f promoters. The expression of several Pi starvation-induced genes was increased in 35S:MIM156 and 35S:rSPL3 plants, including high-affinity Pi transporters, Mt4/TPS1-like genes and phosphatases. Collectively, our results suggest that the miR156-SPL3-Pht1;5 (-PLDZ2 and -miR399f) pathways constitute a component of the Pi deficiency-induced regulatory mechanism of Arabidopsis. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Impact of field number and beam angle on functional image-guided lung cancer radiotherapy planning

NASA Astrophysics Data System (ADS)

Tahir, Bilal A.; Bragg, Chris M.; Wild, Jim M.; Swinscoe, James A.; Lawless, Sarah E.; Hart, Kerry A.; Hatton, Matthew Q.; Ireland, Rob H.

2017-09-01

To investigate the effect of beam angles and field number on functionally-guided intensity modulated radiotherapy (IMRT) normal lung avoidance treatment plans that incorporate hyperpolarised helium-3 magnetic resonance imaging (3He MRI) ventilation data. Eight non-small cell lung cancer patients had pre-treatment 3He MRI that was registered to inspiration breath-hold radiotherapy planning computed tomography. IMRT plans that minimised the volume of total lung receiving  ⩾20 Gy (V20) were compared with plans that minimised 3He MRI defined functional lung receiving  ⩾20 Gy (fV20). Coplanar IMRT plans using 5-field manually optimised beam angles and 9-field equidistant plans were also evaluated. For each pair of plans, the Wilcoxon signed ranks test was used to compare fV20 and the percentage of planning target volume (PTV) receiving 90% of the prescription dose (PTV90). Incorporation of 3He MRI led to median reductions in fV20 of 1.3% (range: 0.2-9.3% p  =  0.04) and 0.2% (range: 0 to 4.1%; p  =  0.012) for 5- and 9-field arrangements, respectively. There was no clinically significant difference in target coverage. Functionally-guided IMRT plans incorporating hyperpolarised 3He MRI information can reduce the dose received by ventilated lung without comprising PTV coverage. The effect was greater for optimised beam angles rather than uniformly spaced fields.

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

PubMed Central

Kim, So Yoon; Rane, Sushil G.

2011-01-01

Cell division and cell differentiation are intricately regulated processes vital to organ development. Cyclin-dependent kinases (Cdks) are master regulators of the cell cycle that orchestrate the cell division and differentiation programs. Cdk1 is essential to drive cell division and is required for the first embryonic divisions, whereas Cdks 2, 4 and 6 are dispensable for organogenesis but vital for tissue-specific cell development. Here, we illustrate an important role for Cdk4 in regulating early pancreas development. Pancreatic development involves extensive morphogenesis, proliferation and differentiation of the epithelium to give rise to the distinct cell lineages of the adult pancreas. The cell cycle molecules that specify lineage commitment within the early pancreas are unknown. We show that Cdk4 and its downstream transcription factor E2f1 regulate mouse pancreas development prior to and during the secondary transition. Cdk4 deficiency reduces embryonic pancreas size owing to impaired mesenchyme development and fewer Pdx1+ pancreatic progenitor cells. Expression of activated Cdk4R24C kinase leads to increased Nkx2.2+ and Nkx6.1+ cells and a rise in the number and proliferation of Ngn3+ endocrine precursors, resulting in expansion of the β cell lineage. We show that E2f1 binds and activates the Ngn3 promoter to modulate Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results suggest that Cdk4 promotes β cell development by directing E2f1-mediated activation of Ngn3 and increasing the pool of endocrine precursors, and identify Cdk4 as an important regulator of early pancreas development that modulates the proliferation potential of pancreatic progenitors and endocrine precursors. PMID:21490060

Simultaneous modulated accelerated radiation therapy for esophageal cancer: a feasibility study.

PubMed

Zhang, Wu-Zhe; Chen, Jian-Zhou; Li, De-Rui; Chen, Zhi-Jian; Guo, Hong; Zhuang, Ting-Ting; Li, Dong-Sheng; Zhou, Ming-Zhen; Chen, Chuang-Zhen

2014-10-14

To establish the feasibility of simultaneous modulated accelerated radiation therapy (SMART) in esophageal cancer (EC). Computed tomography (CT) datasets of 10 patients with upper or middle thoracic squamous cell EC undergoing chemoradiotherapy were used to generate SMART, conventionally-fractionated three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (cf-IMRT) plans, respectively. The gross target volume (GTV) of the esophagus, positive regional lymph nodes (LN), and suspected lymph nodes (LN ±) were contoured for each patient. The clinical target volume (CTV) was delineated with 2-cm longitudinal and 0.5- to 1.0-cm radial margins with respect to the GTV and with 0.5-cm uniform margins for LN and LN(±). For the SMART plans, there were two planning target volumes (PTVs): PTV66 = (GTV + LN) + 0.5 cm and PTV54 = CTV + 0.5 cm. For the 3DCRT and cf-IMRT plans, there was only a single PTV: PTV60 = CTV + 0.5 cm. The prescribed dose for the SMART plans was 66 Gy/30 F to PTV66 and 54 Gy/30 F to PTV54. The dose prescription to the PTV60 for both the 3DCRT and cf-IMRT plans was set to 60 Gy/30 F. All the plans were generated on the Eclipse 10.0 treatment planning system. Fulfillment of the dose criteria for the PTVs received the highest priority, followed by the spinal cord, heart, and lungs. The dose-volume histograms were compared. Clinically acceptable plans were achieved for all the SMART, cf-IMRT, and 3DCRT plans. Compared with the 3DCRT plans, the SMART plans increased the dose delivered to the primary tumor (66 Gy vs 60 Gy), with improved sparing of normal tissues in all patients. The Dmax of the spinal cord, V20 of the lungs, and Dmean and V50 of the heart for the SMART and 3DCRT plans were as follows: 38.5 ± 2.0 vs 44.7 ± 0.8 (P = 0.002), 17.1 ± 4.0 vs 25.8 ± 5.0 (P = 0.000), 14.4 ± 7.5 vs 21.4 ± 11.1 (P = 0.000), and 4.9 ± 3.4 vs 12.9 ± 7.6 (P = 0.000), respectively. In contrast to the cf-IMRT plans, the SMART plans permitted a simultaneous dose escalation (6 Gy) to the primary tumor while demonstrating a significant trend of a lower irradiation dose to all organs at risk except the spinal cord, for which no significant difference was found. SMART offers the potential for a 6 Gy simultaneous escalation in the irradiation dose delivered to the primary tumor of EC and improves the sparing of normal tissues.

Simultaneous modulated accelerated radiation therapy for esophageal cancer: A feasibility study

PubMed Central

Zhang, Wu-Zhe; Chen, Jian-Zhou; Li, De-Rui; Chen, Zhi-Jian; Guo, Hong; Zhuang, Ting-Ting; Li, Dong-Sheng; Zhou, Ming-Zhen; Chen, Chuang-Zhen

2014-01-01

AIM: To establish the feasibility of simultaneous modulated accelerated radiation therapy (SMART) in esophageal cancer (EC). METHODS: Computed tomography (CT) datasets of 10 patients with upper or middle thoracic squamous cell EC undergoing chemoradiotherapy were used to generate SMART, conventionally-fractionated three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (cf-IMRT) plans, respectively. The gross target volume (GTV) of the esophagus, positive regional lymph nodes (LN), and suspected lymph nodes (LN±) were contoured for each patient. The clinical target volume (CTV) was delineated with 2-cm longitudinal and 0.5- to 1.0-cm radial margins with respect to the GTV and with 0.5-cm uniform margins for LN and LN(±). For the SMART plans, there were two planning target volumes (PTVs): PTV66 = (GTV + LN) + 0.5 cm and PTV54 = CTV + 0.5 cm. For the 3DCRT and cf-IMRT plans, there was only a single PTV: PTV60 = CTV + 0.5 cm. The prescribed dose for the SMART plans was 66 Gy/30 F to PTV66 and 54 Gy/30 F to PTV54. The dose prescription to the PTV60 for both the 3DCRT and cf-IMRT plans was set to 60 Gy/30 F. All the plans were generated on the Eclipse 10.0 treatment planning system. Fulfillment of the dose criteria for the PTVs received the highest priority, followed by the spinal cord, heart, and lungs. The dose-volume histograms were compared. RESULTS: Clinically acceptable plans were achieved for all the SMART, cf-IMRT, and 3DCRT plans. Compared with the 3DCRT plans, the SMART plans increased the dose delivered to the primary tumor (66 Gy vs 60 Gy), with improved sparing of normal tissues in all patients. The Dmax of the spinal cord, V20 of the lungs, and Dmean and V50 of the heart for the SMART and 3DCRT plans were as follows: 38.5 ± 2.0 vs 44.7 ± 0.8 (P = 0.002), 17.1 ± 4.0 vs 25.8 ± 5.0 (P = 0.000), 14.4 ± 7.5 vs 21.4 ± 11.1 (P = 0.000), and 4.9 ± 3.4 vs 12.9 ± 7.6 (P = 0.000), respectively. In contrast to the cf-IMRT plans, the SMART plans permitted a simultaneous dose escalation (6 Gy) to the primary tumor while demonstrating a significant trend of a lower irradiation dose to all organs at risk except the spinal cord, for which no significant difference was found. CONCLUSION: SMART offers the potential for a 6 Gy simultaneous escalation in the irradiation dose delivered to the primary tumor of EC and improves the sparing of normal tissues. PMID:25320535

Gadolinium-modulated 19F signals from Perfluorocarbon Nanoparticles as a New Strategy for Molecular Imaging

PubMed Central

Neubauer, Anne M.; Myerson, Jacob; Caruthers, Shelton D.; Hockett, Franklin D.; Winter, Patrick M.; Chen, Junjie; Gaffney, Patrick J.; Robertson, J. David; Lanza, Gregory M.; Wickline, Samuel A.

2008-01-01

Recent advances in the design of fluorinated nanoparticles for magnetic resonance molecular imaging have enabled specific detection of 19F nuclei, providing unique and quantifiable spectral signatures. However, a pressing need for signal enhancement exists because the total 19F in imaging voxels is often limited. By directly incorporating a relaxation agent (gadolinium) into the lipid monolayer that surrounds the perfluorocarbon, a marked augmentation of the 19F signal from 200nm nanoparticles was achieved. This design increases the magnetic relaxation rate of the 19F nuclei 4-fold at 1.5 T and effects a 125% increase in signal, an effect which is maintained when they are targeted to human plasma clots. By varying the surface concentration of gadolinium, the relaxation effect can be quantitatively modulated to tailor particle properties. This novel strategy dramatically improves the sensitivity and range of 19F MRI/MRS and forms the basis for designing contrast agents capable of sensing their surface chemistry. PMID:18956457

Synergistic regulation of competence development in Bacillus subtilis by two Rap-Phr systems.

PubMed

Bongiorni, Cristina; Ishikawa, Shu; Stephenson, Sophie; Ogasawara, Naotake; Perego, Marta

2005-07-01

The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity.

Dosimetric evaluation of 4 different treatment modalities for curative-intent stereotactic body radiation therapy for isolated thoracic spinal metastases

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

Yang, Jun; Department of Oncology, First Affiliated Hospital of Xinxiang Medical University, 88 Jiankang Road, Weihui, Henan, 453100; Ma, Lin

2016-07-01

To investigate the dosimetric characteristics of 4 SBRT-capable dose delivery systems, CyberKnife (CK), Helical TomoTherapy (HT), Volumetric Modulated Arc Therapy (VMAT) by Varian RapidArc (RA), and segmental step-and-shoot intensity-modulated radiation therapy (IMRT) by Elekta, on isolated thoracic spinal lesions. CK, HT, RA, and IMRT planning were performed simultaneously for 10 randomly selected patients with 6 body types and 6 body + pedicle types with isolated thoracic lesions. The prescription was set with curative intent and dose of either 33 Gy in 3 fractions (3F) or 40 Gy in 5F to cover at least 90% of the planning target volume (PTV),more » correspondingly. Different dosimetric indices, beam-on time, and monitor units (MUs) were evaluated to compare the advantages/disadvantages of each delivery modality. In ensuring the dose-volume constraints for cord and esophagus of the premise, CK, HT, and RA all achieved a sharp conformity index (CI) and a small penumbra volume compared to IMRT. RA achieved a CI comparable to those from CK, HT, and IMRT. CK had a heterogeneous dose distribution in the target as its radiosurgical nature with less dose uniformity inside the target. CK had the longest beam-on time and the largest MUs, followed by HT and RA. IMRT presented the shortest beam-on time and the least MUs delivery. For the body-type lesions, CK, HT, and RA satisfied the target coverage criterion in 6 cases, but the criterion was satisfied in only 3 (50%) cases with the IMRT technique. For the body + pedicle-type lesions, HT satisfied the criterion of the target coverage of ≥90% in 4 of the 6 cases, and reached a target coverage of 89.0% in another case. However, the criterion of the target coverage of ≥90% was reached in 2 cases by CK and RA, and only in 1 case by IMRT. For curative-intent SBRT of isolated thoracic spinal lesions, RA is the first choice for the body-type lesions owing to its delivery efficiency (time); the second choice is CK or HT; HT is the preferential choice for the body + pedicle-type lesions. This study suggests further clinical investigations with longer follow-up for these studied cases.« less

Evaluation of dose coverage to target volume and normal tissue sparing in the adjuvant radiotherapy of gastric cancers: 3D-CRT compared with dynamic IMRT.

PubMed

Murthy, Kk; Shukeili, Ka; Kumar, Ss; Davis, Ca; Chandran, Rr; Namrata, S

2010-01-01

To assess the potential advantage of intensity-modulated radiotherapy (IMRT) over 3D-conformal radiotherapy (3D-CRT) planning in postoperative adjuvant radiotherapy for patients with gastric carcinoma. In a retrospective study, for plan comparison, dose distribution was recalculated in 15 patients treated with 3D-CRT on the contoured structures of same CT images using an IMRT technique. 3D-conformal plans with three fields and four-fields were compared with seven-field dynamic IMRT plans. The different plans were compared by analyzing the dose coverage of planning target volume using TV(95), D(mean), uniformity index, conformity index and homogeneity index parameters. To assess critical organ sparing, D(mean), D(max), dose to one-third and two-third volumes of the OARs and percentage of volumes receiving more than their tolerance doses were compared. The average dose coverage values of PTV with 3F-CRT and 4F-CRT plans were comparable, where as IMRT plans achieved better target coverage(p<0.001) with higher conformity index value of 0.81±0.07 compared to both the 3D-CRT plans. The doses to the liver and bowel reduced significantly (p<0.001) with IMRT plans compared to other 3D-CRT plans. For all OARs the percentage of volumes receiving more than their tolerance doses were reduced with the IMRT plans. This study showed that a better target coverage and significant dose reduction to OARs could be achieved with the IMRT plans. The IMRT can be preferred with caution for organ motion. The authors are currently studying organ motion in the upper abdomen to use IMRT for patient treatment.

A fixed-jaw method to protect critical organs during intensity-modulated radiotherapy

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

Chen, Jiayun; Chen, Xinyuan; Huang, Manni, E-mail: dai_jianrong@163.com

2014-01-01

Intensity-modulated radiotherapy (IMRT) plays an important role in cancer radiotherapy. For some patients being treated with IMRT, the extremely low tolerances of critical organs (such as lens, ovaries, and testicles) cannot be met during treatment planning. The aim of this article is to introduce a new planning method to overcome that problem. In current planning practice, jaw positions are automatically set to cover all target volumes by the planning system (e.g., Pinnacle{sup 3} system). Because of such settings, critical organs may be fully blocked by the multileaf collimator (MLC), but they still sit in the field that is shaped bymore » collimator jaws. These critical organs receive doses from the transmission and leakage of MLC leaves. We manually fixed jaw positions to block them to further reduce such doses. This method has been used for different treatment sites in our clinic, and it was thoroughly evaluated in patients with radical hysterectomy plus ovarian transposition after surgery. For each patient, 2 treatment plans were designed with the same optimization parameters: the original plan with automatically chosen jaw positions (called O-plan) and the plan with fixed-jaw positions (named F-plan). In the F-plan, the jaws were manually fixed to block the ovaries. For target coverage, the mean conformity index (CI) of the F-plan (1.28 ± 0.02) was remarkably lower than that of the O-plan (1.53 ± 0.09) (p < 0.05). The F-plan and the O-plan performed similarly in target dose homogeneity. Meanwhile, for the critical organ sparing, the mean dose of both ovaries were much lower in the F-plan than that in the O-plan (p < 0.05). The V{sub 20}, V{sub 30}, and V{sub 40} of bladder were also lower in the F-plan (93.57 ± 1.98, 73.99 ± 5.76, and 42.33 ± 3.7, respectively) than those in the O-plan (97.98 ± 1.11, 85.07 ± 4.04, and 49.71 ± 3.63, respectively) (p < 0.05). The maximum dose to the spinal cord planning organ at risk (OAR) volume (PRV) in the O-plan (3940.24 ± 102.8) was higher than that in the F-plan (3628.18 ± 131.45) with significant differences (p < 0.01). For other OARs, there were no significant differences in doses between these 2 plans except that the high-dose regions of the rectum were higher for V{sub 40} in the O-plan than that in the F-plan (p < 0.01). But the monitor units (MUs) in the F-plan were 1.4 times as much as that in the O-plan. Thus the treatment time could be longer by using the F-plan. As it results in more MUs in spite of better plan quality, it is recommended to be used only in situations in which clinical requirements to critical organs cannot be met with the regular method.« less

Prone breast forward intensity-modulated radiotherapy for Asian women with early left breast cancer: factors for cardiac sparing and clinical outcomes

PubMed Central

Chen, Jenny Ling-Yu; Cheng, Jason Chia-Hsien; Kuo, Sung-Hsin; Chan, Hsing-Min; Huang, Yu-Sen; Chen, Yu-Hsuan

2013-01-01

Since December 2009, after breast-conserving surgery for Stage 0–I cancer of the left breast, 21 women with relatively pendulous breasts underwent computed tomography prone and supine simulations. The adjuvant radiotherapy was 50 Gy in 25 fractions to the left breast alone. Four plans—conventional wedged tangents and forward intensity-modulated radiotherapy (fIMRT) in supine and prone positions—were generated. fIMRT generated better homogeneity in both positions. Prone position centralized the breast tissue by gravity and also shortened the breast width which led to better conformity in both planning techniques. Prone fIMRT significantly reduced doses to left lung, Level I and Level II axilla. The mean cardiac doses did not differ between positions. Among the four plans, prone fIMRT produced the best target dosimetry and normal organ sparing. In subgroup analysis, patients with absolute breast depth > 7 cm in the prone position or breast depth difference > 3 cm between positions had significant cardiac sparing with prone fIMRT. Sixteen patients with significant cardiac sparing in prone position were treated using prone fIMRT and the others using supine fIMRT. All patients received a supine electron tumor bed boost of 10 Gy in 5 fractions. No patients developed Grade 2 or worse acute or late toxicities. There was no difference in the number of segments or beams, monitor units, treatment time, or positioning reproducibility between prone and supine positions. At a median follow-up time of 26.8 months, no locoregional or distant recurrence or death was noted. PMID:23504450

Practical experience and challenges in the operation of medical cyclotron.

PubMed

Kumar, Rajeev; Sonkawade, Rajendra G; Pandey, Anil K; Tripathi, Madhavi; Damle, Nishikant A; Kumar, Praveen; Bal, Chandra S

2017-01-01

The aim of this article was to share 10 years of operational experience of medical cyclotron and to provide working knowledge on the same. This experience has helped us gain working knowledge on cyclotron operation with practical points, which may help in improving F yield, minimizing the breakdown time, and help in the prevention of the occurrence of unusual events. Our facility has a self-shielded radioisotope delivery system eclipse 111 medical cyclotron with an 11 MeV proton beam in use for the past 10 years to produce positron emitters - namely, F, N, and F-2 gas - for PET imaging. During F production, we have followed a set protocol comprising the following: monitoring target pressure, rinsing the target with O water just immediately after bombardment, ion source feedback, radiofrequency (RF) feedback, and recording any unusual events that occurred during the operation. Besides this, enrichment of O water, target volume, target current, energy of the beam, variation in argon pressure on the target, bombardment duration, target status (new or old target or total number of previous bombardments on the same target), status of the delivery lines from target to the radiochemistry module (old or new) were also recorded. Rinsing with O water immediately after bombardment increases the life of the target and delivery line. The frequent problems encountered were with the ion source, RF, and target foil rupture. These problems were solved by rebuilding the ion source, changing the fuse of RF, and rebuilding the target. F yield can be increased by rinsing with O water immediately after bombardment. The effect of target leak - that is, rupture of vacuum window - can be avoided by immediate stoppage of bombardment.

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif.

PubMed

Molinos-Albert, Luis M; Bilbao, Eneritz; Agulló, Luis; Marfil, Silvia; García, Elisabet; Rodríguez de la Concepción, Maria Luisa; Izquierdo-Useros, Nuria; Vilaplana, Cristina; Nieto-Garai, Jon A; Contreras, F-Xabier; Floor, Martin; Cardona, Pere J; Martinez-Picado, Javier; Clotet, Bonaventura; Villà-Freixa, Jordi; Lorizate, Maier; Carrillo, Jorge; Blanco, Julià

2017-01-13

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

MicroRNA-424/E2F6 feedback loop modulates cell invasion, migration and EMT in endometrial carcinoma

PubMed Central

Lu, Zheng; Nian, Zhou; Jingjing, Zhang; Tao, Luo; Quan, Li

2017-01-01

Our previous study explored the roles of microRNA-424 (miR-424) in the development of endometrial carcinoma (EC) and analyzed the miR-424/E2F7 axis in EC cell growth. In this study, we investigated the status of miR-424 in human endometrial cancer tissues, which were collected from a cohort of Zunyi patients. We found that the expression level of miR-424 was associated with clinical tumor stage, cell differentiation, lymph node metastasis and cell migration ability. Cell function experiments demonstrated that miR-424 overexpression suppressed the invasion and migration abilities of endometrial carcinoma cells in vitro. Bioinformatic predictions and dual-luciferase reporter assays suggested E2F6 as a possible target of miR-424. RT-PCR and western blot assays demonstrated that miR-424 transfection reduced the expression level of E2F6, while inhibiting miR-424 with ASO-miR-424 (antisense oligonucleotides of miR-424) increased the expression level of E2F6. Cell function experiments indicated that E2F6 transfection rescued the EC cell phenotype induced by miR-424. In addition, we also found that E2F6 negatively regulated miR-424 expression in EC cells. In summary, our results demonstrated that the miR-424/E2F6 feedback loop modulates cell invasion, migration and EMT in EC and that the miR-424/E2Fs regulation network may serve as a new and potentially important therapeutic target in EC. PMID:29371986

Laser frequency-offset locking based on the frequency modulation spectroscopy with higher harmonic detection

NASA Astrophysics Data System (ADS)

Wang, Anqi; Meng, Zhixin; Feng, Yanying

2017-10-01

We design a fiber electro-optic modulator (FEOM)-based laser frequency-offset locking system using frequency modulation spectroscopy (FMS) with the 3F modulation. The modulation signal and the frequency-offset control signal are simultaneously loaded on the FEOM by a mixer in order to suppress the frequency and power jitter caused by internal modulation on the current or piezoelectric ceramic transducer (PZT). It is expected to accomplish a fast locking, a widely tunable frequency-offset, a sensitive and rapid detection of narrow spectral features with the 3F modulation. The laser frequency fluctuation is limited to +/-1MHz and its overlapping Allan deviation is around 10-12 in twenty minutes, which successfully meets the requirements of the cold atom interferometer.

Comparing the quality of passively-scattered proton and photon tomotherapy plans for brain and head and neck disease sites.

PubMed

Kainz, Kristofer; Firat, Selim; Wilson, J Frank; Schultz, Christopher; Siker, Malika; Wang, Andrew; Olson, Dan; Li, X Allen

2015-03-21

We compare the quality of photon IMRT (helical tomotherapy) with classic proton plans for brain, head and neck tumors, in terms of target dose uniformity and conformity along with organ-at-risk (OAR) sparing. Plans were created for twelve target volumes among eight cases. All patients were originally planned and treated using helical tomotherapy. Proton plans were generated using a passively-scattered beam model with a maximum range of 32 g cm(-2) (225 MeV), range modulation in 0.5 g cm(-2) increments and range compensators with 4.8 mm milling tool diameters. All proton plans were limited to two to four beams. Plan quality was compared using uniformity index (UI), conformation number (CN) and a EUD-based plan quality index (fEUD). For 11 of the 12 targets, UI was improved for the proton plan; on average, UI was 1.05 for protons versus 1.08 for tomotherapy. For 7 of the 12 targets, the tomotherapy plan exhibited more favorable CN. For proximal OARs, the improved dose conformity to the target volume from tomotherapy led to a lower maximum dose. For distal OARs, the maximum dose was much lower for proton plans. For 6 of the 8 cases, near-total avoidance for distal OARs provided by protons leads to improved fEUD. However, if distal OARs are excluded in the fEUD calculation, the proton plans exhibit better fEUD in only 3 of the 8 cases. The distal OAR sparing and target dose uniformity are generally better with passive-scatter proton planning than with photon tomotherapy; proton therapy may be preferred if the clinician deems those attributes critical. However, tomotherapy may serve equally as well as protons for cases where superior target dose conformity from tomotherapy leads to plan quality nearly identical to or better than protons and for cases where distal OAR sparing is not concerning.

Enhancing Motor Network Activity Using Real-Time Functional MRI Neurofeedback of Left Premotor Cortex

PubMed Central

Marins, Theo F.; Rodrigues, Erika C.; Engel, Annerose; Hoefle, Sebastian; Basílio, Rodrigo; Lent, Roberto; Moll, Jorge; Tovar-Moll, Fernanda

2015-01-01

Neurofeedback by functional magnetic resonance imaging (fMRI) is a technique of potential therapeutic relevance that allows individuals to be aware of their own neurophysiological responses and to voluntarily modulate the activity of specific brain regions, such as the premotor cortex (PMC), important for motor recovery after brain injury. We investigated (i) whether healthy human volunteers are able to up-regulate the activity of the left PMC during a right hand finger tapping motor imagery (MI) task while receiving continuous fMRI-neurofeedback, and (ii) whether successful modulation of brain activity influenced non-targeted motor control regions. During the MI task, participants of the neurofeedback group (NFB) received ongoing visual feedback representing the level of fMRI responses within their left PMC. Control (CTL) group participants were shown similar visual stimuli, but these were non-contingent on brain activity. Both groups showed equivalent levels of behavioral ratings on arousal and MI, before and during the fMRI protocol. In the NFB, but not in CLT group, brain activation during the last run compared to the first run revealed increased activation in the left PMC. In addition, the NFB group showed increased activation in motor control regions extending beyond the left PMC target area, including the supplementary motor area, basal ganglia and cerebellum. Moreover, in the last run, the NFB group showed stronger activation in the left PMC/inferior frontal gyrus when compared to the CTL group. Our results indicate that modulation of PMC and associated motor control areas can be achieved during a single neurofeedback-fMRI session. These results contribute to a better understanding of the underlying mechanisms of MI-based neurofeedback training, with direct implications for rehabilitation strategies in severe brain disorders, such as stroke. PMID:26733832

Inhibition of glycogen synthase kinase 3beta ameliorates triptolide-induced acute cardiac injury by desensitizing mitochondrial permeability transition

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

Wang, Wenwen; Yang, Yanqin; Xiong, Zhewen

Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes. Our study aimed to investigate the role of GSK-3β in TP-induced cardiotoxicity. Inhibition of GSK-3β activity by SB 216763, a potent and selective GSK-3more » inhibitor, prominently ameliorated the detrimental effects in C57BL/6J mice with TP administration, which was associated with a correction of GSK-3β overactivity. Consistently, in TP-treated H9c2 cells, SB 216763 treatment counteracted GSK-3β overactivity, improved cell viability, and prevented apoptosis by modulating the expression of Bcl-2 family proteins. Mechanistically, GSK-3β interacted with and phosphorylated cyclophilin F (Cyp-F), a key regulator of mitochondrial permeability transition pore (mPTP). GSK-3β inhibition prevented the phosphorylation and activation of Cyp-F, and desensitized mPTP. Our findings suggest that pharmacological targeting of GSK-3β could represent a promising therapeutic strategy for protecting against cardiotoxicity induced by TP. - Highlights: • GSK-3β inhibition ameliorates TP-induced cardiotoxicity in vitro and in vivo. • GSK-3β controls Cyp-F activation, and regulates mPTP and apoptosis in H9c2 cells. • The protective effect is attributed to GSK-3β activity rather than to protein level. • GSK-3β may be a promising target against TP-induced cardiotoxicity.« less

Remember the source: dissociating frontal and parietal contributions to episodic memory.

PubMed

Donaldson, David I; Wheeler, Mark E; Petersen, Steve E

2010-02-01

Event-related fMRI studies reveal that episodic memory retrieval modulates lateral and medial parietal cortices, dorsal middle frontal gyrus (MFG), and anterior PFC. These regions respond more for recognized old than correctly rejected new words, suggesting a neural correlate of retrieval success. Despite significant efforts examining retrieval success regions, their role in retrieval remains largely unknown. Here we asked the question, to what degree are the regions performing memory-specific operations? And if so, are they all equally sensitive to successful retrieval, or are other factors such as error detection also implicated? We investigated this question by testing whether activity in retrieval success regions was associated with task-specific contingencies (i.e., perceived targetness) or mnemonic relevance (e.g., retrieval of source context). To do this, we used a source memory task that required discrimination between remembered targets and remembered nontargets. For a given region, the modulation of neural activity by a situational factor such as target status would suggest a more domain-general role; similarly, modulations of activity linked to error detection would suggest a role in monitoring and control rather than the accumulation of evidence from memory per se. We found that parietal retrieval success regions exhibited greater activity for items receiving correct than incorrect source responses, whereas frontal retrieval success regions were most active on error trials, suggesting that posterior regions signal successful retrieval whereas frontal regions monitor retrieval outcome. In addition, perceived targetness failed to modulate fMRI activity in any retrieval success region, suggesting that these regions are retrieval specific. We discuss the different functions that these regions may support and propose an accumulator model that captures the different pattern of responses seen in frontal and parietal retrieval success regions.

Modulation of post-stroke degenerative and regenerative processes and subacute protection by site-targeted inhibition of the alternative pathway of complement.

PubMed

Alawieh, Ali; Elvington, Andrew; Zhu, Hong; Yu, Jin; Kindy, Mark S; Atkinson, Carl; Tomlinson, Stephen

2015-12-30

Complement promotes neuroinflammation and injury in models of stroke. However, complement is also being increasingly implicated in repair and regeneration after central nervous system (CNS) injury, and some complement deficiencies have been shown to provide acute, but not subacute, protection after murine stroke. Here, we investigate the dual role of complement in injury and repair after cerebral ischemia and reperfusion. We used complement-deficient mice and different complement inhibitors in a model of transient middle cerebral artery occlusion to investigate complement-dependent cellular and molecular changes that occur through the subacute phase after stroke. C3 deficiency and site-targeted complement inhibition with either CR2-Crry (inhibits all pathways) or CR2-fH (inhibits alternative pathway) significantly reduced infarct size, reduced apoptotic cell death, and improved neurological deficit score in the acute phase after stroke. However, only in CR2-fH-treated mice was there sustained protection with no evolution of injury in the subacute phase. Whereas both inhibitors significantly reduced microglia/macrophage activation and astrogliosis in the subacute phase, only CR2-fH improved neurological deficit and locomotor function, maintained neurogenesis markers, enhanced neuronal migration, and increased VEGF expression. These findings in CR2-fH-treated mice correlated with improved performance in spatial learning and passive avoidance tasks. The complement anaphylatoxins have been implicated in repair and regenerative mechanisms after CNS injury, and in this context CR2-fH significantly reduced, but did not eliminate the generation of C5a within the brain, unlike CR2-Crry that completely blocked C5a generation. Gene expression profiling revealed that CR2-fH treatment downregulated genes associated with apoptosis, TGFβ signaling, and neutrophil activation, and decreased neutrophil infiltration was confirmed by immunohistochemistry. CR2-fH upregulated genes for neural growth factor and mediators of neurogenesis and neuronal migration. Live animal imaging demonstrated that following intravenous injection, CR2-fH targeted specifically to the post-ischemic brain, with a tissue half-life of 48.5 h. Finally, unlike C3 deficiency, targeted complement inhibition did not increase susceptibility to lethal post-stroke infection, an important consideration for stroke patients. Ischemic brain tissue-targeted and selective inhibition of alternative complement pathway provide self-limiting inhibition of complement activation and reduces acute injury while maintaining complement-dependent recovery mechanisms into the subacute phase after stroke.

Gene modules associated with breast cancer distant metastasis-free survival in the PAM50 molecular subtypes.

PubMed

Liu, Rong; Zhang, Wei; Liu, Zhao-Qian; Zhou, Hong-Hao

2016-04-19

To identify PAM50 subtype-specific associations between distant metastasis-free survival (DMFS) in breast cancer (BC) patients and gene modules describing potentially targetable oncogenic pathways, a comprehensive analysis evaluating the prognostic efficacy of published gene signatures in 2027 BC patients from 13 studies was conducted. We calculated 21 gene modules and computed hazard ratios (HRs) for DMFS for one-unit increases in module score, with and without adjustment for clinical characteristics. By comparing gene expression to survival outcomes, we derived four subtype-specific prognostic signatures for BC. Univariate and multivariate analyses showed that in the luminal A subgroup, E2F3, PTEN and GGI gene module scores were associated with clinical outcome. In the luminal B tumors, RAS was associated with DMFS and in the basal-like tumors, ER was associated with DMFS. Our defined gene modules predicted high-risk patients in multivariate analyses for the basal-like (HR: 2.19, p=2.5×10-4), luminal A (HR: 3.03, p=7.2×10-5), luminal B (HR: 3.00, p=2.4×10-10) and HER2+ (HR: 5.49, p=9.7×10-10) subgroups. We found that different modules are associated with DMFS in different BC subtypes. The results of this study could help to identify new therapeutic strategies for specific molecular subgroups of BC, and could enhance efforts to improve patient-specific therapy options.

Near-infrared diode laser absorption sensor for rapid measurements of temperature and water vapor in a shock tube

NASA Astrophysics Data System (ADS)

Li, H.; Farooq, A.; Jeffries, J. B.; Hanson, R. K.

2007-11-01

A fast-response (100 kHz) tunable diode laser absorption sensor is developed for measurements of temperature and H2O concentration in shock tubes, e.g. for studies of combustion chemistry. Gas temperature is determined from the ratio of fixed-wavelength laser absorption of two H2O transitions near 7185.60 cm-1 and 7154.35 cm-1, which are selected using design rules for the target temperature range of 1000-2000 K and pressure range of 1-2 atm. Wavelength modulation spectroscopy is employed with second-harmonic detection (WMS-2f) to improve the sensor sensitivity and accuracy. Normalization of the second-harmonic signal by the first-harmonic signal is used to remove the need for calibration and minimize interference from emission, scattering, beam steering, and window fouling. The laser modulation depth for each H2O transition is optimized to maximize the WMS-2f signal for the target test conditions. The WMS-2f sensor is first validated in mixtures of H2O and Ar in a heated cell for the temperature range of 500-1200 K (P=1 atm), yielding an accuracy of 1.9% for temperature and 1.4% for H2O concentration measurements. Shock wave tests with non-reactive H2O-Ar mixtures are then conducted to demonstrate the sensor accuracy (1.5% for temperature and 1.4% for H2O concentration) and response time at higher temperatures (1200-1700 K, P=1.3-1.6 atm).

Respiratory syncytial virus modifies microRNAs regulating host genes that affect virus replication

PubMed Central

Bakre, Abhijeet; Mitchell, Patricia; Coleman, Jonathan K.; Jones, Les P.; Saavedra, Geraldine; Teng, Michael; Tompkins, S. Mark

2012-01-01

Respiratory syncytial virus (RSV) causes substantial morbidity and life-threatening lower respiratory tract disease in infants, young children and the elderly. Understanding the host response to RSV infection is critical for developing disease-intervention approaches. The role of microRNAs (miRNAs) in post-transcriptional regulation of host genes responding to RSV infection is not well understood. In this study, it was shown that RSV infection of a human alveolar epithelial cell line (A549) induced five miRNAs (let-7f, miR-24, miR-337-3p, miR-26b and miR-520a-5p) and repressed two miRNAs (miR-198 and miR-595), and showed that RSV G protein triggered let-7f expression. Luciferase–untranslated region reporters and miRNA mimics and inhibitors validated the predicted targets, which included cell-cycle genes (CCND1, DYRK2 and ELF4), a chemokine gene (CCL7) and the suppressor of cytokine signalling 3 gene (SOCS3). Modulating let-7 family miRNA levels with miRNA mimics and inhibitors affected RSV replication, indicating that RSV modulates host miRNA expression to affect the outcome of the antiviral host response, and this was mediated in part through RSV G protein expression. PMID:22894925

Synergistic Regulation of Competence Development in Bacillus subtilis by Two Rap-Phr Systems† ‡

PubMed Central

Bongiorni, Cristina; Ishikawa, Shu; Stephenson, Sophie; Ogasawara, Naotake; Perego, Marta

2005-01-01

The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity. PMID:15968044

Emotion Regulation Training for Treating Warfighters with Combat-Related PTSD Using Real-Time fMRI and EEG-Assisted Neurofeedback

DTIC Science & Technology

2014-10-01

Real-Time fMRI and EEG -Assisted Neurofeedback . PRINCIPAL INVESTIGATOR: Jerzy Bodurka RECIPIENT: Laureate Institute for Brain Research REPORT...imaging neurofeedback (rtfMRI-nf) training with concurrent electroencephalography ( EEG ) recordings to directly target and modulate the emotion...the project and are actively enrolling veterans to complete rtfMRI-nf neurofeedback training with simultaneous EEG recordings, and a pre-, post

Armored Combat Vehicles Science and Technology Plan

DTIC Science & Technology

1982-11-01

APPLICATION OF SENSORS Investigate the seismic, acoustic, and electromagnetic signatures of military and intruder -type targets and the theoretical aspects...a prototype sampling system which has the capability to monitor ambieut air both outside and inside vehicles and provide an early warning to the crew...and through various processing modules provide automated functions for simultaneous tracking of targets and automitic recognition, 74 f’," SENSING

Wavelength-modulation-spectroscopy for real-time, in situ NO detection in combustion gases with a 5.2 μm quantum-cascade laser

NASA Astrophysics Data System (ADS)

Chao, X.; Jeffries, J. B.; Hanson, R. K.

2012-03-01

A mid-infrared absorption strategy with calibration-free wavelength-modulation-spectroscopy (WMS) has been developed and demonstrated for real-time, in situ detection of nitric oxide in particulate-laden combustion-exhaust gases up to temperatures of 700 K. An external-cavity quantum-cascade laser (ECQCL) near 5.2 μm accessed the fundamental absorption band of NO, and a wavelength-scanned, 1 f-normalized WMS with second-harmonic detection (WMS-2 f/1 f) strategy was developed. Due to the external-cavity laser architecture, large nonlinear intensity modulation (IM) was observed when the wavelength was modulated by injection-current modulation, and the IM indices were also found to be strongly wavelength-dependent as the center wavelength was scanned with piezoelectric tuning of the cavity. A quantitative model of the 1 f-normalized WMS-2 f signal was developed and validated under laboratory conditions. A sensor was subsequently designed, built and demonstrated for real-time, in situ measurements of NO across a 3 m path in the particulate-laden exhaust of a pulverized-coal-fired power plant boiler. The 1 f-normalized WMS-2 f method proved to have better noise immunity for non-absorption transmission, than wavelength-scanned direct absorption. A 0.3 ppm-m detection limit was estimated using the R15.5 transition near 1927 cm-1 with 1 s averaging. Mid-infrared QCL-based NO absorption with 1 f-normalized WMS-2 f detection shows excellent promise for practical sensing in the combustion exhaust.

Thioredoxin Selectivity for Thiol-based Redox Regulation of Target Proteins in Chloroplasts*

PubMed Central

Yoshida, Keisuke; Hara, Satoshi; Hisabori, Toru

2015-01-01

Redox regulation based on the thioredoxin (Trx) system is believed to ensure light-responsive control of various functions in chloroplasts. Five Trx subtypes have been reported to reside in chloroplasts, but their functional diversity in the redox regulation of Trx target proteins remains poorly clarified. To directly address this issue, we studied the Trx-dependent redox shifts of several chloroplast thiol-modulated enzymes in vitro and in vivo. In vitro assays using a series of Arabidopsis recombinant proteins provided new insights into Trx selectivity for the redox regulation as well as the underpinning for previous suggestions. Most notably, by combining the discrimination of thiol status with mass spectrometry and activity measurement, we identified an uncharacterized aspect of the reductive activation of NADP-malate dehydrogenase; two redox-active Cys pairs harbored in this enzyme were reduced via distinct utilization of Trxs even within a single polypeptide. In our in vitro assays, Trx-f was effective in reducing all thiol-modulated enzymes analyzed here. We then investigated the in vivo physiological relevance of these in vitro findings, using Arabidopsis wild-type and Trx-f-deficient plants. Photoreduction of fructose-1,6-bisphosphatase was partially impaired in Trx-f-deficient plants, but the global impact of Trx-f deficiency on the redox behaviors of thiol-modulated enzymes was not as striking as expected from the in vitro data. Our results provide support for the in vivo functionality of the Trx system and also highlight the complexity and plasticity of the chloroplast redox network. PMID:25878252

JAK2V617F influences epigenomic changes in myeloproliferative neoplasms.

PubMed

Chen, Chih-Cheng; Chiu, Chia-Chen; Lee, Kuan-Der; Hsu, Chia-Chen; Chen, Hong-Chi; Huang, Tim H-M; Hsiao, Shu-Huei; Leu, Yu-Wei

2017-12-16

Negative valine (V) to phenylalanine (F) switch at the Janus kinase (JAK2) 617 codon (V617F) is the dominant driver mutation in patients with myeloproliferative neoplasms (MPNs). JAK2V617F was proved to be sufficient for cell transformation; however, independent mutations might influence the following epigenomic modifications. To assess the JAK2V617F-induced downstream epigenomic changes without interferences, we profiled the epigenomic changes in ectopically expressed JAK2V617F in Ba/F3 cells. Antibodies against phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and enhancer of zeste homolog 2 (EZH2) were used for chromatin-immunoprecipitation sequencing (ChIP-seq) to detect the downstream epigenomic targets in the JAK2-STAT3 signaling pathway. To confirm the JAK2V617F-induced epigenetic changes in vivo, DNA methylation changes in the target loci in patients with MPNs were detected through methylation-specific polymerase chain reaction and were clustered against the changes within controls. We found that ectopically expressed JAK2V617F in Ba/F3 cells reduced the binding specificity; it was associated with cis-regulatory elements and recognized DNA motifs in both pSTAT3-downstream and EZH2-associated targets. Overlapping target loci between the control and JAK2V617F were <3% and 0.4%, respectively, as identified through pSTAT3 and EZH2 ChIP-seq. Furthermore, the methylation changes in the direct target loci (FOXH1, HOXC9, and SRF) were clustered independently from the control locus (L1TD1) and other mutation genes (HMGA2 and Lin28A) in the analyzed MPN samples. Therefore, JAK2V617F influences target binding in both pSTAT3 and EZH2. Without mutations in epigenetic regulators, JAK2V617F can induce downstream epigenomic modifications. Thus, epigenetic changes in JAK2 downstream targets might be trackable in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

PubMed Central

Lee, Nancy Y.; Mechalakos, James G.; Nehmeh, Sadek; Lin, Zhixiong; Squire, Olivia D.; Cai, Shangde; Chan, Kelvin; Zanzonico, Pasquale B.; Greco, Carlo; Ling, Clifton C.; Humm, John L.; Schöder, Heiko

2010-01-01

Purpose Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTVh) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTVh increases the tumor control probability. This study examined the feasibility of fluorine-18–labeled fluoromisonidazole positron emission tomography/computed tomography (18F-FMISO PET/CT)–guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients. Methods and Materials 18F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and 18F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated 18F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate 18F-FMISO PET/CT-guided IMRT plans. Results The heterogeneous distribution of 18F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing 18F-FMISO PET/CT–guided IMRT for 10 HNC patients achieved 84 Gy to the GTVh and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTVh for 2 patients and were successful in 1, with normal tissue sparing. Conclusion It was feasible to dose escalate the GTVh to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients. PMID:17869020

Modulation of Hippocampal Synaptic Transmission by the Kynurenine Pathway Member Xanthurenic Acid and Other VGLUT Inhibitors

PubMed Central

Neale, S A; Copeland, C S; Uebele, V N; Thomson, F J; Salt, T E

2013-01-01

Xanthurenic acid (XA), an endogenous kynurenine, is a known vesicular glutamate transport (VGLUT) inhibitor and has also been proposed as an mGlu2/3 receptor agonist. Changes in these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders; however, little is known of how XA affects synaptic transmission. We therefore investigated the effects of XA on synaptic transmission at two hippocampal glutamatergic pathways and evaluated the ability of XA to bind to mGlu2/3 receptors. Field excitatory postsynaptic potentials (fEPSPs) were recorded from either the dentate gyrus (DG) or CA1 region of mouse hippocampal slices in vitro. Addition of XA to the bathing medium (1–10 mM) resulted in a dose-related reduction of fEPSP amplitudes (up to 52% reduction) in both hippocampal regions. In the DG, the VGLUT inhibitors Congo Red and Rose Bengal, and the mGlu2/3 agonist LY354740, also reduced fEPSPs (up to 80% reduction). The mGlu2/3 antagonist LY341495 reversed the LY354740 effect, but not the XA effect. LY354740, but not XA, also reduced DG paired-pulse depression. XA had no effect on specific binding of 1 nM [3H]LY341495 to membranes with human mGlu2 receptors. We conclude that XA can modulate synaptic transmission via a mechanism that may involve VGLUT inhibition rather than activation of mGlu2/3 receptors. This could be important in the pathophysiology of nervous system disorders including schizophrenia and might represent a target for developing novel pharmacological therapies. PMID:23303071

Frequency-dependent tACS modulation of BOLD signal during rhythmic visual stimulation.

PubMed

Chai, Yuhui; Sheng, Jingwei; Bandettini, Peter A; Gao, Jia-Hong

2018-05-01

Transcranial alternating current stimulation (tACS) has emerged as a promising tool for modulating cortical oscillations. In previous electroencephalogram (EEG) studies, tACS has been found to modulate brain oscillatory activity in a frequency-specific manner. However, the spatial distribution and hemodynamic response for this modulation remains poorly understood. Functional magnetic resonance imaging (fMRI) has the advantage of measuring neuronal activity in regions not only below the tACS electrodes but also across the whole brain with high spatial resolution. Here, we measured fMRI signal while applying tACS to modulate rhythmic visual activity. During fMRI acquisition, tACS at different frequencies (4, 8, 16, and 32 Hz) was applied along with visual flicker stimulation at 8 and 16 Hz. We analyzed the blood-oxygen-level-dependent (BOLD) signal difference between tACS-ON vs tACS-OFF, and different frequency combinations (e.g., 4 Hz tACS, 8 Hz flicker vs 8 Hz tACS, 8 Hz flicker). We observed significant tACS modulation effects on BOLD responses when the tACS frequency matched the visual flicker frequency or the second harmonic frequency. The main effects were predominantly seen in regions that were activated by the visual task and targeted by the tACS current distribution. These findings bridge different scientific domains of tACS research and demonstrate that fMRI could localize the tACS effect on stimulus-induced brain rhythms, which could lead to a new approach for understanding the high-level cognitive process shaped by the ongoing oscillatory signal. © 2018 Wiley Periodicals, Inc.

Observation of strong oscillations of areal mass in an unsupported shock wave produced by a short laser pulse

NASA Astrophysics Data System (ADS)

Aglitskiy, Y.; Karasik, M.; Velikovich, A. L.; Serlin, V.; Weaver, J. L.; Kessler, T. J.; Schmitt, A. J.; Obenschain, S. P.; Metzler, N.; Oh, J.

2011-10-01

The first experimental study of hydrodynamic perturbation evolution in a strong unsupported shock wave, which is immediately followed by a rarefaction wave, is reported. Our planar solid polystyrene laser-machined targets, 50 to 100 μm thick, rippled from the front side with a single-mode wavelength 30 or 45 μm and peak-to-valley amplitude 4 to 6 μm, were irradiated with a 350 ps long Nike KrF laser pulse at peak intensity of up to 330 TW/cm2. The perturbation evolution in the target was observed using face-on monochromatic x-ray radiography while the pulse lasted and for 3 to 4 ns after it ended. While the driving pulse was on, the areal mass modulation amplitude in the target was observed to grow by a factor of up to ~4 due to the ablative Richtmyer-Meshkov instability. After the end of the pulse, while the strong unsupported shock wave propagated through the unperturbed target, the theoretically predicted large oscillations of the areal mass [A. L. Velikovich et al., Phys. Plasmas 10, 3270 (2003)] were observed. Multiple phase reversals of the areal mass modulation have been detected. Work supported by DOE/NNSA and Office of Naval Research.

Imaging Caspase-3 Activation as a Marker of Apoptosis-Targeted Treatment Response in Cancer

PubMed Central

Chen, Delphine L.; Engle, Jacquelyn T.; Griffin, Elizabeth A.; Miller, J. Philip; Chu, Wenhua; Zhou, Dong; Mach, Robert H.

2016-01-01

Purpose We tested whether positron emission tomography (PET) with the caspase-3 targeted isatin analog [18F]WC-4-116 could image caspase-3 activation in response to an apoptosis-inducing anticancer therapy. Procedures [18F]WC-4-116 uptake was determined in etoposide-treated EL4 cells. Biodistribution studies with [18F]WC-4-116 and [18F]ICMT-18, a non-caspase-3-targeted tracer, as well as [18F]WC-4-116 microPET imaging assessed responses in Colo205 tumor bearing mice treated with death receptor 5 (DR5) targeted agonist antibodies. Immunohistochemical staining and enzyme assays confirmed caspase-3 activation. Two-way analysis of variance or Student’s t-test assessed for treatment-related changes in tracer uptake. Results [18F]WC-4-116 increased 8 ± 2-fold in etoposide-treated cells. The [18F]WC-4-116 %ID/g also increased significantly in tumors with high caspase-3 enzyme activity (p < 0.05). [18F]ICMT-18 tumor uptake did not differ in tumors with high or low caspase-3 enzyme activity. Conclusions [18F]WC-4-116 uptake in vivo reflects increased caspase-3 activation and may be useful for detecting caspase-3 mediated apoptosis treatment responses in cancer. PMID:25344147

Traveling wave electrode design of electro-optically modulated coupled-cavity surface-emitting lasers.

PubMed

Zujewski, Mateusz; Thienpont, Hugo; Panajotov, Krassimir

2012-11-19

We present a novel design of an electro-optically modulated coupled-cavity vertical-cavity surface-emitting laser (CC-VCSEL) with traveling wave electrodes of the modulator cavity, which allows to overcome the RC time constant of a traditional lumped electrode structures. The CC-VCSEL optical design is based on longitudinal mode switching which has recently experimentally demonstrated a record modulation speed. We carry out segmented transmission line electrical design of the modulator cavity in order to compensate for the low impedance of the modulator section and to match the 50 Ω electrical network. We have optimized two types of highly efficient modulator structures reaching -3 dB electrical cut-off frequency of f(cut-off) = 330 GHz with maximum reflection of -22 dB in the range from f(LF) = 100 MHz to f(cut-off) and 77 - 89% modulation efficiency.

Ada Compiler Validation Summary Report. Certificate Number: 920918S1. 11275 U.S. Navy Ada/M, Version 4.5 (/NO OPTIMIZE) VAX 8550/8600/8650 (Cluster) = VHSIC Processor Module (VPM) AN/AYK-14 (Bare Board)

DTIC Science & Technology

1992-10-27

REPORT 1lr.I IMrF:MTATION PAGE OrM ft 00401 Hocq~i AD-A 265 4 3 7 : 6o tM0*lo i ue oWoo-fwva"o o "t "VoMaag ion 4LaVils HW~aiy. S, UAl 1204, k*Vinto...Porcessor Module (VPM) AN/AYK-14 (Bare Board) (target), 920918S1.11275 6. AUTHOR(S) National Institute of Standards and Technology Gaithersburg, MD USA 7 ...Summary Report ( VSR ) gives an account of the testing of this Ada implementation. For any technical terms used in this report, the reader is referred

SU-E-T-63: Carotid Sparing Tomohelical Three Dimensional Conformal Radiotherapy for T1N0 Glottic Cancer

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

Hong, C; Ju, S; Ahn, Y

2014-06-01

Purpose: We investigated the dosimetric benefit and treatment efficiency of carotid-sparing TomoHelical (TH) three-dimensional conformal radiotherapy (3DCRT) for early glottic cancer. Methods: Computed tomography (CT) simulation was performed for 10 patients with early-stage (T1N0M0) glottic squamous cell carcinoma. The clinical target volume, planning target volume (PTV), carotid artery (CA), and spinal cord (SP) were delineated for each CT data set. Two-field 3DCRT (2F-3DCRT), three-field intensity-modulated radiation therapy (IMRT) (3F-IMRT), TomoHelical-IMRT (TH-IMRT), and TH-3DCRT plans were generated, with a total prescribed dose of 67.5 Gy in 30 fractions to the PTV for each patient. In order to evaluate plan quality, dosimetricmore » characteristics were compared in terms of the conformity index (CI) and homogeneity index (HI) for the PTV, V35, V50, and V63 for the CAs and in terms of the maximum dose for the SP. Additionally, treatment planning and delivery times were compared to evaluate treatment efficiency. Results: The CIs for 3F-IMRT (0.650±0.05), TH-IMRT (0.643±0.03), and TH-3DCRT (0.631±0.03) were much better than that for 2F-3DCRT (0.318±0.03). The HIs for TH-IMRT (1.053±0.01) and TH-3DCRT (1.055±0.01) were slightly better than those for 2F-3DCRT (1.062±0.01) and 3F-IMRT (1.091±0.007). 2F-3DCRT showed poor CA sparing in terms of the V35, V50, and V63 compared to 3F-IMRT, TH-IMRT, and TH-3DCRT (p<0.05), whereas there was no significant dose difference between 3F-IMRT, TH-IMRT, and TH-3DCRT (p>0.05). The maximum dose to the SP with all plans was below 45 Gy. The treatment planning times for 2F-3DCRT (5.9±0.66 min) and TH-3DCRT (7.32±0.94 min) were much lower than those for 3F-IMRT (45.51±2.76 min) and TH-IMRT (35.58±4.41 min), whereas the delivery times with all plans was below 3 minutes. Conclusion: TH-3DCRT showed excellent carotid sparing capability, comparable to that with TH-IMRT, with high treatment efficiency and short planning and treatment times, comparable to those for 2F-3DCRT, while maintaining good PTV coverage. This work was supported by the Technology Innovation Program, 10040362, Development of an integrated management solution for radiation therapy funded by the Ministry of Knowledge Economy (MKE, Korea)« less

Dissociation in decision bias mechanism between probabilistic information and previous decision

PubMed Central

Kaneko, Yoshiyuki; Sakai, Katsuyuki

2015-01-01

Target detection performance is known to be influenced by events in the previous trials. It has not been clear, however, whether this bias effect is due to the previous sensory stimulus, motor response, or decision. Also it remains open whether or not the previous trial effect emerges via the same mechanism as the effect of knowledge about the target probability. In the present study, we asked normal human subjects to make a decision about the presence or absence of a visual target. We presented a pre-cue indicating the target probability before the stimulus, and also a decision-response mapping cue after the stimulus so as to tease apart the effect of decision from that of motor response. We found that the target detection performance was significantly affected by the probability cue in the current trial and also by the decision in the previous trial. While the information about the target probability modulated the decision criteria, the previous decision modulated the sensitivity to target-relevant sensory signals (d-prime). Using functional magnetic resonance imaging (fMRI), we also found that activation in the left intraparietal sulcus (IPS) was decreased when the probability cue indicated a high probability of the target. By contrast, activation in the right inferior frontal gyrus (IFG) was increased when the subjects made a target-present decision in the previous trial, but this change was observed specifically when the target was present in the current trial. Activation in these regions was associated with individual-difference in the decision computation parameters. We argue that the previous decision biases the target detection performance by modulating the processing of target-selective information, and this mechanism is distinct from modulation of decision criteria due to expectation of a target. PMID:25999844

Scannerless loss modulated flash color range imaging

DOEpatents

Sandusky, John V [Albuquerque, NM; Pitts, Todd Alan [Rio Rancho, NM

2008-09-02

Scannerless loss modulated flash color range imaging methods and apparatus are disclosed for producing three dimensional (3D) images of a target within a scene. Apparatus and methods according to the present invention comprise a light source providing at least three wavelengths (passbands) of illumination that are each loss modulated, phase delayed and simultaneously directed to illuminate the target. Phase delayed light backscattered from the target is spectrally filtered, demodulated and imaged by a planar detector array. Images of the intensity distributions for the selected wavelengths are obtained under modulated and unmodulated (dc) illumination of the target, and the information contained in the images combined to produce a 3D image of the target.

Scannerless loss modulated flash color range imaging

DOEpatents

Sandusky, John V [Albuquerque, NM; Pitts, Todd Alan [Rio Rancho, NM

2009-02-24

Scannerless loss modulated flash color range imaging methods and apparatus are disclosed for producing three dimensional (3D) images of a target within a scene. Apparatus and methods according to the present invention comprise a light source providing at least three wavelengths (passbands) of illumination that are each loss modulated, phase delayed and simultaneously directed to illuminate the target. Phase delayed light backscattered from the target is spectrally filtered, demodulated and imaged by a planar detector array. Images of the intensity distributions for the selected wavelengths are obtained under modulated and unmodulated (dc) illumination of the target, and the information contained in the images combined to produce a 3D image of the target.

SU-F-T-611: Critical Analysis and Efficacy of Linac Based (Beam Modulator) and Cyberknife Treatment Plans for Acoustic Neuroma/schwannoma

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

KP, Karrthick; Kataria, T; Thiyagarajan, R

Purpose: To study the critical analysis and efficacy of Linac and Cyberknife (CK) treatment plans for acoustic neuroma/schwannoma. Methods: Twelve of acoustic neuroma/schwannoma patients were taken for these study that. Treatment plans were generated in Multiplan treatment planning system (TPS) for CK using 5,7.5 and 10mm diameter collimators. Target volumes were in the range of 0.280 cc to 9.256 cc. Prescription dose (Rx) ranges from 1150cGy to 1950cGy delivered over 1 to 3 Fractions. For same patients stereotactic Volumetric modulated arc plans were generated using Elekta Linac with MLC thickness of 4mm in Monaco TPS. Appropriate calculation algorithms and gridmore » size were used with same Rx and organ at risk (OAR) constrains for both Linac and CK plans. Treatment plans were developed to achieve at least 95% of the target volume to receive the Rx. The dosimetric indices such as conformity index (CI), coverage, OAR dose and volume receiving 50% of Rx (V50%) were used to evaluate the plans. Results: Target volumes ranges from 0.280 cc to 3.5cc shows the CI of 1.16±0.109 and 1.53±0.360 for cyberknife and Linac plans respectively. For small volume targets, the OARs were well spared in CK plans. There are no significant differences in CI and OAR doses were observed between CK and Linac plans that have the target volume >3.5 cc. Perhaps the V50% were lesser in CK plans, and found to be 12.8± 8.4 and 22.8 ± 15.0 for CK and Linac respectively. Conclusion: The analysis shows the importance of collimator size for small volume targets. The target volumes >3.5 cc can be treated in Linac as comparable with CK. For targets <3.5cc CK plans showed superior plan quality with better CI and OAR sparing than the Linac based plans. Further studies may require evaluating the clinical advantage of CK robotic system.« less

Development of 24GHz Rectenna for Receiving and Rectifying Modulated Waves

NASA Astrophysics Data System (ADS)

Shinohara, Naoki; Hatano, Ken

2014-11-01

In this paper, we show experimental results of RF-DC conversion with modulated 24GHz waves. We have already developed class-F MMIC rectenna with resonators for higher harmonics at no modulated 24GHz microwave for RF energy transfer. Dimensions of the MMIC rectifying circuit is 1 mm × 3 mm on GaAs. Maximum RF-DC conversion efficiency is measured 47.9% for a 210 mW microwave input of 24 GHz with a 120 Ω load. The class-F rectenna is based on a single shunt full-wave rectifier. For future application of a simultaneous energy and information transfer system or an energy harvesting from broadcasting waves, input microwave will be modulated. In this paper, we show an experimental result of RF-DC conversion of the class-F rectenna with 24GHz waves modulated by 16QAM as 1st modulation and OFDM as 2nd modulation.

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

PubMed Central

Molinos-Albert, Luis M.; Bilbao, Eneritz; Agulló, Luis; Marfil, Silvia; García, Elisabet; Concepción, Maria Luisa Rodríguez de la; Izquierdo-Useros, Nuria; Vilaplana, Cristina; Nieto-Garai, Jon A.; Contreras, F.-Xabier; Floor, Martin; Cardona, Pere J.; Martinez-Picado, Javier; Clotet, Bonaventura; Villà-Freixa, Jordi; Lorizate, Maier; Carrillo, Jorge; Blanco, Julià

2017-01-01

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants. PMID:28084464

An fMRI investigation into the effect of preceding stimuli during visual oddball tasks.

PubMed

Fajkus, Jiří; Mikl, Michal; Shaw, Daniel Joel; Brázdil, Milan

2015-08-15

This study investigates the modulatory effect of stimulus sequence on neural responses to novel stimuli. A group of 34 healthy volunteers underwent event-related functional magnetic resonance imaging while performing a three-stimulus visual oddball task, involving randomly presented frequent stimuli and two types of infrequent stimuli - targets and distractors. We developed a modified categorization of rare stimuli that incorporated the type of preceding rare stimulus, and analyzed the event-related functional data according to this sequence categorization; specifically, we explored hemodynamic response modulation associated with increasing rare-to-rare stimulus interval. For two consecutive targets, a modulation of brain function was evident throughout posterior midline and lateral temporal cortex, while responses to targets preceded by distractors were modulated in a widely distributed fronto-parietal system. As for distractors that follow targets, brain function was modulated throughout a set of posterior brain structures. For two successive distractors, however, no significant modulation was observed, which is consistent with previous studies and our primary hypothesis. The addition of the aforementioned technique extends the possibilities of conventional oddball task analysis, enabling researchers to explore the effects of the whole range of rare stimuli intervals. This methodology can be applied to study a wide range of associated cognitive mechanisms, such as decision making, expectancy and attention. Copyright © 2015 Elsevier B.V. All rights reserved.

Emotional Intent Modulates The Neural Substrates Of Creativity: An fMRI Study of Emotionally Targeted Improvisation in Jazz Musicians.

PubMed

McPherson, Malinda J; Barrett, Frederick S; Lopez-Gonzalez, Monica; Jiradejvong, Patpong; Limb, Charles J

2016-01-04

Emotion is a primary motivator for creative behaviors, yet the interaction between the neural systems involved in creativity and those involved in emotion has not been studied. In the current study, we addressed this gap by using fMRI to examine piano improvisation in response to emotional cues. We showed twelve professional jazz pianists photographs of an actress representing a positive, negative or ambiguous emotion. Using a non-ferromagnetic thirty-five key keyboard, the pianists improvised music that they felt represented the emotion expressed in the photographs. Here we show that activity in prefrontal and other brain networks involved in creativity is highly modulated by emotional context. Furthermore, emotional intent directly modulated functional connectivity of limbic and paralimbic areas such as the amygdala and insula. These findings suggest that emotion and creativity are tightly linked, and that the neural mechanisms underlying creativity may depend on emotional state.

The immediate and late effects of thyroid hormone (triiodothyronine) on murine coagulation gene transcription.

PubMed

Salloum-Asfar, Salam; Boelen, Anita; Reitsma, Pieter H; van Vlijmen, Bart J M

2015-01-01

Thyroid dysfunction is associated with changes in coagulation. The aim of our study was to gain more insight into the role of thyroid hormone in coagulation control. C57Black/6J mice received a low-iodine diet and drinking water supplemented with perchlorate to suppress endogenous triiodothyronine (T3) and thyroxine (T4) production. Under these conditions, the impact of exogenous T3 on plasma coagulation, and hepatic and vessel-wall-associated coagulation gene transcription was studied in a short- (4 hours) and long-term (14 days) setting. Comparing euthyroid conditions (normal mice), with hypothyroidism (conditions of a shortage of thyroid hormone) and those with replacement by incremental doses of T3, dosages of 0 and 0.5 μg T3/mouse/day were selected to study the impact of T3 on coagulation gene transcription. Under these conditions, a single injection of T3 injection increased strongly hepatic transcript levels of the well-characterized T3-responsive genes deiodinase type 1 (Dio1) and Spot14 within 4 hours. This coincided with significantly reduced mRNA levels of Fgg, Serpinc1, Proc, Proz, and Serpin10, and the reduction of the latter three persisted upon daily treatment with T3 for 14 days. Prolonged T3 treatment induced a significant down-regulation in factor (F) 2, F9 and F10 transcript levels, while F11 and F12 levels increased. Activity levels in plasma largely paralleled these mRNA changes. Thbd transcript levels in the lung (vessel-wall-associated coagulation) were significantly up-regulated after a single T3 injection, and persisted upon prolonged T3 exposure. Two-week T3 administration also resulted in increased Vwf and Tfpi mRNA levels, whereas Tf levels decreased. These data showed that T3 has specific effects on coagulation, with Fgg, Serpinc1, Proc, Proz, Serpin10 and Thbd responding rapidly, making these likely direct thyroid hormone receptor targets. F2, F9, F10, F11, F12, Vwf, Tf and Tfpi are late responding genes and probably indirectly modulated by T3.

The CF Canada-Sick Kids Program in individual CF therapy: A resource for the advancement of personalized medicine in CF.

PubMed

Eckford, Paul D W; McCormack, Jacqueline; Munsie, Lise; He, Gengming; Stanojevic, Sanja; Pereira, Sergio L; Ho, Karen; Avolio, Julie; Bartlett, Claire; Yang, Jin Ye; Wong, Amy P; Wellhauser, Leigh; Huan, Ling Jun; Jiang, Jia Xin; Ouyang, Hong; Du, Kai; Klingel, Michelle; Kyriakopoulou, Lianna; Gonska, Tanja; Moraes, Theo J; Strug, Lisa J; Rossant, Janet; Ratjen, Felix; Bear, Christine E

2018-04-20

Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses. The CFIT program is generating: 1) nasal cells from drug naïve patients suitable for culture and the study of drug responses in vitro, 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators. To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors. This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Compact TDLAS based optical sensor for ppb-level ethane detection by use of a 3.34 μm room-temperature CW interband cascade laser

DOE PAGES

Li, Chunguang; Dong, Lei; Zheng, Chuantao; ...

2016-03-26

A mid-infrared ethane (C 2H 6) sensor based on a wavelength modulation spectroscopy (WMS) technique was developed using a thermoelectrically cooled (TEC), continuous-wave (CW) interband cascade laser (ICL) emitting at 3.34 μm and a dense multi-pass gas cell (MPGC, 17 × 6.5 × 5.5 cm 3) with a 54.6 m optical path length. A compact optical sensor system with a physical size of 35.5 × 18 × 12.5 cm 3 was designed and constructed. An ICL was employed for targeting a strong C 2H 6 line at 2996.88 cm -1 at <100 Torr gas pressure in the fundamental absorption bandmore » of C 2H 6. The sensor performance, including the minimum detection limit (MDL) and the stability were improved by reducing the effect of laser power drift by means of the 2f/1f-WMS technique. A MDL of ~1.2 parts per billion (ppbv) for 2f-WMS and ~1.0 ppbv for 2f/1f-WMS were achieved, respectively, with a measurement time of 4 s. The MDL was further improved from 299 pptv (@108 s for 2f-WMS) to 239 pptv (@208 s for 2f/1f-WMS), based on an Allan deviation analysis.The rise time (@0 → 100 ppbv) and fall time (@100 → 0 ppbv) were determined to be ~64 s and ~48 s,respectively, at a gas pressure of <100 Torr for the C 2H 6 sensor operation.« less

Compact TDLAS based optical sensor for ppb-level ethane detection by use of a 3.34 μm room-temperature CW interband cascade laser

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

Li, Chunguang; Dong, Lei; Zheng, Chuantao

A mid-infrared ethane (C 2H 6) sensor based on a wavelength modulation spectroscopy (WMS) technique was developed using a thermoelectrically cooled (TEC), continuous-wave (CW) interband cascade laser (ICL) emitting at 3.34 μm and a dense multi-pass gas cell (MPGC, 17 × 6.5 × 5.5 cm 3) with a 54.6 m optical path length. A compact optical sensor system with a physical size of 35.5 × 18 × 12.5 cm 3 was designed and constructed. An ICL was employed for targeting a strong C 2H 6 line at 2996.88 cm -1 at <100 Torr gas pressure in the fundamental absorption bandmore » of C 2H 6. The sensor performance, including the minimum detection limit (MDL) and the stability were improved by reducing the effect of laser power drift by means of the 2f/1f-WMS technique. A MDL of ~1.2 parts per billion (ppbv) for 2f-WMS and ~1.0 ppbv for 2f/1f-WMS were achieved, respectively, with a measurement time of 4 s. The MDL was further improved from 299 pptv (@108 s for 2f-WMS) to 239 pptv (@208 s for 2f/1f-WMS), based on an Allan deviation analysis.The rise time (@0 → 100 ppbv) and fall time (@100 → 0 ppbv) were determined to be ~64 s and ~48 s,respectively, at a gas pressure of <100 Torr for the C 2H 6 sensor operation.« less

Dose distribution of secondary radiation in a water phantom for a proton pencil beam-EURADOS WG9 intercomparison exercise.

PubMed

Stolarczyk, L; Trinkl, S; Romero-Expósito, M; Mojżeszek, N; Ambrozova, I; Domingo, C; Davídková, M; Farah, J; Kłodowska, M; Knežević, Ž; Liszka, M; Majer, M; Miljanić, S; Ploc, O; Schwarz, M; Harrison, R M; Olko, P

2018-04-19

Systematic 3D mapping of out-of-field doses induced by a therapeutic proton pencil scanning beam in a 300  ×  300  ×  600 mm 3 water phantom was performed using a set of thermoluminescence detectors (TLDs): MTS-7 ( 7 LiF:Mg,Ti), MTS-6 ( 6 LiF:Mg,Ti), MTS-N ( nat LiF:Mg,Ti) and TLD-700 ( 7 LiF:Mg,Ti), radiophotoluminescent (RPL) detectors GD-352M and GD-302M, and polyallyldiglycol carbonate (PADC)-based (C 12 H 18 O 7 ) track-etched detectors. Neutron and gamma-ray doses, as well as linear energy transfer distributions, were experimentally determined at 200 points within the phantom. In parallel, the Geant4 Monte Carlo code was applied to calculate neutron and gamma radiation spectra at the position of each detector. For the cubic proton target volume of 100  ×  100  ×  100 mm 3 (spread out Bragg peak with a modulation of 100 mm) the scattered photon doses along the main axis of the phantom perpendicular to the primary beam were approximately 0.5 mGy Gy -1 at a distance of 100 mm and 0.02 mGy Gy -1 at 300 mm from the center of the target. For the neutrons, the corresponding values of dose equivalent were found to be ~0.7 and ~0.06 mSv Gy -1 , respectively. The measured neutron doses were comparable with the out-of-field neutron doses from a similar experiment with 20 MV x-rays, whereas photon doses for the scanning proton beam were up to three orders of magnitude lower.

Dose distribution of secondary radiation in a water phantom for a proton pencil beam—EURADOS WG9 intercomparison exercise

NASA Astrophysics Data System (ADS)

Stolarczyk, L.; Trinkl, S.; Romero-Expósito, M.; Mojżeszek, N.; Ambrozova, I.; Domingo, C.; Davídková, M.; Farah, J.; Kłodowska, M.; Knežević, Ž.; Liszka, M.; Majer, M.; Miljanić, S.; Ploc, O.; Schwarz, M.; Harrison, R. M.; Olko, P.

2018-04-01

Systematic 3D mapping of out-of-field doses induced by a therapeutic proton pencil scanning beam in a 300  ×  300  ×  600 mm3 water phantom was performed using a set of thermoluminescence detectors (TLDs): MTS-7 (7LiF:Mg,Ti), MTS-6 (6LiF:Mg,Ti), MTS-N (natLiF:Mg,Ti) and TLD-700 (7LiF:Mg,Ti), radiophotoluminescent (RPL) detectors GD-352M and GD-302M, and polyallyldiglycol carbonate (PADC)-based (C12H18O7) track-etched detectors. Neutron and gamma-ray doses, as well as linear energy transfer distributions, were experimentally determined at 200 points within the phantom. In parallel, the Geant4 Monte Carlo code was applied to calculate neutron and gamma radiation spectra at the position of each detector. For the cubic proton target volume of 100  ×  100  ×  100 mm3 (spread out Bragg peak with a modulation of 100 mm) the scattered photon doses along the main axis of the phantom perpendicular to the primary beam were approximately 0.5 mGy Gy‑1 at a distance of 100 mm and 0.02 mGy Gy‑1 at 300 mm from the center of the target. For the neutrons, the corresponding values of dose equivalent were found to be ~0.7 and ~0.06 mSv Gy‑1, respectively. The measured neutron doses were comparable with the out-of-field neutron doses from a similar experiment with 20 MV x-rays, whereas photon doses for the scanning proton beam were up to three orders of magnitude lower.

Evaluation of Mean Glandular Dose and Modulation Transfer Function for Different Tube Potentials and Target-Filter Combinations in Computed Radiography Mammography

PubMed Central

Abdul Aziz,, Siti Aishah; Mohd Saparudin, Abdul Khaliq; Harun, Ahmad Zaky

2013-01-01

Background: Different target-filter combinations in computed radiography have different impacts on the dose and image quality in digital radiography. This study aims to evaluate the mean glandular dose (MGD) and modulation transfer function (MTF) of various target-filter combinations by investigating the signal intensities of X-ray beams. Methods: General Electric (GE) Senographe DMR Plus mammography unit was used for MGD and MTF evaluation. The measured MGD was compared with the dose reference level (DRL), whereas the MTF was evaluated using ImageJ 1.46o software. A modified Mammography Accreditation Phantom RMI 156 was exposed using different target-filter combinations of molybdenum-molybdenum (Mo-Mo), molybdenum-rhodium (Mo-Rh) and rhodium-rhodium (Rh-Rh) at two different tube voltages, 26 kV and 32 kV with 50 mAs. Results: In the MGD evaluations, all target-filters gave an MGD value of < 1.5 mGy. The one-way ANOVA test showed a highly significant interaction between the MGD and the kilovoltage and target-filter material used (26 kV: F (2,12) = 49,234, P = 0.001;32 kV: F (2,12) = 89,972, P = 0.001). A Tukey post-hoc test revealed that the MGD for 26 kV and 32 kV was highly affected by the target-filter combinations. The test of homogeneity of variances indicates that the MGD varies significantly for 26 kV and 32 kV images (0.045 and 0.030 (P < 0.05), respectively). However, the one-way ANOVA for the MTF shows that no significant difference exists between the target-filter combinations used with 26 kV and 32 kV images either in parallel or perpendicular to the chest wall side F (2,189) = 0.26, P > 0.05). Conclusion: Higher tube voltage and atomic number target-filter yield higher MGD values. However, the MTF is independent of the X-ray energy and the type of target-filter combinations used. PMID:23966821

Twinned or not twinned, that is the question: crystallization and preliminary crystallographic analysis of the 2F1(3)F1 module pair of human fibronectin.

PubMed

Rudiño-Piñera, Enrique; Schwarz-Linek, Ulrich; Potts, Jennifer R; Garman, Elspeth F

2004-07-01

Human fibronectin (Fn) is a large multidomain protein found in the extracellular matrix and plasma. It is involved in many cellular processes, including cell adhesion and migration during embryogenesis and wound healing. The ability to bind Fn is a characteristic that has been demonstrated for a number of pathogens. For Staphylococcus aureus and Streptococcus pyogenes in particular, Fn-binding bacterial proteins (FnBPs) have been shown to mediate not only bacterial adhesion to host cells but also the uptake of bacteria by the cells. FnBPs interact with the amino-terminal region of Fn, where five type I ((1-5)F1) Fn modules are located. Although the structures of two F1 module pairs have been determined by NMR, no X-ray structures have been reported. To explore the conformational interactions between modules and the binding properties of FnBPs, the (2)F1(3)F1 module pair was crystallized using the vapour-diffusion method at 298 K. 12 X-ray diffraction data sets have been collected: six on an in-house rotating anode (three native, one Pt derivative and two peptide-bound) and six at synchrotron-radiation sources (two native and four derivative). Following analysis of these data, some of which have very high multiplicity (up to 50), probable space-group assignments were made (P42(1)2, P4(1)2(1)2 or P4(3)2(1)2) and the possibly twinned nature of the crystals was investigated using six different tests. The results presented here suggest that the crystals are not twinned.

Comparative analysis of SmartArc‐based dual arc volumetric‐modulated arc radiotherapy (VMAT) versus intensity‐modulated radiotherapy (IMRT) for nasopharyngeal carcinoma

PubMed Central

Chao, Pei‐Ju; Ting, Hui‐Min; Lo, Su‐Hua; Wang, Yu‐Wen; Tuan, Chiu‐Ching; Fang, Fu‐Min

2011-01-01

The purpose of this study was to evaluate and quantify the planning performance of SmartArc‐based volumetric‐modulated arc radiotherapy (VMAT) versus fixed‐beam intensity‐modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) using a sequential mode treatment plan. The plan quality and performance of dual arc‐VMAT (DA‐VMAT) using the Pinnacle3 Smart‐Arc system (clinical version 9.0; Philips, Fitchburg, WI, USA) were evaluated and compared with those of seven‐field (7F)‐IMRT in 18 consecutive NPC patients. Analysis parameters included the conformity index (CI) and homogeneity index (HI) for the planning target volume (PTV), maximum and mean dose, normal tissue complication probability (NTCP) for the specified organs at risk (OARs), and comprehensive quality index (CQI) for an overall evaluation in the 11 OARs. Treatment delivery time, monitor units per fraction (MU/fr), and gamma (Γ3mm,3%) evaluations were also analyzed. DA‐VMAT achieved similar target coverage and slightly better homogeneity than conventional 7F‐IMRT with a similar CI and HI. NTCP values were only significantly lower in the left parotid gland (for xerostomia) for DA‐VMAT plans. The mean value of CQI at 0.98±0.02 indicated a 2% benefit in sparing OARs by DA‐VMAT. The MU/fr used and average delivery times appeared to show improved efficiencies in DA‐VMAT. Each technique demonstrated high accuracy in dose delivery in terms of a high‐quality assurance (QA) passing rate (>98%) of the (Γ3mm,3%) criterion. The major difference between DA‐VMAT and 7F‐IMRT using a sequential mode for treating NPC cases appears to be improved efficiency, resulting in a faster delivery time and the use of fewer MU/fr. PACS number: 87.53.Tf, 87.55.x, 87.55.D, 87.55.dk PMID:22089015

Effects of Semantic Context and Fundamental Frequency Contours on Mandarin Speech Recognition by Second Language Learners.

PubMed

Zhang, Linjun; Li, Yu; Wu, Han; Li, Xin; Shu, Hua; Zhang, Yang; Li, Ping

2016-01-01

Speech recognition by second language (L2) learners in optimal and suboptimal conditions has been examined extensively with English as the target language in most previous studies. This study extended existing experimental protocols (Wang et al., 2013) to investigate Mandarin speech recognition by Japanese learners of Mandarin at two different levels (elementary vs. intermediate) of proficiency. The overall results showed that in addition to L2 proficiency, semantic context, F0 contours, and listening condition all affected the recognition performance on the Mandarin sentences. However, the effects of semantic context and F0 contours on L2 speech recognition diverged to some extent. Specifically, there was significant modulation effect of listening condition on semantic context, indicating that L2 learners made use of semantic context less efficiently in the interfering background than in quiet. In contrast, no significant modulation effect of listening condition on F0 contours was found. Furthermore, there was significant interaction between semantic context and F0 contours, indicating that semantic context becomes more important for L2 speech recognition when F0 information is degraded. None of these effects were found to be modulated by L2 proficiency. The discrepancy in the effects of semantic context and F0 contours on L2 speech recognition in the interfering background might be related to differences in processing capacities required by the two types of information in adverse listening conditions.

Electron impact ionization cross section studies of C2Fx (x = 1 - 6) and C3Fx (x = 1 - 8) fluorocarbon species

NASA Astrophysics Data System (ADS)

Gupta, Dhanoj; Choi, Heechol; Song, Mi-Young; Karwasz, Grzegorz P.; Yoon, Jung-Sik

2017-05-01

The total ionization cross section for C2Fx (x = 1 - 6) and C3Fx (x = 1 - 8) fluorocarbon species are studied with the Binary-Encounter Bethe (BEB) model using various orbital parameters calculated from restricted/unrestricted Hartree-Fock (RHF/UHF) and Density Functional Theory (DFT). All the targets were optimized for their minimal structures and energies with several ab-initio methods with the aug-cc-pVTZ basis set. Among them, the present results with RHF/UHF orbital energies showed good agreement with the experimental results for stable targets C2F6, C2F4, C3F6 and C3F8. The results with the DFT (ωB97X/ωB97X-D) showed a reasonable agreement with the recent calculation of Bull et al. [J.N. Bull, M. Bart, C. Vallance, P.W. Harland, Phys. Rev. A 88, 062710 (2013)] for C2F6, C3F6 and C3F8 targets. The ionization cross section for C2F, C2F2, C2F3, C3F, C3F2, C3F3, C3F4, C3F5 and C3F7 were computed for the first time in the present study. We have also computed the vertical ionization potentials and polarizability for all the targets and compared them with other experimental and theoretical values. A good agreement is found between the present and the previous results. The calculated polarizability in turn is used to study the correlation with maximum ionization cross section and in general a good correlation is found among them, confirming the consistency and reliability of the present data. The cross section data reported in this article are very important for plasma modeling especially related to fluorocarbon plasmas. Contribution to the Topical Issue "Atomic and Molecular Data and their Applications", edited by Gordon W.F. Drake, Jung-Sik Yoon, Daiji Kato, Grzegorz Karwasz.

[Comparation study of incidental irradiation dose to the internal mammary chain during postmastectomy radiotherapy for patients treated with different irradiation techniques].

PubMed

Wang, W; Meng, Y T; Song, Y F; Sun, T; Xu, M; Shao, Q; Zhang, Y J; Li, J B

2018-05-23

Objective: To evaluated the unplanned coverage dose to the internal mammary chain (IMC) in patient treated with postmastectomy radiotherapy (PMRT). Methods: One hundred and thirty eight patients with breast cancer receiving radiotherapy (RT) in our hospital were retrospectively analyzed. Patients were divided into three groups: three-dimensional conformal radiotherapy (3D-CRT) group, forward intensity-modulated radiotherapy (F-IMRT) group and inverse IMRT (I-IMRT) group. The IMC were contoured according to Radiation Therapy Oncology Group (RTOG) consensus, and were not include into the planning target volume (PTV). The incidental irradiation dose to IMC among the three groups and the first three intercostal spaces IMC (ICS-IMC 1-3) were all compared, and explored the relationship between the mean doses (Dmean) of IMC and the OARs (ipsilateral lung and heart). Results: The dose delivered to IMC showed no difference in CRT, F-IMRT and I-IMRT(33.80 Gy, 29.65 Gy and 32.95 Gy). And 10.42%, 2.04%, and 9.76% patients achieved ≥45 Gy when treated with CRT, F-IMRT and I-IMRT. For the IMC dose in the first three intercostal spaces (ICS1-3), there was no difference to the three treatment plannings. The Dmean, V(20), V(30), V(40) and V(50) of the ICS-IMC2 and ICS-IMC3 were all obviously superior than ICS-IMC1 for all these three plannings. Moderate positive correlation was founded between Dmean for IMC and Dmean for heart for left breast cancer patients underwent CRT ( r =0.338, P =0.01). Whereas for F-IMRT and I-IMRT groups, positive correlation were founded between Dmean for IMC and Dmean and V(20) for ipsilateral lung for all patients (F-IMRT: r =0.366, P =0.010; r =0.318, P =0.026; I-IMRT: r =0.427, P =0.005; r =0.411, P =0.008). Conclusions: In 3D-CRT, F-IMRT and I-IMRT planning methods, partial patients get IMC irradiated doses that could achieve therapeutic doses. Compared with 3D-CRT, F-IMRT and I-IMRT further reduced the dose of irradiated organs. However, there is no difference in the dose coverage of IMC for the three planned approaches when the IMC made an unplanned target.

Feasibility of the partial-single arc technique in RapidArc planning for prostate cancer treatment

PubMed Central

Rana, Suresh; Cheng, ChihYao

2013-01-01

The volumetric modulated arc therapy (VMAT) technique, in the form of RapidArc, is widely used to treat prostate cancer. The full-single arc (f-SA) technique in RapidArc planning for prostate cancer treatment provides efficient treatment, but it also delivers a higher radiation dose to the rectum. This study aimed to compare the dosimetric results from the new partial-single arc (p-SA) technique with those from the f-SA technique in RapidArc planning for prostate cancer treatment. In this study, 10 patients with low-risk prostate cancer were selected. For each patient, two sets of RapidArc plans (f-SA and p-SA) were created in the Eclipse treatment planning system. The f-SA plan was created using one full arc, and the p-SA plan was created using planning parameters identical to those of the f-SA plan but with anterior and posterior avoidance sectors. Various dosimetric parameters of the f-SA and p-SA plans were evaluated and compared for the same target coverage and identical plan optimization parameters. The f-SA and p-SA plans showed an average difference of ±1% for the doses to the planning target volume (PTV), and there were no clear differences in dose homogeneity or plan conformity. In comparison to the f-SA technique, the p-SA technique reduced the doses to the rectum by approximately 6.1% to 21.2%, to the bladder by approximately 10.3% to 29.5%, and to the penile bulb by approximately 2.2%. In contrast, the dose to the femoral heads, the integral dose, and the number of monitor units were higher in the p-SA plans by approximately 34.4%, 7.7%, and 9.2%, respectively. In conclusion, it is feasible to use the p-SA technique for RapidArc planning for prostate cancer treatment. For the same PTV coverage and identical plan optimization parameters, the p-SA technique is better in sparing the rectum and bladder without compromising plan conformity or target homogeneity when compared to the f-SA technique. PMID:23845140

A Systematic Review of Known Mechanisms of Hydroxyurea-induced Foetal Haemoglobin for Treatment of Sickle Cell Disease

PubMed Central

Pule, Gift D.; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S.; Wonkam, Ambroise

2016-01-01

Aims To report on molecular mechanisms of foetal haemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of Sickle Cell Disease (SCD). Study Design Systematic review. Results Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways, that modulate γ-globin expression (cAMP/cGMP; Giα/JNK/Jun; methylation and microRNA). Three main molecular pathways have been reported: 1) Epigenetic modifications, transcriptional events and signalling pathways involved in HU-mediated response, 2) Signalling pathways involving HU-mediated response and 3) Post-transcriptional pathways (regulation by microRNAs). Conclusions The complete picture of HU-mediated mechanisms of HbF production in SCD remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome. PMID:26327494

Regulating the ethylene response of a plant by modulation of F-box proteins

DOEpatents

Guo, Hongwei [Beijing, CN; Ecker, Joseph R [Carlsbad, CA

2011-03-08

The invention relates to transgenic plants having reduced sensitivity to ethylene as a result of having a recombinant nucleic acid encoding an F-box protein that interacts with a EIN3 involved in an ethylene response of plants, and a method of producing a transgenic plant with reduced ethylene sensitivity by transforming the plant with a nucleic acid sequence encoding an F-box protein. The inventions also relates to methods of altering the ethylene response in a plant by modulating the activity or expression of an F-box protein.

Scannerless laser range imaging using loss modulation

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

Sandusky, John V

2011-08-09

A scannerless 3-D imaging apparatus is disclosed which utilizes an amplitude modulated cw light source to illuminate a field of view containing a target of interest. Backscattered light from the target is passed through one or more loss modulators which are modulated at the same frequency as the light source, but with a phase delay .delta. which can be fixed or variable. The backscattered light is demodulated by the loss modulator and detected with a CCD, CMOS or focal plane array (FPA) detector to construct a 3-D image of the target. The scannerless 3-D imaging apparatus, which can operate inmore » the eye-safe wavelength region 1.4-1.7 .mu.m and which can be constructed as a flash LADAR, has applications for vehicle collision avoidance, autonomous rendezvous and docking, robotic vision, industrial inspection and measurement, 3-D cameras, and facial recognition.« less

Scannerless laser range imaging using loss modulation

DOEpatents

Sandusky, John V [Albuquerque, NM

2011-08-09

A scannerless 3-D imaging apparatus is disclosed which utilizes an amplitude modulated cw light source to illuminate a field of view containing a target of interest. Backscattered light from the target is passed through one or more loss modulators which are modulated at the same frequency as the light source, but with a phase delay .delta. which can be fixed or variable. The backscattered light is demodulated by the loss modulator and detected with a CCD, CMOS or focal plane array (FPA) detector to construct a 3-D image of the target. The scannerless 3-D imaging apparatus, which can operate in the eye-safe wavelength region 1.4-1.7 .mu.m and which can be constructed as a flash LADAR, has applications for vehicle collision avoidance, autonomous rendezvous and docking, robotic vision, industrial inspection and measurement, 3-D cameras, and facial recognition.

Wavelength modulation diode laser absorption spectroscopy for high-pressure gas sensing

NASA Astrophysics Data System (ADS)

Sun, K.; Chao, X.; Sur, R.; Jeffries, J. B.; Hanson, R. K.

2013-03-01

A general model for 1 f-normalized wavelength modulation absorption spectroscopy with nf detection (i.e., WMS- nf) is presented that considers the performance of injection-current-tuned diode lasers and the reflective interference produced by other optical components on the line-of-sight (LOS) transmission intensity. This model explores the optimization of sensitive detection of optical absorption by species with structured spectra at elevated pressures. Predictions have been validated by comparison with measurements of the 1 f-normalized WMS- nf (for n = 2-6) lineshape of the R(11) transition in the 1st overtone band of CO near 2.3 μm at four different pressures ranging from 5 to 20 atm, all at room temperature. The CO mole fractions measured by 1 f-normalized WMS-2 f, 3 f, and 4 f techniques agree with calibrated mixtures within 2.0 %. At conditions where absorption features are significantly broadened and large modulation depths are required, uncertainties in the WMS background signals due to reflective interference in the optical path can produce significant error in gas mole fraction measurements by 1 f-normalized WMS-2 f. However, such potential errors can be greatly reduced by using the higher harmonics, i.e., 1 f-normalized WMS- nf with n > 2. In addition, less interference from pressure-broadened neighboring transitions has been observed for WMS with higher harmonics than for WMS-2 f.

A psychoacoustic method for studying the necessary and sufficient perceptual cues of American English fricative consonants in noise.

PubMed

Li, Feipeng; Trevino, Andrea; Menon, Anjali; Allen, Jont B

2012-10-01

In a previous study on plosives, the 3-Dimensional Deep Search (3DDS) method for the exploration of the necessary and sufficient cues for speech perception was introduced (Li et al., (2010). J. Acoust. Soc. Am. 127(4), 2599-2610). Here, this method is used to isolate the spectral cue regions for perception of the American English fricatives /∫, 3, s, z, f, v, θ, δ in time, frequency, and intensity. The fricatives are analyzed in the context of consonant-vowel utterances, using the vowel /α/. The necessary cues were found to be contained in the frication noise for /∫, 3, s, z, f, v/. 3DDS analysis isolated the cue regions of /s, z/ between 3.6 and 8 [kHz] and /∫, 3/ between 1.4 and 4.2 [kHz]. Some utterances were found to contain acoustic components that were unnecessary for correct perception, but caused listeners to hear non-target consonants when the primary cue region was removed; such acoustic components are labeled "conflicting cue regions." The amplitude modulation of the high-frequency frication region by the fundamental F0 was found to be a sufficient cue for voicing. Overall, the 3DDS method allows one to analyze the effects of natural speech components without initial assumptions about where perceptual cues lie in time-frequency space or which elements of production they correspond to.

Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension.

PubMed

Tiani, Carolina; Garcia-Pras, Ester; Mejias, Marc; de Gottardi, Andrea; Berzigotti, Annalisa; Bosch, Jaime; Fernandez, Mercedes

2009-02-01

Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension. Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed. Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels. This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.

MicroRNA-188 suppresses G1/S transition by targeting multiple cyclin/CDK complexes.

PubMed

Wu, Jiangbin; Lv, Qing; He, Jie; Zhang, Haoxiang; Mei, Xueshuang; Cui, Kai; Huang, Nunu; Xie, Weidong; Xu, Naihan; Zhang, Yaou

2014-10-11

Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB-irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control. Overexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F transcriptional activity. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation. This study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway.

Type III CRISPR-Cas systems can provide redundancy to counteract viral escape from type I systems.

PubMed

Silas, Sukrit; Lucas-Elio, Patricia; Jackson, Simon A; Aroca-Crevillén, Alejandra; Hansen, Loren L; Fineran, Peter C; Fire, Andrew Z; Sánchez-Amat, Antonio

2017-08-17

CRISPR-Cas-mediated defense utilizes information stored as spacers in CRISPR arrays to defend against genetic invaders. We define the mode of target interference and role in antiviral defense for two CRISPR-Cas systems in Marinomonas mediterranea . One system (type I-F) targets DNA. A second system (type III-B) is broadly capable of acquiring spacers in either orientation from RNA and DNA, and exhibits transcription-dependent DNA interference. Examining resistance to phages isolated from Mediterranean seagrass meadows, we found that the type III-B machinery co-opts type I-F CRISPR-RNAs. Sequencing and infectivity assessments of related bacterial and phage strains suggests an 'arms race' in which phage escape from the type I-F system can be overcome through use of type I-F spacers by a horizontally-acquired type III-B system. We propose that the phage-host arms race can drive selection for horizontal uptake and maintenance of promiscuous type III interference modules that supplement existing host type I CRISPR-Cas systems.

Quorum Sensing Extracellular Death Peptides Enhance the Endoribonucleolytic Activities of Mycobacterium tuberculosis MazF Toxins

PubMed Central

Nigam, Akanksha; Kumar, Sathish

2018-01-01

ABSTRACT mazEF is a toxin-antitoxin module located on chromosomes of most bacteria. MazF toxins are endoribonucleases antagonized by MazE antitoxins. Previously, we characterized several quorum sensing peptides called "extracellular death factors" (EDFs). When secreted from bacterial cultures, EDFs induce interspecies cell death. EDFs also enhance the endoribonucleolytic activity of Escherichia coli MazF. Mycobacterium tuberculosis carries several mazEF modules. Among them, the endoribonucleolytic activities of MazF proteins mt-1, mt-3, and mt-6 were identified. MazF-mt6 and MazF-mt-3 cleave M. tuberculosis rRNAs. Here we report the in vitro effects of EDFs on the endoribonucleolytic activities of M. tuberculosis MazFs. Escherichia coli EDF (EcEDF) and the three Pseudomonas aeruginosa EDFs (PaEDFs) individually enhance the endoribonucleolytic activities of MazF-mt6 and MazF-mt3 and overcome the inhibitory effect of MazE-mt3 or MazE-mt6 on the endoribonucleolytic activities of the respective toxins. We propose that these EDFs can serve as a basis for a novel class of antibiotics against M. tuberculosis. PMID:29717013

Cortical Coupling Reflects Bayesian Belief Updating in the Deployment of Spatial Attention.

PubMed

Vossel, Simone; Mathys, Christoph; Stephan, Klaas E; Friston, Karl J

2015-08-19

The deployment of visuospatial attention and the programming of saccades are governed by the inferred likelihood of events. In the present study, we combined computational modeling of psychophysical data with fMRI to characterize the computational and neural mechanisms underlying this flexible attentional control. Sixteen healthy human subjects performed a modified version of Posner's location-cueing paradigm in which the percentage of cue validity varied in time and the targets required saccadic responses. Trialwise estimates of the certainty (precision) of the prediction that the target would appear at the cued location were derived from a hierarchical Bayesian model fitted to individual trialwise saccadic response speeds. Trial-specific model parameters then entered analyses of fMRI data as parametric regressors. Moreover, dynamic causal modeling (DCM) was performed to identify the most likely functional architecture of the attentional reorienting network and its modulation by (Bayes-optimal) precision-dependent attention. While the frontal eye fields (FEFs), intraparietal sulcus, and temporoparietal junction (TPJ) of both hemispheres showed higher activity on invalid relative to valid trials, reorienting responses in right FEF, TPJ, and the putamen were significantly modulated by precision-dependent attention. Our DCM results suggested that the precision of predictability underlies the attentional modulation of the coupling of TPJ with FEF and the putamen. Our results shed new light on the computational architecture and neuronal network dynamics underlying the context-sensitive deployment of visuospatial attention. Spatial attention and its neural correlates in the human brain have been studied extensively with the help of fMRI and cueing paradigms in which the location of targets is pre-cued on a trial-by-trial basis. One aspect that has so far been neglected concerns the question of how the brain forms attentional expectancies when no a priori probability information is available but needs to be inferred from observations. This study elucidates the computational and neural mechanisms under which probabilistic inference governs attentional deployment. Our results show that Bayesian belief updating explains changes in cortical connectivity; in that directional influences from the temporoparietal junction on the frontal eye fields and the putamen were modulated by (Bayes-optimal) updates. Copyright © 2015 Vossel et al.

Comparative study of CXC chemokines modulation in brown trout (Salmo trutta) following infection with a bacterial or viral pathogen.

PubMed

Gorgoglione, Bartolomeo; Zahran, Eman; Taylor, Nick G H; Feist, Stephen W; Zou, Jun; Secombes, Christopher J

2016-03-01

Chemokine modulation in response to pathogens still needs to be fully characterised in fish, in view of the recently described novel chemokines present. This paper reports the first comparative study of CXC chemokine genes transcription in salmonids (brown trout), with a particular focus on the fish specific CXC chemokines (CXCL_F). Adopting new primer sets, optimised to specifically target mRNA, a RT-qPCR gene screening was carried out. Constitutive gene expression was assessed first in six tissues from SPF brown trout. Transcription modulation was next investigated in kidney and spleen during septicaemic infection induced by a RNA virus (Viral Haemorrhagic Septicaemia virus, genotype Ia) or by a Gram negative bacterium (Yersinia ruckeri, ser. O1/biot. 2). From each target organ specific pathogen burden, measured detecting VHSV-glycoprotein or Y. ruckeri 16S rRNA, and IFN-γ gene expression were analysed for their correlation to chemokine transcription. Both pathogens modulated CXC chemokine gene transcript levels, with marked up-regulation seen in some cases, and with both temporal and tissue specific effects apparent. For example, Y. ruckeri strongly induced chemokine transcription in spleen within 24h, whilst VHS generally induced the largest increases at 3d.p.i. in both tissues. This study gives clues to the role of the novel CXC chemokines, in comparison to the other known CXC chemokines in salmonids. Copyright © 2016 Elsevier Ltd. All rights reserved.

Method for selective recovery of PET-usable quantities of [.sup.18 F] fluoride and [.sup.13 N] nitrate/nitrite from a single irradiation of low-enriched [.sup.18 O] water

DOEpatents

Ferrieri, Richard A.; Schlyer, David J.; Shea, Colleen

1995-06-13

A process for simultaneously producing PET-usable quantities of [.sup.13 N]NH.sub.3 and [.sup.18 F]F.sup.- for radiotracer synthesis is disclosed. The process includes producing [.sup.13 N]NO.sub.2.sup.- /NO.sub.3.sup.- and [.sup.18 F]F.sup.- simultaneously by exposing a low-enriched (20%-30%) [.sup.18 O]H.sub.2 O target to proton irradiation, sequentially isolating the [.sup.13 N]NO.sub.2.sup.- /NO.sub.3.sup.- and [.sup.18 F]F.sup.- from the [.sup.18 O]H.sub.2 O target, and reducing the [.sup.13 N]NO.sub.2.sup.- /NO.sub.3.sup.- to [.sup.13 N]NH.sub.3. The [.sup.13 N]NH.sub.3 and [.sup.18 F]F.sup.- products are then conveyed to a laboratory for radiotracer applications. The process employs an anion exchange resin for isolation of the isotopes from the [.sup.18 O]H.sub.2 O, and sequential elution of [.sup.13 N]NO.sub.2.sup.- /NO.sub.3.sup.- and [ .sup.18 F]F.sup.- fractions. Also the apparatus is disclosed for simultaneously producing PET-usable quantities of [.sup.13 N]NH.sub.3 and [.sup.18 F]F.sup.- from a single irradiation of a single low-enriched [.sup.18 O]H.sub.2 O target.

Birefringence and incipient plastic deformation in elastically overdriven [100] CaF2 under shock compression

NASA Astrophysics Data System (ADS)

Li, Y.; Zhou, X. M.; Cai, Y.; Liu, C. L.; Luo, S. N.

2018-04-01

[100] CaF2 single crystals are shock-compressed via symmetric planar impact, and the flyer plate-target interface velocity histories are measured with a laser displacement interferometry. The shock loading is slightly above the Hugoniot elastic limit to investigate incipient plasticity and its kinetics, and its effects on optical properties and deformation inhomogeneity. Fringe patterns demonstrate different features in modulation of fringe amplitude, including birefringence and complicated modulations. The birefringence is attributed to local lattice rotation accompanying incipient plasticity. Spatially resolved measurements show inhomogeneity in deformation, birefringence, and fringe pattern evolutions, most likely caused by the inhomogeneity associated with lattice rotation and dislocation slip. Transiently overdriven elastic states are observed, and the incubation time for incipient plasticity decreases inversely with increasing overdrive by the elastic shock.

Two years of experience with the [ 18F]FDG production module

NASA Astrophysics Data System (ADS)

Kim, Sang Wook; Hur, Min Goo; Chai, Jong-Seo; Park, Jeong Hoon; Yu, Kook Hyun; Jeong, Cheol Ki; Lee, Goung Jin; Min, Young Don; Yang, Seung Dae

2007-08-01

Chemistry module for a conventional [18F]FDG production by using tetrabutylammonium bicarbonate (TBA) and an acidic hydrolysis has been manufactured and evaluated. In this experiment, 75 mM (pH 7.5-7.8) of TBA solution and a ca. 2-curies order of [18F]-fluoride have been used for the evaluation. The commercial acidic purification cartridge was purchased from GE or UKE. The operation system (OS) was programmed with Lab-View which was selected because of its easy customization of the OS. Small sized solenoid valves (Burkert; type 6124) were selected to reduce the module dimensions (W 350 × D 270 × H 250). The total time for the synthesis of [18F]FDG was 30 ± 3 min. The production yield of [18F]FDG was 60 ± 2% on an average at EOS, with the decay uncorrected. This experimental data show that the traditional chemistry module can provide a good [18F]FDG production yield by optimizing the operational conditions. The radiochemical purity, radionuclidic purity, acidity, residual solvent, osmolality and endotoxin were determined to assess the quality of [18F]FDG. The examined contents for the quality control of [18F]FDG were found to be suitable for a clinical application.

Target identification in Fusobacterium nucleatum by subtractive genomics approach and enrichment analysis of host-pathogen protein-protein interactions.

PubMed

Kumar, Amit; Thotakura, Pragna Lakshmi; Tiwary, Basant Kumar; Krishna, Ramadas

2016-05-12

Fusobacterium nucleatum, a well studied bacterium in periodontal diseases, appendicitis, gingivitis, osteomyelitis and pregnancy complications has recently gained attention due to its association with colorectal cancer (CRC) progression. Treatment with berberine was shown to reverse F. nucleatum-induced CRC progression in mice by balancing the growth of opportunistic pathogens in tumor microenvironment. Intestinal microbiota imbalance and the infections caused by F. nucleatum might be regulated by therapeutic intervention. Hence, we aimed to predict drug target proteins in F. nucleatum, through subtractive genomics approach and host-pathogen protein-protein interactions (HP-PPIs). We also carried out enrichment analysis of host interacting partners to hypothesize the possible mechanisms involved in CRC progression due to F. nucleatum. In subtractive genomics approach, the essential, virulence and resistance related proteins were retrieved from RefSeq proteome of F. nucleatum by searching against Database of Essential Genes (DEG), Virulence Factor Database (VFDB) and Antibiotic Resistance Gene-ANNOTation (ARG-ANNOT) tool respectively. A subsequent hierarchical screening to identify non-human homologous, metabolic pathway-independent/pathway-specific and druggable proteins resulted in eight pathway-independent and 27 pathway-specific druggable targets. Co-aggregation of F. nucleatum with host induces proinflammatory gene expression thereby potentiates tumorigenesis. Hence, proteins from IBDsite, a database for inflammatory bowel disease (IBD) research and those involved in colorectal adenocarcinoma as interpreted from The Cancer Genome Atlas (TCGA) were retrieved to predict drug targets based on HP-PPIs with F. nucleatum proteome. Prediction of HP-PPIs exhibited 186 interactions contributed by 103 host and 76 bacterial proteins. Bacterial interacting partners were accounted as putative targets. And enrichment analysis of host interacting partners showed statistically enriched terms that were in positive correlation with CRC, atherosclerosis, cardiovascular, osteoporosis, Alzheimer's and other diseases. Subtractive genomics analysis provided a set of target proteins suggested to be indispensable for survival and pathogenicity of F. nucleatum. These target proteins might be considered for designing potent inhibitors to abrogate F. nucleatum infections. From enrichment analysis, it was hypothesized that F. nucleatum infection might enhance CRC progression by simultaneously regulating multiple signaling cascades which could lead to up-regulation of proinflammatory responses, oncogenes, modulation of host immune defense mechanism and suppression of DNA repair system.

Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia.

PubMed

Li, Sheng; Wang, Chengzhong; Wang, Weikai; Liu, Weidong; Zhang, Guiqin

2018-05-01

This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR-520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL.

Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR.

PubMed

Rubenstein, R C; Zeitlin, P L

2000-02-01

The most common mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), DeltaF508, is a trafficking mutant that has prolonged associations with molecular chaperones and is rapidly degraded, at least in part by the ubiquitin-proteasome system. Sodium 4-phenylbutyrate (4PBA) improves DeltaF508-CFTR trafficking and function in vitro in cystic fibrosis epithelial cells and in vivo. To further understand the mechanism of action of 4PBA, we tested the hypothesis that 4PBA modulates the targeting of DeltaF508-CFTR for ubiquitination and degradation by reducing the expression of Hsc70 in cystic fibrosis epithelial cells. IB3-1 cells (genotype DeltaF508/W1282X) that were treated with 0.05-5 mM 4PBA for 2 days in culture demonstrated a dose-dependent reduction in Hsc70 protein immunoreactivity and mRNA levels. Immunoprecipitation with Hsc70-specific antiserum demonstrated that Hsc70 and CFTR associated under control conditions and that treatment with 4PBA reduced these complexes. Levels of immunoreactive Hsp40, Hdj2, Hsp70, Hsp90, and calnexin were unaffected by 4PBA treatment. These data suggest that 4PBA may improve DeltaF508-CFTR trafficking by allowing a greater proportion of mutant CFTR to escape association with Hsc70.

Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones.

PubMed

Higuchi, Robert I; Thompson, Anthony W; Chen, Jyun-Hung; Caferro, Thomas R; Cummings, Marquis L; Deckhut, Charlotte P; Adams, Mark E; Tegley, Christopher M; Edwards, James P; López, Francisco J; Kallel, E Adam; Karanewsky, Donald S; Schrader, William T; Marschke, Keith B; Zhi, Lin

2007-10-01

A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.

Emotional Intent Modulates The Neural Substrates Of Creativity: An fMRI Study of Emotionally Targeted Improvisation in Jazz Musicians

PubMed Central

McPherson, Malinda J.; Barrett, Frederick S.; Lopez-Gonzalez, Monica; Jiradejvong, Patpong; Limb, Charles J.

2016-01-01

Emotion is a primary motivator for creative behaviors, yet the interaction between the neural systems involved in creativity and those involved in emotion has not been studied. In the current study, we addressed this gap by using fMRI to examine piano improvisation in response to emotional cues. We showed twelve professional jazz pianists photographs of an actress representing a positive, negative or ambiguous emotion. Using a non-ferromagnetic thirty-five key keyboard, the pianists improvised music that they felt represented the emotion expressed in the photographs. Here we show that activity in prefrontal and other brain networks involved in creativity is highly modulated by emotional context. Furthermore, emotional intent directly modulated functional connectivity of limbic and paralimbic areas such as the amygdala and insula. These findings suggest that emotion and creativity are tightly linked, and that the neural mechanisms underlying creativity may depend on emotional state. PMID:26725925

Sensitive detection of temperature behind reflected shock waves using wavelength modulation spectroscopy of CO2 near 2.7 μm

NASA Astrophysics Data System (ADS)

Farooq, A.; Jeffries, J. B.; Hanson, R. K.

2009-07-01

Tunable diode-laser absorption of CO2 near 2.7 μm incorporating wavelength modulation spectroscopy with second-harmonic detection (WMS-2f) is used to provide a new sensor for sensitive and accurate measurement of the temperature behind reflected shock waves in a shock-tube. The temperature is inferred from the ratio of 2f signals for two selected absorption transitions, at 3633.08 and 3645.56 cm-1, belonging to the ν 1+ ν 3 combination vibrational band of CO2 near 2.7 μm. The modulation depths of 0.078 and 0.063 cm-1 are optimized for the target conditions of the shock-heated gases ( P˜1-2 atm, T˜800-1600 K). The sensor is designed to achieve a high sensitivity to the temperature and a low sensitivity to cold boundary-layer effects and any changes in gas pressure or composition. The fixed-wavelength WMS-2f sensor is tested for temperature and CO2 concentration measurements in a heated static cell (600-1200 K) and in non-reactive shock-tube experiments (900-1700 K) using CO2-Ar mixtures. The relatively large CO2 absorption strength near 2.7 μm and the use of a WMS-2f strategy minimizes noise and enables measurements with lower concentration, higher accuracy, better sensitivity and improved signal-to-noise ratio (SNR) relative to earlier work, using transitions in the 1.5 and 2.0 μm CO2 combination bands. The standard deviation of the measured temperature histories behind reflected shock waves is less than 0.5%. The temperature sensor is also demonstrated in reactive shock-tube experiments of n-heptane oxidation. Seeding of relatively inert CO2 in the initial fuel-oxidizer mixture is utilized to enable measurements of the pre-ignition temperature profiles. To our knowledge, this work represents the first application of wavelength modulation spectroscopy to this new class of diode lasers near 2.7 μm.

Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging.

PubMed

Mu, Linjing; Müller Herde, Adrienne; Rüefli, Pascal M; Sladojevich, Filippo; Milicevic Sephton, Selena; Krämer, Stefanie D; Thompson, Andrew J; Schibli, Roger; Ametamey, Simon M; Lochner, Martin

2016-11-16

Serotonin-gated ionotropic 5-HT 3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT 3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (K i = 0.26 ± 0.05 nM) similar to the parent drug (K i = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18 F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl- 11 C)-N-granisetron ([ 11 C]2) through N-alkylation with [ 11 C]CH 3 I, respectively. Both compounds [ 18 F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [ 11 C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [ 18 F]15 and [ 11 C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT 3 receptors at significant levels. Subsequent PET experiments suggested that [ 18 F]15 and [ 11 C]2 are of limited utility for the PET imaging of brain 5-HT 3 receptors in vivo.

Structural Modification of (-)-Epigallocatechin Gallate (EGCG) Shows Significant Enhancement in Mitochondrial Biogenesis.

PubMed

Ha, Taewoong; Kim, Mi Kyoung; Park, Kwang-Su; Jung, Woong; Choo, Hyunah; Chong, Youhoon

2018-04-18

(-)-Epigallocatechin-3-gallate (EGCG) is known as a mitochondria-targeted molecule that can prevent mitochondrial deterioration and induce mitochondrial biogenesis by modulating key regulators of mitochondrial metabolism. In this study, we tackled whether derivatization of EGCG could result in enhancement of its effects on mitochondrial biogenesis. EGCG, EGCG peracetate (AcEGCG), and its 4″- O-alkyl substituted congeners prepared by previously reported procedures were biologically evaluated. Interestingly, EGCG and AcEGCG were only marginally effective in inducing mitochondrial biogenesis, while AcEGCG congeners with an alkyl group at the 4″- O position showed significantly increased biological activity compared to their parent compound. Among these series, 3f with a methyl-branched carbonate chain at the 4″- O position of the AcEGCG scaffold showed the most enhancement in inducing mitochondrial biogenesis. Hepa1-6 cells treated with 3f exhibited increases in both mitochondrial mass (1.5 times) and relative mtDNA content to nDNA (1.5 times). As a mitochondrial biogenesis enhancer, 3f also increased expression levels of regulators for mitochondrial function, including PGC-1α (4.0 fold), p-AMPK (2.5 fold), SIRT1 (4.2 fold), ERRα (1.8 fold), NRF-1 (1.6 fold), NRF-2 (1.7 fold), and mtTFA (1.6 folds). Investigation of oxidative phosphorylation by mitochondria in the presence of 3f revealed that 3f increased the NAD + /NADH ratio, the amount of cytochrome c, ATP synthesis, and oxygen consumption in Hepa1-6 cells by 2.2, 1.4, 1.5, and 2.1 fold, respectively. Taken together, these results warrant an extensive structure-activity relationship study for EGCG derivatives to develop novel mitochondrial biogenesis enhancers.

T36. THE ANTIPSYCHOTIC-LIKE PROPERTIES OF EVENAMIDE (NW-3509) REFLECT THE MODULATION OF GLUTAMATERGIC DYSREGULATION

PubMed Central

Bortolato, Marco; Faravelli, Laura; Anand, Ravi

2018-01-01

Abstract Background The lack of adequate benefit with current 5HT2 / D2 antipsychotics in large proportions of schizophrenic patients suggests it is essential to modulate other mechanisms for improving symptoms of schizophrenia (SCZ). Increasing evidence implicates NMDAr hypofunction, and hippocampal hyperactivity, in the dysregulation not only of mesolimbic DA neurons but also of Glu neurons, leading to increasing synaptic activity of Glu in the PFC. Injection of NMDAr antagonists (PCP, ketamine) at doses that produce psychotomimetic effects lead to a downstream increase of Glu neurotransmission at non-NMDAr. The excessive firing and the hyper-glutamatergic tone represent alternative targets of treatment for SCZ ultimately affecting positive, negative, cognitive symptoms. The addition of Glu release inhibitors may augment the benefits of the antipsychotics in patients showing inadequate response. Evenamide uniquely does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with more than 130 different targets that are involved in CNS activity, except sodium channels. Preclinical data suggests that by the modulation of the firing abnormalities, evenamide normalizes the aberrant spread of Glu excitatory transmission that occurs in the brains of patients with SCZ. Evenamide showed efficacy in animal models relevant to SCZ (sensory motor gating, mania, psychosis, depression, impulse control, cognition, social interaction), in monotherapy and as an add on to first or second generation antipsychotics irrespective of whether impairment was either spontaneous, induced by amphetamine or NMDAr antagonists or stress. Evenamide, has also shown significant benefit in a p.c phase 2 trial as an add-on to risperidone and aripiprazole in patients worsening on dopaminergic/serotoninergic antagonist medication, suggesting it acts through other mechanisms. New animal data further confirm evenamide’s activity in reducing SCZ symptoms provoked by Glu alteration. Methods Effects of evenamide (EVE 1.25, 5, 15 mg/kg PO) to restore the impaired information processing (a deficit observed in SCZ), were evaluated in the rat model of the Pre-Pulse Inhibition (PPI) deficit induced by injection of the NMDAr antagonist ketamine (KET 6 mg/kg, SC). Clozapine (CLO 7.5 mg/kg, IP) was used as a positive control. Results PPI analysis showed significant main effects for KET to lower PPI levels [F(1,264)=139.67, P<0.0001], for EVE [F(3,264)=3.14, P<0.05] and CLO to enhance PPI levels [F(1,98)=30.89, P<0.001]. Notably, significant EVE x KET [F(3,264)=2.79, P<0.05] and CLO x KET interactions [F(1,98)=5.45, P<0.05] were found. Post-hoc analyses (Tukey’s) revealed that KET significantly lowered PPI (P<0.0001) for each group; both EVE (5 mg/kg) and CLO significantly increased PPI in KET-treated rats (P=0.02; p<0.001). Discussion Evenamide as monotherapy has similar effect to clozapine in reversing ketamine- induced worsening of PPI. Together with previously demonstrated effects to reverse PCP-induced PPI and social interaction deficits, this further supports its potential to affect both positive and negative symptoms of SCZ by targeting altered Glu transmission. Efficacy of evenamide as an add-on to antipsychotics would revolutionize development of novel antipsychotics that would target aberrant firing and Glu transmission in SCZ. Two clinical trials have been planned to support the hypothesis that the addition of evenamide should add a non-dopaminergic mechanism for augmenting antipsychotic efficacy in patients who are not responding adequately to current antipsychotic, and in patients with treatment resistant SCZ who are not responding/worsening on clozapine.

Method for selective recovery of PET-usable quantities of [{sup 18}F] fluoride and [{sup 13}N] nitrate/nitrite from a single irradiation of low-enriched [{sup 18}O] water

DOEpatents

Ferrieri, R.A.; Schlyer, D.J.; Shea, C.

1995-06-13

A process for simultaneously producing PET-usable quantities of [{sup 13}N]NH{sub 3} and [{sup 18}F]F{sup {minus}} for radiotracer synthesis is disclosed. The process includes producing [{sup 13}N]NO{sub 2}{sup {minus}}/NO{sub 3}{sup {minus}}and [{sup 18}F]F{sup {minus}} simultaneously by exposing a low-enriched (20%-30%) [{sup 18}O]H{sub 2}O target to proton irradiation, sequentially isolating the [{sup 13}N]NO{sub 2}{sup {minus}}/NO{sub 3}{sup {minus}} and [{sup 18}F]F{sup {minus}} from the [{sup 18}O]H{sub 2}O target, and reducing the [{sup 13}N]NO{sub 2}{sup {minus}}/NO{sub 3}{sup {minus}} to [{sup 13}N]NH{sub 3}. The [{sup 13}N]NH{sub 3} and [{sup 18}F]F{sup {minus}} products are then conveyed to a laboratory for radiotracer applications. The process employs an anion exchange resin for isolation of the isotopes from the [{sup 18}O]H{sub 2}O, and sequential elution of [{sup 13}N]NO{sub 2}{sup {minus}}/NO{sub 3}{sup {minus}} and [{sup 18}F]F{sup {minus}} fractions. Also the apparatus is disclosed for simultaneously producing PET-usable quantities of [{sup 13}N]NH{sub 3} and [{sup 18}F]F{sup {minus}} from a single irradiation of a single low-enriched [{sup 18}O]H{sub 2}O target. 2 figs.

Function Specifications for the A-7E Function Driver Module.

DTIC Science & Technology

1981-11-27

Computer interface specifications (HEN181). The services and values provided by the Shared Services module are accurately described in the Shared Services Module...None$) FD.7.l.3.1 FD.7.1.7.1 5517a FD.App3 -5 Appendix 3 Event List (Alphabetical) Events Signalled by other Shared Services submodules @F( ABSCI+ip az...the Shared Services and Device Interface modules. Al; Answer this question for each table that appears in the function driver specification being

E2F1 somatic mutation within miRNA target site impairs gene regulation in colorectal cancer.

PubMed

Lopes-Ramos, Camila M; Barros, Bruna P; Koyama, Fernanda C; Carpinetti, Paola A; Pezuk, Julia; Doimo, Nayara T S; Habr-Gama, Angelita; Perez, Rodrigo O; Parmigiani, Raphael B

2017-01-01

Genetic studies have largely concentrated on the impact of somatic mutations found in coding regions, and have neglected mutations outside of these. However, 3' untranslated regions (3' UTR) mutations can also disrupt or create miRNA target sites, and trigger oncogene activation or tumor suppressor inactivation. We used next-generation sequencing to widely screen for genetic alterations within predicted miRNA target sites of oncogenes associated with colorectal cancer, and evaluated the functional impact of a new somatic mutation. Target sequencing of 47 genes was performed for 29 primary colorectal tumor samples. For 71 independent samples, Sanger methodology was used to screen for E2F1 mutations in miRNA predicted target sites, and the functional impact of these mutations was evaluated by luciferase reporter assays. We identified germline and somatic alterations in E2F1. Of the 100 samples evaluated, 3 had germline alterations at the MIR205-5p target site, while one had a somatic mutation at MIR136-5p target site. E2F1 gene expression was similar between normal and tumor tissues bearing the germline alteration; however, expression was increased 4-fold in tumor tissue that harbored a somatic mutation compared to that in normal tissue. Luciferase reporter assays revealed both germline and somatic alterations increased E2F1 activity relative to wild-type E2F1. We demonstrated that somatic mutation within E2F1:MIR136-5p target site impairs miRNA-mediated regulation and leads to increased gene activity. We conclude that somatic mutations that disrupt miRNA target sites have the potential to impact gene regulation, highlighting an important mechanism of oncogene activation.

Design and testing of an energy-absorbing crewseat for the F/FB-111 aircraft. Volume 3: Data from crew module testing

NASA Technical Reports Server (NTRS)

Shane, S. J.

1985-01-01

Over the past years, several papers and reports have documented the unacceptably high injury rate during the escape sequence (including the ejection and ground impact) of the crew module for F/FB-111 aircraft. This report documents a program to determine if the injury potential could be reduced by replacing the existing crewseats with energy absorbing crewseats. An energy absorbing test seat was designed using much of the existing seat hardware. An extensive dynamic seat test series, designed to duplicate various crew module ground impact conditions, was conducted at a sled test facility. Comparative tests with operational F-111 crewseats were also conducted. After successful dynamic testing of the seat, more testing was conducted with the seats mounted in an F-111 crew module. Both swing tests and vertical drop tests werre conducted. The vertical drop tests were used to obtain comparative data between the energy absorbing and operational seats.

Alternative laser system for cesium magneto-optical trap via optical injection locking to sideband of a 9-GHz current-modulated diode laser.

PubMed

Diao, Wenting; He, Jun; Liu, Zhi; Yang, Baodong; Wang, Junmin

2012-03-26

By optical injection of an 852-nm extended-cavity diode laser (master laser) to lock the + 1-order sideband of a ~9-GHz-current-modulated diode laser (slave laser), we generate a pair of phase-locked lasers with a frequency difference up to ~9-GHz for a cesium (Cs) magneto-optical trap (MOT) with convenient tuning capability. For a cesium MOT, the master laser acts as repumping laser, locked to the Cs 6S₁/₂ (F = 3) - 6P₃/₂ (F' = 4) transition. When the + 1-order sideband of the 8.9536-GHz-current-modulated slave laser is optically injection-locked, the carrier operates on the Cs 6S₁/₂ (F = 4) - 6P₃/₂ (F' = 5) cooling cycle transition with -12 MHz detuning and acts as cooling/trapping laser. When carrying a 9.1926-GHz modulation signal, this phase-locked laser system can be applied in the fields of coherent population trapping and coherent manipulation of Cs atomic ground states.

Detection of Metallic and Electronic Radar Targets by Acoustic Modulation of Electromagnetic Waves

DTIC Science & Technology

2017-07-01

reradiated wave is captured by the radar’s receive antenna. The presence of measurable EM energy at any discrete multiple of the audio frequency away...the radar receiver (Rx). The presence of measurable EM energy at any discrete multiple of faudio away from the original RF carrier fRF (i.e., at any n

An electric noise component with density 1/f identified on ISEE 3

NASA Technical Reports Server (NTRS)

Hoang, S.; Steinberg, J. L.; Couturier, P.; Feldman, W. C.

1982-01-01

The properties of the 1/f noise detected at the terminals of ISEE 3 antennas are described and related to the solar wind parameters. The 1/f noise was observed with the radio receivers of the three-dimensional radio mapping experiment using the S and Z dipole antennas. The noise spectra contained a negative spectral index component at frequencies lower than 0.7 of the plasma frequency, and 5-10 times the predicted thermal noise for the Z antenna. S-antenna measurements of the 1/f component revealed it to be deeply spin modulated with a minimum electric field in the direction of the solar wind. Modulation increases with increasing frequency, becomes negligible when the 1/f intensity is negligible with respect to the thermal noise, and increases with solar wind velocity. The possibilities that the noise is due either to waves or currents are discussed.

Key achievements in elementary R&D on water-cooled solid breeder blanket for ITER test blanket module in JAERI

NASA Astrophysics Data System (ADS)

Suzuki, S.; Enoeda, M.; Hatano, T.; Hirose, T.; Hayashi, K.; Tanigawa, H.; Ochiai, K.; Nishitani, T.; Tobita, K.; Akiba, M.

2006-02-01

This paper presents the significant progress made in the research and development (R&D) of key technologies on the water-cooled solid breeder blanket for the ITER test blanket modules in JAERI. Development of module fabrication technology, bonding technology of armours, measurement of thermo-mechanical properties of pebble beds, neutronics studies on a blanket module mockup and tritium release behaviour from a Li2TiO3 pebble bed under neutron-pulsed operation conditions are summarized. With the improvement of the heat treatment process for blanket module fabrication, a fine-grained microstructure of F82H can be obtained by homogenizing it at 1150 °C followed by normalizing it at 930 °C after the hot isostatic pressing process. Moreover, a promising bonding process for a tungsten armour and an F82H structural material was developed using a solid-state bonding method based on uniaxial hot compression without any artificial compliant layer. As a result of high heat flux tests of F82H first wall mockups, it has been confirmed that a fatigue lifetime correlation, which was developed for the ITER divertor, can be made applicable for the F82H first wall mockup. As for R&D on the breeder material, Li2TiO3, the effect of compression loads on effective thermal conductivity of pebble beds has been clarified for the Li2TiO3 pebble bed. The tritium breeding ratio of a simulated multi-layer blanket structure has successfully been measured using 14 MeV neutrons with an accuracy of 10%. The tritium release rate from the Li2TiO3 pebble has also been successfully measured with pulsed neutron irradiation, which simulates ITER operation.

Modulated magnetic structure of F e3P O7 as seen by 57Fe Mössbauer spectroscopy

NASA Astrophysics Data System (ADS)

Sobolev, A. V.; Akulenko, A. A.; Glazkova, I. S.; Pankratov, D. A.; Presniakov, I. A.

2018-03-01

The paper reports results of the 57Fe Mössbauer measurements on an F e3P O4O3 powder sample recorded at various temperatures, including the point of magnetic phase transition TN≈163 K . The spectra measured above TN consist of a quadrupole doublet with high quadrupole splitting of Δ300 K≈1.10 mm /s , emphasizing that F e3 + ions are located in crystal positions with a strong electric-field gradient (EFG). To predict the sign and orientation of the main components of the EFG tensor, we calculated the EFG using the density-functional-theory approach. In the temperature range T

Ecological landscape elements: long-term monitoring in Great Britain, the Countryside Survey 1978-2007 and beyond

NASA Astrophysics Data System (ADS)

Wood, Claire M.; Bunce, Robert G. H.; Norton, Lisa R.; Maskell, Lindsay C.; Smart, Simon M.; Scott, W. Andrew; Henrys, Peter A.; Howard, David C.; Wright, Simon M.; Brown, Michael J.; Scott, Rod J.; Stuart, Rick C.; Watkins, John W.

2018-04-01

The Countryside Survey (CS) of Great Britain (GB) provides a unique and statistically robust series of datasets, consisting of an extensive set of repeated ecological measurements at a national scale, covering a time span of 29 years. CS was first undertaken in 1978 to provide a baseline for ecological and land use change monitoring in the rural environment of GB, following a stratified random design, based on 1 km squares. Originally, eight random 1 km squares were drawn from each of 32 environmental classes, thus comprising 256 sample squares in the 1978 survey. The number of these sites increased to 382 in 1984, 506 in 1990, 569 in 1998 and 591 in 2007. Detailed information regarding vegetation types and land use was mapped in all five surveys, allowing reporting by defined standard habitat classifications. Additionally, point and linear landscape features (such as trees and hedgerows) are available from all surveys after 1978. From these stratified, randomly located sample squares, information can be converted into national estimates, with associated error terms. Other data, relating to soils, freshwater and vegetation, were also sampled on analogous dates. However, the present paper describes only the surveys of landscape features and habitats. The resulting datasets provide a unique, comprehensive, quantitative ecological coverage of extent and change in these features in GB. Basic results are presented and their implications discussed. However, much opportunity for further analyses remains. Data from each of the survey years are available via the following DOIs: Landscape area data 1978: https://doi.org/10.5285/86c017ba-dc62-46f0-ad13-c862bf31740e, 1984: https://doi.org/10.5285/b656bb43-448d-4b2c-aade-7993aa243ea3, 1990: https://doi.org/10.5285/94f664e5-10f2-4655-bfe6-44d745f5dca7, 1998: https://doi.org/10.5285/1e050028-5c55-42f4-a0ea-c895d827b824, and 2007: https://doi.org/10.5285/bf189c57-61eb-4339-a7b3-d2e81fdde28d; Landscape linear feature data 1984: https://doi.org/10.5285/a3f5665c-94b2-4c46-909e-a98be97857e5, 1990: https://doi.org/10.5285/311daad4-bc8c-485a-bc8a-e0d054889219, 1998: https://doi.org/10.5285/8aaf6f8c-c245-46bb-8a2a-f0db012b2643 and 2007: https://doi.org/10.5285/e1d31245-4c0a-4dee-b36c-b23f1a697f88, Landscape point feature data 1984: https://doi.org/10.5285/124b872e-036e-4dd3-8316-476b5f42c16e, 1990: https://doi.org/10.5285/1481bc63-80d7-4d18-bcba-8804aa0a9e1b, 1998: https://doi.org/10.5285/ed10944f-40c8-4913-b3f5-13c8e844e153 and 2007: https://doi.org/10.5285/55dc5fd7-d3f7-4440-b8a7-7187f8b0550b.

[18F]MEL050 as a melanin-targeted PET tracer: Fully automated radiosynthesis and comparison to 18F-FDG for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases.

PubMed

Rizzo-Padoin, Nathalie; Chaussard, Michael; Vignal, Nicolas; Kotula, Ewa; Tsoupko-Sitnikov, Vadim; Vaz, Sofia; Hontonnou, Fortune; Liu, Wang-Qing; Poyet, Jean-Luc; Vidal, Michel; Merlet, Pascal; Hosten, Benoit; Sarda-Mantel, Laure

2016-12-01

Melanoma is a highly malignant cutaneous tumor of melanin-producing cells. MEL050 is a synthetic benzamide-derived molecule that specifically binds to melanin with high affinity. Our aim was to implement a fully automated radiosynthesis of [ 18 F]MEL050, using for the first time, the AllInOne™ synthesis module (Trasis), and to evaluate the potential of [ 18 F]MEL050 for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases, and to compare it with that of [ 18 F]FDG. Automated radiosynthesis of [ 18 F]MEL050, including HPLC purification and formulation, were performed on an AllInOne™ synthesis module. [ 18 F]MEL050 was synthesized using a one-step bromine-for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumor) or intravenous (pulmonary metastases) injection of B16-F10-luc2 cells in NMRI mice. The maximum percentage of [ 18 F]MEL050 Injected Dose per g of lung tissue (%ID/g Max) was determined on PET images, compared to [ 18 F]FDG and correlated to in vivo bioluminescence imaging. The automated radiosynthesis of [ 18 F]MEL050 required an overall radiosynthesis time of 48min, with a yield of 13-18% (not-decay corrected) and radiochemical purity higher than 99%. [ 18 F]MEL050 PET/CT images were concordant with bioluminescence imaging, showing increased radiotracer uptake in all primary subcutaneous tumors and pulmonary metastases of mice. PET quantification of radiotracers uptake in tumors and muscles demonstrated similar tumor-to-background ratio (TBR) with [ 18 F]MEL050 and [ 18 F]FDG in subcutaneous tumors and higher TBR with [ 18 F]MEL050 than with [ 18 F]FDG in pulmonary metastases. We successfully implemented the radiosynthesis of [ 18 F]MEL050 using the AllInOne™ module, including HPLC purification and formulation. In vivo PET/CT validation of [ 18 F]MEL050 was obtained in mouse models of pigmented melanoma, where higher [ 18 F]MEL050 uptake was observed in sub-millimetric pulmonary metastases, comparatively to [ 18 F]FDG. Copyright © 2016 Elsevier Inc. All rights reserved.

N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection

PubMed Central

Jagdeo, Julienne M.; Dufour, Antoine; Klein, Theo; Solis, Nestor; Kleifeld, Oded; Kizhakkedathu, Jayachandran; Luo, Honglin; Overall, Christopher M.

2018-01-01

ABSTRACT Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative in vitro proteomics-based approach, termed terminal amine isotopic labeling of substrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3Cpros) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3Cpro in vitro including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3Cpro-targeted substrates were also cleaved in virus-infected cells but not noncleavable mutant proteins designed from the TAILS-identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3Cpro promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3Cpro substrates in vivo, we conclude that N-terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner. IMPORTANCE Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection. Although several host protein targets have been identified, the entire list of proteins that are targeted is not known. In this study, we used a novel unbiased proteomics approach to identify ∼100 novel host targets of the enterovirus 3C protease, thus providing further insights into the network of cellular pathways that are modulated to promote virus infection. PMID:29437971

Folic acid-targeted magnetic Tb-doped CeF3 fluorescent nanoparticles as bimodal probes for cellular fluorescence and magnetic resonance imaging.

PubMed

Ma, Zhi-Ya; Liu, Yu-Ping; Bai, Ling-Yu; An, Jie; Zhang, Lin; Xuan, Yang; Zhang, Xiao-Shuai; Zhao, Yuan-Di

2015-10-07

Magnetic fluorescent nanoparticles (NPs) have great potential applications for diagnostics, imaging and therapy. We developed a facile polyol method to synthesize multifunctional Fe3O4@CeF3:Tb@CeF3 NPs with small size (<20 nm), high water solubility and good biocompatibility. The NPs were modified by ligand exchange reactions with citric acid (CA) to obtain carboxyl-functionalized NPs (Fe3O4@CeF3:Tb@CeF3-COOH). Folic acid (FA) as an affinity ligand was then covalently conjugated onto NPs to yield Fe3O4@CeF3:Tb@CeF3-FA NPs. They were then applied as multimodal imaging agents for simultaneous in vitro targeted fluorescence imaging and magnetic resonance imaging (MRI) of HeLa cells with overexpressed folate receptors (FR). The results indicated that these NPs had strong luminescence and enhanced T2-weighted MR contrast and would be promising candidates as multimodal probes for both fluorescence and MRI imaging.

Testosterone-induced modulation of peroxisomal morphology and peroxisome-related gene expression in brown trout (Salmo trutta f. fario) primary hepatocytes.

PubMed

Lopes, Célia; Malhão, Fernanda; Guimarães, Cláudia; Pinheiro, Ivone; Gonçalves, José F; Castro, L Filipe C; Rocha, Eduardo; Madureira, Tânia V

2017-12-01

Disruption of androgenic signaling has been linked to possible cross-modulation with other hormone-mediated pathways. Therefore, our objective was to explore effects caused by testosterone - T (1, 10 and 50μM) in peroxisomal signaling of brown trout hepatocytes. To study the underlying paths involved, several co-exposure conditions were tested, with flutamide - F (anti-androgen) and ICI 182,780 - ICI (anti-estrogen). Molecular and morphological approaches were both evaluated. Peroxisome proliferator-activated receptor alpha (PPARα), catalase and urate oxidase were the selected targets for gene expression analysis. The vitellogenin A gene was also included as a biomarker of estrogenicity. Peroxisome relative volumes were estimated by immunofluorescence, and transmission electron microscopy was used for qualitative morphological control. The single exposures of T caused a significant down-regulation of urate oxidase (10 and 50μM) and a general up-regulation of vitellogenin. A significant reduction of peroxisome relative volumes and smaller peroxisome profiles were observed at 50μM. Co-administration of T and ICI reversed the morphological modifications and vitellogenin levels. The simultaneous exposure of T and F caused a significant and concentration-dependent diminishing in vitellogenin expression. Together, the findings suggest that in the tested model, T acted via both androgen and estrogen receptors to shape the peroxisomal related targets. Copyright © 2017 Elsevier B.V. All rights reserved.

Metrology Camera System Using Two-Color Interferometry

NASA Technical Reports Server (NTRS)

Dubovitsky, Serge; Liebe, Carl Christian; Peters, Robert; Lay, Oliver

2007-01-01

A metrology system that contains no moving parts simultaneously measures the bearings and ranges of multiple reflective targets in its vicinity, enabling determination of the three-dimensional (3D) positions of the targets with submillimeter accuracy. The system combines a direction-measuring metrology camera and an interferometric range-finding subsystem. Because the system is based partly on a prior instrument denoted the Modulation Sideband Technology for Absolute Ranging (MSTAR) sensor and because of its 3D capability, the system is denoted the MSTAR3D. Developed for use in measuring the shape (for the purpose of compensating for distortion) of large structures like radar antennas, it can also be used to measure positions of multiple targets in the course of conventional terrestrial surveying. A diagram of the system is shown in the figure. One of the targets is a reference target having a known, constant distance with respect to the system. The system comprises a laser for generating local and target beams at a carrier frequency; a frequency shifting unit to introduce a frequency shift offset between the target and local beams; a pair of high-speed modulators that apply modulation to the carrier frequency in the local and target beams to produce a series of modulation sidebands, the highspeed modulators having modulation frequencies of FL and FM; a target beam launcher that illuminates the targets with the target beam; optics and a multipixel photodetector; a local beam launcher that launches the local beam towards the multi-pixel photodetector; a mirror for projecting to the optics a portion of the target beam reflected from the targets, the optics being configured to focus the portion of the target beam at the multi-pixel photodetector; and a signal-processing unit connected to the photodetector. The portion of the target beam reflected from the targets produces spots on the multi-pixel photodetector corresponding to the targets, respectively, and the signal-processing unit centroids the spots to determine bearings of the targets, respectively. As the spots oscillate in intensity because they are mixed with the local laser beam that is flood illuminating the focal plane, the phase of oscillation of each spot is measured, the phase of sidebands in the oscillation of each spot being proportional to a distance to the corresponding target relative to the reference target A.

Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.

PubMed

Jones, Gareth W; McLeod, Louise; Kennedy, Catherine L; Bozinovski, Steven; Najdovska, Meri; Jenkins, Brendan J

2015-02-01

Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F):Stat3(-/+):ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F):ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed. Aortic plaque development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) mice were significantly reduced (3-fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F):ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/-) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) and gp130(F/F):Stat3(-/+):ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F):Stat3(-/+):ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F):ApoE(-/-) (ApoE(F/F:ApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells. Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Development of a self contained heat rejection module, phase 2 and 3

NASA Technical Reports Server (NTRS)

Fleming, M. L.

1976-01-01

The fabrication and testing of a prototype deployable radiator system is described. Vapor compression with a conventional aircraft compressor yielded a net heat rejection effect at high environments while returning low temperature (10 F and 35 F) conditioned fluid to the payload thermal control system. The system is compatible with shuttle orbiter payloads, free flying experiment modules launched from the shuttle, or by another launch vehicle.

Type III CRISPR-Cas systems can provide redundancy to counteract viral escape from type I systems

PubMed Central

Silas, Sukrit; Lucas-Elio, Patricia; Jackson, Simon A; Aroca-Crevillén, Alejandra; Hansen, Loren L; Fineran, Peter C

2017-01-01

CRISPR-Cas-mediated defense utilizes information stored as spacers in CRISPR arrays to defend against genetic invaders. We define the mode of target interference and role in antiviral defense for two CRISPR-Cas systems in Marinomonas mediterranea. One system (type I-F) targets DNA. A second system (type III-B) is broadly capable of acquiring spacers in either orientation from RNA and DNA, and exhibits transcription-dependent DNA interference. Examining resistance to phages isolated from Mediterranean seagrass meadows, we found that the type III-B machinery co-opts type I-F CRISPR-RNAs. Sequencing and infectivity assessments of related bacterial and phage strains suggests an ‘arms race’ in which phage escape from the type I-F system can be overcome through use of type I-F spacers by a horizontally-acquired type III-B system. We propose that the phage-host arms race can drive selection for horizontal uptake and maintenance of promiscuous type III interference modules that supplement existing host type I CRISPR-Cas systems. PMID:28826484

Genome-Wide Identification and Expression of Xenopus F-Box Family of Proteins.

PubMed

Saritas-Yildirim, Banu; Pliner, Hannah A; Ochoa, Angelica; Silva, Elena M

2015-01-01

Protein degradation via the multistep ubiquitin/26S proteasome pathway is a rapid way to alter the protein profile and drive cell processes and developmental changes. Many key regulators of embryonic development are targeted for degradation by E3 ubiquitin ligases. The most studied family of E3 ubiquitin ligases is the SCF ubiquitin ligases, which use F-box adaptor proteins to recognize and recruit target proteins. Here, we used a bioinformatics screen and phylogenetic analysis to identify and annotate the family of F-box proteins in the Xenopus tropicalis genome. To shed light on the function of the F-box proteins, we analyzed expression of F-box genes during early stages of Xenopus development. Many F-box genes are broadly expressed with expression domains localized to diverse tissues including brain, spinal cord, eye, neural crest derivatives, somites, kidneys, and heart. All together, our genome-wide identification and expression profiling of the Xenopus F-box family of proteins provide a foundation for future research aimed to identify the precise role of F-box dependent E3 ubiquitin ligases and their targets in the regulatory circuits of development.

Iron regulatory protein 1 is not required for the modulation of ferritin and transferrin receptor expression by iron in a murine pro-B lymphocyte cell line

PubMed Central

Schalinske, Kevin L.; Blemings, Kenneth P.; Steffen, Daniel W.; Chen, Opal S.; Eisenstein, Richard S.

1997-01-01

Iron regulatory proteins (IRPs) are cytoplasmic RNA binding proteins that are central components of a sensory and regulatory network that modulates vertebrate iron homeostasis. IRPs regulate iron metabolism by binding to iron responsive element(s) (IREs) in the 5′ or 3′ untranslated region of ferritin or transferrin receptor (TfR) mRNAs. Two IRPs, IRP1 and IRP2, have been identified previously. IRP1 exhibits two mutually exclusive functions as an RNA binding protein or as the cytosolic isoform of aconitase. We demonstrate that the Ba/F3 family of murine pro-B lymphocytes represents the first example of a mammalian cell line that fails to express IRP1 protein or mRNA. First, all of the IRE binding activity in Ba/F3-gp55 cells is attributable to IRP2. Second, synthesis of IRP2, but not of IRP1, is detectable in Ba/F3-gp55 cells. Third, the Ba/F3 family of cells express IRP2 mRNA at a level similar to other murine cell lines, but IRP1 mRNA is not detectable. In the Ba/F3 family of cells, alterations in iron status modulated ferritin biosynthesis and TfR mRNA level over as much as a 20- and 14-fold range, respectively. We conclude that IRP1 is not essential for regulation of ferritin or TfR expression by iron and that IRP2 can act as the sole IRE-dependent mediator of cellular iron homeostasis. PMID:9380695

3D surface reconstruction for laparoscopic computer-assisted interventions: comparison of state-of-the-art methods

NASA Astrophysics Data System (ADS)

Groch, A.; Seitel, A.; Hempel, S.; Speidel, S.; Engelbrecht, R.; Penne, J.; Höller, K.; Röhl, S.; Yung, K.; Bodenstedt, S.; Pflaum, F.; dos Santos, T. R.; Mersmann, S.; Meinzer, H.-P.; Hornegger, J.; Maier-Hein, L.

2011-03-01

One of the main challenges related to computer-assisted laparoscopic surgery is the accurate registration of pre-operative planning images with patient's anatomy. One popular approach for achieving this involves intraoperative 3D reconstruction of the target organ's surface with methods based on multiple view geometry. The latter, however, require robust and fast algorithms for establishing correspondences between multiple images of the same scene. Recently, the first endoscope based on Time-of-Flight (ToF) camera technique was introduced. It generates dense range images with high update rates by continuously measuring the run-time of intensity modulated light. While this approach yielded promising results in initial experiments, the endoscopic ToF camera has not yet been evaluated in the context of related work. The aim of this paper was therefore to compare its performance with different state-of-the-art surface reconstruction methods on identical objects. For this purpose, surface data from a set of porcine organs as well as organ phantoms was acquired with four different cameras: a novel Time-of-Flight (ToF) endoscope, a standard ToF camera, a stereoscope, and a High Definition Television (HDTV) endoscope. The resulting reconstructed partial organ surfaces were then compared to corresponding ground truth shapes extracted from computed tomography (CT) data using a set of local and global distance metrics. The evaluation suggests that the ToF technique has high potential as means for intraoperative endoscopic surface registration.

Spatial Tuning Shifts Increase the Discriminability and Fidelity of Population Codes in Visual Cortex

PubMed Central

2017-01-01

Selective visual attention enables organisms to enhance the representation of behaviorally relevant stimuli by altering the encoding properties of single receptive fields (RFs). Yet we know little about how the attentional modulations of single RFs contribute to the encoding of an entire visual scene. Addressing this issue requires (1) measuring a group of RFs that tile a continuous portion of visual space, (2) constructing a population-level measurement of spatial representations based on these RFs, and (3) linking how different types of RF attentional modulations change the population-level representation. To accomplish these aims, we used fMRI to characterize the responses of thousands of voxels in retinotopically organized human cortex. First, we found that the response modulations of voxel RFs (vRFs) depend on the spatial relationship between the RF center and the visual location of the attended target. Second, we used two analyses to assess the spatial encoding quality of a population of voxels. We found that attention increased fine spatial discriminability and representational fidelity near the attended target. Third, we linked these findings by manipulating the observed vRF attentional modulations and recomputing our measures of the fidelity of population codes. Surprisingly, we discovered that attentional enhancements of population-level representations largely depend on position shifts of vRFs, rather than changes in size or gain. Our data suggest that position shifts of single RFs are a principal mechanism by which attention enhances population-level representations in visual cortex. SIGNIFICANCE STATEMENT Although changes in the gain and size of RFs have dominated our view of how attention modulates visual information codes, such hypotheses have largely relied on the extrapolation of single-cell responses to population responses. Here we use fMRI to relate changes in single voxel receptive fields (vRFs) to changes in population-level representations. We find that vRF position shifts contribute more to population-level enhancements of visual information than changes in vRF size or gain. This finding suggests that position shifts are a principal mechanism by which spatial attention enhances population codes for relevant visual information. This poses challenges for labeled line theories of information processing, suggesting that downstream regions likely rely on distributed inputs rather than single neuron-to-neuron mappings. PMID:28242794

Loss of Cbl-PI3K Interaction Modulates the Periosteal Response to Fracture by Enhancing Osteogenic Commitment and Differentiation

PubMed Central

Scanlon, Vanessa; Walia, Bhavita; Yu, Jungeun; Hansen, Marc; Drissi, Hicham; Maye, Peter; Sanjay, Archana

2018-01-01

The periosteum contains multipotent skeletal progenitors that contribute to bone repair. The signaling pathways regulating the response of periosteal cells to fracture are largely unknown. Phosphatidylinositol-3 Kinase (PI3K), a prominent lipid kinase, is a major signaling protein downstream of several factors that regulate osteoblast differentiation. Cbl is an E3 ubiquitin ligase and a major adaptor protein that binds to the p85 regulatory subunit and modulates PI3K activity. Substitution of tyrosine 737 to phenylalanine (Y737F) in Cbl abolishes the interaction between Cbl and the p85 subunit without affecting the Cbl’s ubiquitin ligase function. Here, we investigated the role of PI3K signaling during the very early stages of fracture healing using OsterixRFP reporter mice. We found that the absence of PI3K regulation by Cbl resulted in robust periosteal thickening, with increased proliferation of periosteal cells. While the multipotent properties of periosteal progenitors to differentiate into chondrocytes and adipocytes did not change, osteogenic differentiation in the absence of Cbl-PI3K interaction was highly augmented. The increased stability and nuclear localization of Osterix observed in periosteal cells lacking Cbl-PI3K interaction may explain this enhanced osteogenic differentiation since the expression of Osterix transcriptional target genes including osteocalcin and BSP are increased in YF cells. Overall, our findings highlight a hitherto unexplored and novel role for Cbl and PI3K in modulating the osteogenic response of periosteal cells during the early stages of fracture repair. PMID:27884787

Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation.

PubMed

Scanlon, Vanessa; Walia, Bhavita; Yu, Jungeun; Hansen, Marc; Drissi, Hicham; Maye, Peter; Sanjay, Archana

2017-02-01

The periosteum contains multipotent skeletal progenitors that contribute to bone repair. The signaling pathways regulating the response of periosteal cells to fracture are largely unknown. Phosphatidylinositol-3 Kinase (PI3K), a prominent lipid kinase, is a major signaling protein downstream of several factors that regulate osteoblast differentiation. Cbl is an E3 ubiquitin ligase and a major adaptor protein that binds to the p85 regulatory subunit and modulates PI3K activity. Substitution of tyrosine 737 to phenylalanine (Y737F) in Cbl abolishes the interaction between Cbl and p85 subunit without affecting the Cbl's ubiquitin ligase function. Here, we investigated the role of PI3K signaling during the very early stages of fracture healing using Osterix RFP reporter mice. We found that the absence of PI3K regulation by Cbl resulted in robust periosteal thickening, with increased proliferation of periosteal cells. While the multipotent properties of periosteal progenitors to differentiate into chondrocytes and adipocytes did not change, osteogenic differentiation in the absence of Cbl-PI3K interaction was highly augmented. The increased stability and nuclear localization of Osterix observed in periosteal cells lacking Cbl-PI3K interaction may explain this enhanced osteogenic differentiation since the expression of Osterix transcriptional target genes including osteocalcin and BSP are increased in YF cells. Overall, our findings highlight a hitherto unexplored and novel role for Cbl and PI3K in modulating the osteogenic response of periosteal cells during the early stages of fracture repair. Copyright © 2016 Elsevier Inc. All rights reserved.

Selenium nanoparticles prevents lead acetate-induced hypothyroidism and oxidative damage of thyroid tissues in male rats through modulation of selenoenzymes and suppression of miR-224.

PubMed

Atteia, Hebatallah Husseini; Arafa, Manar Hamed; Prabahar, Kousalya

2018-03-01

Selenium nanoparticles (Se-NPs) are customizable drug delivery vehicles that show good bioavailability, higher efficacy and lower toxicity than ordinary Se. Pre-treatment of male rats with these NPs has been recently shown to exert a protective effect against chromium-induced thyroid dysfunction. This study, therefore, aimed to investigate and characterize the potential protective mechanism of Se-NPs against lead (Pb) acetate-induced thyrotoxicity. We found that prophylactic and concurrent treatment of Pb acetate-exposed rats with Nano-Se (0.5 mg/kg, i.p) for 15 wk significantly alleviated the decrease in free triiodothyronine (fT3) and free thyroxine (fT4) levels as well as fT3/fT4 ratio% and the increase in thyroid stimulating hormone (TSH) levels to approach control values. This was accompanied by a reduction in the accumulation of Pb in serum and thyroid tissues as well as maintenance of thyroidal pro-oxidant/antioxidant balance and iodothyronine deiodinase type 1 (ID1), an essential enzyme for metabolizing of T4 into active T3, gene expression. Surprisingly, miR-224, a direct complementary target of ID1 mRNA, expression in the thyroid tissues was significantly down-regulated in Nano-Se-pre- and co-treated Pb acetate intoxicated animals. Such changes in miR-224 expression were negatively correlated with the changes in ID1 gene expression and serum fT3 level. These results suggest that Se-NPs can rescue from Pb-induced impairment of thyroid function through the maintenance of selenoproteins and down-regulation of miR-224. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics | Office of Cancer Genomics

Cancer.gov

High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics.

Ganoderma lucidum polysaccharides in human monocytic leukemia cells: from gene expression to network construction

PubMed Central

Cheng, Kun-Chieh; Huang, Hsuan-Cheng; Chen, Jenn-Han; Hsu, Jia-Wei; Cheng, Hsu-Chieh; Ou, Chern-Han; Yang, Wen-Bin; Chen, Shui-Tein; Wong, Chi-Huey; Juan, Hsueh-Fen

2007-01-01

Background Ganoderma lucidum has been widely used as a herbal medicine for promoting health and longevity in China and other Asian countries. Polysaccharide extracts from Ganoderma lucidum have been reported to exhibit immuno-modulating and anti-tumor activities. In previous studies, F3, the active component of the polysaccharide extract, was found to activate various cytokines such as IL-1, IL-6, IL-12, and TNF-α. This gave rise to our investigation on how F3 stimulates immuno-modulating or anti-tumor effects in human leukemia THP-1 cells. Results Here, we integrated time-course DNA microarray analysis, quantitative PCR assays, and bioinformatics methods to study the F3-induced effects in THP-1 cells. Significantly disturbed pathways induced by F3 were identified with statistical analysis on microarray data. The apoptosis induction through the DR3 and DR4/5 death receptors was found to be one of the most significant pathways and play a key role in THP-1 cells after F3 treatment. Based on time-course gene expression measurements of the identified pathway, we reconstructed a plausible regulatory network of the involved genes using reverse-engineering computational approach. Conclusion Our results showed that F3 may induce death receptor ligands to initiate signaling via receptor oligomerization, recruitment of specialized adaptor proteins and activation of caspase cascades. PMID:17996095

Ganoderma lucidum polysaccharides in human monocytic leukemia cells: from gene expression to network construction.

PubMed

Cheng, Kun-Chieh; Huang, Hsuan-Cheng; Chen, Jenn-Han; Hsu, Jia-Wei; Cheng, Hsu-Chieh; Ou, Chern-Han; Yang, Wen-Bin; Chen, Shui-Tein; Wong, Chi-Huey; Juan, Hsueh-Fen

2007-11-09

Ganoderma lucidum has been widely used as a herbal medicine for promoting health and longevity in China and other Asian countries. Polysaccharide extracts from Ganoderma lucidum have been reported to exhibit immuno-modulating and anti-tumor activities. In previous studies, F3, the active component of the polysaccharide extract, was found to activate various cytokines such as IL-1, IL-6, IL-12, and TNF-alpha. This gave rise to our investigation on how F3 stimulates immuno-modulating or anti-tumor effects in human leukemia THP-1 cells. Here, we integrated time-course DNA microarray analysis, quantitative PCR assays, and bioinformatics methods to study the F3-induced effects in THP-1 cells. Significantly disturbed pathways induced by F3 were identified with statistical analysis on microarray data. The apoptosis induction through the DR3 and DR4/5 death receptors was found to be one of the most significant pathways and play a key role in THP-1 cells after F3 treatment. Based on time-course gene expression measurements of the identified pathway, we reconstructed a plausible regulatory network of the involved genes using reverse-engineering computational approach. Our results showed that F3 may induce death receptor ligands to initiate signaling via receptor oligomerization, recruitment of specialized adaptor proteins and activation of caspase cascades.

Ada Compiler Validation Summary Report. Certificate Number: 920918S1. 11273 U.S. Navy, Ada/M, Version 4.5 /OPTIMIZE) VAX 8550/8600/8650 (Cluster) = VHSIC Processor Module (VPM) AN/AYK-14 (Bare Board)

DTIC Science & Technology

1992-10-27

Module (VPM) AN/AYK-14 (Bare Board) (target), 920918S1.11273 6. AUTHOR(S) National Institute of Standards and Technology Gaithersburg, MD USA 7 ...Validation Procedures (Pro90] against the Ada Standard (Ada83] using the current Ada Compiler Validation Capability (ACVC). This Validation Summary Report ( VSR ...l..V-20 => ’ $MAXLENINTBASEDLITERAL "-Ŗ:" & (l..V-5 1> 𔃺’) & ൓:" $MAXLENREALBASEDLITERAL ൘:" & (i..V- 7 => 𔃺’) & "F.E:" $MAXSTRINGLITERAL

Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition.

PubMed

Kawashima, Mitsuhiko; Ariji, Takaki; Kameoka, Satoru; Ueda, Takashi; Kohno, Ryosuke; Nishio, Teiji; Arahira, Satoko; Motegi, Atsushi; Zenda, Sadamoto; Akimoto, Tetsuo; Tahara, Makoto; Hayashi, Ryuichi

2013-12-01

The objective of the study was to evaluate locoregional control after intensity-modulated radiotherapy for nasopharyngeal cancer using a target definition along with anatomical boundaries. Forty patients with biopsy-proven squamous cell or non-keratinizing carcinoma of the nasopharynx who underwent intensity-modulated radiotherapy between April 2006 and November 2009 were reviewed. There were 10 females and 30 males with a median age of 48 years (range, 17-74 years). More than half of the patients had T3/4 (n = 21) and/or N2/3 (n = 24) disease. Intensity-modulated radiotherapy was administered as 70 Gy/33 fractions with or without concomitant chemotherapy. The clinical target volume was contoured along with muscular fascia or periosteum, and the prescribed radiotherapy dose was determined for each anatomical compartment and lymph node level in the head and neck. One local recurrence was observed at Meckel's cave on the periphery of the high-risk clinical target volume receiving a total dose of <63 Gy. Otherwise, six locoregional failures were observed within irradiated volume receiving 70 Gy. Local and nodal control rates at 3 years were 91 and 89%, respectively. Adverse events were acceptable, and 25 (81%) of 31 patients who were alive without recurrence at 2 years had xerostomia of ≤Grade 1. The overall survival rate at 3 years was 87%. Target definition along with anatomically defined boundaries was feasible without compromise of the therapeutic ratio. It is worth testing this method further to minimize the unnecessary irradiated volume and to standardize the target definition in intensity-modulated radiotherapy for nasopharyngeal cancer.

EBP1 is a novel E2F target gene regulated by transforming growth factor-β.

PubMed

Judah, David; Chang, Wing Y; Dagnino, Lina

2010-11-10

Regulation of gene expression requires transcription factor binding to specific DNA elements, and a large body of work has focused on the identification of such sequences. However, it is becoming increasingly clear that eukaryotic transcription factors can exhibit widespread, nonfunctional binding to genomic DNA sites. Conversely, some of these proteins, such as E2F, can also modulate gene expression by binding to non-consensus elements. E2F comprises a family of transcription factors that play key roles in a wide variety of cellular functions, including survival, differentiation, activation during tissue regeneration, metabolism, and proliferation. E2F factors bind to the Erb3-binding protein 1 (EBP1) promoter in live cells. We now show that E2F binding to the EBP1 promoter occurs through two tandem DNA elements that do not conform to typical consensus E2F motifs. Exogenously expressed E2F1 activates EBP1 reporters lacking one, but not both sites, suggesting a degree of redundancy under certain conditions. E2F1 increases the levels of endogenous EBP1 mRNA in breast carcinoma and other transformed cell lines. In contrast, in non-transformed primary epidermal keratinocytes, E2F, together with the retinoblastoma family of proteins, appears to be involved in decreasing EBP1 mRNA abundance in response to growth inhibition by transforming growth factor-β1. Thus, E2F is likely a central coordinator of multiple responses that culminate in regulation of EBP1 gene expression, and which may vary depending on cell type and context.

Automated synthesis of N-(2-[18 F]Fluoropropionyl)-l-glutamic acid as an amino acid tracer for tumor imaging on a modified [18 F]FDG synthesis module.

PubMed

Liu, Shaoyu; Sun, Aixia; Zhang, Zhanwen; Tang, Xiaolan; Nie, Dahong; Ma, Hui; Jiang, Shende; Tang, Ganghua

2017-06-15

N-(2-[ 18 F]Fluoropropionyl)-l-glutamic acid ([ 18 F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [ 18 F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [ 18 F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2-step on-column hydrolysis procedure, including 18 F-fluorination and on-column hydrolysis reaction. [ 18 F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [ 18 F]fluoride using the tosylated precursor 2. The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [ 18 F]FPGLU, a brominated precursor 3 was also used for the preparation of [ 18 F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on-column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module. Copyright © 2017 John Wiley & Sons, Ltd.

Mutations in the Cytoplasmic Domain of the Newcastle Disease Virus Fusion Protein Confer Hyperfusogenic Phenotypes Modulating Viral Replication and Pathogenicity

PubMed Central

Samal, Sweety; Khattar, Sunil K.; Paldurai, Anandan; Palaniyandi, Senthilkumar; Zhu, Xiaoping; Collins, Peter L.

2013-01-01

The Newcastle disease virus (NDV) fusion protein (F) mediates fusion of viral and host cell membranes and is a major determinant of NDV pathogenicity. In the present study, we demonstrate the effects of functional properties of F cytoplasmic tail (CT) amino acids on virus replication and pathogenesis. Out of a series of C-terminal deletions in the CT, we were able to rescue mutant viruses lacking two or four residues (rΔ2 and rΔ4). We further rescued viral mutants with individual amino acid substitutions at each of these four terminal residues (rM553A, rK552A, rT551A, and rT550A). In addition, the NDV F CT has two conserved tyrosine residues (Y524 and Y527) and a dileucine motif (LL536-537). In other paramyxoviruses, these residues were shown to affect fusion activity and are central elements in basolateral targeting. The deletion of 2 and 4 CT amino acids and single tyrosine substitution resulted in hyperfusogenic phenotypes and increased viral replication and pathogenesis. We further found that in rY524A and rY527A viruses, disruption of the targeting signals did not reduce the expression on the apical or basolateral surface in polarized Madin-Darby canine kidney cells, whereas in double tyrosine mutant, it was reduced on both the apical and basolateral surfaces. Interestingly, in rL536A and rL537A mutants, the F protein expression was more on the apical than on the basolateral surface, and this effect was more pronounced in the rL537A mutant. We conclude that these wild-type residues in the NDV F CT have an effect on regulating F protein biological functions and thus modulating viral replication and pathogenesis. PMID:23843643

Mutations in the cytoplasmic domain of the Newcastle disease virus fusion protein confer hyperfusogenic phenotypes modulating viral replication and pathogenicity.

PubMed

Samal, Sweety; Khattar, Sunil K; Paldurai, Anandan; Palaniyandi, Senthilkumar; Zhu, Xiaoping; Collins, Peter L; Samal, Siba K

2013-09-01

The Newcastle disease virus (NDV) fusion protein (F) mediates fusion of viral and host cell membranes and is a major determinant of NDV pathogenicity. In the present study, we demonstrate the effects of functional properties of F cytoplasmic tail (CT) amino acids on virus replication and pathogenesis. Out of a series of C-terminal deletions in the CT, we were able to rescue mutant viruses lacking two or four residues (rΔ2 and rΔ4). We further rescued viral mutants with individual amino acid substitutions at each of these four terminal residues (rM553A, rK552A, rT551A, and rT550A). In addition, the NDV F CT has two conserved tyrosine residues (Y524 and Y527) and a dileucine motif (LL536-537). In other paramyxoviruses, these residues were shown to affect fusion activity and are central elements in basolateral targeting. The deletion of 2 and 4 CT amino acids and single tyrosine substitution resulted in hyperfusogenic phenotypes and increased viral replication and pathogenesis. We further found that in rY524A and rY527A viruses, disruption of the targeting signals did not reduce the expression on the apical or basolateral surface in polarized Madin-Darby canine kidney cells, whereas in double tyrosine mutant, it was reduced on both the apical and basolateral surfaces. Interestingly, in rL536A and rL537A mutants, the F protein expression was more on the apical than on the basolateral surface, and this effect was more pronounced in the rL537A mutant. We conclude that these wild-type residues in the NDV F CT have an effect on regulating F protein biological functions and thus modulating viral replication and pathogenesis.

Perceptual load modulates anterior cingulate cortex response to threat distractors in generalized social anxiety disorder.

PubMed

Wheaton, Michael G; Fitzgerald, Daniel A; Phan, K Luan; Klumpp, Heide

2014-09-01

Generalized social anxiety disorder (gSAD) is associated with impoverished anterior cingulate cortex (ACC) engagement during attentional control. Attentional Control Theory proposes such deficiencies may be offset when demands on resources are increased to execute goals. To test the hypothesis attentional demands affect ACC response 23 patients with gSAD and 24 matched controls performed an fMRI task involving a target letter in a string of identical targets (low load) or a target letter in a mixed letter string (high load) superimposed on fearful, angry, and neutral face distractors. Regardless of load condition, groups were similar in accuracy and reaction time. Under low load gSAD patients showed deficient rostral ACC recruitment to fearful (vs. neutral) distractors. For high load, increased activation to fearful (vs. neutral) distractors was observed in gSAD suggesting a compensatory function. Results remained after controlling for group differences in depression level. Findings indicate perceptual demand modulates ACC in gSAD. Copyright © 2014 Elsevier B.V. All rights reserved.

Center-of-gravity effects in the perception of high front vowels

NASA Astrophysics Data System (ADS)

Jacewicz, Ewa; Feth, Lawrence L.

2002-05-01

When two formant peaks are close in frequency, changing their amplitude ratio can shift the perceived vowel quality. This center-of-gravity effect (COG) was studied particularly in back vowels whose F1 and F2 are close in frequency. Chistovich and Lublinskaja (1979) show that the effect occurs when the frequency separation between the formants does not exceed 3.5 bark. The COG and critical distance effects were manifested when a two-formant reference signal was matched by a single-formant target of variable frequency. This study investigates whether the COG effect extends to closely spaced higher formants as in English /i/ and /I/. In /i/, the frequency separation between F2, F3, and F4 does not exceed 3.5 bark, suggesting the existence of one COG which may affect all three closely spaced formants (F2=2030, F3=2970, F4=3400 Hz). In /I/, each of the F2-F3 and F3-F4 separations is less than 3.5 bark but the F2-F4 separation exceeds the critical distance, indicating two COGs (F2=1780, F3=2578, F4=3400 Hz). We examine the COG effects using matching of four-formant reference signals, in which we change the amplitude ratios, by two-formant targets with variable frequency of F2. The double-staircase adaptive procedure is used. [Work supported by an INRS award from NIH to R. Fox.

STS-79 CREW COMMANDER WILLIAM F. READDY AT PAD 39A FOR TCDT

NASA Technical Reports Server (NTRS)

1996-01-01

With the Space Shuttle Atlantis as a backdrop, STS-79 Commander William F. Readdy answers questions posed by reporters at Launch Pad 39A. Readdy and the other five members of the STS-79 crew, Pilot Terrence W. Wilcutt and Mission Specialists Jay Apt, Carl E. Walz, Tom Akers, and John E. Blaha, are at KSC for the Terminal Countdown Demonstration Test (TCDT), a dress rehearsal for the launch targeted for mid-September. STS-79 will be the fourth Shuttle-Mir docking and the first flight of the SPACEHAB Double Module.

Superspace description of wagnerite-group minerals (Mg,Fe,Mn)2(PO4)(F,OH)

PubMed Central

Lazic, Biljana; Armbruster, Thomas; Chopin, Christian; Grew, Edward S.; Baronnet, Alain; Palatinus, Lukas

2014-01-01

Reinvestigation of more than 40 samples of minerals belonging to the wagnerite group (Mg, Fe, Mn)2(PO4)(F,OH) from diverse geological environments worldwide, using single-crystal X-ray diffraction analysis, showed that most crystals have incommensurate structures and, as such, are not adequately described with known polytype models (2b), (3b), (5b), (7b) and (9b). Therefore, we present here a unified superspace model for the structural description of periodically and aperiodically modulated wagnerite with the (3+1)-dimensional superspace group C2/c(0β0)s0 based on the average triplite structure with cell parameters a ≃ 12.8, b ≃ 6.4, c ≃ 9.6 Å, β ≃ 117° and the modulation vectors q = β b*. The superspace approach provides a way of simple modelling of the positional and occupational modulation of Mg/Fe and F/OH in wagnerite. This allows direct comparison of crystal properties. PMID:24675594

Doppler-Only Synthetic Aperture Radar

DTIC Science & Technology

2006-12-01

5 B. TARGET RECOGNITION TECHNIQUES .................................................6 1. Cooperative Targets...6 3. Techniques ............................................................................................6 C. TARGET RECOGNITION...3. Implementation of High Range Resolution Techniques .................12 F. TWO-DIMENSIONAL IMAGING

Conversion coefficients for determination of dispersed photon dose during radiotherapy: NRUrad input code for MCNP.

PubMed

Shahmohammadi Beni, Mehrdad; Ng, C Y P; Krstic, D; Nikezic, D; Yu, K N

2017-01-01

Radiotherapy is a common cancer treatment module, where a certain amount of dose will be delivered to the targeted organ. This is achieved usually by photons generated by linear accelerator units. However, radiation scattering within the patient's body and the surrounding environment will lead to dose dispersion to healthy tissues which are not targets of the primary radiation. Determination of the dispersed dose would be important for assessing the risk and biological consequences in different organs or tissues. In the present work, the concept of conversion coefficient (F) of the dispersed dose was developed, in which F = (Dd/Dt), where Dd was the dispersed dose in a non-targeted tissue and Dt is the absorbed dose in the targeted tissue. To quantify Dd and Dt, a comprehensive model was developed using the Monte Carlo N-Particle (MCNP) package to simulate the linear accelerator head, the human phantom, the treatment couch and the radiotherapy treatment room. The present work also demonstrated the feasibility and power of parallel computing through the use of the Message Passing Interface (MPI) version of MCNP5.

Conversion coefficients for determination of dispersed photon dose during radiotherapy: NRUrad input code for MCNP

PubMed Central

Krstic, D.; Nikezic, D.

2017-01-01

Radiotherapy is a common cancer treatment module, where a certain amount of dose will be delivered to the targeted organ. This is achieved usually by photons generated by linear accelerator units. However, radiation scattering within the patient’s body and the surrounding environment will lead to dose dispersion to healthy tissues which are not targets of the primary radiation. Determination of the dispersed dose would be important for assessing the risk and biological consequences in different organs or tissues. In the present work, the concept of conversion coefficient (F) of the dispersed dose was developed, in which F = (Dd/Dt), where Dd was the dispersed dose in a non-targeted tissue and Dt is the absorbed dose in the targeted tissue. To quantify Dd and Dt, a comprehensive model was developed using the Monte Carlo N-Particle (MCNP) package to simulate the linear accelerator head, the human phantom, the treatment couch and the radiotherapy treatment room. The present work also demonstrated the feasibility and power of parallel computing through the use of the Message Passing Interface (MPI) version of MCNP5. PMID:28362837

Dual integrin and gastrin-releasing peptide receptor targeted tumor imaging using 18F-labeled PEGylated RGD-bombesin heterodimer 18F-FB-PEG3-Glu-RGD-BBN.

PubMed

Liu, Zhaofei; Yan, Yongjun; Chin, Frederic T; Wang, Fan; Chen, Xiaoyuan

2009-01-22

Radiolabeled RGD and bombesin peptides have been extensively investigated for tumor integrin alpha(v)beta(3) and GRPR imaging, respectively. Due to the fact that many tumors are both integrin and GRPR positive, we designed and synthesized a heterodimeric peptide Glu-RGD-BBN, which is expected to be advantageous over the monomeric peptides for dual-receptor targeting. A PEG(3) spacer was attached to the glutamate alpha-amino group of Glu-RGD-BBN to enhance the (18)F labeling yield and to improve the in vivo kinetics. PEG(3)-Glu-RGD-BBN possesses the comparable GRPR and integrin alpha(v)beta(3) receptor-binding affinities as the corresponding monomers, respectively. The dual-receptor targeting properties of (18)F-FB-PEG(3)-Glu-RGD-BBN were observed in PC-3 tumor model. (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging. This heterodimer strategy may also be an applicable method to develop other molecules with improved in vitro and in vivo characterizations for tumor diagnosis and therapy.

Informatics-Aided Density Functional Theory Study on the Li Ion Transport of Tavorite-Type LiMTO4F (M(3+)-T(5+), M(2+)-T(6+)).

PubMed

Jalem, Randy; Kimura, Mayumi; Nakayama, Masanobu; Kasuga, Toshihiro

2015-06-22

The ongoing search for fast Li-ion conducting solid electrolytes has driven the deployment surge on density functional theory (DFT) computation and materials informatics for exploring novel chemistries before actual experimental testing. Existing structure prototypes can now be readily evaluated beforehand not only to map out trends on target properties or for candidate composition selection but also for gaining insights on structure-property relationships. Recently, the tavorite structure has been determined to be capable of a fast Li ion insertion rate for battery cathode applications. Taking this inspiration, we surveyed the LiMTO4F tavorite system (M(3+)-T(5+) and M(2+)-T(6+) pairs; M is nontransition metals) for solid electrolyte use, identifying promising compositions with enormously low Li migration energy (ME) and understanding how structure parameters affect or modulate ME. We employed a combination of DFT computation, variable interaction analysis, graph theory, and a neural network for building a crystal structure-based ME prediction model. Candidate compositions that were predicted include LiGaPO4F (0.25 eV), LiGdPO4F (0.30 eV), LiDyPO4F (0.30 eV), LiMgSO4F (0.21 eV), and LiMgSeO4F (0.11 eV). With chemical substitutions at M and T sites, competing effects among Li pathway bottleneck size, polyanion covalency, and local lattice distortion were determined to be crucial for controlling ME. A way to predict ME for multiple structure types within the neural network framework was also explored.

SU-F-T-186: A Treatment Planning Study of Normal Tissue Sparing with Robustness Optimized IMPT, 4Pi IMRT, and VMAT for Head and Neck Cases

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

Zhang, J; Li, X; Ding, X

Purpose: We performed a retrospective dosimetric comparison study between the robustness optimized Intensity Modulated Proton Therapy (RO-IMPT), volumetric-modulated arc therapy (VMAT), and the non-coplanar 4? intensity modulated radiation therapy (IMRT). These methods represent the most advanced radiation treatment methods clinically available. We compare their dosimetric performance for head and neck cancer treatments with special focus on the OAR sparing near the tumor volumes. Methods: A total of 11 head and neck cases, which include 10 recurrent cases and one bilateral case, were selected for the study. Different dose levels were prescribed to tumor target depending on disease and location. Threemore » treatment plans were created on commercial TPS systems for a novel noncoplanar 4π method (20 beams), VMAT, and RO-IMPT technique (maximum 4 fields). The maximum patient positioning error was set to 3 mm and the maximum proton range uncertainty was set to 3% for the robustness optimization. Line dose profiles were investigated for OARs close to tumor volumes. Results: All three techniques achieved 98% coverage of the CTV target and most photon plans had less than 110% of the hot spots. The RO-IMPT plans show superior tumor dose homogeneity than 4? and VMAT plans. Although RO-IMPT has greater R50 dose spillage to the surrounding normal tissue than 4π and VMAT, the RO-IMPT plans demonstrate better or comparable OAR (parotid, mandible, carotid, oral cavity, pharynx, and etc.) sparing for structures closely abutting tumor targets. Conclusion: The RO-IMPT’s ability of OAR sparing is benchmarked against the C-arm linac based non-coplanar 4π technique and the standard VMAT method. RO-IMPT consistently shows better or comparable OAR sparing even for tissue structures closely abutting treatment target volume. RO-IMPT further reduces treatment uncertainty associated with proton therapy and delivers robust treatment plans to both unilateral and bilateral head and neck cancer patients with desirable treatment time.« less

N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection.

PubMed

Jagdeo, Julienne M; Dufour, Antoine; Klein, Theo; Solis, Nestor; Kleifeld, Oded; Kizhakkedathu, Jayachandran; Luo, Honglin; Overall, Christopher M; Jan, Eric

2018-04-15

Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative in vitro proteomics-based approach, termed t erminal a mine i sotopic l abeling of s ubstrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3C pro s) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3C pro in vitro including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3C pro -targeted substrates were also cleaved in virus-infected cells but not noncleavable mutant proteins designed from the TAILS-identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3C pro promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3C pro substrates in vivo , we conclude that N-terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner. IMPORTANCE Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection. Although several host protein targets have been identified, the entire list of proteins that are targeted is not known. In this study, we used a novel unbiased proteomics approach to identify ∼100 novel host targets of the enterovirus 3C protease, thus providing further insights into the network of cellular pathways that are modulated to promote virus infection. Copyright © 2018 Jagdeo et al.

The Organization of the Suprachiasmatic Circadian Pacemaker of the Rat and Its Regulation by Neurotransmitters and Modulators

DTIC Science & Technology

1994-02-02

This clock, located in the brain’s suprachiasmatic nucleus (SCN), can be removed in a slice of hypothalamus, main- tained in a. lite support system...slice of hypothalamus, main- 10> tamned in a lite support system for up to 3 days and studied directly. Using this approach, W.. progress in the 3 112...Wmtz .I’’’f’: A.. wklfIfif cm N.. ffttf:T _ ’I.. ’Af.f-:\\f’:f/. IL & Vrf -:fKE It (IMS31 tff’fa/ifft ’if1\\ lhi/ll ff10 1’’ ) imfii/f’/ftfif/f f/f/ill/i!i

The Challenges in Meeting OSD’s Obligation and Expenditure Rate Goals: A Closer Look at Potential Causal Factors, Their Groupings, and How They Modulate

DTIC Science & Technology

2013-10-01

F22 Defense Contract Audit Agency (DCAA) administrative actions 44% 3.92 2.61 F23 Unplanned Congressional adds to Program Baseline (PB) request 43...materialized F21 Program delays from prerequisite events F22 DCAA administrative actions F23 Unplanned Congressional adds to PB request F24...functional areas (F27) and Tenure of PM and others in key positions (F46); and DCMA administrative actions (F36) and DCAA administrative actions ( F22

Separation negatives from Kodak film types SO-368 and SO-242

NASA Technical Reports Server (NTRS)

Weinstein, M. S.

1972-01-01

Two master resolution friskets were produced on Kodak film types SO-368 and SO-242. These target masters consisted of 21 density steps with three-bar resolution targets at five modulation levels within each step. The target masters were contact printed onto Kodak separation negative film, type 4131, using both a contact printing frame and enlarger as one method of exposure, and a Miller-Holzwarth contact printer as the other exposing device. Red, green, and blue Wratten filters were used to filter the exposing source. Tray processing was done with DK-50 developer diluted 1:2 at a temperature of 70 F. The resolution values were read for the SO-368 and SO-242 target masters, and the red, green, and blue separation negatives.

Surface-state depopulation on small Ag(111) terraces.

PubMed

Morgenstern, Karina; Braun, Kai-Felix; Rieder, Karl-Heinz

2002-11-25

The dependence of the local density of states near the Fermi energy E(F) on the width of terraces T is investigated by tunneling scanning spectroscopy on Ag(111) at 7 K. With decreasing T, the electronic density in the occupied surface state shifts monotonically towards E(F), leading to a depopulation at T=3.2 nm in quantitative agreement with a Fabry-Pérot model. Depopulation coincides with a switch from confinement by terrace modulation to step modulation.

MiR-34a Inhibits Viability and Invasion of Human Papillomavirus-Positive Cervical Cancer Cells by Targeting E2F3 and Regulating Survivin.

PubMed

Geng, Dianzhong; Song, Xiaohua; Ning, Fangling; Song, Qianhua; Yin, Honghua

2015-05-01

Previous studies confirmed that high-risk human papillomavirus (HR-HPV) infection is a risk factor of cervical cancer, and the infection was associated with significantly reduced miR-34a expression during carcinogenesis. However, the downstream targets of miR-34a and their roles are still not well understood. This study explored the regulative role of miR-34a on E2F3 and survivin expression and the viability and invasion of HPV-positive cervical cancer cells. MiR-34a and survivin expression in 56 cases of HR-HPV-positive patients, 28 cases of HR-HPV-negative patients, and 28 normal cases without HR-HPV infections were measured. Human papillomavirus-18-positive HeLa cervical cancer cells and HPV-16-positive SiHa cells were used to explore the effect of miR-34a on cell viability and invasion. The molecular target of miR-34a was also explored in cervical cancer cells. The results showed that miR-34a overexpression could inhibit HPV-positive cancer cell viability, whereas its downregulation promoted cell viability. E2F3 is a direct target of miR-34a in HPV-positive cervical cancer cells. By targeting E2F3, miR-34a could regulate the expression of survivin. Thus, through regulating E2F3 and survivin, miR-34a could reduce the viability and invasion of HPV-positive cervical cancer cells. This study confirmed a novel miR-34a-E2F3-survivin axis in the tumor suppressor role of miR-34a in cervical cancer.

You prime what you code: The fAIM model of priming of pop-out

PubMed Central

Meeter, Martijn

2017-01-01

Our visual brain makes use of recent experience to interact with the visual world, and efficiently select relevant information. This is exemplified by speeded search when target- and distractor features repeat across trials versus when they switch, a phenomenon referred to as intertrial priming. Here, we present fAIM, a computational model that demonstrates how priming can be explained by a simple feature-weighting mechanism integrated into an established model of bottom-up vision. In fAIM, such modulations in feature gains are widespread and not just restricted to one or a few features. Consequentially, priming effects result from the overall tuning of visual features to the task at hand. Such tuning allows the model to reproduce priming for different types of stimuli, including for typical stimulus dimensions such as ‘color’ and for less obvious dimensions such as ‘spikiness’ of shapes. Moreover, the model explains some puzzling findings from the literature: it shows how priming can be found for target-distractor stimulus relations rather than for their absolute stimulus values per se, without an explicit representation of relations. Similarly, it simulates effects that have been taken to reflect a modulation of priming by an observers’ goals—without any representation of goals in the model. We conclude that priming is best considered as a consequence of a general adaptation of the brain to visual input, and not as a peculiarity of visual search. PMID:29166386

STERILE APETALA modulates the stability of a repressor protein complex to control organ size in Arabidopsis thaliana

PubMed Central

Wang, Zhibiao; Ru, Licong; Baekelandt, Alexandra; Goossens, Alain; Xu, Ran; Zhu, Zhengge; Inzé, Dirk; Li, Yunhai

2018-01-01

Organ size control is of particular importance for developmental biology and agriculture, but the mechanisms underlying organ size regulation remain elusive in plants. Meristemoids, which possess stem cell-like properties, have been recognized to play important roles in leaf growth. We have recently reported that the Arabidopsis F-box protein STERILE APETALA (SAP)/SUPPRESSOR OF DA1 (SOD3) promotes meristemoid proliferation and regulates organ size by influencing the stability of the transcriptional regulators PEAPODs (PPDs). Here we demonstrate that KIX8 and KIX9, which function as adaptors for the corepressor TOPLESS and PPD, are novel substrates of SAP. SAP interacts with KIX8/9 and modulates their protein stability. Further results show that SAP acts in a common pathway with KIX8/9 and PPD to control organ growth by regulating meristemoid cell proliferation. Thus, these findings reveal a molecular mechanism by which SAP targets the KIX-PPD repressor complex for degradation to regulate meristemoid cell proliferation and organ size. PMID:29401459

Rationale and design of dal-PLAQUE: A study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography

PubMed Central

Fayad, Zahi A.; Mani, Venkatesh; Woodward, Mark; Kallend, David; Bansilal, Sameer; Pozza, Joseph; Burgess, Tracy; Fuster, Valentin; Rudd, James H. F.; Tawakol, Ahmed; Farkouh, Michael E.

2014-01-01

dal-PLAQUE is a placebo-controlled multicenter study designed to assess the effect of dalcetrapib on imaging measures of plaque inflammation and plaque burden. dal-PLAQUE is a multimodality imaging study in the context of the large dal-HEART Program. Decreased high-density lipoprotein cholesterol is linked to increased risk of coronary heart disease (CHD). Dalcetrapib, a compound that increases high-density lipoprotein cholesterol by modulating cholesteryl ester transfer protein, is being studied to assess if it can reduce the progression of atherosclerotic disease and thereby decrease cardiovascular morbidity and mortality. Patients with CHD or CHD-risk equivalents were randomized to receive 600 mg dalcetrapib or placebo daily for 24 months, in addition to conventional lipid-lowering medication and other medications for cardiovascular risk factors. The primary outcomes are the effect of dalcetrapib on 18F-fluorodeoxyglucose positron emission tomography target-to-background ratio after 6 months and magnetic resonance imaging (MRI) plaque burden (wall area, wall thickness, total vessel area, and wall area/total vessel area ratio) after 12 months. Secondary objectives include positron emission tomography target-to-background ratio at 3 months and MRI plaque burden at 6 and 24 months; plaque composition at 6, 12, and 24 months; and aortic compliance at 6 months. A tertiary objective is to examine the dynamic contrast-enhanced MRI parameters of plaque neovascularization. In total, 189 subjects entered screening, and 130 were randomized. dal-PLAQUE will provide important information on the effects of dalcetrapib on markers of inflammation and atherosclerotic plaque burden and, thereby, on the safety of cholesteryl ester transfer protein modulation with dalcetrapib. Results are expected in 2011. PMID:21835280

Clinical application of diadenosine tetraphosphate (Ap4A:F-1500) for controlled hypotension.

PubMed

Kikuta, Y; Ohiwa, E; Okada, K; Watanabe, A; Haruki, S

1999-01-01

In our animal study, it was revealed that diadenosine tetraphosphate (Ap4A:F-1500) has a dose-dependent hypotension effect of up to 60% decrease in mean arterial pressure compared to control value. Furthermore, in healthy male volunteers, the safety of Ap4A up to 4 mg.min-1 was confirmed. In patients who require surgical procedures under general anesthesia together with controlled hypotension, hypotension was induced by Ap4A in order to examine its hypotensive effect and modulating action on the blood pressure. Ten patients who required controlled hypotension and who were scheduled for elective surgery under general anesthesia were studied. Anesthesia was maintained with isoflurane (n = 7) or sevoflurane (n = 3) in oxygen-nitrous oxide. Controlled hypotension was induced by Ap4A administered at a rate of 10-20 micrograms.kg-1.min-1. The dose was adjusted at a maximum rate of 80 micrograms.kg-1.min-1 until the target blood pressure was achieved. Arterial blood pressure and heart rate were monitored. Arterial samples were drawn at 4 separate time points to measure the concentration of Ap4A in the plasma. The time required for attaining the target blood pressure after initiation of Ap4A infusion was about 16 min, and the time lapse between withdrawal of infusion to recovery of blood pressure was about 18 min. No reflex tachycardia was observed during infusion of Ap4A and no rebound hypertension was evident after withdrawal. The plasma Ap4A concentration increased in response to the acceleration rate of Ap4A administration with a tendency of augmented hypotensive effect. As it produces an excellent hypotensive effect together with a modulating action on blood pressure, Ap4A was assessed as useful in producing controlled hypotension.

Correlation of Factor IXa Subsite Modulations with Effects on Substrate Discrimination

PubMed Central

Neuenschwander, Pierre F.; Deadmond, Kimberly J.; Zepeda, Karla; Rutland, Joshua

2012-01-01

Summary Background A key feature of factor IXa (fIXa) is its allosteric transformation from an enzymatically latent form into a potent procoagulant. Whilst several small molecules have been found capable of partially effecting fIXa function (i.e. ethylene glycol, calcium ion and LMWH), the resulting modest changes in peptidolytic activity have made the study of their mechanisms of action challenging. Since these effects yield hints into potential regulatory forces that may be operational in full expression of fIXa coagulant activity, their description remains of high interest. Studies of crystal structures have yielded insight into structural changes induced by these effectors, but there remains a paucity of information to correlate any given structural change with specific consequences on fIXa function. Objectives To correlate structural changes induced by these modulators with defined consequences in fIXa substrate discrimination and function. Methods A peptidomics-based MS approach was used to examine patterns of hydrolysis of four combinatorial chemistry-derived pentapeptide libraries by fIXa under various conditions in a soluble, active enzyme system. Results Ethylene glycol specifically alters the S3 subsite of fIXa to render it more tolerant to side chains at the P3 substrate position, while calcium enhances tolerance at the S2 subsite. In contrast, LMWH alters both S2 and S1' subsites. Conclusions These results demonstrate the role of plasticity in regulating fIXa function with respect to discrimination of extended substrate sequences, as well as provide crucial insight into active site modulations that may be capitalized upon by various physiological cofactors of fIXa and in future drug design. PMID:22212890

Stereo Viewing Modulates Three-Dimensional Shape Processing During Object Recognition: A High-Density ERP Study

PubMed Central

2017-01-01

The role of stereo disparity in the recognition of 3-dimensional (3D) object shape remains an unresolved issue for theoretical models of the human visual system. We examined this issue using high-density (128 channel) recordings of event-related potentials (ERPs). A recognition memory task was used in which observers were trained to recognize a subset of complex, multipart, 3D novel objects under conditions of either (bi-) monocular or stereo viewing. In a subsequent test phase they discriminated previously trained targets from untrained distractor objects that shared either local parts, 3D spatial configuration, or neither dimension, across both previously seen and novel viewpoints. The behavioral data showed a stereo advantage for target recognition at untrained viewpoints. ERPs showed early differential amplitude modulations to shape similarity defined by local part structure and global 3D spatial configuration. This occurred initially during an N1 component around 145–190 ms poststimulus onset, and then subsequently during an N2/P3 component around 260–385 ms poststimulus onset. For mono viewing, amplitude modulation during the N1 was greatest between targets and distracters with different local parts for trained views only. For stereo viewing, amplitude modulation during the N2/P3 was greatest between targets and distracters with different global 3D spatial configurations and generalized across trained and untrained views. The results show that image classification is modulated by stereo information about the local part, and global 3D spatial configuration of object shape. The findings challenge current theoretical models that do not attribute functional significance to stereo input during the computation of 3D object shape. PMID:29022728

Task-irrelevant fear enhances amygdala-FFG inhibition and decreases subsequent face processing.

PubMed

Schulte Holthausen, Barbara; Habel, Ute; Kellermann, Thilo; Schelenz, Patrick D; Schneider, Frank; Christopher Edgar, J; Turetsky, Bruce I; Regenbogen, Christina

2016-09-01

Facial threat is associated with changes in limbic activity as well as modifications in the cortical face-related N170. It remains unclear if task-irrelevant threat modulates the response to a subsequent facial stimulus, and whether the amygdala's role in early threat perception is independent and direct, or modulatory. In 19 participants, crowds of emotional faces were followed by target faces and a rating task while simultaneous EEG-fMRI were recorded. In addition to conventional analyses, fMRI-informed EEG analyses and fMRI dynamic causal modeling (DCM) were performed. Fearful crowds reduced EEG N170 target face amplitudes and increased responses in a fMRI network comprising insula, amygdala and inferior frontal cortex. Multimodal analyses showed that amygdala response was present ∼60 ms before the right fusiform gyrus-derived N170. DCM indicated inhibitory connections from amygdala to fusiform gyrus, strengthened when fearful crowds preceded a target face. Results demonstrated the suppressing influence of task-irrelevant fearful crowds on subsequent face processing. The amygdala may be sensitive to task-irrelevant fearful crowds and subsequently strengthen its inhibitory influence on face-responsive fusiform N170 generators. This provides spatiotemporal evidence for a feedback mechanism of the amygdala by narrowing attention in order to focus on potential threats. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Theta band oscillations reflect more than entrainment: behavioral and neural evidence demonstrates an active chunking process.

PubMed

Teng, Xiangbin; Tian, Xing; Doelling, Keith; Poeppel, David

2017-10-17

Parsing continuous acoustic streams into perceptual units is fundamental to auditory perception. Previous studies have uncovered a cortical entrainment mechanism in the delta and theta bands (~1-8 Hz) that correlates with formation of perceptual units in speech, music, and other quasi-rhythmic stimuli. Whether cortical oscillations in the delta-theta bands are passively entrained by regular acoustic patterns or play an active role in parsing the acoustic stream is debated. Here, we investigate cortical oscillations using novel stimuli with 1/f modulation spectra. These 1/f signals have no rhythmic structure but contain information over many timescales because of their broadband modulation characteristics. We chose 1/f modulation spectra with varying exponents of f, which simulate the dynamics of environmental noise, speech, vocalizations, and music. While undergoing magnetoencephalography (MEG) recording, participants listened to 1/f stimuli and detected embedded target tones. Tone detection performance varied across stimuli of different exponents and can be explained by local signal-to-noise ratio computed using a temporal window around 200 ms. Furthermore, theta band oscillations, surprisingly, were observed for all stimuli, but robust phase coherence was preferentially displayed by stimuli with exponents 1 and 1.5. We constructed an auditory processing model to quantify acoustic information on various timescales and correlated the model outputs with the neural results. We show that cortical oscillations reflect a chunking of segments, > 200 ms. These results suggest an active auditory segmentation mechanism, complementary to entrainment, operating on a timescale of ~200 ms to organize acoustic information. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

A 16-ch module for thermal neutron detection using ZnS:6LiF scintillator with embedded WLS fibers coupled to SiPMs and its dedicated readout electronics

NASA Astrophysics Data System (ADS)

Mosset, J.-B.; Stoykov, A.; Greuter, U.; Gromov, A.; Hildebrandt, M.; Panzner, T.; Schlumpf, N.

2017-02-01

A scalable 16-ch thermal neutron detection system has been developed in the framework of the upgrade of a neutron diffractometer. The detector is based on a ZnS:6LiF scintillator with embedded WLS fibers which are read out with SiPMs. In this paper, we present the 16-ch module, the dedicated readout electronics, a direct comparison between the performance of the diffractometer obtained with the current 3He detector and with the 16-ch detection module, and the channel-to-channel uniformity.

Apollo experience report: Development of guidance targeting techniques for the command module and launch vehicle

NASA Technical Reports Server (NTRS)

Yencharis, J. D.; Wiley, R. F.; Davis, R. S.; Holmes, Q. A.; Zeiler, K. T.

1972-01-01

The development of the guidance targeting techniques for the Apollo command module and launch vehicle is discussed for four types of maneuvers: (1) translunar injection, (2) translunar midcourse, (3) lunar orbit insertion, and (4) return to earth. The development of real-time targeting programs for these maneuvers and the targeting procedures represented are discussed. The material is intended to convey historically the development of the targeting techniques required to meet the defined target objectives and to illustrate the solutions to problems encountered during that development.

Processing F0 with cochlear implants: Modulation frequency discrimination and speech intonation recognition.

PubMed

Chatterjee, Monita; Peng, Shu-Chen

2008-01-01

Fundamental frequency (F0) processing by cochlear implant (CI) listeners was measured using a psychophysical task and a speech intonation recognition task. Listeners' Weber fractions for modulation frequency discrimination were measured using an adaptive, 3-interval, forced-choice paradigm: stimuli were presented through a custom research interface. In the speech intonation recognition task, listeners were asked to indicate whether resynthesized bisyllabic words, when presented in the free field through the listeners' everyday speech processor, were question-like or statement-like. The resynthesized tokens were systematically manipulated to have different initial-F0s to represent male vs. female voices, and different F0 contours (i.e. falling, flat, and rising) Although the CI listeners showed considerable variation in performance on both tasks, significant correlations were observed between the CI listeners' sensitivity to modulation frequency in the psychophysical task and their performance in intonation recognition. Consistent with their greater reliance on temporal cues, the CI listeners' performance in the intonation recognition task was significantly poorer with the higher initial-F0 stimuli than with the lower initial-F0 stimuli. Similar results were obtained with normal hearing listeners attending to noiseband-vocoded CI simulations with reduced spectral resolution.

Processing F0 with Cochlear Implants: Modulation Frequency Discrimination and Speech Intonation Recognition

PubMed Central

Chatterjee, Monita; Peng, Shu-Chen

2008-01-01

Fundamental frequency (F0) processing by cochlear implant (CI) listeners was measured using a psychophysical task and a speech intonation recognition task. Listeners’ Weber fractions for modulation frequency discrimination were measured using an adaptive, 3-interval, forced-choice paradigm: stimuli were presented through a custom research interface. In the speech intonation recognition task, listeners were asked to indicate whether resynthesized bisyllabic words, when presented in the free field through the listeners’ everyday speech processor, were question-like or statement-like. The resynthesized tokens were systematically manipulated to have different initial F0s to represent male vs. female voices, and different F0 contours (i.e., falling, flat, and rising) Although the CI listeners showed considerable variation in performance on both tasks, significant correlations were observed between the CI listeners’ sensitivity to modulation frequency in the psychophysical task and their performance in intonation recognition. Consistent with their greater reliance on temporal cues, the CI listeners’ performance in the intonation recognition task was significantly poorer with the higher initial-F0 stimuli than with the lower initial-F0 stimuli. Similar results were obtained with normal hearing listeners attending to noiseband-vocoded CI simulations with reduced spectral resolution. PMID:18093766

3D-segmentation of the 18F-choline PET signal for target volume definition in radiation therapy of the prostate.

PubMed

Ciernik, I Frank; Brown, Derek W; Schmid, Daniel; Hany, Thomas; Egli, Peter; Davis, J Bernard

2007-02-01

Volumetric assessment of PET signals becomes increasingly relevant for radiotherapy (RT) planning. Here, we investigate the utility of 18F-choline PET signals to serve as a structure for semi-automatic segmentation for forward treatment planning of prostate cancer. 18F-choline PET and CT scans of ten patients with histologically proven prostate cancer without extracapsular growth were acquired using a combined PET/CT scanner. Target volumes were manually delineated on CT images using standard software. Volumes were also obtained from 18F-choline PET images using an asymmetrical segmentation algorithm. PTVs were derived from CT 18F-choline PET based clinical target volumes (CTVs) by automatic expansion and comparative planning was performed. As a read-out for dose given to non-target structures, dose to the rectal wall was assessed. Planning target volumes (PTVs) derived from CT and 18F-choline PET yielded comparable results. Optimal matching of CT and 18F-choline PET derived volumes in the lateral and cranial-caudal directions was obtained using a background-subtracted signal thresholds of 23.0+/-2.6%. In antero-posterior direction, where adaptation compensating for rectal signal overflow was required, optimal matching was achieved with a threshold of 49.5+/-4.6%. 3D-conformal planning with CT or 18F-choline PET resulted in comparable doses to the rectal wall. Choline PET signals of the prostate provide adequate spatial information amendable to standardized asymmetrical region growing algorithms for PET-based target volume definition for external beam RT.

ATP Synthase, a Target for Dementia and Aging?

PubMed

Larrick, James W; Larrick, Jasmine W; Mendelsohn, Andrew R

2018-02-01

Advancing age is the biggest risk factor for development for the major life-threatening diseases in industrialized nations accounting for >90% of deaths. Alzheimer's dementia (AD) is among the most devastating. Currently approved therapies fail to slow progression of the disease, providing only modest improvements in memory. Recently reported work describes mechanistic studies of J147, a promising therapeutic molecule previously shown to rescue the severe cognitive deficits exhibited by aged, transgenic AD mice. Apparently, J147 targets the mitochondrial alpha-F1-ATP synthase (ATP5A). Modest inhibition of the ATP synthase modulates intracellular calcium to activate AMP-activated protein kinase to inhibit mammalian target of rapamycin, a known mechanism of lifespan extension from worms to mammals.

Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention.

PubMed

Gladine, Cécile; Newman, John W; Durand, Thierry; Pedersen, Theresa L; Galano, Jean-Marie; Demougeot, Céline; Berdeaux, Olivier; Pujos-Guillot, Estelle; Mazur, Andrzej; Comte, Blandine

2014-01-01

The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention. A special emphasis was given to the non-enzymatic metabolites knowing the high susceptibility of DHA to free radical-mediated peroxidation and the increased oxidative stress associated with plaque formation. Atherosclerosis prone mice (LDLR(-/-)) received increasing doses of DHA (0, 0.1, 1 or 2% of energy) during 20 weeks leading to a dose-dependent reduction of atherosclerosis (R(2) = 0.97, p = 0.02), triglyceridemia (R(2) = 0.97, p = 0.01) and cholesterolemia (R(2) = 0.96, p<0.01). Targeted lipidomic analyses revealed that both the profiles of EPA and DHA and their corresponding oxygenated metabolites were substantially modulated in plasma and liver. Notably, the hepatic level of F4-neuroprostanes, a specific class of DHA peroxidized metabolites, was strongly correlated with the hepatic DHA level. Moreover, unbiased statistical analysis including correlation analyses, hierarchical cluster and projection to latent structure discriminate analysis revealed that the hepatic level of F4-neuroprostanes was the variable most negatively correlated with the plaque extent (p<0.001) and along with plasma EPA-derived diols was an important mathematical positive predictor of atherosclerosis prevention. Thus, oxygenated n-3 PUFAs, and F4-neuroprostanes in particular, are potential biomarkers of DHA-associated atherosclerosis prevention. While these may contribute to the anti-atherogenic effects of DHA, further in vitro investigations are needed to confirm such a contention and to decipher the molecular mechanisms of action.

Nonlinear acoustic landmine detection: Comparison of ``off target'' soil background and ``on target'' soil-mine nonlinear effects

NASA Astrophysics Data System (ADS)

Korman, Murray S.

2005-09-01

When airborne sound at two primary tones, f1, f2 (closely spaced near a resonance) excites the soil surface over a buried landmine, soil wave motion interacts with the landmine generating a scattered surface profile which can be measured over the ``target.'' Profiles at f1, f2, and f1-(f2-f1), f2+(f2-f1), 2f1-(f2-f1), f1+f2 and 2f2+(f2-f1) (among others) are measured for a VS 1.6 plastic, inert, anti-tank landmine, buried at 3.6 cm in sifted loess soil. It is observed that the ``on target'' to ``off target'' contrast ratio for the sum frequency component can be ~20 dB higher than for either primary. The vibration interaction between the top-plate interface of a buried plastic landmine and the soil above it appears to exhibit many characteristics of the mesoscopic/nanoscale nonlinear effects that are observed in geomaterials like sandstone. Near resonance, the bending (softening) of a family of increasing amplitude tuning curves, involving the vibration over the landmine, exhibits a linear relationship between the peak particle velocity and corresponding frequency. Tuning curve experiments along with two-tone tests are performed both on and off the mine in an effort to understand the nonlinearities in each case. [Work supported by U.S. Army RDECOM CERDEC, NVESD.

The Instrumentation of a Microfluidic Analyzer Enabling the Characterization of the Specific Membrane Capacitance, Cytoplasm Conductivity, and Instantaneous Young's Modulus of Single Cells.

PubMed

Wang, Ke; Zhao, Yang; Chen, Deyong; Huang, Chengjun; Fan, Beiyuan; Long, Rong; Hsieh, Chia-Hsun; Wang, Junbo; Wu, Min-Hsien; Chen, Jian

2017-06-19

This paper presents the instrumentation of a microfluidic analyzer enabling the characterization of single-cell biophysical properties, which includes seven key components: a microfluidic module, a pressure module, an imaging module, an impedance module, two LabVIEW platforms for instrument operation and raw data processing, respectively, and a Python code for data translation. Under the control of the LabVIEW platform for instrument operation, the pressure module flushes single cells into the microfluidic module with raw biophysical parameters sampled by the imaging and impedance modules and processed by the LabVIEW platform for raw data processing, which were further translated into intrinsic cellular biophysical parameters using the code developed in Python. Based on this system, specific membrane capacitance, cytoplasm conductivity, and instantaneous Young's modulus of three cell types were quantified as 2.76 ± 0.57 μF/cm², 1.00 ± 0.14 S/m, and 3.79 ± 1.11 kPa for A549 cells ( n cell = 202); 1.88 ± 0.31 μF/cm², 1.05 ± 0.16 S/m, and 3.74 ± 0.75 kPa for 95D cells ( n cell = 257); 2.11 ± 0.38 μF/cm², 0.87 ± 0.11 S/m, and 5.39 ± 0.89 kPa for H460 cells ( n cell = 246). As a semi-automatic instrument with a throughput of roughly 1 cell per second, this prototype instrument can be potentially used for the characterization of cellular biophysical properties.

The Instrumentation of a Microfluidic Analyzer Enabling the Characterization of the Specific Membrane Capacitance, Cytoplasm Conductivity, and Instantaneous Young’s Modulus of Single Cells

PubMed Central

Wang, Ke; Zhao, Yang; Chen, Deyong; Huang, Chengjun; Fan, Beiyuan; Long, Rong; Hsieh, Chia-Hsun; Wang, Junbo; Wu, Min-Hsien; Chen, Jian

2017-01-01

This paper presents the instrumentation of a microfluidic analyzer enabling the characterization of single-cell biophysical properties, which includes seven key components: a microfluidic module, a pressure module, an imaging module, an impedance module, two LabVIEW platforms for instrument operation and raw data processing, respectively, and a Python code for data translation. Under the control of the LabVIEW platform for instrument operation, the pressure module flushes single cells into the microfluidic module with raw biophysical parameters sampled by the imaging and impedance modules and processed by the LabVIEW platform for raw data processing, which were further translated into intrinsic cellular biophysical parameters using the code developed in Python. Based on this system, specific membrane capacitance, cytoplasm conductivity, and instantaneous Young’s modulus of three cell types were quantified as 2.76 ± 0.57 μF/cm2, 1.00 ± 0.14 S/m, and 3.79 ± 1.11 kPa for A549 cells (ncell = 202); 1.88 ± 0.31 μF/cm2, 1.05 ± 0.16 S/m, and 3.74 ± 0.75 kPa for 95D cells (ncell = 257); 2.11 ± 0.38 μF/cm2, 0.87 ± 0.11 S/m, and 5.39 ± 0.89 kPa for H460 cells (ncell = 246). As a semi-automatic instrument with a throughput of roughly 1 cell per second, this prototype instrument can be potentially used for the characterization of cellular biophysical properties. PMID:28629175

[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Management. Module I-F-3: Environmental Issues and the Consumer.

ERIC Educational Resources Information Center

Movey, Jan

This competency-based preservice home economics teacher education module on environmental issues and the consumer is the third in a set of seven modules on consumer education related to management. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education [MATCHE]--see CE…

Flexible lock-in detection system based on synchronized computer plug-in boards applied in sensitive gas spectroscopy

NASA Astrophysics Data System (ADS)

Andersson, Mats; Persson, Linda; Svensson, Tomas; Svanberg, Sune

2007-11-01

We present a flexible and compact, digital, lock-in detection system and its use in high-resolution tunable diode laser spectroscopy. The system involves coherent sampling, and is based on the synchronization of two data acquisition cards running on a single standard computer. A software-controlled arbitrary waveform generator is used for laser modulation, and a four-channel analog/digital board records detector signals. Gas spectroscopy is performed in the wavelength modulation regime. The coherently detected signal is averaged a selected number of times before it is stored or analyzed by software-based, lock-in techniques. Multiple harmonics of the modulation signal (1f, 2f, 3f, 4f, etc.) are available in each single data set. The sensitivity is of the order of 10-5, being limited by interference fringes in the measurement setup. The capabilities of the system are demonstrated by measurements of molecular oxygen in ambient air, as well as dispersed gas in scattering materials, such as plants and human tissue.

Flexible lock-in detection system based on synchronized computer plug-in boards applied in sensitive gas spectroscopy.

PubMed

Andersson, Mats; Persson, Linda; Svensson, Tomas; Svanberg, Sune

2007-11-01

We present a flexible and compact, digital, lock-in detection system and its use in high-resolution tunable diode laser spectroscopy. The system involves coherent sampling, and is based on the synchronization of two data acquisition cards running on a single standard computer. A software-controlled arbitrary waveform generator is used for laser modulation, and a four-channel analog/digital board records detector signals. Gas spectroscopy is performed in the wavelength modulation regime. The coherently detected signal is averaged a selected number of times before it is stored or analyzed by software-based, lock-in techniques. Multiple harmonics of the modulation signal (1f, 2f, 3f, 4f, etc.) are available in each single data set. The sensitivity is of the order of 10(-5), being limited by interference fringes in the measurement setup. The capabilities of the system are demonstrated by measurements of molecular oxygen in ambient air, as well as dispersed gas in scattering materials, such as plants and human tissue.

Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands

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

Savechenkov, Pavel Y.; Chiara, David C.; Desai, Rooma

2017-08-01

Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAAR), but the locations of their GABAAR binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAAR, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAAR responses, left-shifting the GABA concentration – response curve for human α1β3γ2 GABAARs expressed in Xenopus oocytes, and enhancing [3H]muscimol binding to α1β3γ2 GABAARs expressed in HEK293 cells. With EC50 of 110 nM, 11-AziAP is one the most potent general anestheticsmore » reported. [3H]F4N3Bzoxy-AP and [3H]11-AziAP, at anesthetic concentrations, photoincorporated into α- and β-subunits of purified α1β3γ2 GABAARs, but labeling at the subunit level was not inhibited by alphaxalone (30 μM). The enhancement of photolabeling by 3H-azietomidate and 3H-mTFD-MPAB in the presence of either of the two steroid photoprobes indicates the neurosteroid binding site is different from, but allosterically related to, the etomidate and barbiturate sites. Our observations are consistent with two hypotheses. First, F4N3Bzoxy-AP and 11-aziAP bind to a high affinity site in such a pose that the 11-photoactivatable moiety, that is rigidly attached to the steroid backbone, points away from the protein. Second, F4N3Bzoxy-AP, 11-aziAP and other steroid anesthetics, which are present at very high concentration at the lipid-protein interface due to their high lipophilicity, act via low affinity sites, as proposed by Akk et al. (Psychoneuroendocrinology 2009, 34S1, S59-S66).« less

Parietal cortex integrates contextual and saliency signals during the encoding of natural scenes in working memory.

PubMed

Santangelo, Valerio; Di Francesco, Simona Arianna; Mastroberardino, Serena; Macaluso, Emiliano

2015-12-01

The Brief presentation of a complex scene entails that only a few objects can be selected, processed indepth, and stored in memory. Both low-level sensory salience and high-level context-related factors (e.g., the conceptual match/mismatch between objects and scene context) contribute to this selection process, but how the interplay between these factors affects memory encoding is largely unexplored. Here, during fMRI we presented participants with pictures of everyday scenes. After a short retention interval, participants judged the position of a target object extracted from the initial scene. The target object could be either congruent or incongruent with the context of the scene, and could be located in a region of the image with maximal or minimal salience. Behaviourally, we found a reduced impact of saliency on visuospatial working memory performance when the target was out-of-context. Encoding-related fMRI results showed that context-congruent targets activated dorsoparietal regions, while context-incongruent targets de-activated the ventroparietal cortex. Saliency modulated activity both in dorsal and ventral regions, with larger context-related effects for salient targets. These findings demonstrate the joint contribution of knowledge-based and saliency-driven attention for memory encoding, highlighting a dissociation between dorsal and ventral parietal regions. © 2015 Wiley Periodicals, Inc.

Design and testing of an energy-absorbing crewseat for the F/FB-111 aircraft. Volume 2: Data from seat testing

NASA Technical Reports Server (NTRS)

Shane, S. J.

1985-01-01

The unacceptably high injury rate during the escape sequence (including the ejection and ground impact) of the crew module for F/FB-111 aircraft is reviewed. A program to determine if the injury potential could be reduced by replacing the existing crewseats with energy absorbing crewseats is presented. An energy absorbing test seat is designed using much of the existing seat hardware. An extensive dynamic seat test series, designed to duplicate various crew module ground impact conditions is conducted at a sled test facility. Comparative tests with operational F-111 crewseats are also conducted. After successful dynamic testing of the seat, more testing is conducted with the seats mounted in an F-111 crew module. Both swing tests and vertical drop tests are conducted. The vertical drop tests are used to obtain comparative data between the energy absorbing and operational seats. Volume 1 describes the energy absorbing test seat and testing conducted, and evaluates the data from both test series. Volume 2 presents the data obtained during the seat test series, while Volume 3 presents the data from the crew module test series.

Phase effects in masking by harmonic complexes: speech recognition.

PubMed

Deroche, Mickael L D; Culling, John F; Chatterjee, Monita

2013-12-01

Harmonic complexes that generate highly modulated temporal envelopes on the basilar membrane (BM) mask a tone less effectively than complexes that generate relatively flat temporal envelopes, because the non-linear active gain of the BM selectively amplifies a low-level tone in the dips of a modulated masker envelope. The present study examines a similar effect in speech recognition. Speech reception thresholds (SRTs) were measured for a voice masked by harmonic complexes with partials in sine phase (SP) or in random phase (RP). The masker's fundamental frequency (F0) was 50, 100 or 200 Hz. SRTs were considerably lower for SP than for RP maskers at 50-Hz F0, but the two converged at 100-Hz F0, while at 200-Hz F0, SRTs were a little higher for SP than RP maskers. The results were similar whether the target voice was male or female and whether the masker's spectral profile was flat or speech-shaped. Although listening in the masker dips has been shown to play a large role for artificial stimuli such as Schroeder-phase complexes at high levels, it contributes weakly to speech recognition in the presence of harmonic maskers with different crest factors at more moderate sound levels (65 dB SPL). Copyright © 2013 Elsevier B.V. All rights reserved.

Ventrolateral prefrontal cortex and the effects of task demand context on facial affect appraisal in schizophrenia.

PubMed

Leitman, David I; Wolf, Daniel H; Loughead, James; Valdez, Jeffrey N; Kohler, Christian G; Brensinger, Colleen; Elliott, Mark A; Turetsky, Bruce I; Gur, Raquel E; Gur, Ruben C

2011-01-01

Schizophrenia patients display impaired performance and brain activity during facial affect recognition. These impairments may reflect stimulus-driven perceptual decrements and evaluative processing abnormalities. We differentiated these two processes by contrasting responses to identical stimuli presented under different contexts. Seventeen healthy controls and 16 schizophrenia patients performed an fMRI facial affect detection task. Subjects identified an affective target presented amongst foils of differing emotions. We hypothesized that targeting affiliative emotions (happiness, sadness) would create a task demand context distinct from that generated when targeting threat emotions (anger, fear). We compared affiliative foil stimuli within a congruent affiliative context with identical stimuli presented in an incongruent threat context. Threat foils were analysed in the same manner. Controls activated right orbitofrontal cortex (OFC)/ventrolateral prefrontal cortex (VLPFC) more to affiliative foils in threat contexts than to identical stimuli within affiliative contexts. Patients displayed reduced OFC/VLPFC activation to all foils, and no activation modulation by context. This lack of context modulation coincided with a 2-fold decrement in foil detection efficiency. Task demands produce contextual effects during facial affective processing in regions activated during affect evaluation. In schizophrenia, reduced modulation of OFC/VLPFC by context coupled with reduced behavioural efficiency suggests impaired ventral prefrontal control mechanisms that optimize affective appraisal.

Role of 5f electrons in the structural stability of light actinide (Th-U) mononitrides under pressure.

PubMed

Modak, P; Verma, Ashok K

2016-03-28

Pressure induced structural sequences and their mechanism for light actinide (Th-U) mononitrides were studied as a function of 5f-electron number using first-principles total energy and electronic structure calculations. Zero pressure lattice constants, bulk module and C11 elastic module vary systematically with 5f-electron number implying its direct role on crystal binding. There is a critical 5f-electron number below which the system makes B1-B2 and above it B1-R3̄m-B2 structural sequence under pressure. Also, the B1-B2 transition pressure increases with increasing 5f-electron number whereas an opposite trend is obtained for the B1-R3̄m transition pressure. The ascending of N p anti-bonding states through the Fermi level at high pressure is responsible for the structural instability of the system. Above the critical 5f-electron number in the system a narrow 5f-band occurs very close to the Fermi level which allows the system to lower its symmetry via band Jahn-Teller type lattice distortion and the system undergoes a B1-R3̄m phase transition. However, below the critical 5f-electron number this mechanism is not favorable due to a lack of sufficient 5f-state occupancy and thus the system undergoes a B1-B2 phase transition like other ionic solids.

Observation of TiF +by Velocity Modulation Laser Spectroscopy and Analysis of the [17.6] 3Δ-X3Φ System

NASA Astrophysics Data System (ADS)

Focsa, C.; Pinchemel, B.; Collet, D.; Huet, T. R.

1998-06-01

The molecular ion TiF+has been observed for the first time using high-resolution spectroscopy. The ions were produced in the positive column of an AC glow discharge with a gas mixture of He/TiF4. A single-mode cw dye laser along with the velocity modulation detection technique was used to record an absorption spectrum in the spectral region 16 800-18 600 cm-1. The observed system was assigned to the 0-0 and 1-1 bands of the [17.6]3Δ-X3Φ transition of TiF+. The rotational analysis of the main subbands has been performed up toJvalues equal to 77 and 56 for the 0-0 and 1-1 bands, respectively. Despite a careful search, no intercombination band was observed. A set of effective molecular parameters has been determined, characterizing thev= 0, 1 levels of the [17.6]3Δ andX3Φ states. The spin-orbit constantsAeand the vibrational constants ωe, ωexehave been estimated for both electronic states, as well as their equilibrium distancesRe(1.7509 and 1.7800) Å for the [17.6]3Δ andX3Φ states, respectively).

SU-F-T-395: Evaluation of Best Dosimetry Achievable with VMAT and IMRT Treatment Techniques Targeting Borderline Resectable Pancreatic Cancer

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

Harpool, K; Schnell, E; Herman, T

Purpose: To determine from retrospective study the most appropriate technique for targeting small borderline operable pancreatic cancer surrounding blood vessels by evaluating the dosimetry and normal tissue sparing achievable using Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT). Methods: Treatment plans from ten patients who have undergone treatment with a prescribed dose of 4950 cGy, at 275 cGy per fraction, were analyzed. All plans were replanned using Eclipse TPS (Varian Medical Systems, Palo Alto, CA) with complementary VMAT or IMRT techniques to obtain paired data sets for comparison. The coverage to at least 95% of the plannedmore » target volume (PTV) was normalized to receive 100% of the prescription dose. The normal tissue constraints followed the quantitative analysis of normal tissue effects in the clinic (QUANTEC) guidelines and the organs at risks (OARs) were liver, kidneys, spinal cord and bowel. The plan evaluation was based on conformity index (CI), homogeneity index (HI), uniformity index (UI), DVH parameters, and student’s-t statistics (2 tails). Results: The VMAT technique delivered less maximum dose to the right kidney, left kidney, total kidney, liver, spinal cord, and bowel by 9.3%, 5.9%, 6.7%, 3.9%, 15.1%, 3.9%, and 4.3%, respectively. The averaged V15 for the total kidney was 10.21% for IMRT and 7.29% for VMAT. The averaged V20 for the bowel was 19.89% for IMRT and 14.06% for VMAT. On average, the CI for IMRT was 1.20 and 1.16 for VMAT (p = 0.20). The HI was 0.08 for both techniques (p = 0.91) and UI was 1.05 and 1.06 for IMRT and VMAT respectively (p = 0.59). Conclusion: Both techniques achieve adequate PTV coverage. Although VMAT techniques show better normal tissue sparing from excessive dose, no significant differences were observed. Slight discrepancies may rise from different versions of calculation algorithms.« less

Responses of Middle-Frequency Modulations in Vocal Fundamental Frequency to Different Vocal Intensities and Auditory Feedback.

PubMed

Lee, Shao-Hsuan; Fang, Tuan-Jen; Yu, Jen-Fang; Lee, Guo-She

2017-09-01

Auditory feedback can make reflexive responses on sustained vocalizations. Among them, the middle-frequency power of F0 (MFP) may provide a sensitive index to access the subtle changes in different auditory feedback conditions. Phonatory airflow temperature was obtained from 20 healthy adults at two vocal intensity ranges under four auditory feedback conditions: (1) natural auditory feedback (NO); (2) binaural speech noise masking (SN); (3) bone-conducted feedback of self-generated voice (BAF); and (4) SN and BAF simultaneously. The modulations of F0 in low-frequency (0.2 Hz-3 Hz), middle-frequency (3 Hz-8 Hz), and high-frequency (8 Hz-25 Hz) bands were acquired using power spectral analysis of F0. Acoustic and aerodynamic analyses were used to acquire vocal intensity, maximum phonation time (MPT), phonatory airflow, and MFP-based vocal efficiency (MBVE). SN and high vocal intensity decreased MFP and raised MBVE and MPT significantly. BAF showed no effect on MFP but significantly lowered MBVE. Moreover, BAF significantly increased the perception of voice feedback and the sensation of vocal effort. Altered auditory feedback significantly changed the middle-frequency modulations of F0. MFP and MBVE could well detect these subtle responses of audio-vocal feedback. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecule Labeling.

PubMed

Billaud, Emilie M F; Vidal, Aurélien; Vincenot, Amélie; Besse, Sophie; Bouchon, Bernadette; Debiton, Eric; Miot-Noirault, Elisabeth; Miladi, Imen; Rbah-Vidal, Latifa; Auzeloux, Philippe; Chezal, Jean-Michel

2015-02-12

The new readily available prosthetic group, tetrafluorophenyl 4-fluoro-3-iodobenzoate (TFIB), designed for both molecular imaging and targeted radionuclide therapy purposes was radiolabeled either with fluorine or iodine radionuclides with excellent radiochemical yields and purities. These radiolabeled tags were conjugated to N,N-diethylethylenediamine to give melanin-targeting radiotracers [ (125) I]9 and [ (18) F]9, which were successfully evaluated by PET and gamma scintigraphic imaging in B16F0 pigmented melanoma-bearing C57BL/6J mice. Then, radiolabeled [ (125) I]/[ (18) F]TFIB was used to tag tumor-targeting peptides (i.e., PEG3[c(RGDyK)]2 and NDP-MSH targeting αvβ3 integrin and MC1R receptors, respectively) in mild conditions and with good radiochemical yields (47-83% d.c.) and purities (>99%). The resulting radiolabeled peptides were assessed both in vitro and by PET imaging in animal models.

Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecule Labeling

PubMed Central

2014-01-01

The new readily available prosthetic group, tetrafluorophenyl 4-fluoro-3-iodobenzoate (TFIB), designed for both molecular imaging and targeted radionuclide therapy purposes was radiolabeled either with fluorine or iodine radionuclides with excellent radiochemical yields and purities. These radiolabeled tags were conjugated to N,N-diethylethylenediamine to give melanin-targeting radiotracers [125I]9 and [18F]9, which were successfully evaluated by PET and gamma scintigraphic imaging in B16F0 pigmented melanoma-bearing C57BL/6J mice. Then, radiolabeled [125I]/[18F]TFIB was used to tag tumor-targeting peptides (i.e., PEG3[c(RGDyK)]2 and NDP-MSH targeting αvβ3 integrin and MC1R receptors, respectively) in mild conditions and with good radiochemical yields (47–83% d.c.) and purities (>99%). The resulting radiolabeled peptides were assessed both in vitro and by PET imaging in animal models. PMID:25699145

Modulators of 14-3-3 Protein–Protein Interactions

PubMed Central

2017-01-01

Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein–protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as “undruggable” targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products. PMID:28968506

Automated production at the curie level of no-carrier-added 6-[(18)F]fluoro-L-dopa and 2-[(18)F]fluoro-L-tyrosine on a FASTlab synthesizer.

PubMed

Lemaire, C; Libert, L; Franci, X; Genon, J-L; Kuci, S; Giacomelli, F; Luxen, A

2015-06-15

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and 2-[(18)F]fluoro-L-tyrosine ([(18)F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high- performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand-alone HPLC. [(18)F]FDOPA and [(18)F]FTYR were produced in 36.3 ± 3.0% (n = 8) and 50.5 ± 2.7% (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95%, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [(18)F]FDOPA and [(18)F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment. Copyright © 2015 John Wiley & Sons, Ltd.

Mutations at Tyrosine 88, Lysine 92 and Tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tat-induced inhibition of dopamine transport

PubMed Central

Midde, Narasimha M.; Yuan, Yaxia; Quizon, Pamela M.; Sun, Wei-Lun; Huang, Xiaoqin; Zhan, Chang-Guo; Zhu, Jun

2015-01-01

HIV-1 transactivator of transcription (Tat) protein disrupts the dopamine (DA) neurotransmission by inhibiting DA transporter (DAT) function, leading to increased neurocognitive impairment in HIV-1 infected individuals. Through integrated computational modeling and pharmacological studies, we have demonstrated that mutation of tyrosine470 (Y470H) of human DAT (hDAT) attenuates Tat-induced inhibition of DA uptake by changing the transporter conformational transitions. The present study examined the functional influences of other substitutions at tyrosine470 (Y470F and Y470A) and tyrosine88 (Y88F) and lysine92 (K92M), two other relevant residues for Tat binding to hDAT, in Tat-induced inhibitory effects on DA transport. Y88F, K92M and Y470A attenuated Tat-induced inhibition of DA transport, implicating the functional relevance of these residues for Tat binding to hDAT. Compared to wild type hDAT, Y470A and K92M but not Y88F reduced the maximal velocity of [3H]DA uptake without changes in the Km. Y88F and K92M enhanced IC50 values for DA inhibition of [3H]DA uptake and [3H]WIN35,428 binding but decreased IC50 for cocaine and GBR12909 inhibition of [3H]DA uptake, suggesting that these residues are critical for substrate and these inhibitors. Y470F, Y470A, Y88F and K92M attenuated zinc-induced increase of [3H]WIN35,428 binding. Moreover, only Y470A and K92M enhanced DA efflux relative to wild type hDAT, suggesting mutations of these residues differentially modulate transporter conformational transitions. These results demonstrate Tyr88 and Lys92 along with Tyr470 as functional recognition residues in hDAT for Tat-induced inhibition of DA transport and provide mechanistic insights into identifying target residues on the DAT for Tat binding. PMID:25604666

[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Economically Depressed Areas Strand: Management. Module III-F-3: Marketing Practices in Relation to Low Income Clientele.

ERIC Educational Resources Information Center

California State Univ., Fresno. Dept. of Home Economics.

This competency-based preservice home economics teacher education module on marketing practices in relation to low income clientele is the third in a set of three modules on management in economically depressed areas (EDAs). (This set is part of a larger set of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking…

Mach-Zehnder modulator modulated radio-over-fiber transmission system using dual wavelength linearization

NASA Astrophysics Data System (ADS)

Zhu, Ran; Hui, Ming; Shen, Dongya; Zhang, Xiupu

2017-02-01

In this paper, dual wavelength linearization (DWL) technique is studied to suppress odd and even order nonlinearities simultaneously in a Mach-Zehnder modulator (MZM) modulated radio-over-fiber (RoF) transmission system. A theoretical model is given to analyze the DWL employed for MZM. In a single-tone test, the suppressions of the second order harmonic distortion (HD2) and third order harmonic distortion (HD3) at the same time are experimentally verified at different bias voltages of the MZM. The measured spurious-free dynamic ranges (SFDRs) with respect to the HD2 and HD3 are improved simultaneously compared to using a single laser. The output P1 dB is also improved by the DWL technique. Moreover, a WiFi signal is transmitted in the RoF system to test the linearization for broadband signal. The result shows that more than 1 dB improvement of the error vector magnitude (EVM) is obtained by the DWL technique.

Absorption sensor for CO in combustion gases using 2.3 µm tunable diode lasers

NASA Astrophysics Data System (ADS)

Chao, X.; Jeffries, J. B.; Hanson, R. K.

2009-11-01

Tunable diode laser absorption spectroscopy of CO was studied in the controlled laboratory environments of a heated cell and a combustion exhaust rig. Two absorption lines, R(10) and R(11) in the first overtone band of CO near 2.3 µm, were selected from a HITRAN simulation to minimize interference from water vapor at a representative combustion exhaust temperature (~1200 K). The linestrengths and collision broadening coefficients for these lines were measured in a heated static cell. This database was then used in a comparative study of direct absorption and wavelength-modulation absorption. CO concentration measurements using scanned-wavelength direct absorption (DA) and wavelength modulation with the second-harmonic signal normalized by the first-harmonic signal (WMS-2f/1f) all agreed with those measured by a conventional gas sampling analyzer over the range from <10 ppm to 2.3%. As expected, water vapor was found to be the dominant source of background interference for CO detection in combustion flows at high temperatures. Water absorption was measured to a high spectral resolution within the wavelength region 4295-4301 cm-1 at 1100 K, and shown to produce <10 ppm level interference for CO detection in combustion exhausts at temperatures up to 1200 K. We found that the WMS-2f/1f strategy avoids the need for WMS calibration measurements but requires characterization of the wavelength and injection-current intensity modulation of the specific diode laser. We conclude that WMS-2f/1f using the selected R(10) or R(11) transitions in the CO overtone band holds good promise for sensitive in situ detection of ppm-level CO in combustion flows, with high resistance to interference absorption from H2O.

Synthesis and DNA binding properties of 1-(3-aminopropyl)-imidazole-containing triamide f-Im*PyIm: a novel diamino polyamide designed to target 5'-ACGCGT-3'.

PubMed

Satam, Vijay; Babu, Balaji; Porte, Alexander; Savagian, Mia; Lee, Megan; Smeltzer, Thomas; Liu, Yang; Ramos, Joseph; Wilson, W David; Lin, Shicai; Kiakos, Kostantinos; Hartley, John A; Lee, Moses

2012-09-15

A novel diamino/dicationic polyamide f-Im(*)PyIm (5) that contains an orthogonally positioned aminopropyl chain on an imidazole (Im(*)) moiety was designed to target 5'-ACGCGT-3'. The DNA binding properties of the diamino polyamide 5, determined by CD, ΔT(M), DNase I footprinting, SPR, and ITC studies, were compared with those of its monoamino/monocationic counterpart f-ImPyIm (1) and its diamino/dicationic isomer f-ImPy(*)Im (2), which has the aminopropyl group attached to the central pyrrole unit (Py(*)). The results gave evidence for the minor groove binding and selectivity of polyamide 5 for the cognate sequence 5'-ACGCGT-3', and with strong affinity (K(eq)=2.3×10(7) M(-1)). However, the binding affinities varied according to the order: f-ImPy(*)Im (2)>f-ImPyIm (1)≥f-Im(*)PyIm (5) confirming that the second amino group can improve affinity, but its position within the polyamide can affect affinity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Modular Air Defense Effectiveness Model, Program Documentation and User’s Guide. Volume II. MADEM Programmer Manual.

DTIC Science & Technology

1980-01-31

Nuclear Agency 13 NUMFIER OF PAGES Washington, D.C. 20305 534 14 MONITORING AGENCY NAME 8 ADDRESS(,! itI(reI t &,n, ( f n ... o.I.n. Offi,e) 15...Initialization 13 3. Storage Management 13 4. Event Control 14 E. Diagnostics 17 1. Debug Routines 17 2. Data Structure Display Routines 19 F . Software...Structures 71 1. Player Lists 72 2. C2 Trees 78 3. Passive Target List 86 F . RED Structures 89 1. Red Theater Commander 90 2. Potential Target List 98 3

United States Air Force Weapons Laboratory Research Scholar Program, 1983-1984.

DTIC Science & Technology

1984-10-01

voltage upon passing through an RC circuit .) The phase shift is given by = tan-Tf (3) * where T is the cavity lifetime and f is the modulation ...spark in air at the external terminals of a filter module has * S. . . . . .. S ** . * * * * Page 8-18 approximately the same effect on the circuit as a... module usually contains a metal oxide varistor(s), and perhaps also 3 an RFI filter circuit . We shall discuss line conditioners and surge protection

Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

PubMed Central

Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen

2017-01-01

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs. PMID:28251165

Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells.

PubMed

Spiess, Katja; Jeppesen, Mads G; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen; Kledal, Thomas N; Rosenkilde, Mette M

2017-01-01

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX 3 CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX 3 CR1, the endogenous receptor for CX 3 CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs.

WE-F-16A-03: 3D Printer Application in Proton Therapy: A Novel Method to Deliver Passive-Scattering Proton Beams with a Fixed Range and Modulation for SRS and SRT

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

Ding, X; Witztum, A; Liang, X

2014-06-15

Purpose: To present a novel technique to deliver passive-scattering proton beam with fixed range and modulation using a 3D printed patient-specific bolus for proton stereotactic radiosurgery and radiotherapy. Methods: A CIRS head phantom was used to simulate a patient with a small brain lesion. A custom bolus was created in the Eclipse Treatment Planning System (TPS) to compensate for the different water equivalent depths from the patient surface to the target from multiple beam directions. To simulate arc therapy, a plan was created on the initial CT using three passive-scattering proton beams with a fixed range and modulations irradiating frommore » different angles. The DICOM-RT structure file of the bolus was exported from the TPS and converted to STL format for 3D printing. The phantom was rescanned with the printed custom bolus and head cup to verify the dose distribution comparing to the initial plan. EBT3 films were placed in the sagital plane of the target to verify the delivered dose distribution. The relative stopping power of the printing material(ABSplus-P430) was measured using the Zebra multi-plate ion chamber. Results: The relative stopping power of the 3D printing material, ABSplus-P430 was 1.05 which is almost water equivalent. The dose difference between verification CT and Initial CT is almost negligible. Film measurement also confirmed the accuracy for this new proton delivery technique. Conclusion: Our method using 3D printed range modifiers simplify the treatment delivery of multiple passive-scattering beams in treatment of small lesion in brain. This technique makes delivery of multiple beam more efficient and can be extended to allow arc therapy with proton beams. The ability to create and construct complex patient specific bolus structures provides a new dimension in creating optimized quality treatment plans not only for proton therapy but also for electron and photon therapy.« less

Identification of microRNAs regulating Escherichia coli F18 infection in Meishan weaned piglets.

PubMed

Wu, Zhengchang; Qin, Weiyun; Wu, Seng; Zhu, Guoqiang; Bao, Wenbin; Wu, Shenglong

2016-11-03

Escherichia coli F18 is mainly responsible for post-weaning diarrhea (PWD) in piglets. The molecular regulation of E. coli F18 resistance in Chinese domestic weaned piglets is still obscure. We used Meishan piglets as model animals to test their susceptibility to E. coli F18. Small RNA duodenal libraries were constructed for E. coli F18-sensitive and -resistant weaned piglets challenged with E. coli F18 and sequenced using Illumina Solexa high-throughput sequencing technology. Sequencing results showed that 3,475,231 and 37,198,259 clean reads were obtained, with 311 known miRNAs differently expressed in resistant and sensitive groups, respectively. Twenty-four miRNAs, including 15 up-regulated and 9 down-regulated, demonstrated more than a 2-fold differential expression between the F18-resistant and -sensitive piglets. Stem-loop RT-qPCR showed that miR-136, miR-196b, miR-499-5p and miR-218-3p significantly expressed in intestinal tissue (p < 0.05). KEGG pathway analysis for target genes revealed that differently expressed miRNAs were involved in infectious diseases, signal transduction and immune system pathways. Interestingly, the expression of miR-218-3p in intestinal tissue had a very significant negative correlation with target DLG5 (P < 0.01). Based on the expression correlation between miRNA and target genes analysis, we speculate that miR-218-3p targeting to DLG5, appears to be very promising candidate for miRNAs involved in response to E. coli F18 infection. The present study provides improved database information on pig miRNAs, better understanding of the genetic basis of E. coli F18 resistance in local Chinese pig breeds and lays a new foundation for identifying novel markers of E. coli F18 resistance. This article was reviewed by Neil R Smalheiser and Weixiong Zhang.

Depicting changes in tumor biology in response to cetuximab mono- or combination therapy by apoptosis and proliferation imaging using 18F-ICMT-11 and 3'-Deoxy-3'-[18F]Fluorothymidine (18F-FLT) PET.

PubMed

Heinzmann, Kathrin; Nguyen, Quang-De; Honess, Davina Jean; Smith, Donna-Michelle; Stribbling, Stephen; Brickute, Diana; Barnes, Christopher; Griffiths, John Richard; Aboagye, Eric Ofori

2018-05-24

Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7-specific isatin-5-sulfonamide 18 F-ICMT-11 and 3'-Deoxy-3'-[ 18 F]Fluorothymidine ( 18 F-FLT), were employed to detect early treatment-induced changes in tumor biology and whether any changes indicate response to cetuximab, administered as mono- or combination therapy with gemcitabine. Methods: Effects of single or repeated doses of the anti-Epidermal Growth Factor Receptor (EGFR) antibody cetuximab (10mg/kg on day 1 only or day 1 and 2) and/or a single dose of gemcitabine (125mg/kg; day 2) were investigated in mice bearing cetuximab-sensitive H1975 tumors (non-small cell lung cancer) by 18 F-ICMT-11 or 18 F-FLT-PET (day 3). Imaging was also performed in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer) after two doses of cetuximab (day 1 and 2). For imaging/histology comparison, tumors were evaluated for proliferation (Ki67; thymidine kinase 1, TK1), cell death (cleaved caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)) and target engagement (EGFR expression) by immunohistochemistry, immunofluorescence and immunoblot, respectively. Tumor and plasma were analysed for thymidine and gemcitabine metabolites by liquid chromatography-mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. 18 F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab- (75%) and combination-treatment (46%). While one dose of cetuximab was insufficient to induce apoptosis it did affect proliferation. Significant reduction in tumor 18 F-FLT uptake (44 to 50%; P < 0.001) induced by cetuximab mono- and combination-therapy were paralleled with a clear decrease in proliferation (%Ki67 decrease: 72 to 95%; P < 0.0001) and followed by marked tumor growth delay. TK1 expression and tumor thymidine concentrations were profoundly reduced. Neither imaging tracer depicted the gemcitabine-induced tumor changes. However, cleaved caspase-3 and Ki67 staining were not significantly different while TK1 expression and thymidine concentrations increased after gemcitabine-treatment. No cetuximab-induced modulation of the imaging tracers or other response markers was detected in the insensitive model HCT116. Conclusion: 18 F-ICMT-11 and 18 F-FLT are valuable tools to assess cetuximab-sensitivity depicting distinct and time-variant aspects of treatment response. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Web-based Interspecies Correlation Estimation (Web-ICE) for Acute Toxicity: User Manual 3.2

EPA Science Inventory

The Web-ICE Endangered Species module simultaneously estimates toxicity to taxa representing threatened or endangered species using up to 25 surrogates. This module batch processes toxicity values for endangered species from all species, genus, and family level models available f...

Is continuous infusion of imipenem always the best choice?

PubMed

Suchánková, Hana; Lipš, Michal; Urbánek, Karel; Neely, Michael N; Strojil, Jan

2017-03-01

Monte Carlo simulations allow prediction and comparison of concentration-time profiles arising from different dosing regimens in a defined population, provided a population pharmacokinetic model has been established. The aims of this study were to evaluate the population pharmacokinetics of imipenem in critically ill patients with hospital-acquired pneumonia (HAP) and to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) using EUCAST data. A two-compartment model based on a data set of 19 subjects was employed. Various dosage regimens at 0.5-h and 3-h infusion rates and as continuous infusion were evaluated against the pharmacodynamic targets of 20%fT >MIC , 40%fT >MIC and 100%fT >MIC . For the target of 40%fT >MIC , all 0.5-h infusion regimens achieved optimal exposures (CFR ≥ 90%) against Escherichia coli and Staphylococcus aureus, with nearly optimal exposure against Klebsiella pneumoniae (CFR ≥ 89.4%). The 3-h infusions and continuous infusion exceeded 97% CFR against all pathogens with the exception of Pseudomonas aeruginosa and Acinetobacter spp., where the maximum CFRs were 85.5% and 88.4%, respectively. For the 100%fT >MIC target, only continuous infusion was associated with nearly optimal exposures. Higher PTAs for the targets of 40%fT >MIC and 100%fT >MIC were achieved with 3-h infusions and continuous infusion in comparison with 0.5-h infusions; however, continuous infusion carries a risk of not reaching the MIC of less susceptible pathogens in a higher proportion of patients. In critically ill patients with HAP with risk factors for Gram-negative non-fermenting bacteria, maximum doses administered as extended infusions may be necessary. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Integromics network meta-analysis on cardiac aging offers robust multi-layer modular signatures and reveals micronome synergism.

PubMed

Dimitrakopoulou, Konstantina; Vrahatis, Aristidis G; Bezerianos, Anastasios

2015-03-04

The avalanche of integromics and panomics approaches shifted the deciphering of aging mechanisms from single molecular entities to communities of them. In this orientation, we explore the cardiac aging mechanisms - risk factor for multiple cardiovascular diseases - by capturing the micronome synergism and detecting longevity signatures in the form of communities (modules). For this, we developed a meta-analysis scheme that integrates transcriptome expression data from multiple cardiac-specific independent studies in mouse and human along with proteome and micronome interaction data in the form of multiple independent weighted networks. Modularization of each weighted network produced modules, which in turn were further analyzed so as to define consensus modules across datasets that change substantially during lifespan. Also, we established a metric that determines - from the modular perspective - the synergism of microRNA-microRNA interactions as defined by significantly functionally associated targets. The meta-analysis provided 40 consensus integromics modules across mouse datasets and revealed microRNA relations with substantial collective action during aging. Three modules were reproducible, based on homology, when mapped against human-derived modules. The respective homologs mainly represent NADH dehydrogenases, ATP synthases, cytochrome oxidases, Ras GTPases and ribosomal proteins. Among various observations, we corroborate to the involvement of miR-34a (included in consensus modules) as proposed recently; yet we report that has no synergistic effect. Moving forward, we determined its age-related neighborhood in which HCN3, a known heart pacemaker channel, was included. Also, miR-125a-5p/-351, miR-200c/-429, miR-106b/-17, miR-363/-92b, miR-181b/-181d, miR-19a/-19b, let-7d/-7f, miR-18a/-18b, miR-128/-27b and miR-106a/-291a-3p pairs exhibited significant synergy and their association to aging and/or cardiovascular diseases is supported in many cases by a disease database and previous studies. On the contrary, we suggest that miR-22 has not substantial impact on heart longevity as proposed recently. We revised several proteins and microRNAs recently implicated in cardiac aging and proposed for the first time modules as signatures. The integromics meta-analysis approach can serve as an efficient subvening signature tool for more-oriented better-designed experiments. It can also promote the combinational multi-target microRNA therapy of age-related cardiovascular diseases along the continuum from prevention to detection, diagnosis, treatment and outcome.

Highlights of DAMA/LIBRA

NASA Astrophysics Data System (ADS)

Bernabei, R.; Belli, P.; d'Angelo, A.; d'Angelo, S.; Di Marco, A.; Montecchia, F.; Incicchitti, A.; Cappella, F.; Caracciolo, V.; Cerulli, R.; Dai, C. J.; He, H. L.; Kuang, H. H.; Ma, X. H.; Sheng, X. D.; Wang, R. G.; Ye, Z. P.

2016-11-01

The DAMA project develops and uses new/improved low background scintillation detectors to investigate the Dark Matter (DM) particle component(s) in the galactic halo and rare processes deep underground at the Gran Sasso National Laboratory (LNGS) of the I.N.F.N.. Here some highlights of DAMA/LIBRA (Large sodium Iodide Bulk for Rare processes) as a unique apparatus in direct DM investigation for its full sensitive mass, target material, intrinsic radio-purity, methodological approach and all the controls performed on the experimental parameters are outlined. The DAMA/LIBRA-phase1 and the former DAMA/NaI data (cumulative exposure 1.33 ton × yr, corresponding to 14 annual cycles) have reached a model-independent evidence at 9.3 σ C.L. for the presence of DM particles in the galactic halo exploiting the DM annual modulation signature with highly radio-pure NaI(Tl) target. Some of the perspectives of the presently running DAMA/LIBRA-phase2 are summarised and the powerful tools offered by a model independent strategy of DM investigation are pointed out.

Electron impact elastic and excitation cross-sections of the isomers of C4F6 molecule for plasma modeling

NASA Astrophysics Data System (ADS)

Gupta, Dhanoj; Song, Mi-Young; Baluja, K. L.; Choi, Heechol; Yoon, Jung-Sik

2018-06-01

We report the calculations of elastic (along with its symmetry components) and electronic excitation cross sections by electron impact of the three isomers of C4F6, namely, hexafluoro-1,3-butadiene (1,3-C4F6), hexafluoro-2-butyne (2-C4F6), and hexafluorocyclobutene (c-C4F6) belonging to the point groups C2, D3d, and C2v, respectively, using the R-matrix approach. The electron energy range is from 0.01 eV to 12 eV. We have employed the cc-pVTZ basis set for C and F atoms to generate self-consistent field molecular orbitals to construct the target states for all the isomers included in our calculations. All the target states are constructed by including correlation effects in a configuration interaction (CI) approach. The target properties such as vertical excitation energies and dipole moment of all the isomers are in reasonable agreement with the literature values. Differences in the cross sections of these isomers are strongly influenced by the effect of correlation and polarization effects and their geometrical extent. We have included the ground state and many excited states of each isomer in the trial wave function of the entire scattering system. The resulting elastic cross sections are compared with the available experimental results. The agreement is reasonably good for energies above 5 eV. The shape resonances detected at 2.57, 2.95, and 3.20 eV for c-C4F6, 1,3-C4F6, and 2-C4F6 isomers are associated with the negative anion formation of C3F3- as observed in the mass spectrometry experiments. We have also performed 1-state CI calculation for all the isomers that include only the correlated ground state. The position of resonances shifts to lower energies as the number of target states is increased compared to 1-state calculation for all the isomers. The elastic cross section for 2-C4F6 isomer is larger than the other isomers because of its larger spatial extent. The present cross section data are important for plasma simulation and modeling, especially related to fluorocarbon plasma.

Observation of TiF+ by Velocity Modulation Laser Spectroscopy and Analysis of the

PubMed

Focsa; Pinchemel; Collet; Huet

1998-06-01

The molecular ion TiF+ has been observed for the first time using high-resolution spectroscopy. The ions were produced in the positive column of an AC glow discharge with a gas mixture of He/TiF4. A single-mode cw dye laser along with the velocity modulation detection technique was used to record an absorption spectrum in the spectral region 16 800-18 600 cm-1. The observed system was assigned to the 0-0 and 1-1 bands of the [17.6]3Delta-X3Phi transition of TiF+. The rotational analysis of the main subbands has been performed up to J values equal to 77 and 56 for the 0-0 and 1-1 bands, respectively. Despite a careful search, no intercombination band was observed. A set of effective molecular parameters has been determined, characterizing the v = 0, 1 levels of the [17.6]3Delta and X3Phi states. The spin-orbit constants Ae and the vibrational constants omegae, omegaexe have been estimated for both electronic states, as well as their equilibrium distances Re (1.7509 and 1.7800) Å for the [17.6]3Delta and X3Phi states, respectively). Copyright 1998 Academic Press.

Combining Fourier phase encoding and broadband inversion toward J-edited spectra

NASA Astrophysics Data System (ADS)

Lin, Yulan; Guan, Quanshuai; Su, Jianwei; Chen, Zhong

2018-06-01

Nuclear magnetic resonance (NMR) spectra are often utilized for gathering accurate information relevant to molecular structures and composition assignments. In this study, we develop a homonuclear encoding approach based on imparting a discrete phase modulation of the targeted cross peaks, and combine it with a pure shift experiments (PSYCHE) based J-modulated scheme, providing simple 2D J-edited spectra for accurate measurement of scalar coupling networks. Chemical shifts and J coupling constants of protons coupled to the specific protons are demonstrated along the F2 and F1 dimensions, respectively. Polychromatic pulses by Fourier phase encoding were performed to simultaneously detect several coupling networks. Proton-proton scalar couplings are chosen by a polychromatic pulse and a PSYCHE element. Axis peaks and unwanted couplings are complete eradicated by incorporating a selective COSY block as a preparation period. The theoretical principles and the signal processing procedure are laid out, and experimental observations are rationalized on the basis of theoretical analyses.

Superpixel-based spatial amplitude and phase modulation using a digital micromirror device.

PubMed

Goorden, Sebastianus A; Bertolotti, Jacopo; Mosk, Allard P

2014-07-28

We present a superpixel method for full spatial phase and amplitude control of a light beam using a digital micromirror device (DMD) combined with a spatial filter. We combine square regions of nearby micromirrors into superpixels by low pass filtering in a Fourier plane of the DMD. At each superpixel we are able to independently modulate the phase and the amplitude of light, while retaining a high resolution and the very high speed of a DMD. The method achieves a measured fidelity F = 0.98 for a target field with fully independent phase and amplitude at a resolution of 8 × 8 pixels per diffraction limited spot. For the LG10 orbital angular momentum mode the calculated fidelity is F = 0.99993, using 768 × 768 DMD pixels. The superpixel method reduces the errors when compared to the state of the art Lee holography method for these test fields by 50% and 18%, with a comparable light efficiency of around 5%. Our control software is publicly available.

SU-F-BRD-01: A Novel 4D Robust Optimization Mitigates Interplay Effect in Intensity-Modulated Proton Therapy for Lung Cancer

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

Liu, W; Shen, J; Stoker, J

2015-06-15

Purpose: To compare the impact of interplay effect on 3D and 4D robustly optimized intensity-modulated proton therapy (IMPT) plans to treat lung cancer. Methods: Two IMPT plans were created for 11 non-small-cell-lung-cancer cases with 6–14 mm spots. 3D robust optimization generated plans on average CTs with the internal gross tumor volume density overridden to deliver 66 CGyE in 33 fractions to the internal target volume (ITV). 4D robust optimization generated plans on 4D CTs with the delivery of prescribed dose to the clinical target volume (CTV). In 4D optimization, the CTV of individual 4D CT phases received non-uniform doses tomore » achieve a uniform cumulative dose. Dose evaluation software was developed to model time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Patient anatomy voxels were mapped from phase to phase via deformable image registration to score doses. Indices from dose-volume histograms were used to compare target coverage, dose homogeneity, and normal-tissue sparing. DVH indices were compared using Wilcoxon test. Results: Given the presence of interplay effect, 4D robust optimization produced IMPT plans with better target coverage and homogeneity, but slightly worse normal tissue sparing compared to 3D robust optimization (unit: Gy) [D95% ITV: 63.5 vs 62.0 (p=0.014), D5% - D95% ITV: 6.2 vs 7.3 (p=0.37), D1% spinal cord: 29.0 vs 29.5 (p=0.52), Dmean total lung: 14.8 vs 14.5 (p=0.12), D33% esophagus: 33.6 vs 33.1 (p=0.28)]. The improvement of target coverage (D95%,4D – D95%,3D) was related to the ratio RMA3/(TVx10−4), with RMA and TV being respiratory motion amplitude (RMA) and tumor volume (TV), respectively. Peak benefit was observed at ratios between 2 and 10. This corresponds to 125 – 625 cm3 TV with 0.5-cm RMA. Conclusion: 4D optimization produced more interplay-effect-resistant plans compared to 3D optimization. It is most effective when respiratory motion is modest compared to TV. NIH/NCI K25CA168984; Eagles Cancer Research Career Development; The Lawrence W. and Marilyn W. Matteson Fund for Cancer Research; Mayo ASU Seed Grant; The Kemper Marley Foundation.« less

Free-form reflective optics for mid-infrared camera and spectrometer on board SPICA

NASA Astrophysics Data System (ADS)

Fujishiro, Naofumi; Kataza, Hirokazu; Wada, Takehiko; Ikeda, Yuji; Sakon, Itsuki; Oyabu, Shinki

2017-11-01

SPICA (Space Infrared Telescope for Cosmology and Astrophysics) is an astronomical mission optimized for mid-and far-infrared astronomy with a cryogenically cooled 3-m class telescope, envisioned for launch in early 2020s. Mid-infrared Camera and Spectrometer (MCS) is a focal plane instrument for SPICA with imaging and spectroscopic observing capabilities in the mid-infrared wavelength range of 5-38μm. MCS consists of two relay optical modules and following four scientific optical modules of WFC (Wide Field Camera; 5'x 5' field of view, f/11.7 and f/4.2 cameras), LRS (Low Resolution Spectrometer; 2'.5 long slits, prism dispersers, f/5.0 and f/1.7 cameras, spectral resolving power R ∼ 50-100), MRS (Mid Resolution Spectrometer; echelles, integral field units by image slicer, f/3.3 and f/1.9 cameras, R ∼ 1100-3000) and HRS (High Resolution Spectrometer; immersed echelles, f/6.0 and f/3.6 cameras, R ∼ 20000-30000). Here, we present optical design and expected optical performance of MCS. Most parts of MCS optics adopt off-axis reflective system for covering the wide wavelength range of 5-38μm without chromatic aberration and minimizing problems due to changes in shapes and refractive indices of materials from room temperature to cryogenic temperature. In order to achieve the high specification requirements of wide field of view, small F-number and large spectral resolving power with compact size, we employed the paraxial and aberration analysis of off-axial optical systems (Araki 2005 [1]) which is a design method using free-form surfaces for compact reflective optics such as head mount displays. As a result, we have successfully designed compact reflective optics for MCS with as-built performance of diffraction-limited image resolution.

Programming mRNA decay to modulate synthetic circuit resource allocation

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

Venturelli, Ophelia S.; Tei, Mika; Bauer, Stefan

Synthetic circuits embedded in host cells compete with cellular processes for limited intracellular resources. Here we show how funnelling of cellular resources, after global transcriptome degradation by the sequence-dependent endoribonuclease MazF, to a synthetic circuit can increase production. Target genes are protected from MazF activity by recoding the gene sequence to eliminate recognition sites, while preserving the amino acid sequence. The expression of a protected fluorescent reporter and flux of a high-value metabolite are significantly enhanced using this genome-scale control strategy. Proteomics measurements discover a host factor in need of protection to improve resource redistribution activity. A computational model demonstratesmore » that the MazF mRNA-decay feedback loop enables proportional control of MazF in an optimal operating regime. Transcriptional profiling of MazF-induced cells elucidates the dynamic shifts in transcript abundance and discovers regulatory design elements. Altogether, our results suggest that manipulation of cellular resource allocation is a key control parameter for synthetic circuit design.« less

Programming mRNA decay to modulate synthetic circuit resource allocation

DOE PAGES

Venturelli, Ophelia S.; Tei, Mika; Bauer, Stefan; ...

2017-04-26

Synthetic circuits embedded in host cells compete with cellular processes for limited intracellular resources. Here we show how funnelling of cellular resources, after global transcriptome degradation by the sequence-dependent endoribonuclease MazF, to a synthetic circuit can increase production. Target genes are protected from MazF activity by recoding the gene sequence to eliminate recognition sites, while preserving the amino acid sequence. The expression of a protected fluorescent reporter and flux of a high-value metabolite are significantly enhanced using this genome-scale control strategy. Proteomics measurements discover a host factor in need of protection to improve resource redistribution activity. A computational model demonstratesmore » that the MazF mRNA-decay feedback loop enables proportional control of MazF in an optimal operating regime. Transcriptional profiling of MazF-induced cells elucidates the dynamic shifts in transcript abundance and discovers regulatory design elements. Altogether, our results suggest that manipulation of cellular resource allocation is a key control parameter for synthetic circuit design.« less

Modulated visible spectra properties of Pr:Ca1-xRxF2+x(R=Y, La, Gd) crystals

NASA Astrophysics Data System (ADS)

Yu, Hao; Qian, Xiaobo; Wu, Qinghui; Ma, Fengkai; Wang, Jingya; Xu, Jun; Su, Liangbi

2017-10-01

The spectroscopic properties of the 1.0 at.%Pr:Ca0.97R0.02F2.03(R=Y, La, Gd) crystals are investigated. X-diffraction and room temperature absorption spectra have been registered and analyzed. The emission spectra and decay curves of the crystals were obtained at room temperature. The photoluminescence intensity in the visible region is significantly enhanced by co-doping R3+ ions in Pr:CaF2 crystal. The different effects among the R3+ (Y3+, La3+ and Gd3+) regulating ions on the crystals were observed and compared. Pr:Ca0.97La0.02F2.03 and Pr:Ca0.97Y0.02F2.03 crystals have substantially strong emission at blue and orange region, while the Pr:Ca0.97Gd0.02F2.03 crystal is more suitable for the red emission emitting.

Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting

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

Ge, Xin; Lyu, Pengwei; Cao, Zhang

miRNAs, sorting as non-coding RNAs, are differentially expressed in breast tumor and act as tumor promoters or suppressors. miR-206 could suppress the progression of breast cancer, the mechanism of which remains unclear. The study here was aimed to investigate the effect of miR-206 on human breast cancers. We found that miR-206 was down-regulated while one of its predicted targets, 6-Phosphofructo-2-kinase (PFKFB3) was up-regulated in human breast carcinomas. 17β-estradiol dose-dependently decreased miR-206 expression as well as enhanced PFKFB3 mRNA and protein expression in estrogen receptor α (ERα) positive breast cancer cells. Furthermore, we identified that miR-206 directly interacted with 3′-untranslated regionmore » (UTR) of PFKFB3 mRNA. miR-206 modulated PFKFB3 expression in MCF-7, T47D and SUM159 cells, which was influenced by 17β-estradiol depending on ERα expression. In addition, miR-206 overexpression impeded fructose-2,6-bisphosphate (F2,6BP) production, diminished lactate generation and reduced cell proliferation and migration in breast cancer cells. In conclusion, our study demonstrated that miR-206 regulated PFKFB3 expression in breast cancer cells, thereby stunting glycolysis, cell proliferation and migration. - Highlights: • miR-206 was down-regulated and PFKFB3 was up-regulated in human breast carcinomas. • 17β-estradiol regulated miR-206 and PFKFB3 expression in ERα+ cancer cells. • miR-206directly interacted with 3′-UTR of PFKFB3 mRNA. • miR-206 fructose-2,6-bisphosphate (F2,6BP) impeded production and lactate generation. • miR-206 reduced cell proliferation and migration in breast cancer cells.« less

Influenza A virus protein PB1-F2 exacerbates IFN-beta expression of human respiratory epithelial cells.

PubMed

Le Goffic, Ronan; Bouguyon, Edwige; Chevalier, Christophe; Vidic, Jasmina; Da Costa, Bruno; Leymarie, Olivier; Bourdieu, Christiane; Decamps, Laure; Dhorne-Pollet, Sophie; Delmas, Bernard

2010-10-15

The PB1-F2 protein of the influenza A virus (IAV) contributes to viral pathogenesis by a mechanism that is not well understood. PB1-F2 was shown to modulate apoptosis and to be targeted by the CD8(+) T cell response. In this study, we examined the downstream effects of PB1-F2 protein during IAV infection by measuring expression of the cellular genes in response to infection with wild-type WSN/33 and PB1-F2 knockout viruses in human lung epithelial cells. Wild-type virus infection resulted in a significant induction of genes involved in innate immunity. Knocking out the PB1-F2 gene strongly decreased the magnitude of expression of cellular genes implicated in antiviral response and MHC class I Ag presentation, suggesting that PB1-F2 exacerbates innate immune response. Biological network analysis revealed the IFN pathway as a link between PB1-F2 and deregulated genes. Using quantitative RT-PCR and IFN-β gene reporter assay, we determined that PB1-F2 mediates an upregulation of IFN-β expression that is dependent on NF-κB but not on AP-1 and IFN regulatory factor-3 transcription factors. Recombinant viruses knocked out for the PB1-F2 and/or the nonstructural viral protein 1 (the viral antagonist of the IFN response) genes provide further evidence that PB1-F2 increases IFN-β expression and that nonstructural viral protein 1 strongly antagonizes the effect of PB1-F2 on the innate response. Finally, we compared the effect of PB1-F2 variants taken from several IAV strains on IFN-β expression and found that PB1-F2-mediated IFN-β induction is significantly influenced by its amino acid sequence, demonstrating its importance in the host cell response triggered by IAV infection.

SU-E-T-811: Volumetric Modulated Arc Therapy Vs. C-IMRT for the Treatment of Upper Thoracic Esophageal Cancer

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

Zhang, W; Wu, L; Lu, J

2015-06-15

Purpose: To compare plans using volumetric-modulated arc therapy (VMAT) with conventional sliding window intensity-modulated radiation therapy (c-IMRT) to treat upper thoracic esophageal cancer (EC). Methods: CT datasets of 11 patients with upper thoracic EC were identified. Four plans were generated for each patient: c-IMRT with 5 fields (5F) and VMAT with a single arc (1A), two arcs (2A), or three arcs (3A). The prescribed doses were 64 Gy/32 F for the primary tumor (planning target volume 64, PTV64). The dose-volume histogram data, the number of monitoring units (MUs) and the treatment time (TT) for the different plans were compared. Results:more » All of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan. The CI of the PTV64 was improved by increasing the number of arcs in the VMAT plans. The maximum spinal cord dose and the planning risk volume of the spinal cord dose for the two techniques were similar. The 2A- and 3A-VMAT plans yielded lower mean lung doses and heart V50 than the c-IMRT. The V20 and V30 for the lungs in all of the VMAT plans were lower than those in the c-IMRT plan, at the expense of increasing V5, V10 and V13. The VMAT plan resulted in significant reductions in MUs and TT. Conclusion: The 2A-VMAT plan appeared to spare the lungs from moderate-dose irradiation most effectively of all plans, at the expense of increasing the low-dose irradiation volume, and also significantly reduced the number of required MUs and the TT. The CI of the PTVs and the OARs was improved by increasing the arc-number from 1 to 2. however, no significant improvement was observed using the 3A-VMAT, except for an increase in the TT. This work was sponsored by Shantou University Medical College Clinical Research Enhancement Initiative(NO.201424)« less

Improved synthesis of [(18)F]FLETT via a fully automated vacuum distillation method for [(18)F]2-fluoroethyl azide purification.

PubMed

Ackermann, Uwe; Plougastel, Lucie; Goh, Yit Wooi; Yeoh, Shinn Dee; Scott, Andrew M

2014-12-01

The synthesis of [(18)F]2-fluoroethyl azide and its subsequent click reaction with 5-ethynyl-2'-deoxyuridine (EDU) to form [(18)F]FLETT was performed using an iPhase FlexLab module. The implementation of a vacuum distillation method afforded [(18)F]2-fluoroethyl azide in 87±5.3% radiochemical yield. The use of Cu(CH3CN)4PF6 and TBTA as catalyst enabled us to fully automate the [(18)F]FLETT synthesis without the need for the operator to enter the radiation field. [(18)F]FLETT was produced in higher overall yield (41.3±6.5%) and shorter synthesis time (67min) than with our previously reported manual method (32.5±2.5% in 130min). Copyright © 2014 Elsevier Ltd. All rights reserved.

Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

PubMed Central

Alteri, Claudia; Surdo, Matteo; Bellocchi, Maria Concetta; Saccomandi, Patrizia; Continenza, Fabio; Armenia, Daniele; Parrotta, Lucia; Carioti, Luca; Costa, Giosuè; Fourati, Slim; Di Santo, Fabiola; Scutari, Rossana; Barbaliscia, Silvia; Fedele, Valentina; Carta, Stefania; Balestra, Emanuela; Alcaro, Stefano; Marcelin, Anne Genevieve; Calvez, Vincent; Ceccherini-Silberstein, Francesca; Artese, Anna

2015-01-01

Incomplete APOBEC3G/F neutralization by a defective HIV-1Vif protein can promote genetic diversification by inducing G-to-A mutations in the HIV-1 genome. The HIV-1 Env V3 loop, critical for coreceptor usage, contains several putative APOBEC3G/F target sites. Here, we determined if APOBEC3G/F, in the presence of Vif-defective HIV-1 virus, can induce G-to-A mutations at V3 positions critical to modulation of CXCR4 usage. Peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from 2 HIV-1-negative donors were infected with CCR5-using 81.A-VifWT virus (i.e., with wild-type [WT] Vif protein), 81.A-VifE45G, or 81.A-VifK22E (known to incompletely/partially neutralize APOBEC3G/F). The rate of G-toA mutations was zero or extremely low in 81.A-VifWT- and 81.A-VifE45G-infected PBMC from both donors. Conversely, G-to-A enrichment was detected in 81.A-VifK22E-infected PBMC (prevalence ranging from 2.18% at 7 days postinfection [dpi] to 3.07% at 21 dpi in donor 1 and from 10.49% at 7 dpi to 8.69% at 21 dpi in donor 2). A similar scenario was found in MDM. G-to-A mutations occurred at 8 V3 positions, resulting in nonsynonymous amino acid substitutions. Of them, G24E and E25K strongly correlated with phenotypically/genotypically defined CXCR4-using viruses (P = 0.04 and 5.5e−7, respectively) and increased the CXCR4 N-terminal binding affinity for V3 (WT, −40.1 kcal/mol; G24E, −510 kcal/mol; E25K, −522 kcal/mol). The analysis of paired V3 and Vif DNA sequences from 84 HIV-1-infected patients showed that the presence of a Vif-defective virus correlated with CXCR4 usage in proviral DNA (P = 0.04). In conclusion, incomplete APOBEC3G/F neutralization by a single Vif amino acid substitution seeds a CXCR4-using proviral reservoir. This can have implications for the success of CCR5 antagonist-based therapy, as well as for the risk of disease progression. PMID:26055363

Glycogen synthase kinase-3β (GSK3β) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice

PubMed Central

Zhang, Ping; Katz, Jenny; Michalek, Suzanne M.

2011-01-01

Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3β inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3β. Inhibition of GSK3β resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-α, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3β regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-κB and CREB. Inhibition of GSK3β by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-γ contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-γ produced. IFN-γ potentiated F. tularensis LVS-induced cytokine production by increasing GSK3β activity and the nuclear translocation of NF-κB. Taken together, these results demonstrate a regulatory function of GSK3β in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3β may represent a novel therapeutic approach in the treatment of tularemia. PMID:18929413

Intracavity Faraday modulation spectroscopy (INFAMOS): A tool for radical detection

NASA Astrophysics Data System (ADS)

Gianella, Michele; Pinto, Tomas H. P.; Wu, Xia; Ritchie, Grant A. D.

2017-08-01

We present the intra-cavity Faraday modulation spectroscopy technique, whereby optical feedback cavity-enhanced spectroscopy is coupled with Faraday modulation spectroscopy to greatly enhance the interaction path length of a laser beam with a paramagnetic sample in a magnetic field. We describe a first prototype based upon a cw quantum cascade laser targeting a selection of fundamental rovibrational R-branch transitions of nitric oxide (1890 cm-1), consisting of a linear cavity (finesse F =6300 ) and a water-cooled solenoid. We demonstrate a minimum detectable Verdet constant of Vmin=4.7 ×10-14 rad cm-1 G-1 H z-1/2 (at SNR = 1), corresponding to a single-pass rotation angle of 1.6 ×10-10 rad Hz-1/2 and a limit of detection of 0.21 ppbv Hz-1/2 NO.

Final Report for PV Incubator Subcontract No. NAT-0-99013-01: June 14, 2010 - March 2, 2012

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

Ghosal, K.

2012-04-01

The goal of the subcontract is to scale up Semprius' novel micro-cell based modules to an annualized rate of 500 kW of receivers and 10 kW of modules, in support of the DOE 2020 Sunshot Initiative goals. The statement of work (SOW) was broken up into two Phases. Phase I was directed towards process development efforts towards addressing fundamental manufacturing metrics such as yield, die per wafer, automation and throughput. Phase II objectives are to scale to an annualized production rate of 500 kW of receivers and 10 kW of modules, while improving cell efficiency, module efficiency and transfer yield.more » Semprius has met all the technical milestones and deliverables for the contract. All subtasks were completed earlier than expected and the results exceeded the technical targets. In particular, 3J cell efficiency of 41.2% exceeded the target of 38%, module efficiency of 28.3% exceeded the target of 28% and transfer yield of 96.4% exceeds the target of 95%, with all tasks completed well ahead of schedule. Also, devices fabricated from 1st use GaAs substrates and substrates with two re-uses have been shown to be identical.« less

Differential expression of microRNAs in Francisella tularensis-infected human macrophages: miR-155-dependent downregulation of MyD88 inhibits the inflammatory response.

PubMed

Bandyopadhyay, Sarmistha; Long, Matthew E; Allen, Lee-Ann H

2014-01-01

Francisella tularensis is a Gram-negative, facultative intracellular pathogen that replicates in the cytosol of macrophages and is the causative agent of the potentially fatal disease tularemia. A characteristic feature of F. tularensis is its limited proinflammatory capacity, but the mechanisms that underlie the diminished host response to this organism are only partially defined. Recently, microRNAs have emerged as important regulators of immunity and inflammation. In the present study we investigated the microRNA response of primary human monocyte-derived macrophages (MDMs) to F. tularensis and identified 10 microRNAs that were significantly differentially expressed after infection with the live vaccine strain (LVS), as judged by Taqman Low Density Array profiling. Among the microRNAs identified, miR-155 is of particular interest as its established direct targets include components of the Toll-like receptor (TLR) pathway, which is essential for innate defense and proinflammatory cytokine production. Additional studies demonstrated that miR-155 acted by translational repression to downregulate the TLR adapter protein MyD88 and the inositol 5'-phosphatase SHIP-1 in MDMs infected with F. tularensis LVS or the fully virulent strain Schu S4. Kinetic analyses indicated that miR-155 increased progressively 3-18 hours after infection with LVS or Schu S4, and target proteins disappeared after 12-18 hours. Dynamic modulation of MyD88 and SHIP-1 was confirmed using specific pre-miRs and anti-miRs to increase and decrease miR-155 levels, respectively. Of note, miR-155 did not contribute to the attenuated cytokine response triggered by F. tularensis phagocytosis. Instead, this microRNA was required for the ability of LVS-infected cells to inhibit endotoxin-stimulated TNFα secretion 18-24 hours after infection. Thus, our data are consistent with the ability of miR-155 to act as a global negative regulator of the inflammatory response in F. tularensis-infected human macrophages.

Dosimetric effect of Elekta Beam Modulator micromultileaf in three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer

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

Carosi, Alessandra, E-mail: alessandra.carosi@katamail.com; Ingrosso, Gianluca; Ponti, Elisabetta

2014-07-01

The purpose of this study is to analyze the dosimetric effect of Elekta Beam Modulator in 3-dimensional conformal radiation therapy (3DCRT) and in intensity-modulated radiation therapy (IMRT) for localized prostate cancer. We compared treatment plans developed with 2 different Elekta multileaf collimators (MLC): Beam Modulator micro-MLC (mMLC) (4-mm leaf width at the isocenter) and standard MLC (10-mm leaf width at the isocenter). The comparison was performed for 15 patients with localized prostate cancer in 3DCRT and IMRT delivery; a total of 60 treatment plans were processed. The dose-volume histograms were used to provide the quantitative comparison between plans. In particular,more » we analyzed differences between rectum and bladder sparing in terms of a set of appropriate Vx (percentage of organ at risk [OAR] volume receiving the x dose) and differences between target conformity and coverage in terms of coverage factor and conformation number. Our analysis demonstrates that in 3DCRT there is an advantage in the use of Elekta Beam Modulator mMLC in terms of organ sparing; in particular, a significant decrease in rectal V{sub 60} and V{sub 50} (p = 0.001) and in bladder V{sub 70} and V{sub 65} (p = 0.007 and 0.002, respectively) was found. Moreover, a better target dose conformity was obtained (p = 0.002). IMRT plans comparison demonstrated no significant differences between the use of the 4 or 10-mm MLCs. Our analysis shows that in 3DCRT the use of the Elekta Beam Modulator mMLC gives a gain in target conformity and in OARs dose sparing whereas in IMRT plans there is no advantage.« less

Calibration-free wavelength modulation spectroscopy for gas concentration measurements using a quantum cascade laser

NASA Astrophysics Data System (ADS)

Wei, Min; Kan, RuiFeng; Chen, Bing; Xu, ZhenYu; Yang, ChenGuang; Chen, Xiang; Xia, HuiHui; Hu, Mai; He, Yabai; Liu, JianGuo; Fan, XueLi; Wang, Wei

2017-05-01

We report the development of an accurate calibration-free wavelength-scanned wavelength modulation spectroscopy system based on the temporal wavelength response of a current-modulated quantum cascade laser (QCL) for gas concentration detections. Accurate measurements and determination of the QCL output intensity and wavelength response to current modulation enabled calculations of 1f-normalized 2f signal to obtain spectroscopic information with and without gas absorption in the beam path. The gas concentration was retrieved by fitting a simulation spectrum based on spectral line parameters to the background-subtracted 1f-normalized 2f signal based on measurements. In this paper, we demonstrate the performance of the developed system for the CH4 detection by applying an infrared QCL (at 7.84 µm or 1275 cm-1) to probe its two infrared transition lines at 1275.042 cm-1 and 1275.387 cm-1. The experimental results indicated very good agreements between measurements and modeling, for integrated absorbance ranging from 0.0057 cm-1 to 0.11 cm-1 (or absorbance ranging from 0.029 to 0.57). The extracted integrated absorbance was highly linear ( R = 0.99996) to the gas sample concentration. Deviations between the nominal sample gas concentrations and the extracted gas concentrations calculated based on HITRAN spectroscopic parameters were within 3.5%.

Semaphorin 3F Is a Bifunctional Guidance Cue for Dopaminergic Axons and Controls Their Fasciculation, Channeling, Rostral Growth, and Intracortical Targeting

PubMed Central

Kolk, Sharon M.; Gunput, Rou-Afza F.; Tran, Tracy S.; van den Heuvel, Dianne M. A.; Prasad, Asheeta A.; Hellemons, Anita J. C. G. M.; Adolfs, Youri; Ginty, David D.; Kolodkin, Alex L.; Burbach, J. Peter H.; Smidt, Marten P.; Pasterkamp, R. Jeroen

2010-01-01

Dopaminergic neurons in the mesodiencephalon (mdDA neurons) make precise synaptic connections with targets in the forebrain via the mesostriatal, mesolimbic, and mesoprefrontal pathways. Because of the functional importance of these remarkably complex ascending axon pathways and their implication in human disease, the mechanisms underlying the development of these connections are of considerable interest. Despite extensive in vitro studies, the molecular determinants that ensure the perfect formation of these pathways in vivo remain mostly unknown. Here, we determine the embryonic origin and ontogeny of the mouse mesoprefrontal pathway and use these data to reveal an unexpected requirement for semaphorin 3F (Sema3F) and its receptor neuropilin-2 (Npn-2) during mdDA pathway development using tissue culture approaches and analysis of sema3F−/−, npn-2−/−, and npn-2−/−;TH-Cre mice. We show that Sema3F is a bifunctional guidance cue for mdDA axons, some of which have the remarkable ability to regulate their responsiveness to Sema3F as they develop. During early developmental stages, Sema3F chemorepulsion controls previously uncharacterized aspects of mdDA pathway development through both Npn-2-dependent (axon fasciculation and channeling) and Npn-2-independent (rostral growth) mechanisms. Later on, chemoattraction mediated by Sema3F and Npn-2 is required to orient mdDA axon projections in the cortical plate of the medial prefrontal cortex. This latter finding demonstrates that regulation of axon orientation in the target field occurs by chemoattractive mechanisms, and this is likely to also apply to other neural systems. In all, this study provides a framework for additional dissection of the molecular basis of mdDA pathway development and disease. PMID:19812329

New production systems at ISOLDE

NASA Astrophysics Data System (ADS)

Hagebø, E.; Hoff, P.; Jonsson, O. C.; Kugler, E.; Omtvedt, J. P.; Ravn, H. L.; Steffensen, K.

1992-08-01

New target systems for the ISOLDE on-line mass separator facility are presented. Targets of carbides, metal/graphite mixtures, foils of refractory metals, molten metals and oxides have been tested. Beams of high intensity of neutron-rich isotopes of a large number of elements are obtained from a uranium carbide target with a hot plasma-discharge ion source. A target of ZrO 2 has been shown to provide high intensity beams of neutron-deficient isotopes of Mn, Cu, Zn, Ga, Ge, As, Se, Br, Kr and Rb, while a SiC target with a hot plasma ion source gives intense beams of radioactive isotopes of a number of light elements. All these systems are rather chemically unselective. Chemically selective performance has been obtained for several systems, i.e.: the production of neutron-deficient Au from ( 3He, pχn) reactions on a Pt/graphite target with a hot plasma ion source; the production of neutron-deficient Lu and LuF + and Hf and HfF 3+ from a Ta-foil target with a hot plasma ion source under CF 4 addition; the production of neutron-deficient Sr as SrF + and Y as YF 2+ form a Nb-foil target with a W surface ionizer under CF 4 addition; the production of neutron-deficient Se as COSe + from a ZrO 2 target with a hot plasma ion source under O 2 addition; and the production of radioactive F from a SiC target with a hot plasma ion source operating in Al vapour.

Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma.

PubMed

Halwani, Rabih; Sultana, Asma; Vazquez-Tello, Alejandro; Jamhawi, Amer; Al-Masri, Abeer A; Al-Muhsen, Saleh

2017-11-01

In a subset of severe asthma patients, chronic airway inflammation is associated with infiltration of neutrophils, Th-17 cells and elevated expression of Th-17-derived cytokines (e.g., interleukin [IL]-17, IL-21, IL-22). Peripheral neutrophils from allergic asthmatics are known to express higher IL-17 cytokine levels than those from healthy subjects, but the regulatory mechanisms involved are not well understood. We hypothesize that Th-17 regulatory cytokines could modulate IL-17 expression in neutrophils. Peripheral blood neutrophils isolated from asthmatics were stimulated with IL-21, IL-23, and IL-6 cytokines and their ability to produce IL-17A and IL-17F was determined relative to healthy controls. Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels were measured in stimulated neutrophil using flow cytometry. The requirement for STAT3 phosphorylation was determined by blocking its activation using a specific chemical inhibitor. Stimulating asthmatic neutrophils with IL-21, 23, and 6 enhanced the production of IL-17A and IL-17F at significantly higher levels comparatively to healthy controls. Stimulating neutrophils with IL-21, IL-23, and IL-6 cytokines enhanced STAT3 phosphorylation, in all cases. Interestingly, inhibiting STAT3 phosphorylation using a specific chemical inhibitor dramatically blocked the ability of neutrophils to produce IL-17, demonstrating that STAT3 activation is the major factor mediating IL-17 gene expression. These findings suggest that neutrophil infiltration in lungs of severe asthmatics may represent an important source of pro-inflammatory IL-17A and -F cytokines, a production enhanced by Th-17 regulatory cytokines, and thus providing a feedback mechanism that sustains inflammation. Our results suggest that STAT3 pathway could be a potential target for regulating neutrophilic inflammation during severe asthma.

Intensity-modulated salvage radiotherapy with simultaneous integrated boost for local recurrence of prostate carcinoma: a pilot study on the place of PET-choline for guiding target volume delineation.

PubMed

Wahart, Aurélien; Guy, Jean-Baptiste; Vallard, Alexis; Geissler, Benjamin; Ben Mrad, Majed; Falk, Alexander T; Prevot, Nathalie; de Laroche, Guy; Rancoule, Chloé; Chargari, Cyrus; Magné, Nicolas

2016-01-01

The aim of this study was to report the first cases of salvage radiotherapy (RT) using the intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) targeted on choline positron emission tomography (PET) uptake in a local recurrent prostate cancer, after a radical prostatectomy. Four patients received salvage irradiation for biochemical relapse that occurred after the initial radical prostatectomy. The relapse occurred from 10 months to 6 years with PSA levels ranging from 2.35 to 4.86 ng ml(-1). For each patient, an (18)F-choline PET-CT showed a focal choline uptake in prostatic fossa, with standardized uptake value calculated on the basis of predicted lean body mass (SUL) max of 3.3-6.8. No involved lymph node or distant metastases were diagnosed. IMRT doses were of 62.7 Gy (1.9 Gy/fraction, 33 fractions), with a SIB of 69.3 Gy (2.1 Gy/fraction, 33 fractions) to a PET-guided target volume. Acute toxicities were limited. We observed no gastrointestinal toxicity ≥grade 2 and only one grade 2 genitourinary toxicity. At 1-month follow-up evaluation, no complication and a decrease in PSA level (6.8-43.8% of the pre-therapeutic level) were reported. After 4 months, a decrease in PSA level was obtained for all the patients, ranging from 30% to 70%. At a median follow-up of 15 months, PSA level was controlled for all the patients, but one of them experienced a distant lymph node recurrence. Salvage irradiation to the prostate bed with SIB guided by PET-CT is feasible, with biological efficacy and no major acute toxicity. IMRT with PET-oriented SIB for salvage treatment of prostate cancer is possible, without major acute toxicity.

The real-time fMRI neurofeedback based stratification of Default Network Regulation Neuroimaging data repository.

PubMed

McDonald, Amalia R; Muraskin, Jordan; Dam, Nicholas T Van; Froehlich, Caroline; Puccio, Benjamin; Pellman, John; Bauer, Clemens C C; Akeyson, Alexis; Breland, Melissa M; Calhoun, Vince D; Carter, Steven; Chang, Tiffany P; Gessner, Chelsea; Gianonne, Alyssa; Giavasis, Steven; Glass, Jamie; Homann, Steven; King, Margaret; Kramer, Melissa; Landis, Drew; Lieval, Alexis; Lisinski, Jonathan; Mackay-Brandt, Anna; Miller, Brittny; Panek, Laura; Reed, Hayley; Santiago, Christine; Schoell, Eszter; Sinnig, Richard; Sital, Melissa; Taverna, Elise; Tobe, Russell; Trautman, Kristin; Varghese, Betty; Walden, Lauren; Wang, Runtang; Waters, Abigail B; Wood, Dylan C; Castellanos, F Xavier; Leventhal, Bennett; Colcombe, Stanley J; LaConte, Stephen; Milham, Michael P; Craddock, R Cameron

2017-02-01

This data descriptor describes a repository of openly shared data from an experiment to assess inter-individual differences in default mode network (DMN) activity. This repository includes cross-sectional functional magnetic resonance imaging (fMRI) data from the Multi Source Interference Task, to assess DMN deactivation, the Moral Dilemma Task, to assess DMN activation, a resting state fMRI scan, and a DMN neurofeedback paradigm, to assess DMN modulation, along with accompanying behavioral and cognitive measures. We report technical validation from n=125 participants of the final targeted sample of 180 participants. Each session includes acquisition of one whole-brain anatomical scan and whole-brain echo-planar imaging (EPI) scans, acquired during the aforementioned tasks and resting state. The data includes several self-report measures related to perseverative thinking, emotion regulation, and imaginative processes, along with a behavioral measure of rapid visual information processing. Technical validation of the data confirms that the tasks deactivate and activate the DMN as expected. Group level analysis of the neurofeedback data indicates that the participants are able to modulate their DMN with considerable inter-subject variability. Preliminary analysis of behavioral responses and specifically self-reported sleep indicate that as many as 73 participants may need to be excluded from an analysis depending on the hypothesis being tested. The present data are linked to the enhanced Nathan Kline Institute, Rockland Sample and builds on the comprehensive neuroimaging and deep phenotyping available therein. As limited information is presently available about individual differences in the capacity to directly modulate the default mode network, these data provide a unique opportunity to examine DMN modulation ability in relation to numerous phenotypic characteristics. Copyright © 2016 Elsevier Inc. All rights reserved.

Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

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

Guo, Tai L., E-mail: tlguo1@uga.edu; Wang, Yunbiao; Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102

Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiationmore » of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet. • Genistein modulation of neutrophils is associated with blood glucose levels.« less

Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging.

PubMed

Due, Deborah L; Huettel, Scott A; Hall, Warren G; Rubin, David C

2002-06-01

The authors sought to increase understanding of the brain mechanisms involved in cigarette addiction by identifying neural substrates modulated by visual smoking cues in nicotine-deprived smokers. Event-related functional magnetic resonance imaging (fMRI) was used to detect brain activation after exposure to smoking-related images in a group of nicotine-deprived smokers and a nonsmoking comparison group. Subjects viewed a pseudo-random sequence of smoking images, neutral nonsmoking images, and rare targets (photographs of animals). Subjects pressed a button whenever a rare target appeared. In smokers, the fMRI signal was greater after exposure to smoking-related images than after exposure to neutral images in mesolimbic dopamine reward circuits known to be activated by addictive drugs (right posterior amygdala, posterior hippocampus, ventral tegmental area, and medial thalamus) as well as in areas related to visuospatial attention (bilateral prefrontal and parietal cortex and right fusiform gyrus). In nonsmokers, no significant differences in fMRI signal following exposure to smoking-related and neutral images were detected. In most regions studied, both subject groups showed greater activation following presentation of rare target images than after exposure to neutral images. In nicotine-deprived smokers, both reward and attention circuits were activated by exposure to smoking-related images. Smoking cues are processed like rare targets in that they activate attentional regions. These cues are also processed like addictive drugs in that they activate mesolimbic reward regions.

EFFECT OF TRICHLOROETHYLENE ON DNA METHYLATION AND EXPRESSION OF EARLY-INTERMEDIATE PROTOONCOGENES IN THE LIVER OF B6C3F1 MICE. (R825384)

EPA Science Inventory

Trichloroethylene (TCE) is a multimedia environmental pollution that is carcinogenic in mouse liver. The ability of TCE to modulate DNA methylation and the expression of immediate-early protooncogenes was evaluated. Female B6C3F1 mice were administered 1000 mg/kg TCE by gavage 5 ...

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO MALE F344/N RATS AND B6C3F1 MICE

EPA Science Inventory

A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F1 mice. Mouse: Target concentrations of BDCM (dissolved in deionized water containing 0.25% emulphor) were 0.05, ...

A Study of the Time Dependence in Fracture Processes Relating to Service Life Prediction of Adhesive Joints and Advanced Composites.

DTIC Science & Technology

1981-04-30

fluid temperature should exceed 145°F. The flow control module contains all the hydraulic circuit elements necessary for both the pressure line to and...are contained in three basic modules : 1) the hydraulic power supply, 2) a flow control module containing valving, accumulators and filters, and 3) the...hydraulic transient overpressures, is located in the flow control module , as are the high and low pressure filters. The load frame (MTS Systems Corp

E2F8 as a Novel Therapeutic Target for Lung Cancer

PubMed Central

Park, Sin-Aye; Platt, James; Lee, Jong Woo; López-Giráldez, Francesc; Herbst, Roy S.

2015-01-01

Background: The E2F members have been divided into transcription activators (E2F1-E2F3) and repressors (E2F4-E2F8). E2F8 with E2F7 has been known to play an important physiologic role in embryonic development and cell cycle regulation by repressing E2F1. However, the function of E2F8 in cancer cells is unknown. Methods: E2F8 expression was assessed by immunoblotting or immunofluorescence staining in human lung cancer (LC) cells and tissues from LC patients (n = 45). Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of E2F8 in LC. Microarray analysis was used to determine the target genes of E2F8. The regulation of E2F8 on the expression of ubiquitin-like PHD and RING domain-containing 1 (UHRF1), one of E2F8 target genes, was determined using chromatin immunoprecipitation and promoter activity assays. Human LC xenograft models were used to determine the effects of inhibiting E2F8 by siRNAs (n = 7 per group) or antisense morpholino (n = 8 per group) on tumor growth. Survival was analyzed using the Kaplan-Meier method and group differences by the Student’s t test. All statistical tests were two-sided. Results: LC tumors overexpressed E2F8 compared with normal lung tissues. Depletion of E2F8 inhibited cell proliferation and tumor growth. E2F8 knockdown statistically significantly reduced the expression of UHRF1 (~60%-70%, P < .001), and the direct binding of E2F8 on the promoter of UHRF1 was identified. Kaplan-Meier analysis with a public database showed prognostic significance of aberrant E2F8 expression in LC (HR = 1.91 95% CI = 1.21 to 3.01 in chemo-naïve patients, P = .0047). Conclusions: We demonstrated that E2F8 is overexpressed in LC and is required for the growth of LC cells. These findings implicate E2F8 as a novel therapeutic target for LC treatment. PMID:26089541

Brucella Modulates Secretory Trafficking via Multiple Type IV Secretion Effector Proteins

PubMed Central

Myeni, Sebenzile; Child, Robert; Ng, Tony W.; Kupko, John J.; Wehrly, Tara D.; Porcella, Stephen F.; Knodler, Leigh A.; Celli, Jean

2013-01-01

The intracellular pathogenic bacterium Brucella generates a replicative vacuole (rBCV) derived from the endoplasmic reticulum via subversion of the host cell secretory pathway. rBCV biogenesis requires the expression of the Type IV secretion system (T4SS) VirB, which is thought to translocate effector proteins that modulate membrane trafficking along the endocytic and secretory pathways. To date, only a few T4SS substrates have been identified, whose molecular functions remain unknown. Here, we used an in silico screen to identify putative T4SS effector candidate proteins using criteria such as limited homology in other bacterial genera, the presence of features similar to known VirB T4SS effectors, GC content and presence of eukaryotic-like motifs. Using β-lactamase and CyaA adenylate cyclase reporter assays, we identified eleven proteins translocated into host cells by Brucella, five in a VirB T4SS-dependent manner, namely BAB1_0678 (BspA), BAB1_0712 (BspB), BAB1_0847 (BspC), BAB1_1671 (BspE) and BAB1_1948 (BspF). A subset of the translocated proteins targeted secretory pathway compartments when ectopically expressed in HeLa cells, and the VirB effectors BspA, BspB and BspF inhibited protein secretion. Brucella infection also impaired host protein secretion in a process requiring BspA, BspB and BspF. Single or combined deletions of bspA, bspB and bspF affected Brucella ability to replicate in macrophages and persist in the liver of infected mice. Taken together, these findings demonstrate that Brucella modulates secretory trafficking via multiple T4SS effector proteins that likely act coordinately to promote Brucella pathogenesis. PMID:23950720

Low-voltage differentially-signaled modulators.

PubMed

Zortman, William A; Lentine, Anthony L; Trotter, Douglas C; Watts, Michael R

2011-12-19

For exascale computing applications, viable optical solutions will need to operate using low voltage signaling and with low power consumption. In this work, the first differentially signaled silicon resonator is demonstrated which can provide a 5dB extinction ratio using 3fJ/bit and 500mV signal amplitude at 10Gbps. Modulation with asymmetric voltage amplitudes as low as 150mV with 3dB extinction are demonstrated at 10Gbps as well. Differentially signaled resonators simplify and expand the design space for modulator implementation and require no special drivers.

(18)F-glyco-RGD peptides for PET imaging of integrin expression: efficient radiosynthesis by click chemistry and modulation of biodistribution by glycosylation.

PubMed

Maschauer, Simone; Haubner, Roland; Kuwert, Torsten; Prante, Olaf

2014-02-03

Glycosylation frequently improves the biokinetics and clearance properties of macromolecules in vivo and could therefore be used for the design of radiopharmaceuticals for positron emission tomography (PET). Recently, we have developed a click chemistry method for (18)F-fluoroglycosylation of alkyne-bearing RGD-peptides targeting the integrin receptor. To investigate whether this strategy could yield an (18)F-labeled RGD glycopeptide with favorable biokinetics, we generated a series of new RGD glycopeptides, varying the 6-fluoroglycosyl residue from monosaccharide to disaccharide units, which provided the glucosyl ([(19)F]6Glc-RGD, 4b), galactosyl ([(19)F]Gal-RGD, 4c), maltosyl ([(19)F]Mlt-RGD, 4e), and cellobiosyl ([(19)F]Cel-RGD, 4f) conjugated peptides in high yields and purities of >97%. All of these RGD glycopeptides showed high affinity to αvβ3 (11-55 nM), αvβ5 (6-14 nM), and to αvβ3-positive U87MG cells (90-395 nM). (18)F-labeling of the various carbohydrate precursors (1a-f) using cryptate-assisted reaction conditions (CH3CN, 85 °C, 10 min) gave (18)F-labeled glycosyl azides in radiochemical yields (RCYs) of up to 84% ([(18)F]2b). The deacetylation and subsequent click reaction with the alkyne-bearing cyclic RGD peptide proceeded in one-pot reactions with RCYs as high as 81% in 15-20 min at 60 °C, using a minimal amount of peptide precursor (100 nmol). Optimization of the radiosynthesis strategy gave a decay-uncorrected RCY of 16-24% after 70-75 min (based on [(18)F]fluoride). Due to their high-yield radiosyntheses, the glycopeptides [(18)F]6Glc-RGD and [(18)F]Mlt-RGD were chosen for comparative biodistribution studies and dynamic small-animal PET imaging using U87MG tumor-bearing nude mice. [(18)F]6Glc-RGD and [(18)F]Mlt-RGD showed significantly decreased liver and kidney uptake by PET relative to the 2-[(18)F]fluoroglucosyl analog [(18)F]2Glc-RGD, and showed specific tumor uptake in vivo. Notably, [(18)F]Mlt-RGD revealed uptake and retention in the U87MG tumor comparable to that of [(18)F]Galacto-RGD. Both [(18)F]6Glc-RGD and [(18)F]Mlt-RGD were obtained by a reliable and easy click chemistry-based procedure, much more rapidly than was [(18)F]Galacto-RGD. Due to its favorable biodistribution and tissue clearance in vivo, [(18)F]Mlt-RGD represents a viable alternative radiotracer for imaging integrin expression in solid tumors by PET.

Emerging structural details of transient amyloid-β oligomers suggest designs for effective small molecule modulators

NASA Astrophysics Data System (ADS)

Chandra, Bappaditya; Halder, Swagata; Adler, Juliane; Korn, Alexander; Huster, Daniel; Maiti, Sudipta

2017-05-01

Small oligomers are the major toxic species in many amyloid related diseases, but they are difficult to characterize and target. Here we construct tetra-peptides FXFX (X = F/K), designed to exploit cation-π, π-π and hydrophobic interactions to disrupt the critical F19-L34 contact recently found in Aβ40 oligomers. FRFR accelerates Aβ40 aggregation, and strongly inhibits its binding to lipid membranes, which is important in the context of toxicity. FKFK lacks both of these effects, which correlates with the weaker interaction of K with aromatic residues. Thus it appears possible to tune specific contacts in the oligomer and effectively change its properties.

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle.

PubMed

Pignier, Christophe; Keller, Markus; Vié, Bruno; Vacher, Bernard; Santelli, Maurice; Niggli, Ernst; Egger, Marcel; Le Grand, Bruno

2006-04-01

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

In vitro effects of polychlorinated biphenyls on human platelets.

PubMed Central

Raulf, M; König, W

1991-01-01

Incubation of human platelets with polychlorinated biphenyls (PCB) induced and modulated cellular responses to a different degree. 3,3',4,4'-tetrachlorobiphenyl (TCB) was a more potent inducer of platelet aggregation, serotonin release and 12-HETE generation compared to the other PCB [2,2',3,3'-TCB,3,3'-dichlorobiphenyl (DCB),2,2',4,5,5'-pentachlorobiphenyl (PCB)]. 3,3',4,4'-TCB showed synergistic effects, in combination with other PCB, such as an enhanced formation of 12-HETE, when 3,3'-DCB and 2,2',3,3'-TCB were applied simultaneously. The combined incubation of platelets with PCB and sodium fluoride (NaF), an activator of G-proteins, resulted in synergistic 12-HETE generation compared to stimulation with NaF or PCB alone. Furthermore, when platelets were incubated with the PCB the enzymatic steps controlling the metabolism of the platelet-activating factor (PAF) were modulated. A direct relationship between the extent of platelet activation and the chloro-substitution pattern of PCB exists. PMID:1901832

The Retinoblastoma Tumor Suppressor Regulates a Xenobiotic Detoxification Pathway

PubMed Central

Sáenz Robles, Maria Teresa; Case, Ashley; Chong, Jean-Leon; Leone, Gustavo; Pipas, James M.

2011-01-01

The retinoblastoma tumor suppressor (pRb) regulates cell cycle entry, progression and exit by controlling the activity of the E2F-family of transcription factors. During cell cycle exit pRb acts as a transcriptional repressor by associating with E2F proteins and thereby inhibiting their ability to stimulate the expression of genes required for S phase. Indeed, many tumors harbor mutations in the RB gene and the pRb-E2F pathway is compromised in nearly all types of cancers. In this report we show that both pRb and its interacting partners, the transcriptional factors E2F1-2-3, act as positive modulators of detoxification pathways important for metabolizing and clearing xenobiotics—such as toxins and drugs—from the body. Using a combination of conventional molecular biology techniques and microarray analysis of specific cell populations, we have analyzed the detoxification pathway in murine samples in the presence or absence of pRb and/or E2F1-2-3. In this report, we show that both pRb and E2F1-2-3 act as positive modulators of detoxification pathways in mice, challenging the conventional view of E2F1-2-3 as transcriptional repressors negatively regulated by pRb. These results suggest that mutations altering the pRb-E2F axis may have consequences beyond loss of cell cycle control by altering the ability of tissues to remove toxins and to properly metabolize anticancer drugs, and might help to understand the formation and progression rates of different types of cancer, as well as to better design appropriate therapies based on the particular genetic composition of the tumors. PMID:22022495

SU-E-T-398: Feasibility of Automated Tools for Robustness Evaluation of Advanced Photon and Proton Techniques in Oropharyngeal Cancer

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

Liu, H; Liang, X; Kalbasi, A

2014-06-01

Purpose: Advanced radiotherapy (RT) techniques such as proton pencil beam scanning (PBS) and photon-based volumetric modulated arc therapy (VMAT) have dosimetric advantages in the treatment of head and neck malignancies. However, anatomic or alignment changes during treatment may limit robustness of PBS and VMAT plans. We assess the feasibility of automated deformable registration tools for robustness evaluation in adaptive PBS and VMAT RT of oropharyngeal cancer (OPC). Methods: We treated 10 patients with bilateral OPC with advanced RT techniques and obtained verification CT scans with physician-reviewed target and OAR contours. We generated 3 advanced RT plans for each patient: protonmore » PBS plan using 2 posterior oblique fields (2F), proton PBS plan using an additional third low-anterior field (3F), and a photon VMAT plan using 2 arcs (Arc). For each of the planning techniques, we forward calculated initial (Ini) plans on the verification scans to create verification (V) plans. We extracted DVH indicators based on physician-generated contours for 2 target and 14 OAR structures to investigate the feasibility of two automated tools (contour propagation (CP) and dose deformation (DD)) as surrogates for routine clinical plan robustness evaluation. For each verification scan, we compared DVH indicators of V, CP and DD plans in a head-to-head fashion using Student's t-test. Results: We performed 39 verification scans; each patient underwent 3 to 6 verification scan. We found no differences in doses to target or OAR structures between V and CP, V and DD, and CP and DD plans across all patients (p > 0.05). Conclusions: Automated robustness evaluation tools, CP and DD, accurately predicted dose distributions of verification (V) plans using physician-generated contours. These tools may be further developed as a potential robustness screening tool in the workflow for adaptive treatment of OPC using advanced RT techniques, reducing the need for physician-generated contours.« less

Comparison of DFT-S-orthogonal frequency division multiplexing and single-carrier in a radio-over-fiber system

NASA Astrophysics Data System (ADS)

Wang, Kaihui; Li, Xinying; Yu, Jianjun

2017-09-01

DFT-S-orthogonal frequency division multiplexing (OFDM) and single-carrier (SC) modulation are two typical modulation formats in radio-over-fiber (RoF) systems. They may have respective advantages and disadvantages in different scenarios. Therefore, bit error ratio comparison results of these two modulation formats will be useful for designing and optimizing the practical RoF system. We experimentally compare these two modulation formats in a long wireless distance RoF system at W-band. It can be concluded that DFT-S-OFDM and SC modulation have similar performances in a RoF system with transmission distance over 80-km fiber and 224-m wireless link.

Angle-dependent modulated spectral peaks of proton beams generated in ultrashort intense laser-solid interactions

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

Su, L. N.; Hu, Z. D.; Zheng, Y.

2014-09-15

Proton acceleration from 4 μm thick aluminum foils irradiated by 30-TW Ti:sapphire laser pulses is investigated using an angle-resolved proton energy spectrometer. We find that a modulated spectral peak at ∼0.82 MeV is presented at 2.5° off the target normal direction. The divergence angle of the modulated zone is 3.8°. Two-dimensional particle-in-cell simulations reveal that self-generated toroidal magnetic field at the rear surface of the target foil is responsible for the modulated spectral feature. The field deflects the low energy protons, resulting in the modulated energy spectrum with certain peaks.

A Protocol for the Administration of Real-Time fMRI Neurofeedback Training

PubMed Central

Sherwood, Matthew S.; Diller, Emily E.; Ey, Elizabeth; Ganapathy, Subhashini; Nelson, Jeremy T.; Parker, Jason G.

2017-01-01

Neurologic disorders are characterized by abnormal cellular-, molecular-, and circuit-level functions in the brain. New methods to induce and control neuroplastic processes and correct abnormal function, or even shift functions from damaged tissue to physiologically healthy brain regions, hold the potential to dramatically improve overall health. Of the current neuroplastic interventions in development, neurofeedback training (NFT) from functional Magnetic Resonance Imaging (fMRI) has the advantages of being completely non-invasive, non-pharmacologic, and spatially localized to target brain regions, as well as having no known side effects. Furthermore, NFT techniques, initially developed using fMRI, can often be translated to exercises that can be performed outside of the scanner without the aid of medical professionals or sophisticated medical equipment. In fMRI NFT, the fMRI signal is measured from specific regions of the brain, processed, and presented to the participant in real-time. Through training, self-directed mental processing techniques, that regulate this signal and its underlying neurophysiologic correlates, are developed. FMRI NFT has been used to train volitional control over a wide range of brain regions with implications for several different cognitive, behavioral, and motor systems. Additionally, fMRI NFT has shown promise in a broad range of applications such as the treatment of neurologic disorders and the augmentation of baseline human performance. In this article, we present an fMRI NFT protocol developed at our institution for modulation of both healthy and abnormal brain function, as well as examples of using the method to target both cognitive and auditory regions of the brain. PMID:28872110

A Protocol for the Administration of Real-Time fMRI Neurofeedback Training.

PubMed

Sherwood, Matthew S; Diller, Emily E; Ey, Elizabeth; Ganapathy, Subhashini; Nelson, Jeremy T; Parker, Jason G

2017-08-24

Neurologic disorders are characterized by abnormal cellular-, molecular-, and circuit-level functions in the brain. New methods to induce and control neuroplastic processes and correct abnormal function, or even shift functions from damaged tissue to physiologically healthy brain regions, hold the potential to dramatically improve overall health. Of the current neuroplastic interventions in development, neurofeedback training (NFT) from functional Magnetic Resonance Imaging (fMRI) has the advantages of being completely non-invasive, non-pharmacologic, and spatially localized to target brain regions, as well as having no known side effects. Furthermore, NFT techniques, initially developed using fMRI, can often be translated to exercises that can be performed outside of the scanner without the aid of medical professionals or sophisticated medical equipment. In fMRI NFT, the fMRI signal is measured from specific regions of the brain, processed, and presented to the participant in real-time. Through training, self-directed mental processing techniques, that regulate this signal and its underlying neurophysiologic correlates, are developed. FMRI NFT has been used to train volitional control over a wide range of brain regions with implications for several different cognitive, behavioral, and motor systems. Additionally, fMRI NFT has shown promise in a broad range of applications such as the treatment of neurologic disorders and the augmentation of baseline human performance. In this article, we present an fMRI NFT protocol developed at our institution for modulation of both healthy and abnormal brain function, as well as examples of using the method to target both cognitive and auditory regions of the brain.

Fast and Forceful: Modulation of Response Activation Induced by Shifts of Perceived Depth in Virtual 3D Space

PubMed Central

Plewan, Thorsten; Rinkenauer, Gerhard

2016-01-01

Reaction time (RT) can strongly be influenced by a number of stimulus properties. For instance, there was converging evidence that perceived size rather than physical (i.e., retinal) size constitutes a major determinant of RT. However, this view has recently been challenged since within a virtual three-dimensional (3D) environment retinal size modulation failed to influence RT. In order to further investigate this issue in the present experiments response force (RF) was recorded as a supplemental measure of response activation in simple reaction tasks. In two separate experiments participants’ task was to react as fast as possible to the occurrence of a target located close to the observer or farther away while the offset between target locations was increased from Experiment 1 to Experiment 2. At the same time perceived target size (by varying the retinal size across depth planes) and target type (sphere vs. soccer ball) were modulated. Both experiments revealed faster and more forceful reactions when targets were presented closer to the observers. Perceived size and target type barely affected RT and RF in Experiment 1 but differentially affected both variables in Experiment 2. Thus, the present findings emphasize the usefulness of RF as a supplement to conventional RT measurement. On a behavioral level the results confirm that (at least) within virtual 3D space perceived object size neither strongly influences RT nor RF. Rather the relative position within egocentric (body-centered) space presumably indicates an object’s behavioral relevance and consequently constitutes an important modulator of visual processing. PMID:28018273

Dosimetric comparison of helical tomotherapy, intensity-modulated radiation therapy, volumetric-modulated arc therapy, and 3-dimensional conformal therapy for the treatment of T1N0 glottic cancer

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

Ekici, Kemal, E-mail: drkemal06@hotmail.com; Pepele, Eda K.; Yaprak, Bahaddin

2016-01-01

Various radiotherapy planning methods for T1N0 laryngeal cancer have been proposed to decrease normal tissue toxicity. We compare helical tomotherapy (HT), linac-based intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), and 3-D conformal radiotherapy (3D-CRT) techniques for T1N0 laryngeal cancer. Overall, 10 patients with T1N0 laryngeal cancer were selected and evaluated. Furthermore, 10 radiotherapy treatment plans have been created for all 10 patients, including HT, IMRT, VMAT, and 3D-CRT. IMRT, VMAT, and HT plans vs 3D-CRT plans consistently provided superior planning target volume (PTV) coverage. Similar target coverage was observed between the 3 IMRT modalities. Compared with 3D-CRT, IMRT, HT,more » and VMAT significantly reduced the mean dose to the carotid arteries. VMAT resulted in the lowest mean dose to the submandibular and thyroid glands. Compared with 3D-CRT, IMRT, HT, and VMAT significantly increased the maximum dose to the spinal cord It was observed that the 3 IMRT modalities studied showed superior target coverage with less variation between each plan in comparison with 3D-CRT. The 3D-CRT plans performed better at the D{sub max} of the spinal cord. Clinical investigation is warranted to determine if these treatment approaches would translate into a reduction in radiation therapy–induced toxicities.« less

Diabetes Drug Discovery: hIAPP1-37 Polymorphic Amyloid Structures as Novel Therapeutic Targets.

PubMed

Fernández-Gómez, Isaac; Sablón-Carrazana, Marquiza; Bencomo-Martínez, Alberto; Domínguez, Guadalupe; Lara-Martínez, Reyna; Altamirano-Bustamante, Nelly F; Jiménez-García, Luis Felipe; Pasten-Hidalgo, Karina; Castillo-Rodríguez, Rosa Angélica; Altamirano, Perla; Marrero, Suchitil Rivera; Revilla-Monsalve, Cristina; Valdés-Sosa, Peter; Salamanca-Gómez, Fabio; Garrido-Magaña, Eulalia; Rodríguez-Tanty, Chryslaine; Altamirano-Bustamante, Myriam M

2018-03-19

Human islet amyloid peptide (hIAPP 1-37 ) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP 1-37 ) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP 1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP 1-37 . When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP 1-37 . Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP 1-37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A - F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.

First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

PubMed Central

Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A.; Raynaud, Florence I.; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S.; Kaye, Stan B.; Derynck, Mika K.; Workman, Paul; de Bono, Johann S.

2014-01-01

Purpose This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Results Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily. PMID:25370471

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PubMed

Sarker, Debashis; Ang, Joo Ern; Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A; Raynaud, Florence I; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S; Kaye, Stan B; Derynck, Mika K; Workman, Paul; de Bono, Johann S

2015-01-01

This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. ©2014 American Association for Cancer Research.

Chemical release module facility

NASA Technical Reports Server (NTRS)

Reasoner, D. L.

1980-01-01

The chemical release module provides the capability to conduct: (1) thermite based metal vapor releases; (2) pressurized gas releases; (3) dispersed liquid releases; (4) shaped charge releases from ejected submodules; and (5) diagnostic measurements with pi supplied instruments. It also provides a basic R-F and electrical system for: (1) receiving and executing commands; (2) telemetering housekeeping data; (3) tracking; (4) monitoring housekeeping and control units; and (5) ultrasafe disarming and control monitoring.

Task difficulty modulates brain activation in the emotional oddball task.

PubMed

Siciliano, Rachel E; Madden, David J; Tallman, Catherine W; Boylan, Maria A; Kirste, Imke; Monge, Zachary A; Packard, Lauren E; Potter, Guy G; Wang, Lihong

2017-06-01

Previous functional magnetic resonance imaging (fMRI) studies have reported that task-irrelevant, emotionally salient events can disrupt target discrimination, particularly when attentional demands are low, while others demonstrate alterations in the distracting effects of emotion in behavior and neural activation in the context of attention-demanding tasks. We used fMRI, in conjunction with an emotional oddball task, at different levels of target discrimination difficulty, to investigate the effects of emotional distractors on the detection of subsequent targets. In addition, we distinguished different behavioral components of target detection representing decisional, nondecisional, and response criterion processes. Results indicated that increasing target discrimination difficulty led to increased time required for both the decisional and nondecisional components of the detection response, as well as to increased target-related neural activation in frontoparietal regions. The emotional distractors were associated with activation in ventral occipital and frontal regions and dorsal frontal regions, but this activation was attenuated with increased difficulty. Emotional distraction did not alter the behavioral measures of target detection, but did lead to increased target-related frontoparietal activation for targets following emotional images as compared to those following neutral images. This latter effect varied with target discrimination difficulty, with an increased influence of the emotional distractors on subsequent target-related frontoparietal activation in the more difficult discrimination condition. This influence of emotional distraction was in addition associated specifically with the decisional component of target detection. These findings indicate that emotion-cognition interactions, in the emotional oddball task, vary depending on the difficulty of the target discrimination and the associated limitations on processing resources. Copyright © 2017 Elsevier B.V. All rights reserved.

SCALE: A modular code system for performing standardized computer analyses for licensing evaluation. Functional modules F1--F8 -- Volume 2, Part 1, Revision 4

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

Greene, N.M.; Petrie, L.M.; Westfall, R.M.

SCALE--a modular code system for Standardized Computer Analyses Licensing Evaluation--has been developed by Oak Ridge National Laboratory at the request of the US Nuclear Regulatory Commission. The SCALE system utilizes well-established computer codes and methods within standard analysis sequences that (1) allow an input format designed for the occasional user and/or novice, (2) automate the data processing and coupling between modules, and (3) provide accurate and reliable results. System development has been directed at problem-dependent cross-section processing and analysis of criticality safety, shielding, heat transfer, and depletion/decay problems. Since the initial release of SCALE in 1980, the code system hasmore » been heavily used for evaluation of nuclear fuel facility and package designs. This revision documents Version 4.2 of the system. The manual is divided into three volumes: Volume 1--for the control module documentation; Volume 2--for functional module documentation; and Volume 3--for documentation of the data libraries and subroutine libraries.« less

Dependence of chromatic responses in V1 on visual field eccentricity and spatial frequency: an fMRI study.

PubMed

D'Souza, Dany V; Auer, Tibor; Frahm, Jens; Strasburger, Hans; Lee, Barry B

2016-03-01

Psychophysical sensitivity to red-green chromatic modulation decreases with visual eccentricity, compared to sensitivity to luminance modulation, even after appropriate stimulus scaling. This is likely to occur at a central, rather than a retinal, site. Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to stimuli designed to separately stimulate different afferent channels' [red-green, luminance, and short-wavelength (S)-cone] circular gratings were recorded as a function of visual eccentricity (±10  deg) and spatial frequency (SF) in human primary visual cortex (V1) and further visual areas (V2v, V3v). In V1, the SF tuning of BOLD fMRI responses became coarser with eccentricity. For red-green and luminance gratings, similar SF tuning curves were found at all eccentricities. The pattern for S-cone modulation differed, with SF tuning changing more slowly with eccentricity than for the other two modalities. This may be due to the different retinal distribution with eccentricity of this receptor type. A similar pattern held in V2v and V3v. This would suggest that transformation or spatial filtering of the chromatic (red-green) signal occurs beyond these areas.

High-Temperature Piezoelectric Ceramic Developed

NASA Technical Reports Server (NTRS)

Sayir, Ali; Farmer, Serene C.; Dynys, Frederick W.

2005-01-01

Active combustion control of spatial and temporal variations in the local fuel-to-air ratio is of considerable interest for suppressing combustion instabilities in lean gas turbine combustors and, thereby, achieving lower NOx levels. The actuator for fuel modulation in gas turbine combustors must meet several requirements: (1) bandwidth capability of 1000 Hz, (2) operating temperature compatible with the fuel temperature, which is in the vicinity of 400 F, (3) stroke of approximately 4 mils (100 m), and (4) force of 300 lb-force. Piezoelectric actuators offer the fastest response time (microsecond time constants) and can generate forces in excess of 2000 lb-force. The state-of-the-art piezoceramic material in industry today is Pb(Zr,Ti)O3, called PZT. This class of piezoelectric ceramic is currently used in diesel fuel injectors and in the development of high-response fuel modulation valves. PZT materials are generally limited to operating temperatures of 250 F, which is 150 F lower than the desired operating temperature for gas turbine combustor fuel-modulation injection valves. Thus, there is a clear need to increase the operating temperature range of piezoceramic devices for active combustion control in gas turbine engines.

Within-Hemifield Competition in Early Visual Areas Limits the Ability to Track Multiple Objects with Attention

PubMed Central

Alvarez, George A.; Cavanagh, Patrick

2014-01-01

It is much easier to divide attention across the left and right visual hemifields than within the same visual hemifield. Here we investigate whether this benefit of dividing attention across separate visual fields is evident at early cortical processing stages. We measured the steady-state visual evoked potential, an oscillatory response of the visual cortex elicited by flickering stimuli, of moving targets and distractors while human observers performed a tracking task. The amplitude of responses at the target frequencies was larger than that of the distractor frequencies when participants tracked two targets in separate hemifields, indicating that attention can modulate early visual processing when it is divided across hemifields. However, these attentional modulations disappeared when both targets were tracked within the same hemifield. These effects were not due to differences in task performance, because accuracy was matched across the tracking conditions by adjusting target speed (with control conditions ruling out effects due to speed alone). To investigate later processing stages, we examined the P3 component over central-parietal scalp sites that was elicited by the test probe at the end of the trial. The P3 amplitude was larger for probes on targets than on distractors, regardless of whether attention was divided across or within a hemifield, indicating that these higher-level processes were not constrained by visual hemifield. These results suggest that modulating early processing stages enables more efficient target tracking, and that within-hemifield competition limits the ability to modulate multiple target representations within the hemifield maps of the early visual cortex. PMID:25164651

X-ray variability of Pleiades late-type stars as observed with the ROSAT-PSPC

NASA Astrophysics Data System (ADS)

Marino, A.; Micela, G.; Peres, G.; Sciortino, S.

2003-08-01

We present a comprehensive analysis of X-ray variability of the late-type (dF7-dM) Pleiades stars, detected in all ROSAT-PSPC observations; X-ray variations on short (hours) and medium (months) time scales have been explored. We have grouped the stars in two samples: 89 observations of 42 distinct dF7-dK2 stars and 108 observations of 61 dK3-dM stars. The Kolmogorov-Smirnov test applied on all X-ray photon time series show that the percentage of cases of significant variability is quite similar on both samples, suggesting that the presence of variability does not depend on mass for the time scales and mass range explored. The comparison between the Time X-ray Amplitude Distribution functions (XAD) of the set of dF7-dK2 and of the dK3-dM show that, on short time scales, dK3-dM stars show larger variations than dF7-dK2. A subsample of eleven dF7-dK2 and eleven dK3-dM Pleiades stars allows the study of variability on longer time scales: we found that variability on medium - long time scales is relatively more common among dF7-dK2 stars than among dK3-dM ones. For both dF7-dK2 Pleiades stars and dF7-dK2 field stars, the variability on short time scales depends on Lx while this dependence has not been observed among dK3-dM stars. It may be that the variability among dK3-dM stars is dominated by flares that have a similar luminosity distribution for stars of different Lx, while flaring distribution in dF7-dK2 stars may depend on X-ray luminosity. The lowest mass stars show significant rapid variability (flares?) and no evidence of rotation modulation or cycles. On the contrary, dF7-dK2 Pleiades stars show both rapid variability and variations on longer time scales, likely associated with rotational modulation or cycles.

SU-E-T-245: Detection of the Photon Target Damage in Varian Linac Based On Periodical Quality Assurance Measurements

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

Gao, S; Balter, P; Wang, X

2015-06-15

Purpose: To determine the best dosimetric metric measured by our routine QA devices for diagnosing photon target failure on a Varian C-series linac. Methods: We have retrospectively reviewed and analyzed the dosimetry data from a Varian linac with a target degradation that was undiagnosed for one year. A failure in the daily QA symmetry tests was the first indication of an issue. The beam was steered back to a symmetric shape and water scans indicated the beam energy had changed but stayed within the manufacturer’s specifications and agreed reasonably with our treatment planning system data. After the problem was identifiedmore » and the target was replaced, we retrospectively analyzed our QA data including diagonals normalized flatness (F-DN) from the daily device (DQA3), profiles from an ionization chamber array (IC Profiler), as well as profiles and PDDs from a 3D water Scanner (3DS). These metrics were cross-compared to determine which was the best early indicator of target degradation. Results: A 3% change in FDN measured by the DQA3 was found to be an early indicator of target degradation. It is more sensitive than changes in output, symmetry, flatness or PDD. All beam shape metrics (flatness at dmax and 10 cm depth, and F-DN) indicated an energy increase while the PDD indicated an energy decrease. This disagreement between the beam-shape based energy metrics (F-DN and flatness) and PDD based energy metric may indicate target failure as opposed to an energy change resulting from changes in the incident electron energy. Conclusion: Photon target degradation has been identified as a failure mode for linacs. The manufacturer’s test for this condition is highly invasive and requires machine down time. We have demonstrated that the condition could be caught early based upon data acquired during routine QA activities, such as the F-DN.« less

The Central Conserved Region (CCR) of Respiratory Syncytial Virus (RSV) G Protein Modulates Host miRNA Expression and Alters the Cellular Response to Infection

PubMed Central

Haynes, Lia M.; Anderson, Larry J.

2017-01-01

Respiratory Syncytial Virus (RSV) infects respiratory epithelial cells and deregulates host gene expression by many mechanisms including expression of RSV G protein (RSV G). RSV G protein encodes a central conserved region (CCR) containing a CX3C motif that functions as a fractalkine mimic. Disruption of the CX3C motif (a.a. 182–186) located in the CCR of the G protein has been shown to affect G protein function in vitro and the severity of RSV disease pathogenesis in vivo. We show that infection of polarized Calu3 respiratory cells with recombinant RSV having point mutations in Cys173 and 176 (C173/176S) (rA2-GC12), or Cys186 (C186S) (rA2-GC4) is associated with a decline in the integrity of polarized Calu-3 cultures and decreased virus production. This is accompanied with downregulation of miRNAs let-7f and miR-24 and upregulation of interferon lambda (IFNλ), a primary antiviral cytokine for RSV in rA2-GC12/rA2-GC4 infected cells. These results suggest that residues in the cysteine noose region of RSV G protein can modulate IFN λ expression accompanied by downregulation of miRNAs, and are important for RSV G protein function and targeting. PMID:28671606

The Central Conserved Region (CCR) of Respiratory Syncytial Virus (RSV) G Protein Modulates Host miRNA Expression and Alters the Cellular Response to Infection.

PubMed

Bakre, Abhijeet A; Harcourt, Jennifer L; Haynes, Lia M; Anderson, Larry J; Tripp, Ralph A

2017-07-03

Respiratory Syncytial Virus (RSV) infects respiratory epithelial cells and deregulates host gene expression by many mechanisms including expression of RSV G protein (RSV G). RSV G protein encodes a central conserved region (CCR) containing a CX3C motif that functions as a fractalkine mimic. Disruption of the CX3C motif (a.a. 182-186) located in the CCR of the G protein has been shown to affect G protein function in vitro and the severity of RSV disease pathogenesis in vivo. We show that infection of polarized Calu3 respiratory cells with recombinant RSV having point mutations in Cys173 and 176 (C173/176S) (rA2-GC12), or Cys186 (C186S) (rA2-GC4) is associated with a decline in the integrity of polarized Calu-3 cultures and decreased virus production. This is accompanied with downregulation of miRNAs let-7f and miR-24 and upregulation of interferon lambda (IFNλ), a primary antiviral cytokine for RSV in rA2-GC12/rA2-GC4 infected cells. These results suggest that residues in the cysteine noose region of RSV G protein can modulate IFN λ expression accompanied by downregulation of miRNAs, and are important for RSV G protein function and targeting.

View of Surveyor III in its crater

NASA Image and Video Library

1969-11-20

AS12-48-7121 (20 Nov. 1969) --- An excellent view of the unmanned Surveyor 3 spacecraft which was photographed during the Apollo 12 second extravehicular activity (EVA) on the surface of the moon. The Apollo 12 Lunar Module (LM), with astronauts Charles Conrad Jr., commander, and Alan L. Bean, lunar module pilot, aboard landed within 600 feet of Surveyor 3 in the Ocean of Storms. The television camera and several other pieces were taken from Surveyor 3 and brought back to Earth for scientific examination. Surveyor 3 landed on the side of this small crater in the Ocean of Storms on April 19, 1967. Astronaut Richard F. Gordon Jr., command module pilot, remained with the Apollo 12 Command and Service Modules (CSM) in lunar orbit while Conrad and Bean descended to explore the moon.

E3L and F1L Gene Functions Modulate the Protective Capacity of Modified Vaccinia Virus Ankara Immunization in Murine Model of Human Smallpox.

PubMed

Volz, Asisa; Jany, Sylvia; Freudenstein, Astrid; Lantermann, Markus; Ludwig, Holger; Sutter, Gerd

2018-01-04

The highly attenuated Modified Vaccinia virus Ankara (MVA) lacks most of the known vaccinia virus (VACV) virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in the MVA genome, such as the apoptosis inhibitor genes F1L and E3L . Here, we tested MVA vaccine preparations on the basis of the deletion mutant viruses MVA-ΔF1L and MVA-ΔE3L for efficacy against ectromelia virus (ECTV) challenge infections in mice. In non-permissive human tissue culture the MVA deletion mutant viruses produced reduced levels of the VACV envelope antigen B5. Upon mousepox challenge at three weeks after vaccination, MVA-ΔF1L and MVA-ΔE3L exhibited reduced protective capacity in comparison to wildtype MVA. Surprisingly, however, all vaccines proved equally protective against a lethal ECTV infection at two days after vaccination. Accordingly, the deletion mutant MVA vaccines induced high levels of virus-specific CD8+ T cells previously shown to be essential for rapidly protective MVA vaccination. These results suggest that inactivation of the anti-apoptotic genes F1L or E3L modulates the protective capacity of MVA vaccination most likely through the induction of distinct orthopoxvirus specific immunity in the absence of these viral regulatory proteins.

Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f

PubMed Central

Morimoto, Megumi; Amano, Yuichiro; Oka, Masahiro; Harada, Ayako; Fujita, Hisashi; Hikichi, Yukiko; Tozawa, Ryuichi; Yamaoka, Masuo

2017-01-01

Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia. PMID:29216311

Direct activation of human and mouse Oct4 genes using engineered TALE and Cas9 transcription factors

PubMed Central

Hu, Jiabiao; Lei, Yong; Wong, Wing-Ki; Liu, Senquan; Lee, Kai-Chuen; He, Xiangjun; You, Wenxing; Zhou, Rui; Guo, Jun-Tao; Chen, Xiongfong; Peng, Xianlu; Sun, Hao; Huang, He; Zhao, Hui; Feng, Bo

2014-01-01

The newly developed transcription activator-like effector protein (TALE) and clustered regularly interspaced short palindromic repeats/Cas9 transcription factors (TF) offered a powerful and precise approach for modulating gene expression. In this article, we systematically investigated the potential of these new tools in activating the stringently silenced pluripotency gene Oct4 (Pou5f1) in mouse and human somatic cells. First, with a number of TALEs and sgRNAs targeting various regions in the mouse and human Oct4 promoters, we found that the most efficient TALE-VP64s bound around −120 to −80 bp, while highly effective sgRNAs targeted from −147 to −89-bp upstream of the transcription start sites to induce high activity of luciferase reporters. In addition, we observed significant transcriptional synergy when multiple TFs were applied simultaneously. Although individual TFs exhibited marginal activity to up-regulate endogenous gene expression, optimized combinations of TALE-VP64s could enhance endogenous Oct4 transcription up to 30-fold in mouse NIH3T3 cells and 20-fold in human HEK293T cells. More importantly, the enhancement of OCT4 transcription ultimately generated OCT4 proteins. Furthermore, examination of different epigenetic modifiers showed that histone acetyltransferase p300 could enhance both TALE-VP64 and sgRNA/dCas9-VP64 induced transcription of endogenous OCT4. Taken together, our study suggested that engineered TALE-TF and dCas9-TF are useful tools for modulating gene expression in mammalian cells. PMID:24500196

Direct activation of human and mouse Oct4 genes using engineered TALE and Cas9 transcription factors.

PubMed

Hu, Jiabiao; Lei, Yong; Wong, Wing-Ki; Liu, Senquan; Lee, Kai-Chuen; He, Xiangjun; You, Wenxing; Zhou, Rui; Guo, Jun-Tao; Chen, Xiongfong; Peng, Xianlu; Sun, Hao; Huang, He; Zhao, Hui; Feng, Bo

2014-04-01

The newly developed transcription activator-like effector protein (TALE) and clustered regularly interspaced short palindromic repeats/Cas9 transcription factors (TF) offered a powerful and precise approach for modulating gene expression. In this article, we systematically investigated the potential of these new tools in activating the stringently silenced pluripotency gene Oct4 (Pou5f1) in mouse and human somatic cells. First, with a number of TALEs and sgRNAs targeting various regions in the mouse and human Oct4 promoters, we found that the most efficient TALE-VP64s bound around -120 to -80 bp, while highly effective sgRNAs targeted from -147 to -89-bp upstream of the transcription start sites to induce high activity of luciferase reporters. In addition, we observed significant transcriptional synergy when multiple TFs were applied simultaneously. Although individual TFs exhibited marginal activity to up-regulate endogenous gene expression, optimized combinations of TALE-VP64s could enhance endogenous Oct4 transcription up to 30-fold in mouse NIH3T3 cells and 20-fold in human HEK293T cells. More importantly, the enhancement of OCT4 transcription ultimately generated OCT4 proteins. Furthermore, examination of different epigenetic modifiers showed that histone acetyltransferase p300 could enhance both TALE-VP64 and sgRNA/dCas9-VP64 induced transcription of endogenous OCT4. Taken together, our study suggested that engineered TALE-TF and dCas9-TF are useful tools for modulating gene expression in mammalian cells.

SU-F-T-570: Comparison of Synthetic Diamond, Microionization Chamber, and Radiochromic Film for Absolute Dosimetry of VMAT Radiosurgery

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

Popple, R; Wu, X; Kraus, J

2016-06-15

Purpose: Patient specific quality assurance of stereotactic radiosurgery (SRS) plans is challenging because of small target sizes and high dose gradients. We compared three detectors for dosimetry of VMAT SRS plans. Methods: The dose at the center of seventeen targets was measured using a synthetic diamond detector (2.2 mm diameter, 1 µm thickness), a 0.007 cm{sup 3} ionization chamber, and radiochromic film. Measurements were made in a PMMA phantom in the clinical geometry – all gantry and table angles were delivered as planned. The diamond and chamber positions were offset by 1 cm from the film plane, so the isocentermore » was shifted accordingly to place the center of the target at the detector of interest. To ensure accurate detector placement, the phantom was positioned using kV images. To account for the shift-induced difference in geometry and differing prescription doses between plans, the measurements were normalized to the expected dose calculated by the treatment planning system. Results: The target sizes ranged from 2.8 mm to 34.8 mm (median 14.8 mm). The mean measurement-to-plan ratios were 1.054, 1.076, and 1.023 for RCF, diamond, and chamber, respectively. The mean difference between the chamber and film was −3.2% and between diamond and film was 2.2%. For targets larger than 15 mm, the mean difference relative to film was −0.8% and 0.1% for chamber and diamond, respectively, whereas for targets smaller than 15 mm, the difference was −5.3% and 4.2% for chamber and diamond, respectively. The difference was significant (p=0.005) using the two-sample Kolmogorov-Smirnov test. Conclusion: The detectors agree for target sizes larger than 15 mm. Relative to film, for smaller targets the diamond detector over-responds, whereas the ionization chamber under-responds. Further work is needed to characterize detector response in modulated SRS fields.« less

A DEK Domain-Containing Protein Modulates Chromatin Structure and Function in Arabidopsis[W][OPEN

PubMed Central

Waidmann, Sascha; Kusenda, Branislav; Mayerhofer, Juliane; Mechtler, Karl; Jonak, Claudia

2014-01-01

Chromatin is a major determinant in the regulation of virtually all DNA-dependent processes. Chromatin architectural proteins interact with nucleosomes to modulate chromatin accessibility and higher-order chromatin structure. The evolutionarily conserved DEK domain-containing protein is implicated in important chromatin-related processes in animals, but little is known about its DNA targets and protein interaction partners. In plants, the role of DEK has remained elusive. In this work, we identified DEK3 as a chromatin-associated protein in Arabidopsis thaliana. DEK3 specifically binds histones H3 and H4. Purification of other proteins associated with nuclear DEK3 also established DNA topoisomerase 1α and proteins of the cohesion complex as in vivo interaction partners. Genome-wide mapping of DEK3 binding sites by chromatin immunoprecipitation followed by deep sequencing revealed enrichment of DEK3 at protein-coding genes throughout the genome. Using DEK3 knockout and overexpressor lines, we show that DEK3 affects nucleosome occupancy and chromatin accessibility and modulates the expression of DEK3 target genes. Furthermore, functional levels of DEK3 are crucial for stress tolerance. Overall, data indicate that DEK3 contributes to modulation of Arabidopsis chromatin structure and function. PMID:25387881

NaEuF4/Au@Ag2S nanoparticles-based fluorescence resonant transfer DNA sensor for ultrasensitive detection of DNA energy.

PubMed

Liu, Yuhong; Zhao, Linlin; Zhang, Jin; Zhang, Jinzha; Zhao, Wenbo; Mao, Chun

2016-12-01

The work investigates a new fluorescence resonance energy transfer (FRET) system using NaEuF 4 nanoparticles (NPs) and Au@Ag 2 S NPs as the energy donor-acceptor pair for the first time. The NaEuF 4 /Au@Ag 2 S NPs-based FRET DNA sensor was constructed with NaEuF 4 NPs as the fluorescence (FL) donor and Au@Ag 2 S core-shell NPs as FL acceptor. In order to find the matching energy acceptor, the amount of AgNO 3 and Na 2 S were controlled in the synthesis process to overlap the absorption spectrum of energy acceptor with the emission spectrum of energy donors. The sensitivity of FRET-based DNA sensor can be enhanced and the self-absorption of ligand as well as the background of signals can be decreased because of Eu 3+ which owns large Stokes shifts and narrow emission bands due to f-f electronic transitions of 4f shell. We obtained the efficient FRET system by studying suitable distance between the donor and acceptor. Then the FRET-based DNA sensor was used for the design of specific and sensitive detection of target DNA and the quenching efficiency (ΔFL/F 0 , ΔFL=F-F 0 ) of FL was logarithmically related to the concentration of the target DNA, ranging from 100aM to 100pM. We can realize an ultrasensitive detection of target DNA with a detection limit of 32 aM. This proposed method was feasible to analyse target DNA in real samples with satisfactory results. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2017-11-01

SUBJECT TERMS cell cycle, Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY...screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor, cancer, cell-cycle inhibition, activation...modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography . 3.0 ACCOMPLISHMENTS Summary: We

Optimal Normal Tissue Sparing in Craniospinal Axis Irradiation Using IMRT With Daily Intrafractionally Modulated Junction(s)

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

Kusters, Johannes M.A.M.; Louwe, Rob J.W.; Kollenburg, Peter G.M. van

2011-12-01

Purpose: To develop a treatment technique for craniospinal irradiation using intensity-modulated radiotherapy (IMRT) with improved dose homogeneity at the field junction(s), increased target volume conformity, and minimized dose to the organs at risk (OARs). Methods and Materials: Five patients with high-risk medulloblastoma underwent CT simulation in supine position. For each patient, an IMRT plan with daily intrafractionally modulated junction(s) was generated, as well as a treatment plan based on conventional three-dimensional planning (3DCRT). A dose of 39.6 Gy in 22 daily fractions of 1.8 Gy was prescribed. Dose-volume parameters for target volumes and OARs were compared for the two techniques.more » Results: The maximum dose with IMRT was <107% in all patients. V{sub <95} and V{sub >107} were <1 cm{sup 3} for IMRT compared with 3-9 cm{sup 3} for the craniospinal and 26-43 cm{sup 3} for the spinal-spinal junction with 3DCRT. These observations corresponded with a lower homogeneity index and a higher conformity index for the spinal planning target volume with IMRT. IMRT provided considerable sparing of acute and late reacting tissues. V{sub 75} for the esophagus, gastroesophageal junction, and intestine was 81%, 81%, and 22% with 3DCRT versus 5%, 0%, and 1% with IMRT, respectively. V{sub 75} for the heart and thyroid was 42% and 32% vs. 0% with IMRT. Conclusion: IMRT with daily intrafractionally modulated junction results in a superior target coverage and junction homogeneity compared with 3DCRT. A significant dose reduction can be obtained for acute as well as late-reacting tissues.« less

Protein arginine (N)-methyl transferase 7 (PRMT7) as a potential target for the sensitization of tumor cells to camptothecins.

PubMed

Verbiest, Vincent; Montaudon, Danièle; Tautu, Michel T; Moukarzel, Joyce; Portail, Jean-Pierre; Markovits, Judith; Robert, Jacques; Ichas, François; Pourquier, Philippe

2008-04-30

PRMT7 belongs to the protein arginine methyl-transferases family. We show that downregulation of PRMT7alpha and beta isoforms in DC-3F hamster cells was associated with increased sensitivity to the Top1 inhibitor camptothecin (CPT). This effect was not due to a change in Top1 contents or catalytic activity, or to a difference in the reversal of DNA breaks. Overexpression of PRMT7alpha and beta in DC-3F cells had no effect on CPT sensitivity, whereas it conferred a resistance to DC-3F/9-OH-E cells for which both isoforms are reduced by two- to three-fold as compared to DC-3F parental cells. Finally, downregulation of the human PRMT7 could also sensitize HeLa cells to CPT, suggesting that it could be used as a target to potentiate CPT derivatives.

Not All Attention Orienting is Created Equal: Recognition Memory is Enhanced When Attention Orienting Involves Distractor Suppression

PubMed Central

Markant, Julie; Worden, Michael S.; Amso, Dima

2015-01-01

Learning through visual exploration often requires orienting of attention to meaningful information in a cluttered world. Previous work has shown that attention modulates visual cortex activity, with enhanced activity for attended targets and suppressed activity for competing inputs, thus enhancing the visual experience. Here we examined the idea that learning may be engaged differentially with variations in attention orienting mechanisms that drive driving eye movements during visual search and exploration. We hypothesized that attention orienting mechanisms that engaged suppression of a previously attended location will boost memory encoding of the currently attended target objects to a greater extent than those that involve target enhancement alone To test this hypothesis we capitalized on the classic spatial cueing task and the inhibition of return (IOR) mechanism (Posner, Rafal, & Choate, 1985; Posner, 1980) to demonstrate that object images encoded in the context of concurrent suppression at a previously attended location were encoded more effectively and remembered better than those encoded without concurrent suppression. Furthermore, fMRI analyses revealed that this memory benefit was driven by attention modulation of visual cortex activity, as increased suppression of the previously attended location in visual cortex during target object encoding predicted better subsequent recognition memory performance. These results suggest that not all attention orienting impacts learning and memory equally. PMID:25701278

Bladder radiotherapy treatment: A retrospective comparison of 3-dimensional conformal radiotherapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy plans

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

Pasciuti, Katia, E-mail: k.pasciuti@virgilio.it; Kuthpady, Shrinivas; Anderson, Anne

To examine tumor's and organ's response when different radiotherapy plan techniques are used. Ten patients with confirmed bladder tumors were first treated using 3-dimensional conformal radiotherapy (3DCRT) and subsequently the original plans were re-optimized using the intensity-modulated radiation treatment (IMRT) and volumetric-modulated arc therapy (VMAT)-techniques. Targets coverage in terms of conformity and homogeneity index, TCP, and organs' dose limits, including integral dose analysis were evaluated. In addition, MUs and treatment delivery times were compared. Better minimum target coverage (1.3%) was observed in VMAT plans when compared to 3DCRT and IMRT ones confirmed by a statistically significant conformity index (CI) results.more » Large differences were observed among techniques in integral dose results of the femoral heads. Even if no statistically significant differences were reported in rectum and tissue, a large amount of energy deposition was observed in 3DCRT plans. In any case, VMAT plans provided better organs and tissue sparing confirmed also by the normal tissue complication probability (NTCP) analysis as well as a better tumor control probability (TCP) result. Our analysis showed better overall results in planning using VMAT techniques. Furthermore, a total time reduction in treatment observed among techniques including gantry and collimator rotation could encourage using the more recent one, reducing target movements and patient discomfort.« less

Envelope Interactions in Multi-Channel Amplitude Modulation Frequency Discrimination by Cochlear Implant Users.

PubMed

Galvin, John J; Oba, Sandra I; Başkent, Deniz; Chatterjee, Monita; Fu, Qian-Jie

2015-01-01

Previous cochlear implant (CI) studies have shown that single-channel amplitude modulation frequency discrimination (AMFD) can be improved when coherent modulation is delivered to additional channels. It is unclear whether the multi-channel advantage is due to increased loudness, multiple envelope representations, or to component channels with better temporal processing. Measuring envelope interference may shed light on how modulated channels can be combined. In this study, multi-channel AMFD was measured in CI subjects using a 3-alternative forced-choice, non-adaptive procedure ("which interval is different?"). For the reference stimulus, the reference AM (100 Hz) was delivered to all 3 channels. For the probe stimulus, the target AM (101, 102, 104, 108, 116, 132, 164, 228, or 256 Hz) was delivered to 1 of 3 channels, and the reference AM (100 Hz) delivered to the other 2 channels. The spacing between electrodes was varied to be wide or narrow to test different degrees of channel interaction. Results showed that CI subjects were highly sensitive to interactions between the reference and target envelopes. However, performance was non-monotonic as a function of target AM frequency. For the wide spacing, there was significantly less envelope interaction when the target AM was delivered to the basal channel. For the narrow spacing, there was no effect of target AM channel. The present data were also compared to a related previous study in which the target AM was delivered to a single channel or to all 3 channels. AMFD was much better with multiple than with single channels whether the target AM was delivered to 1 of 3 or to all 3 channels. For very small differences between the reference and target AM frequencies (2-4 Hz), there was often greater sensitivity when the target AM was delivered to 1 of 3 channels versus all 3 channels, especially for narrowly spaced electrodes. Besides the increased loudness, the present results also suggest that multiple envelope representations may contribute to the multi-channel advantage observed in previous AMFD studies. The different patterns of results for the wide and narrow spacing suggest a peripheral contribution to multi-channel temporal processing. Because the effect of target AM frequency was non-monotonic in this study, adaptive procedures may not be suitable to measure AMFD thresholds with interfering envelopes. Envelope interactions among multiple channels may be quite complex, depending on the envelope information presented to each channel and the relative independence of the stimulated channels.

Envelope Interactions in Multi-Channel Amplitude Modulation Frequency Discrimination by Cochlear Implant Users

PubMed Central

2015-01-01

Rationale Previous cochlear implant (CI) studies have shown that single-channel amplitude modulation frequency discrimination (AMFD) can be improved when coherent modulation is delivered to additional channels. It is unclear whether the multi-channel advantage is due to increased loudness, multiple envelope representations, or to component channels with better temporal processing. Measuring envelope interference may shed light on how modulated channels can be combined. Methods In this study, multi-channel AMFD was measured in CI subjects using a 3-alternative forced-choice, non-adaptive procedure (“which interval is different?”). For the reference stimulus, the reference AM (100 Hz) was delivered to all 3 channels. For the probe stimulus, the target AM (101, 102, 104, 108, 116, 132, 164, 228, or 256 Hz) was delivered to 1 of 3 channels, and the reference AM (100 Hz) delivered to the other 2 channels. The spacing between electrodes was varied to be wide or narrow to test different degrees of channel interaction. Results Results showed that CI subjects were highly sensitive to interactions between the reference and target envelopes. However, performance was non-monotonic as a function of target AM frequency. For the wide spacing, there was significantly less envelope interaction when the target AM was delivered to the basal channel. For the narrow spacing, there was no effect of target AM channel. The present data were also compared to a related previous study in which the target AM was delivered to a single channel or to all 3 channels. AMFD was much better with multiple than with single channels whether the target AM was delivered to 1 of 3 or to all 3 channels. For very small differences between the reference and target AM frequencies (2–4 Hz), there was often greater sensitivity when the target AM was delivered to 1 of 3 channels versus all 3 channels, especially for narrowly spaced electrodes. Conclusions Besides the increased loudness, the present results also suggest that multiple envelope representations may contribute to the multi-channel advantage observed in previous AMFD studies. The different patterns of results for the wide and narrow spacing suggest a peripheral contribution to multi-channel temporal processing. Because the effect of target AM frequency was non-monotonic in this study, adaptive procedures may not be suitable to measure AMFD thresholds with interfering envelopes. Envelope interactions among multiple channels may be quite complex, depending on the envelope information presented to each channel and the relative independence of the stimulated channels. PMID:26431043

Quantitative imaging reveals real-time Pou5f3–Nanog complexes driving dorsoventral mesendoderm patterning in zebrafish

PubMed Central

Perez-Camps, Mireia; Tian, Jing; Chng, Serene C; Sem, Kai Pin; Sudhaharan, Thankiah; Teh, Cathleen; Wachsmuth, Malte; Korzh, Vladimir; Ahmed, Sohail; Reversade, Bruno

2016-01-01

Formation of the three embryonic germ layers is a fundamental developmental process that initiates differentiation. How the zebrafish pluripotency factor Pou5f3 (homologous to mammalian Oct4) drives lineage commitment is unclear. Here, we introduce fluorescence lifetime imaging microscopy and fluorescence correlation spectroscopy to assess the formation of Pou5f3 complexes with other transcription factors in real-time in gastrulating zebrafish embryos. We show, at single-cell resolution in vivo, that Pou5f3 complexes with Nanog to pattern mesendoderm differentiation at the blastula stage. Later, during gastrulation, Sox32 restricts Pou5f3–Nanog complexes to the ventrolateral mesendoderm by binding Pou5f3 or Nanog in prospective dorsal endoderm. In the ventrolateral endoderm, the Elabela / Aplnr pathway limits Sox32 levels, allowing the formation of Pou5f3–Nanog complexes and the activation of downstream BMP signaling. This quantitative model shows that a balance in the spatiotemporal distribution of Pou5f3–Nanog complexes, modulated by Sox32, regulates mesendoderm specification along the dorsoventral axis. DOI: http://dx.doi.org/10.7554/eLife.11475.001 PMID:27684073

Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1.

PubMed

Wang, Yan-Xiang; Pang, Wei-Qiang; Zeng, Qing-Xuan; Deng, Zhe-Song; Fan, Tian-Yun; Jiang, Jian-Dong; Deng, Hong-Bin; Song, Dan-Qing

2018-01-01

To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation. Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Modulation of Enhancer Looping and Differential Gene Targeting by Epstein-Barr Virus Transcription Factors Directs Cellular Reprogramming

PubMed Central

McClellan, Michael J.; Wood, C. David; Ojeniyi, Opeoluwa; Cooper, Tim J.; Kanhere, Aditi; Arvey, Aaron; Webb, Helen M.; Palermo, Richard D.; Harth-Hertle, Marie L.; Kempkes, Bettina; Jenner, Richard G.; West, Michelle J.

2013-01-01

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors. PMID:24068937

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells.

PubMed

Thomas, Audrey; Mariani-Floderer, Charlotte; López-Huertas, Maria Rosa; Gros, Nathalie; Hamard-Péron, Elise; Favard, Cyril; Ohlmann, Theophile; Alcamí, José; Muriaux, Delphine

2015-08-01

During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly and particle formation. Activated small Rho GTPases and effectors are regulators of actin dynamics and membrane remodeling. We thus studied the effects of the Rac1, Cdc42, and RhoA GTPases and their specific effectors on HIV-1 Gag membrane localization and viral particle release in T cells. Our results show that activated Rac1 and the IRSp53-Wave2-Arp2/3 signaling pathway are involved in Gag plasma membrane localization and viral particle production. This work uncovers a role for cortical actin through the activation of Rac1 and the IRSp53/Wave2 signaling pathway in HIV-1 particle formation in CD4 T lymphocytes. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells

PubMed Central

Thomas, Audrey; Mariani-Floderer, Charlotte; López-Huertas, Maria Rosa; Gros, Nathalie; Hamard-Péron, Elise; Favard, Cyril; Ohlmann, Theophile; Alcamí, José

2015-01-01

ABSTRACT During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. IMPORTANCE During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly and particle formation. Activated small Rho GTPases and effectors are regulators of actin dynamics and membrane remodeling. We thus studied the effects of the Rac1, Cdc42, and RhoA GTPases and their specific effectors on HIV-1 Gag membrane localization and viral particle release in T cells. Our results show that activated Rac1 and the IRSp53-Wave2-Arp2/3 signaling pathway are involved in Gag plasma membrane localization and viral particle production. This work uncovers a role for cortical actin through the activation of Rac1 and the IRSp53/Wave2 signaling pathway in HIV-1 particle formation in CD4 T lymphocytes. PMID:26018170

Detection of underground pipeline based on Golay waveform design

NASA Astrophysics Data System (ADS)

Dai, Jingjing; Xu, Dazhuan

2017-08-01

The detection of underground pipeline is an important problem in the development of the city, but the research about it is not mature at present. In this paper, based on the principle of waveform design in wireless communication, we design an acoustic signal detection system to detect the location of underground pipelines. According to the principle of acoustic localization, we chose DSP-F28335 as the development board, and use DA and AD module as the master control chip. The DA module uses complementary Golay sequence as emission signal. The AD module acquisiting data synchronously, so that the echo signals which containing position information of the target is recovered through the signal processing. The test result shows that the method in this paper can not only calculate the sound velocity of the soil, but also can locate the location of underground pipelines accurately.

Intracavity Faraday modulation spectroscopy (INFAMOS): A tool for radical detection.

PubMed

Gianella, Michele; Pinto, Tomas H P; Wu, Xia; Ritchie, Grant A D

2017-08-07

We present the intra-cavity Faraday modulation spectroscopy technique, whereby optical feedback cavity-enhanced spectroscopy is coupled with Faraday modulation spectroscopy to greatly enhance the interaction path length of a laser beam with a paramagnetic sample in a magnetic field. We describe a first prototype based upon a cw quantum cascade laser targeting a selection of fundamental rovibrational R-branch transitions of nitric oxide (1890 cm -1 ), consisting of a linear cavity (finesse F=6300) and a water-cooled solenoid. We demonstrate a minimum detectable Verdet constant of V min =4.7×10 -14  rad cm -1  G -1  Hz -1/2 (at SNR = 1), corresponding to a single-pass rotation angle of 1.6×10 -10  rad Hz -1/2 and a limit of detection of 0.21 ppbv Hz -1/2 NO.

Volitional exaggeration of body size through fundamental and formant frequency modulation in humans

PubMed Central

Pisanski, Katarzyna; Mora, Emanuel C.; Pisanski, Annette; Reby, David; Sorokowski, Piotr; Frackowiak, Tomasz; Feinberg, David R.

2016-01-01

Several mammalian species scale their voice fundamental frequency (F0) and formant frequencies in competitive and mating contexts, reducing vocal tract and laryngeal allometry thereby exaggerating apparent body size. Although humans’ rare capacity to volitionally modulate these same frequencies is thought to subserve articulated speech, the potential function of voice frequency modulation in human nonverbal communication remains largely unexplored. Here, the voices of 167 men and women from Canada, Cuba, and Poland were recorded in a baseline condition and while volitionally imitating a physically small and large body size. Modulation of F0, formant spacing (∆F), and apparent vocal tract length (VTL) were measured using Praat. Our results indicate that men and women spontaneously and systemically increased VTL and decreased F0 to imitate a large body size, and reduced VTL and increased F0 to imitate small size. These voice modulations did not differ substantially across cultures, indicating potentially universal sound-size correspondences or anatomical and biomechanical constraints on voice modulation. In each culture, men generally modulated their voices (particularly formants) more than did women. This latter finding could help to explain sexual dimorphism in F0 and formants that is currently unaccounted for by sexual dimorphism in human vocal anatomy and body size. PMID:27687571

On the differential diagnosis of Ménière's disease using low-frequency acoustic biasing of the 2f1-f2 DPOAE.

PubMed

Brown, Daniel J; Gibson, William P R

2011-12-01

We have cyclically suppressed the 2f1-f2 distortion product otoacoustic emission (DPOAE) with low-frequency tones (17-97 Hz) as a way of differentially diagnosing the endolymphatic hydrops assumed to be associated with Ménière's syndrome. Round-window electrocochleography (ECochG) was performed in subjects with sensorineural hearing loss (SNHL) on the day of DPOAE testing, and from which the amplitude of the summating potential (SP) was measured, to support the diagnosis of Ménière's syndrome based on symptoms. To summarize and compare the cyclic patterns of DPOAE modulation in these groups we have used the simplest model of DPOAE generation and modulation, by assuming that the DPOAEs were generated by a 1st-order Boltzmann nonlinearity so that the magnitude of the 2f1-f2 DPOAE resembled the 3rd derivative of the Boltzmann function. We have also assumed that the modulation of the DPOAEs by the low-frequency tones was simply due to a sinusoidal change in the operating point on the Boltzmann nonlinearity. We have found the cyclic DPOAE modulation to be different in subjects with Ménière's syndrome (n = 16) when compared to the patterns in normal subjects (n = 16) and in other control subjects with non-Ménière's SNHL and/or vestibular disorders (n = 13). The DPOAEs of normal and non-Ménière's ears were suppressed more during negative ear canal pressure than during positive ear canal pressure. By contrast, DPOAE modulation in Ménière's ears with abnormal ECochG was greatest during positive ear canal pressures. This test may provide a tool for diagnosing Ménière's in the early stages, and might be used to investigate the pathological mechanism underlying the hearing symptoms of this syndrome. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Bone Marrow Sparing in Intensity Modulated Proton Therapy for Cervical Cancer: Efficacy and Robustness under Range and Setup Uncertainties

PubMed Central

Dinges, Eric; Felderman, Nicole; McGuire, Sarah; Gross, Brandie; Bhatia, Sudershan; Mott, Sarah; Buatti, John; Wang, Dongxu

2015-01-01

Background and Purpose This study evaluates the potential efficacy and robustness of functional bone marrow sparing (BMS) using intensity-modulated proton therapy (IMPT) for cervical cancer, with the goal of reducing hematologic toxicity. Material and Methods IMPT plans with prescription dose of 45 Gy were generated for ten patients who have received BMS intensity-modulated x-ray therapy (IMRT). Functional bone marrow was identified by 18F-flourothymidine positron emission tomography. IMPT plans were designed to minimize the volume of functional bone marrow receiving 5–40 Gy while maintaining similar target coverage and healthy organ sparing as IMRT. IMPT robustness was analyzed with ±3% range uncertainty errors and/or ±3mm translational setup errors in all three principal dimensions. Results In the static scenario, the median dose volume reductions for functional bone marrow by IMPT were: 32% for V5GY, 47% for V10Gy, 54% for V20Gy, and 57% for V40Gy, all with p<0.01 compared to IMRT. With assumed errors, even the worst-case reductions by IMPT were: 23% for V5Gy, 37% for V10Gy, 41% for V20Gy, and 39% for V40Gy, all with p<0.01. Conclusions The potential sparing of functional bone marrow by IMPT for cervical cancer is significant and robust under realistic systematic range uncertainties and clinically relevant setup errors. PMID:25981130

Full-Scale Accelerated Pavement Testing of Warm-Mix Asphalt (WMA) for Airfield Pavements

DTIC Science & Technology

2014-01-01

software and Pavement Engineering Utility (PSEVEN) were used 50 ft 65 ft 130 ft 24 ft Item 3 Sasobit ® Item 4 Evotherm 3G Item 1 HMA... Evotherm 3G Air Top Mid-depth Bottom Target temperature = 109 ºF ERDC/GSL TR-14-3 25 The target pavement temperature for this study was 109 ºF, and it is...the locations of the I-buttons and their layout in relation to the vents. 90 95 100 105 110 115 120 HMA Foamed Asphalt Sasobit Evotherm 3G Av er ag e

8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors.

PubMed

Brunschweiger, Andreas; Koch, Pierre; Schlenk, Miriam; Rafehi, Muhammad; Radjainia, Hamid; Küppers, Petra; Hinz, Sonja; Pineda, Felipe; Wiese, Michael; Hockemeyer, Jörg; Heer, Jag; Denonne, Frédéric; Müller, Christa E

2016-11-01

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A 2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A 1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A 1 and A 2A ARs at similar concentrations representing dual A 1 /A 2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A 1 /A 2A AR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, K i human A 1 : 65.5nM, A 2A : 230nM; K i rat A 1 : 352nM, A 2A : 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, K i human A 1 : 642nM, A 2A : 203nM; K i rat A 1 : 166nM, A 2A : 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A 1 and A 2A ARs and at MAO-B (K i human A 1 : 393nM, human A 2A : 595nM, IC 50 human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach. Copyright © 2016 Elsevier Ltd. All rights reserved.

Progress Report Number 2 for Contract Number N00014-93-C-0051, April 16 thru May 15, 1993

DTIC Science & Technology

1993-05-26

accompanied with subhar the modulation frequency is further decreased to 375 Hz , the signal intensity suddenly shows large f and the frequency spectrum...ccrrespondinrg Pbase p•,tra a strange attracwor (Fig. 3d) at this modulation frequency of 375 Hz . SUMMARY: * A new technique has been developed to create

Study on Utilization of Super Grade Plutonium in Molten Salt Reactor FUJI-U3 using CITATION Code

NASA Astrophysics Data System (ADS)

Wulandari, Cici; Waris, Abdul; Pramuditya, Syeilendra; Asril, Pramutadi AM; Novitrian

2017-07-01

FUJI-U3 type of Molten Salt Reactor (MSR) has a unique design since it consists of three core regions in order to avoid the replacement of graphite as moderator. MSR uses floride as a nuclear fuel salt with the most popular chemical composition is LiF-BeF2-ThF4-233UF4. ThF4 and 233UF4 are the fertile and fissile materials, respectively. On the other hand, LiF and BeF2 working as both fuel and heat transfer medium. In this study, the super grade plutonium will be utilized as substitution of 233U since plutonium is easier to be obtained compared to 233U as main fuel. Neutronics calculation was performed by using PIJ and CITATION modules of SRAC 2002 code with JENDL 3.2 as nuclear data library.

Reward-timing-dependent bidirectional modulation of cortical microcircuits during optical single-neuron operant conditioning.

PubMed

Hira, Riichiro; Ohkubo, Fuki; Masamizu, Yoshito; Ohkura, Masamichi; Nakai, Junichi; Okada, Takashi; Matsuzaki, Masanori

2014-11-24

Animals rapidly adapt to environmental change. To reveal how cortical microcircuits are rapidly reorganized when an animal recognizes novel reward contingency, we conduct two-photon calcium imaging of layer 2/3 motor cortex neurons in mice and simultaneously reinforce the activity of a single cortical neuron with water delivery. Here we show that when the target neuron is not relevant to a pre-trained forelimb movement, the mouse increases the target neuron activity and the number of rewards delivered during 15-min operant conditioning without changing forelimb movement behaviour. The reinforcement bidirectionally modulates the activity of subsets of non-target neurons, independent of distance from the target neuron. The bidirectional modulation depends on the relative timing between the reward delivery and the neuronal activity, and is recreated by pairing reward delivery and photoactivation of a subset of neurons. Reward-timing-dependent bidirectional modulation may be one of the fundamental processes in microcircuit reorganization for rapid adaptation.

Definition of Shifts of Optical Transitions Frequencies due to Pulse Perturbation Action by the Photon Echo Signal Form

NASA Astrophysics Data System (ADS)

Lisin, V. N.; Shegeda, A. M.; Samartsev, V. V.

2015-09-01

A relative phase shift between the different groups of excited dipoles, which appears as result of its frequency splitting due to action of a pulse of electric or magnetic fields, depends on a time, if the pulse overlaps in time with echo-pulse. As а consequence, the echo waveform is changed. The echo time form is modulated. The inverse modulation period well enough approximates Zeeman and pseudo-Stark splitting in the cases of magnetic and, therefore, electrical fields. Thus the g-factors of ground 4I15/2 and excited 4F9/2 optical states of Er3+ ion in LuLiF4 and YLiF4 have been measured and pseudo-Stark shift of R1 line in ruby has been determined.

Contrast-marking prosodic emphasis in Williams syndrome: results of detailed phonetic analysis.

PubMed

Ito, Kiwako; Martens, Marilee A

2017-01-01

Past reports on the speech production of individuals with Williams syndrome (WS) suggest that their prosody is anomalous and may lead to challenges in spoken communication. While existing prosodic assessments confirm that individuals with WS fail to use prosodic emphasis to express contrast, those reports typically lack detailed phonetic analysis of speech data. The present study examines the acoustic properties of speech prosody, aiming for the future development of targeted speech interventions. The study examines the three primary acoustic correlates of prosodic emphasis (duration, intensity, F0) and determines whether individuals with WS have difficulty in producing all or a particular set of the three prosodic cues. Speech produced by 12 individuals with WS and 12 chronological age (CA)-matched typically developing individuals were recorded. A sequential picture-naming task elicited production of target phrases in three contexts: (1) no contrast: gorilla with a racket → rabbit with a balloon; (2) contrast on the animal: fox with a balloon → rabbit with a balloon; and (3) contrast on the object: rabbit with a ball → rabbit with a balloon. The three acoustic correlates of prosodic prominence (duration, intensity and F0) were compared across the three referential contexts. The two groups exhibited striking similarities in their use of word duration and intensity for expressing contrast. Both groups showed the reduction and enhancement of final lengthening, and the enhancement and reduction of intensity difference for the animal contrast and for the object contrast conditions, respectively. The two groups differed in their use of F0: the CA group produced higher F0 for the animal than for the object regardless of the context, and this difference was enhanced when the animal noun was contrastive. In contrast, the WS group produced higher F0 for the object than for the animal when the object was contrastive. The present data contradict previous assessment results that report a lack of prosodic skills to mark contrast in individuals with WS. The methodological differences that may account for this variability are discussed. The present data suggest that individuals with WS produce appropriate prosodic cues to express contrast, although their use of pitch may be somewhat atypical. Additional data and future speech comprehension studies will determine whether pitch modulation can be targeted for speech intervention in individuals with WS. © 2016 Royal College of Speech and Language Therapists.

MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia

PubMed Central

Zheng, Y-S; Zhang, H; Zhang, X-J; Feng, D-D; Luo, X-Q; Zeng, C-W; Lin, K-Y; Zhou, H; Qu, L-H; Zhang, P; Chen, Y-Q

2012-01-01

Acute myeloblastic leukemia (AML) is characterized by the accumulation of abnormal myeloblasts (mainly granulocyte or monocyte precursors) in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, only minority with AML achieve long-term survival. Therefore, further understanding mechanisms of leukemogenesis and exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNA-100 (miR-100), a small non-coding RNA molecule, has been reported as a frequent event aberrantly expressed in patients with AML; however, the molecular basis for this phenotype and the statuses of its downstream targets have not yet been elucidated. In the present study, we found that the expression level of miR-100 in vivo was related to the stage of the maturation block underlying the subtypes of myeloid leukemia. In vitro experiments further demonstrated that miR-100 was required to promote the cell proliferation of promyelocytic blasts and arrest them differentiated to granulocyte/monocyte lineages. Significantly, we identified RBSP3, a phosphatase-like tumor suppressor, as a bona fide target of miR-100 and validated that RBSP3 was involved in cell differentiation and survival in AML. Moreover, we revealed a new pathway that miR-100 regulates G1/S transition and S-phase entry and blocks the terminal differentiation by targeting RBSP3, which partly in turn modulates the cell cycle effectors pRB/E2F1 in AML. These events promoted cell proliferation and blocked granulocyte/monocyte differentiation. Our data highlight an important role of miR-100 in the molecular etiology of AML, and implicate the potential application of miR-100 in cancer therapy. PMID:21643017

Optimization of combined electron and photon beams for breast cancer

NASA Astrophysics Data System (ADS)

Xiong, W.; Li, J.; Chen, L.; Price, R. A.; Freedman, G.; Ding, M.; Qin, L.; Yang, J.; Ma, C.-M.

2004-05-01

Recently, intensity-modulated radiation therapy and modulated electron radiotherapy have gathered a growing interest for the treatment of breast and head and neck tumours. In this work, we carried out a study to combine electron and photon beams to achieve differential dose distributions for multiple target volumes simultaneously. A Monte Carlo based treatment planning system was investigated, which consists of a set of software tools to perform accurate dose calculation, treatment optimization, leaf sequencing and plan analysis. We compared breast treatment plans generated using this home-grown optimization and dose calculation software for different treatment techniques. Five different planning techniques have been developed for this study based on a standard photon beam whole breast treatment and an electron beam tumour bed cone down. Technique 1 includes two 6 MV tangential wedged photon beams followed by an anterior boost electron field. Technique 2 includes two 6 MV tangential intensity-modulated photon beams and the same boost electron field. Technique 3 optimizes two intensity-modulated photon beams based on a boost electron field. Technique 4 optimizes two intensity-modulated photon beams and the weight of the boost electron field. Technique 5 combines two intensity-modulated photon beams with an intensity-modulated electron field. Our results show that technique 2 can reduce hot spots both in the breast and the tumour bed compared to technique 1 (dose inhomogeneity is reduced from 34% to 28% for the target). Techniques 3, 4 and 5 can deliver a more homogeneous dose distribution to the target (with dose inhomogeneities for the target of 22%, 20% and 9%, respectively). In many cases techniques 3, 4 and 5 can reduce the dose to the lung and heart. It is concluded that combined photon and electron beam therapy may be advantageous for treating breast cancer compared to conventional treatment techniques using tangential wedged photon beams followed by a boost electron field.

A general approach for chemical labeling and rapid, spatially controlled protein inactivation

PubMed Central

Marks, Kevin M.; Braun, Patrick D.; Nolan, Garry P.

2004-01-01

Chemical labeling of proteins inside of living cells can enable studies of the location, movement, and function of proteins in vivo. Here we demonstrate an approach for chemical labeling of proteins that uses the high-affinity interaction between an FKBP12 mutant (F36V) and a synthetic, engineered ligand (SLF′). A fluorescein conjugate to the engineered ligand (FL-SLF′) retained binding to FKBP12(F36V) and possessed similar fluorescence properties as parental fluorescein. FL-SLF′ labeled FKBP12(F36V) fusion proteins in live mammalian cells, and was used to monitor the subcellular localization of a membrane targeted FKBP12(F36V) construct. Chemical labeling of FKBP12(F36V) fusion proteins with FL-SLF′ was readily detectable at low expression levels of the FKBP12(F36V) fusion, and the level of fluorescent staining with FL-SLF′ was proportional to the FKBP12(F36V) expression level. This FL-SLF′-FKBP12(F36V) labeling technique was tested in fluorophore assisted laser inactivation (FALI), a light-mediated technique to rapidly inactivate fluorophore-labeled target proteins. FL-SLF′ mediated FALI of a β-galactosidase-FKBP12(F36V) fusion protein, causing rapid inactivation of >90% of enzyme activity upon irradiation in vitro. FL-SLF′ also mediated FALI of a β-galactosidase fusion expressed in living NIH 3T3 cells, where β-galactosidase activity was reduced in 15 s. Thus, FL-SLF′ can be used to monitor proteins in vivo and to target rapid, spatially and temporally defined inactivation of target proteins in living cells in a process that we call FK-FALI. PMID:15218100

Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury.

PubMed

Imahashi, Kenichi; Schneider, Michael D; Steenbergen, Charles; Murphy, Elizabeth

2004-10-01

The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH(i) and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (P<0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F1F0-ATPase. In the presence of oligomycin (Oligo), an F1F0-ATPase inhibitor, the decrease in pH(i) was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH(i) during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2-mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F1F0-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.

E2F8 as a Novel Therapeutic Target for Lung Cancer.

PubMed

Park, Sin-Aye; Platt, James; Lee, Jong Woo; López-Giráldez, Francesc; Herbst, Roy S; Koo, Ja Seok

2015-09-01

The E2F members have been divided into transcription activators (E2F1-E2F3) and repressors (E2F4-E2F8). E2F8 with E2F7 has been known to play an important physiologic role in embryonic development and cell cycle regulation by repressing E2F1. However, the function of E2F8 in cancer cells is unknown. E2F8 expression was assessed by immunoblotting or immunofluorescence staining in human lung cancer (LC) cells and tissues from LC patients (n = 45). Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of E2F8 in LC. Microarray analysis was used to determine the target genes of E2F8. The regulation of E2F8 on the expression of ubiquitin-like PHD and RING domain-containing 1 (UHRF1), one of E2F8 target genes, was determined using chromatin immunoprecipitation and promoter activity assays. Human LC xenograft models were used to determine the effects of inhibiting E2F8 by siRNAs (n = 7 per group) or antisense morpholino (n = 8 per group) on tumor growth. Survival was analyzed using the Kaplan-Meier method and group differences by the Student's t test. All statistical tests were two-sided. LC tumors overexpressed E2F8 compared with normal lung tissues. Depletion of E2F8 inhibited cell proliferation and tumor growth. E2F8 knockdown statistically significantly reduced the expression of UHRF1 (~60%-70%, P < .001), and the direct binding of E2F8 on the promoter of UHRF1 was identified. Kaplan-Meier analysis with a public database showed prognostic significance of aberrant E2F8 expression in LC (HR = 1.91 95% CI = 1.21 to 3.01 in chemo-naïve patients, P = .0047). We demonstrated that E2F8 is overexpressed in LC and is required for the growth of LC cells. These findings implicate E2F8 as a novel therapeutic target for LC treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A 20-Amino Acid Module of Protein Kinase Cϵ Involved in Translocation and Selective Targeting at Cell-Cell Contacts*

PubMed Central

Diouf, Barthélémy; Collazos, Alejandra; Labesse, Gilles; Macari, Françoise; Choquet, Armelle; Clair, Philippe; Gauthier-Rouvière, Cécile; Guérineau, Nathalie C.; Jay, Philippe; Hollande, Frédéric; Joubert, Dominique

2009-01-01

In the pituitary gland, activated protein kinase C (PKC) isoforms accumulate either selectively at the cell-cell contact (α and ϵ) or at the entire plasma membrane (β1 and δ). The molecular mechanisms underlying these various subcellular locations are not known. Here, we demonstrate the existence within PKCϵ of a cell-cell contact targeting sequence (3CTS) that, upon stimulation, is capable of targeting PKCδ, chimerin-α1, and the PKCϵ C1 domain to the cell-cell contact. We show that this selective targeting of PKCϵ is lost upon overexpression of 3CTS fused to a (R-Ahx-R)4 (where Ahx is 6-aminohexanoic acid) vectorization peptide, reflecting a dominant-negative effect of the overexpressed 3CTS on targeting selectivity. 3CTS contains a putative amphipathic α-helix, a 14-3-3-binding site, and the Glu-374 amino acid, involved in targeting selectivity. We show that the integrity of the α-helix is important for translocation but that 14-3-3 is not involved in targeting selectivity. However, PKCϵ translocation is increased when PKCϵ/14-3-3 interaction is abolished, suggesting that phorbol 12-myristate 13-acetate activation may initiate two sets of PKCϵ functions, those depending on 14-3-3 and those depending on translocation to cell-cell contacts. Thus, 3CTS is involved in the modulation of translocation via its 14-3-3-binding site, in cytoplasmic desequestration via the α-helix, and in selective PKCϵ targeting at the cell-cell contact via Glu-374. PMID:19429675

MicroRNA-203 Modulates the Radiation Sensitivity of Human Malignant Glioma Cells

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

Chang, Ji Hyun; Hwang, Yeo Hyun; Lee, David J.

Purpose: We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved. Methods and Materials: Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed. Results: Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNAmore » repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1. Conclusions: These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.« less

Novel compounds TAD-1822-7-F2 and F5 inhibited HeLa cells growth through the JAK/Stat signaling pathway.

PubMed

Yang, Tianfeng; Shi, Xianpeng; Kang, Yuan; Zhu, Man; Fan, Mengying; Zhang, Dongdong; Zhang, Yanmin

2018-07-01

Cervical carcinoma remains the second most common malignancy with a high mortality rate among women worldwide. TAD-1822-7-F2 (F2) and TAD-1822-7-F5 (F5) are novel compounds synthesized on the chemical structure of taspine derivatives, and show an effective suppression for HeLa cells. Our study aims to confirm the potential targets of F2 and F5, and investigate the underlying mechanism of the inhibitory effect on HeLa cells. In this study, Real Time Cell Analysis and crystal violet staining assay were conducted to investigate the effect of F2 and F5 on HeLa cells proliferation. And the analytical methods of surface plasmon resonance and quartz crystal microbalance were established and employed to study the interaction between F2 and F5 and potential target protein JAK2, suggesting that both compounds have strong interaction with the JAK2 protein. Western blot analysis, immunofluorescence staining study and PCR was conducted to investigate the molecules of JAK/Stat signaling pathway. Interestingly, F2 and F5 showed diverse regulation for signaling molecules because of their different chemical structure. F2 increased the expression of JAK2 and downregulated the level of P-JAK1 and P-JAK2, and decreased P-Stat3 (Ser727). While F5 could increase the expression of JAK2 and naturally decrease the phosphorylation of JAK1 and Tyk2, and decreased the expression of P-Stat6. Moreover, F2 and F5 showed the same downregulation on the P-Stat3 (Tyr705). Therefore, F2 and F5 could target the JAK2 protein and prevent the phosphorylation of JAKs to suppress the phosphorylation of the downstream effector Stats, which suggested that F2 and F5 have great potential to be the inhibitors of the JAK/Stat signaling pathway. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Dynamic analysis of a fibre-optic ring resonator excited by a sinewave-modulated laser diode

NASA Astrophysics Data System (ADS)

Pandian, G. Soundra; Seraji, Faramarz

1990-10-01

The present theoretical dynamic analysis of a fiber-optic ring resonator upon excitation by a sinusoidally-modulated laser diode (LD) yields results for such resonator conditions as modulating frequency, amplitude-modulation index, coupler power-coupling coefficient, loop-delay time (tau), and the phase angle between the LD's AM and FM responses. It is found that when the modulation frequency f(m) exceeds a threshold value such that f(m)tau exceeds 0.0002, the output response diverges from steady state and engages in an oscillatory behavior characterized by overshoots. When f(m)tau exceeds 1.0, the output approximates the intensity modulation of the LD.

Synthesis and evaluation of an 18 F-labeled trifluoroborate derivative of 2-nitroimidazole for imaging tumor hypoxia with positron emission tomography.

PubMed

Nunes, Paulo Sérgio Gonçalves; Zhang, Zhengxing; Kuo, Hsiou-Ting; Zhang, Chengcheng; Rousseau, Julie; Rousseau, Etienne; Lau, Joseph; Kwon, Daniel; Carvalho, Ivone; Bénard, François; Lin, Kuo-Shyan

2018-04-01

2-Nitroimidazole-based hypoxia imaging tracers such as 18 F-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, 18 F-AmBF 3 -Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF 3 -Bu-2NI was prepared in 4 steps. 18 F labeling was conducted via 18 F- 19 F isotope exchange reaction, and 18 F-AmBF 3 -Bu-2NI was obtained in 14.8 ± 0.4% (n = 3) decay-corrected radiochemical yield with 24.5 ± 5.2 GBq/μmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT-29 tumor-bearing mice showed that 18 F-AmBF 3 -Bu-2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post-injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post-injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl-trifluoroborate that prevents free diffusion of 18 F-AmBF 3 -Bu-2NI across the cell membrane. Our results suggest that highly hydrophilic 18 F-labeled ammoniomethyl-trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target. Copyright © 2017 John Wiley & Sons, Ltd.

Divided attention modulates semantic activation: evidence from a nonletter-level prime task.

PubMed

Otsuka, Sachio; Kawaguchi, Jun

2007-12-01

Research has recently shown that semantic activation is modulated in proportion to the amount of attention required for letter-level processing of the prime (the attention modulation hypothesis; Smith, Bentin, & Spalek, 2001). In this study, we examined this hypothesis with an auditory divided-attention task. Participants were asked to decide whether the pitch of a probe tone presented with the prime word was higher or lower than the basic tone presented with the fixation cross. Their target task was lexical decision to the target word. Experiment 1 showed that semantic priming was modulated by the amount of attentional resources. Moreover, in Experiment 2, this modulation was also found in a situation that eliminated the possibility of participants' response strategies. Yet, Experiment 3 showed repetition priming to be unaffected. These results support an amended attention modulation hypothesis in which modulation is not limited to letter-level processing.

Depletion of Gut Microbiota Protects against Renal Ischemia-Reperfusion Injury

PubMed Central

Rampanelli, Elena; Stroo, Ingrid; Butter, Loes M.; Teske, Gwendoline J.; Claessen, Nike; Stokman, Geurt; Florquin, Sandrine; Leemans, Jaklien C.; Dessing, Mark C.

2017-01-01

An accumulating body of evidence shows that gut microbiota fulfill an important role in health and disease by modulating local and systemic immunity. The importance of the microbiome in the development of kidney disease, however, is largely unknown. To study this concept, we depleted gut microbiota with broad-spectrum antibiotics and performed renal ischemia-reperfusion (I/R) injury in mice. Depletion of the microbiota significantly attenuated renal damage, dysfunction, and remote organ injury and maintained tubular integrity after renal I/R injury. Gut flora–depleted mice expressed lower levels of F4/80 and chemokine receptors CX3CR1 and CCR2 in the F4/80+ renal resident macrophage population and bone marrow (BM) monocytes than did control mice. Additionally, compared with control BM monocytes, BM monocytes from gut flora–depleted mice had decreased migratory capacity toward CX3CL1 and CCL2 ligands. To study whether these effects were driven by depletion of the microbiota, we performed fecal transplants in antibiotic-treated mice and found that transplant of fecal material from an untreated mouse abolished the protective effect of microbiota depletion upon renal I/R injury. In conclusion, we show that depletion of gut microbiota profoundly protects against renal I/R injury by reducing maturation status of F4/80+ renal resident macrophages and BM monocytes. Therefore, dampening the inflammatory response by targeting microbiota-derived mediators might be a promising therapy against I/R injury. PMID:27927779

Within-hemifield competition in early visual areas limits the ability to track multiple objects with attention.

PubMed

Störmer, Viola S; Alvarez, George A; Cavanagh, Patrick

2014-08-27

It is much easier to divide attention across the left and right visual hemifields than within the same visual hemifield. Here we investigate whether this benefit of dividing attention across separate visual fields is evident at early cortical processing stages. We measured the steady-state visual evoked potential, an oscillatory response of the visual cortex elicited by flickering stimuli, of moving targets and distractors while human observers performed a tracking task. The amplitude of responses at the target frequencies was larger than that of the distractor frequencies when participants tracked two targets in separate hemifields, indicating that attention can modulate early visual processing when it is divided across hemifields. However, these attentional modulations disappeared when both targets were tracked within the same hemifield. These effects were not due to differences in task performance, because accuracy was matched across the tracking conditions by adjusting target speed (with control conditions ruling out effects due to speed alone). To investigate later processing stages, we examined the P3 component over central-parietal scalp sites that was elicited by the test probe at the end of the trial. The P3 amplitude was larger for probes on targets than on distractors, regardless of whether attention was divided across or within a hemifield, indicating that these higher-level processes were not constrained by visual hemifield. These results suggest that modulating early processing stages enables more efficient target tracking, and that within-hemifield competition limits the ability to modulate multiple target representations within the hemifield maps of the early visual cortex. Copyright © 2014 the authors 0270-6474/14/3311526-08$15.00/0.

Regulation of miR394 in Response to Fusarium oxysporum f. sp. cepae (FOC) Infection in Garlic (Allium sativum L).

PubMed

Chand, Subodh K; Nanda, Satyabrata; Joshi, Raj K

2016-01-01

MicroRNAs (miRNAs) are a class of post-transcriptional regulators that negatively regulate gene expression through target mRNA cleavage or translational inhibition and play important roles in plant development and stress response. In the present study, six conserved miRNAs from garlic (Allium sativum L.) were analyzed to identify differentially expressed miRNAs in response to Fusarium oxysporum f. sp. cepae (FOC) infection. Stem-loop RT-PCR revealed that miR394 is significantly induced in garlic seedlings post-treatment with FOC for 72 h. The induction of miR394 expression during FOC infection was restricted to the basal stem plate tissue, the primary site of infection. Garlic miR394 was also upregulated by exogenous application of jasmonic acid. Two putative targets of miR394 encoding F-box domain and cytochrome P450 (CYP450) family proteins were predicted and verified using 5' RLM-RACE (RNA ligase mediated rapid amplification of cDNA ends) assay. Quantitative RT-PCR showed that the transcript levels of the predicted targets were significantly reduced in garlic plants exposed to FOC. When garlic cultivars with variable sensitivity to FOC were exposed to the pathogen, an upregulation of miR394 and down regulation of the targets were observed in both varieties. However, the expression pattern was delayed in the resistant genotypes. These results suggest that miR394 functions in negative modulation of FOC resistance and the difference in timing and levels of expression in variable genotypes could be examined as markers for selection of FOC resistant garlic cultivars.

RB Loss Promotes Prostate Cancer Metastasis

PubMed Central

Thangavel, Chellappagounder; Boopathi, Ettickan; Liu, Yi; Haber, Alex; Ertel, Adam; Bhardwaj, Anshul; Addya, Sankar; Williams, Noelle; Ciment, Stephen J.; Cotzia, Paolo; Dean, Jeffry L.; Snook, Adam; McNair, Chris; Price, Matt; Hernandez, James R.; Zhao, Shuang G.; Birbe, Ruth; McCarthy, James B.; Turley, Eva A.; Pienta, Kenneth J.; Feng, Felix Y.; Dicker, Adam P.; Knudsen, Karen E.; Den, Robert B.

2017-01-01

RB loss occurs commonly in neoplasia but its contributions to advanced cancer have not been assessed directly. Here we show that RB loss in multiple murine models of cancer produces a prometastatic phenotype. Gene expression analyses showed that regulation of the cell motility receptor RHAMM by the RB/E2F pathway was critical for epithelial–mesenchymal transition, motility, and invasion by cancer cells. Genetic modulation or pharmacologic inhibition of RHAMM activity was sufficient and necessary for metastatic phenotypes induced by RB loss in prostate cancer. Mechanistic studies in this setting established that RHAMM stabilized F-actin polymerization by controlling ROCK signaling. Collectively, our findings show how RB loss drives metastatic capacity and highlight RHAMM as a candidate therapeutic target for treating advanced prostate cancer. PMID:27923835

Premature activation of the paramyxovirus fusion protein before target cell attachment with corruption of the viral fusion machinery.

PubMed

Farzan, Shohreh F; Palermo, Laura M; Yokoyama, Christine C; Orefice, Gianmarco; Fornabaio, Micaela; Sarkar, Aurijit; Kellogg, Glen E; Greengard, Olga; Porotto, Matteo; Moscona, Anne

2011-11-04

Paramyxoviruses, including the childhood pathogen human parainfluenza virus type 3, enter host cells by fusion of the viral and target cell membranes. This fusion results from the concerted action of its two envelope glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). The receptor-bound HN triggers F to undergo conformational changes that render it competent to mediate fusion of the viral and cellular membranes. We proposed that, if the fusion process could be activated prematurely before the virion reaches the target host cell, infection could be prevented. We identified a small molecule that inhibits paramyxovirus entry into target cells and prevents infection. We show here that this compound works by an interaction with HN that results in F-activation prior to receptor binding. The fusion process is thereby prematurely activated, preventing fusion of the viral membrane with target cells and precluding viral entry. This first evidence that activation of a paramyxovirus F can be specifically induced before the virus contacts its target cell suggests a new strategy with broad implications for the design of antiviral agents.

Comparison of test performance profile for blood tests of liver fibrosis in chronic hepatitis C.

PubMed

Halfon, Philippe; Bacq, Yannick; De Muret, Anne; Penaranda, Guillaume; Bourliere, Marc; Ouzan, Denis; Tran, Albert; Botta, Danielle; Renou, Christophe; Bréchot, Marie-Claude; Degott, Claude; Paradis, Valérie

2007-03-01

We evaluated the test performance profile (TPP) of blood tests of liver fibrosis. Three hundred and fifty-six patients with C chronic hepatitis were included in two centers. Metavir staging of liver specimens by two independent pathologists and the following tests were evaluated: Fibrotest (FT), APRI, FibroMeter (FM), and Hepascore (HS). Metavir stages were: F0: 4%, F1: 55%, F2: 26%, F3: 11%, and F4: 4%. The AUROCs were not significantly different, respectively, FT, FM, APRI, HS: >or=F2: 0.79, 0.78, 0.76, >or=0.76; F3: 0.81, 0.85, 0.81, 0.81; and F4: 0.86, 0.94, 0.92, 0.89. The TPP relies on the paired comparison of blood-test misclassification based on liver specimen, e.g. FT vs FM, respectively: F0+1: 18 vs 28% (p=0.0003), >or=F2: 43 vs 31% (p=0.004). There was no center effect. In those populations, the four blood tests had a similar performance for significant fibrosis (F>or=2), lying in the lower range of published results which is attributable to a low >or=F2 prevalence, and for >or=F3 and F4. However, FM and FT had performance profiles significantly different as a function of fibrosis stages or diagnostic target (fibrosis cut-off). This has to be considered during the interpretation process. Moreover, the performance should be reported with different diagnostic targets.

Single spin asymmetries of inclusive hadrons produced in electron scattering from a transversely polarized 3 He target

DOE PAGES

Allada, K.; Zhao, Y. X.; Aniol, K.; ...

2014-04-07

We report the first measurement of target single-spin asymmetries (A N) in the inclusive hadron production reaction, e + 3He↑→h+X, using a transversely polarized 3 He target. This experiment was conducted at Jefferson Lab in Hall A using a 5.9-GeV electron beam. Three types of hadrons (π ±, K ± and proton) were detected in the transverse hadron momentum range 0.54 < p T < 0.74 GeV/c. The range of x F for pions was -0.29 < x F< -0.23 and for kaons -0.25 < x F<-0.18. The observed asymmetry strongly depends on the type of hadron. A positive asymmetrymore » is observed for π + and K +. A negative asymmetry is observed for π–. The magnitudes of the asymmetries follow |A π –|<|A π +|<|A K +|. The K – and proton asymmetries are consistent with zero within the experimental uncertainties. The π + and π – asymmetries measured for the 3He target and extracted for neutrons are opposite in sign with a small increase observed as a function of p T.« less

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.

SU-F-T-85: Energy Modulated Electron Postmastectomy Unreconstructed (PU) Chest Wall (CW) Irradiation Technique to Achieve Heart Sparing

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

Hong, L; Ballangrud, A; Mechalakos, J

Purpose: For left-sided PU patients requiring CW and nodal irradiation, sometimes partial wide tangents (PWT) are not feasible due to abnormal chest wall contour or heart position close to the anterior chest wall or unusual wide excision scar. We developed an energy modulated electron chest wall irradiation technique that will achieve heart sparing. Methods: Ten left-sided PU patients were selected for this dosimetry study. If PWT were used, the amount of the ipsilateral lung would be ranged 3.4 to 4.4 cm, and the amount of heart would be ranged 1.3 to 3.8 cm. We used electron paired fields that matchedmore » on the skin to achieve dose conformity to the chest wall. The enface electron fields were designed at extended SSD from a single isocenter and gantry angle with different energy beams using different cutout. Lower energy was used in the central chest wall part and higher energy was used in the periphery of the chest wall. Bolus was used for the electron fields to ensure adequate skin dose coverage. The electron fields were matched to the photon supra-clavicle field in the superior region. Daily field junctions were used to feather the match lines between all the fields. Target volumes and normal tissues were drawn according to institutional protocols. Prescription dose was 2Gy per fraction for a total 50Gy. Dose calculations were done with Eclipse EMC-11031 for Electron and AAA-11031 for photons. Results: Six patients were planned using 6/9MeV, three using 9/12MeV and one 6/12MeV. Target volumes achieved adequate coverage. For heart, V30Gy, V20Gy and Mean Dose were 0.6%±0.6%, 2.7%±1.7%, and 3.0Gy±0.8Gy respectively. For ipsilateral lung, V50Gy, V20Gy, V10Gy and V5Gy were 0.9%±1.1%, 34.3%±5.1%, 51.6%±6.3% and 64.1%±7.5% respectively. Conclusion: For left-sided PU patients with unusual anatomy, energy modulated electron CW irradiation technique can achieve heart sparing with acceptable lung dose.« less

Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage.

PubMed

Alteri, Claudia; Surdo, Matteo; Bellocchi, Maria Concetta; Saccomandi, Patrizia; Continenza, Fabio; Armenia, Daniele; Parrotta, Lucia; Carioti, Luca; Costa, Giosuè; Fourati, Slim; Di Santo, Fabiola; Scutari, Rossana; Barbaliscia, Silvia; Fedele, Valentina; Carta, Stefania; Balestra, Emanuela; Alcaro, Stefano; Marcelin, Anne Genevieve; Calvez, Vincent; Ceccherini-Silberstein, Francesca; Artese, Anna; Perno, Carlo Federico; Svicher, Valentina

2015-08-01

Incomplete APOBEC3G/F neutralization by a defective HIV-1Vif protein can promote genetic diversification by inducing G-to-A mutations in the HIV-1 genome. The HIV-1 Env V3 loop, critical for coreceptor usage, contains several putative APOBEC3G/F target sites. Here, we determined if APOBEC3G/F, in the presence of Vif-defective HIV-1 virus, can induce G-to-A mutations at V3 positions critical to modulation of CXCR4 usage. Peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from 2 HIV-1-negative donors were infected with CCR5-using 81.A-VifWT virus (i.e., with wild-type [WT] Vif protein), 81.A-VifE45G, or 81.A-VifK22E (known to incompletely/partially neutralize APOBEC3G/F). The rate of G-toA mutations was zero or extremely low in 81.A-VifWT- and 81.A-VifE45G-infected PBMC from both donors. Conversely, G-to-A enrichment was detected in 81.A-VifK22E-infected PBMC (prevalence ranging from 2.18% at 7 days postinfection [dpi] to 3.07% at 21 dpi in donor 1 and from 10.49% at 7 dpi to 8.69% at 21 dpi in donor 2). A similar scenario was found in MDM. G-to-A mutations occurred at 8 V3 positions, resulting in nonsynonymous amino acid substitutions. Of them, G24E and E25K strongly correlated with phenotypically/genotypically defined CXCR4-using viruses (P = 0.04 and 5.5e-7, respectively) and increased the CXCR4 N-terminal binding affinity for V3 (WT, -40.1 kcal/mol; G24E, -510 kcal/mol; E25K, -522 kcal/mol). The analysis of paired V3 and Vif DNA sequences from 84 HIV-1-infected patients showed that the presence of a Vif-defective virus correlated with CXCR4 usage in proviral DNA (P = 0.04). In conclusion, incomplete APOBEC3G/F neutralization by a single Vif amino acid substitution seeds a CXCR4-using proviral reservoir. This can have implications for the success of CCR5 antagonist-based therapy, as well as for the risk of disease progression. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

An RRM–ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion

PubMed Central

Collins, Katherine M.; Kainov, Yaroslav A.; Christodolou, Evangelos; Ray, Debashish; Morris, Quaid; Hughes, Timothy; Taylor, Ian A.

2017-01-01

Abstract RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1–ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interaction with the intronic 3΄ site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping. PMID:28379442

An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.

PubMed

Collins, Katherine M; Kainov, Yaroslav A; Christodolou, Evangelos; Ray, Debashish; Morris, Quaid; Hughes, Timothy; Taylor, Ian A; Makeyev, Eugene V; Ramos, Andres

2017-06-20

RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1-ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interaction with the intronic 3΄ site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Automated radiosynthesis of Al[18F]PSMA-11 for large scale routine use.

PubMed

Kersemans, Ken; De Man, Kathia; Courtyn, Jan; Van Royen, Tessa; Piron, Sarah; Moerman, Lieselotte; Brans, Boudewijn; De Vos, Filip

2018-05-01

We report a reproducible automated radiosynthesis for large scale batch production of clinical grade Al[ 18 F]PSMA-11. A SynthraFCHOL module was optimized to synthesize Al[ 18 F]PSMA-11 by Al[ 18 F]-chelation. Results Al[ 18 F]PSMA-11 was synthesized within 35min in a yield of 21 ± 3% (24.0 ± 6.0GBq) and a radiochemical purity > 95%. Batches were stable for 4h and conform the European Pharmacopeia guidelines. The automated synthesis of Al[ 18 F]PSMA-11 allows for large scale production and distribution of Al[ 18 F]PSMA-11. Copyright © 2018 Elsevier Ltd. All rights reserved.

HER2 signaling drives DNA anabolism and proliferation through SRC-3 phosphorylation and E2F1-regulated genes

PubMed Central

Nikolai, Bryan C.; Lanz, Rainer B.; York, Brian; Dasgupta, Subhamoy; Mitsiades, Nicholas; Creighton, Chad J.; Tsimelzon, Anna; Hilsenbeck, Susan G.; Lonard, David M.; Smith, Carolyn L.; O’Malley, Bert W.

2016-01-01

Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2+ tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. While the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor Palbociclib, defines overlap and divergence of adjuvant pharmacological targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacological combinations in pre-clinical models of adjuvant treatment and therapeutic resistance. PMID:26833126

Target-object integration, attention distribution, and object orientation interactively modulate object-based selection.

PubMed

Al-Janabi, Shahd; Greenberg, Adam S

2016-10-01

The representational basis of attentional selection can be object-based. Various studies have suggested, however, that object-based selection is less robust than spatial selection across experimental paradigms. We sought to examine the manner by which the following factors might explain this variation: Target-Object Integration (targets 'on' vs. part 'of' an object), Attention Distribution (narrow vs. wide), and Object Orientation (horizontal vs. vertical). In Experiment 1, participants discriminated between two targets presented 'on' an object in one session, or presented as a change 'of' an object in another session. There was no spatial cue-thus, attention was initially focused widely-and the objects were horizontal or vertical. We found evidence of object-based selection only when targets constituted a change 'of' an object. Additionally, object orientation modulated the sign of object-based selection: We observed a same-object advantage for horizontal objects, but a same-object cost for vertical objects. In Experiment 2, an informative cue preceded a single target presented 'on' an object or as a change 'of' an object (thus, attention was initially focused narrowly). Unlike in Experiment 1, we found evidence of object-based selection independent of target-object integration. We again found that the sign of selection was modulated by the objects' orientation. This result may reflect a meridian effect, which emerged due to anisotropies in the cortical representations when attention is oriented endogenously. Experiment 3 revealed that object orientation did not modulate object-based selection when attention was oriented exogenously. Our findings suggest that target-object integration, attention distribution, and object orientation modulate object-based selection, but only in combination.

The effect of fresh gas flow rate and type of anesthesia machine on time to reach target sevoflurane concentration.

PubMed

Shin, Hye Won; Yu, Hae Na; Bae, Go Eun; Huh, Hyub; Park, Ji Yong; Kim, Ji Young

2017-01-19

Anesthesia machines have been developed by the application of new technology for rapid and easier control of anesthetic concentration. In this study, we used a test lung to investigate whether the time taken to reach the target sevoflurane concentration varies with the rate of fresh gas flow (FGF) and type of anesthesia machine (AM). We measured the times taken to reach the target sevoflurane concentration (2 minimum alveolar concentration = 4%) at variable rates of FGF (0.5, 1, or 3 L/min) and different types of AM (Primus ® , Perseus ® , and Zeus ® [Zeus ® -F; Zeus ® fresh gas mode, Zeus ® -A; Zeus ® auto-mode]). Concomitant ventilation was supplied using 100% O 2. The AMs were connected to a test lung. A sevoflurane vaporizer setting of 6% was used in Primus ® , Perseus ® , and Zeus ® -F; a target end-tidal setting of 4% was used in Zeus ® -A (from a vaporizer setting of 0%). The time taken to reach the target concentration was measured in every group. When the same AM was used (Primus ® , Perseus ® , or Zeus ® -F), the times to target concentration shortened as the FGF rate increased (P < 0.05). Conversely, when the same FGF rate was used, but with different AMs, the time to target concentration was shortest in Perseus ® , followed by Primus ® , and finally by Zeus ® -F (P < 0.05). With regards to both modes of Zeus ® , at FGF rates of 0.5 and 1 L/min, the time to target concentration was shorter in Zeus ® -A than in Zeus ® -F; however, the time was longer in Zeus ® -A than in Zeus ® -F at FGF rate of 3 L/min (P < 0.05). Shorter times taken to reach the target concentration were associated with high FGF rates, smaller internal volume of the AM, proximity of the fresh gas inlets to patients, absence of a decoupling system, and use of blower-driven ventilators in AM.

A non-linear 4-wave resonant model for non-perturbative fast ion interactions with Alfv'enic modes in burning plasmas

NASA Astrophysics Data System (ADS)

Zonca, Fulvio; Chen, Liu

2007-11-01

We adopt the 4-wave modulation interaction model, introduced by Chen et al [1] for analyzing modulational instabilities of the radial envelope of Ion Temperature Gradient driven modes in toroidal geometry, extending it to the modulations on the fast particle distribution function due to nonlinear Alfv'enic mode dynamics, as proposed in Ref. [2]. In the case where the wave-particle interactions are non-perturbative and strongly influence the mode evolution, as in the case of Energetic Particle Modes (EPM) [3], radial distortions (redistributions) of the fast ion source dominate the mode nonlinear dynamics. In this work, we show that the resonant particle motion is secular with a time-scale inversely proportional to the mode amplitude [4] and that the time evolution of the EPM radial envelope can be cast into the form of a nonlinear Schr"odinger equation a la Ginzburg-Landau [5]. [1] L. Chen et al, Phys. Plasmas 7 3129 (2000) [2] F. Zonca et al, Theory of Fusion Plasmas (Bologna: SIF) 17 (2000) [3] L. Chen, Phys. Plasmas 1, 1519 (1994).[4] F. Zonca et al, Nucl. Fusion 45 477 (2005) [5] F. Zonca et al, Plasma Phys. Contr. Fusion 48 B15 (2006)

Three-dimensional fit-to-flow microfluidic assembly.

PubMed

Chen, Arnold; Pan, Tingrui

2011-12-01

Three-dimensional microfluidics holds great promise for large-scale integration of versatile, digitalized, and multitasking fluidic manipulations for biological and clinical applications. Successful translation of microfluidic toolsets to these purposes faces persistent technical challenges, such as reliable system-level packaging, device assembly and alignment, and world-to-chip interface. In this paper, we extended our previously established fit-to-flow (F2F) world-to-chip interconnection scheme to a complete system-level assembly strategy that addresses the three-dimensional microfluidic integration on demand. The modular F2F assembly consists of an interfacial chip, pluggable alignment modules, and multiple monolithic layers of microfluidic channels, through which convoluted three-dimensional microfluidic networks can be easily assembled and readily sealed with the capability of reconfigurable fluid flow. The monolithic laser-micromachining process simplifies and standardizes the fabrication of single-layer pluggable polymeric modules, which can be mass-produced as the renowned Lego(®) building blocks. In addition, interlocking features are implemented between the plug-and-play microfluidic chips and the complementary alignment modules through the F2F assembly, resulting in facile and secure alignment with average misalignment of 45 μm. Importantly, the 3D multilayer microfluidic assembly has a comparable sealing performance as the conventional single-layer devices, providing an average leakage pressure of 38.47 kPa. The modular reconfigurability of the system-level reversible packaging concept has been demonstrated by re-routing microfluidic flows through interchangeable modular microchannel layers.

Aromatic–aromatic interactions between residues in KCa3.1 pore helix and S5 transmembrane segment control the channel gating process

PubMed Central

Garneau, Line; Klein, Hélène; Lavoie, Marie-France; Brochiero, Emmanuelle; Parent, Lucie

2014-01-01

The Ca2+-activated potassium channel KCa3.1 is emerging as a therapeutic target for a large variety of health disorders. One distinguishing feature of KCa3.1 is that the channel open probability at saturating Ca2+ concentrations (Pomax) is low, typically 0.1–0.2 for KCa3.1 wild type. This observation argues for the binding of Ca2+ to the calmodulin (CaM)–KCa3.1 complex, promoting the formation of a preopen closed-state configuration leading to channel opening. We have previously shown that the KCa3.1 active gate is most likely located at the level of the selectivity filter. As Ca2+-dependent gating of KCa3.1 originates from the binding of Ca2+ to CaM in the C terminus, the hypothesis of a gate located at the level of the selectivity filter requires that the conformational change initiated in the C terminus be transmitted to the S5 and S6 transmembrane helices, with a resulting effect on the channel pore helix directly connected to the selectivity filter. A study was thus undertaken to determine to what extent the interactions between the channel pore helix with the S5 and S6 transmembrane segments contribute to KCa3.1 gating. Molecular dynamics simulations first revealed that the largest contact area between the pore helix and the S5 plus S6 transmembrane helices involves residue F248 at the C-terminal end of the pore helix. Unitary current recordings next confirmed that modulating aromatic–aromatic interactions between F248 and W216 of the S5 transmembrane helical segment and/or perturbing the interactions between F248 and residues in S6 surrounding the glycine hinge G274 cause important changes in Pomax. This work thus provides the first evidence for a key contribution of the pore helix in setting Pomax by stabilizing the channel closed configuration through aromatic–aromatic interactions involving F248 of the pore helix. We propose that the interface pore helix/S5 constitutes a promising site for designing KCa3.1 potentiators. PMID:24470490

Small molecule therapeutics targeting F-box proteins in cancer.

PubMed

Liu, Yuan; Mallampalli, Rama K

2016-02-01

The ubiquitin proteasome system (UPS) plays vital roles in maintaining protein equilibrium mainly through proteolytic degradation of targeted substrates. The archetypical SCF ubiquitin E3 ligase complex contains a substrate recognition subunit F-box protein that recruits substrates to the catalytic ligase core for its polyubiquitylation and subsequent proteasomal degradation. Several well-characterized F-box proteins have been demonstrated that are tightly linked to neoplasia. There is mounting information characterizing F-box protein-substrate interactions with the rationale to develop unique therapeutics for cancer treatment. Here we review that how F-box proteins function in cancer and summarize potential small molecule inhibitors for cancer therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence from neurophysiology to neuroimaging

PubMed Central

Smucny, Jason; Tregellas, Jason R

2018-01-01

Patients with schizophrenia self-administer nicotine at rates higher than is self-administered for any other psychiatric illness. Although the reasons are unclear, one hypothesis suggests that nicotine is a form of ‘self-medication’ in order to restore normal levels of nicotinic signaling and target abnormalities in neuronal function associated with cognitive processes. This brief review discusses evidence from neurophysiological and neuroimaging studies in schizophrenia patients that nicotinic agonists may effectively target dysfunctional neuronal circuits in the illness. Evidence suggests that nicotine significantly modulates a number of these circuits, although relatively few studies have used modern neuroimaging techniques (e.g. functional magnetic resonance imaging (fMRI)) to examine the effects of nicotinic drugs on disease-related neurobiology. The neuronal effects of nicotine and other nicotinic agonists in schizophrenia remain a priority for psychiatry research. PMID:28441884

Modulation of 14-3-3/Phosphotarget Interaction by Physiological Concentrations of Phosphate and Glycerophosphates

PubMed Central

Sluchanko, Nikolai N.; Chebotareva, Natalia A.; Gusev, Nikolai B.

2013-01-01

Molecular mechanisms governing selective binding of a huge number of various phosphorylated protein partners to 14-3-3 remain obscure. Phosphate can bind to 14-3-3 and therefore being present at high intracellular concentration, which undergoes significant changes under physiological conditions, phosphate can theoretically regulate interaction of 14-3-3 with phosphorylated targets. In order to check this hypothesis we analyzed effect of phosphate and other natural abundant anions on interaction of 14-3-3 with phosphorylated human small heat shock protein HspB6 (Hsp20) participating in regulation of different intracellular processes. Inorganic phosphate, glycerol-1-phosphate and glycerol-2-phosphate at physiologically relevant concentrations (5-15 mM) significantly destabilized complexes formed by 14-3-3ζ and phosphorylated HspB6 (pHspB6), presumably, via direct interaction with the substrate-binding site of 14-3-3. Phosphate also destabilized complexes between pHspB6 and 14-3-3γ or the monomeric mutant form of 14-3-3ζ. Inorganic sulfate and pyrophosphate were less effective in modulation of 14-3-3 interaction with its target protein. The inhibitory effect of all anions on pHspB6/14-3-3 interaction was concentration-dependent. It is hypothesized that physiological changes in phosphate anions concentration can modulate affinity and specificity of interaction of 14-3-3 with its multiple targets and therefore the actual phosphointeractome of 14-3-3. PMID:23977325

Modulation of 14-3-3/phosphotarget interaction by physiological concentrations of phosphate and glycerophosphates.

PubMed

Sluchanko, Nikolai N; Chebotareva, Natalia A; Gusev, Nikolai B

2013-01-01

Molecular mechanisms governing selective binding of a huge number of various phosphorylated protein partners to 14-3-3 remain obscure. Phosphate can bind to 14-3-3 and therefore being present at high intracellular concentration, which undergoes significant changes under physiological conditions, phosphate can theoretically regulate interaction of 14-3-3 with phosphorylated targets. In order to check this hypothesis we analyzed effect of phosphate and other natural abundant anions on interaction of 14-3-3 with phosphorylated human small heat shock protein HspB6 (Hsp20) participating in regulation of different intracellular processes. Inorganic phosphate, glycerol-1-phosphate and glycerol-2-phosphate at physiologically relevant concentrations (5-15 mM) significantly destabilized complexes formed by 14-3-3ζ and phosphorylated HspB6 (pHspB6), presumably, via direct interaction with the substrate-binding site of 14-3-3. Phosphate also destabilized complexes between pHspB6 and 14-3-3γ or the monomeric mutant form of 14-3-3ζ. Inorganic sulfate and pyrophosphate were less effective in modulation of 14-3-3 interaction with its target protein. The inhibitory effect of all anions on pHspB6/14-3-3 interaction was concentration-dependent. It is hypothesized that physiological changes in phosphate anions concentration can modulate affinity and specificity of interaction of 14-3-3 with its multiple targets and therefore the actual phosphointeractome of 14-3-3.

GHz Modulation of GaAs-Based Bipolar Cascade VCSELs (Preprint)

DTIC Science & Technology

2006-11-01

VCSELs were grown on n+ GaAs substrates by molecular beam epitaxy . The laser cavities consist of 1-, 2-, or 3-stage 52λ microcavi- ties, each containing...AFRL-SN-WP-TP-2006-128 GHz MODULATION OF GaAs-BASED BIPOLAR CASCADE VCSELs (PREPRINT) W.J. Siskaninetz, R.G. Bedford, T.R. Nelson, Jr., J.E...TITLE AND SUBTITLE GHz MODULATION OF GaAs-BASED BIPOLAR CASCADE VCSELs (PREPRINT) 5c. PROGRAM ELEMENT NUMBER 69199F 5d. PROJECT NUMBER 2002 5e

Modelling the effect of electrode displacement on transcranial direct current stimulation (tDCS)

NASA Astrophysics Data System (ADS)

Ramaraju, Sriharsha; Roula, Mohammed A.; McCarthy, Peter W.

2018-02-01

Objective. Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers a low-intensity, direct current to cortical areas with the purpose of modulating underlying brain activity. Recent studies have reported inconsistencies in tDCS outcomes. The underlying assumption of many tDCS studies has been that replication of electrode montage equates to replicating stimulation conditions. It is possible however that anatomical difference between subjects, as well as inherent inaccuracies in montage placement, could affect current flow to targeted areas. The hypothesis that stimulation of a defined brain region will be stable under small displacements was tested. Approach. Initially, we compared the total simulated current flowing through ten specific brain areas for four commonly used tDCS montages: F3-Fp2, C3-Fp2, Fp1-F4, and P3-P4 using the software tool COMETS. The effect of a slight (~1 cm in each of four directions) anode displacement on the simulated regional current density for each of the four tDCS montages was then determined. Current flow was calculated and compared through ten segmented brain areas to determine the effect of montage type and displacement. The regional currents, as well as the localised current densities, were compared with the original electrode location, for each of these new positions. Main results. Recommendations for montages that maximise stimulation current for the ten brain regions are considered. We noted that the extent to which stimulation is affected by electrode displacement varies depending on both area and montage type. The F3-Fp2 montage was found to be the least stable with up to 38% change in average current density in the left frontal lobe while the Fp1-F4 montage was found to the most stable exhibiting only 1% change when electrodes were displaced. Significance. These results indicate that even relatively small changes in stimulation electrode placement appear to result in surprisingly large changes in current densities and distribution.

Apollo 8 Mission image,Target of Opportunity (T/O) 10

NASA Image and Video Library

1968-12-21

Apollo 8,Moon,Target of Opportunity (T/O) 10, Various targets. Latitude 18 degrees South,Longitude 163.50 degrees West. Camera Tilt Mode: High Oblique. Direction: South. Sun Angle 12 degrees. Original Film Magazine was labeled E. Camera Data: 70mm Hasselblad; F-Stop: F-5.6; Shutter Speed: 1/250 second. Film Type: Kodak SO-3400 Black and White,ASA 40. Other Photographic Coverage: Lunar Orbiter 1 (LO I) S-3. Flight Date: December 21-27,1968.

Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

PubMed

Miller, A; McLeod, L; Alhayyani, S; Szczepny, A; Watkins, D N; Chen, W; Enriori, P; Ferlin, W; Ruwanpura, S; Jenkins, B J

2017-05-25

Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130 F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130 F/F :Kras G12D model, but not parental Kras G12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130 F/F :Kras G12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with Kras G12D muscle tissue. These cachectic features of gp130 F/F :Kras G12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130 F/F :Kras G12D :Stat3 -/+ or gp130 F/F :Kras G12D :Il6 -/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130 F/F :Kras G12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130 F/F :Kras G12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.

Low-inductance switch and capacitor energy storage modules made of packages of industrial condensers IK50-3

NASA Astrophysics Data System (ADS)

Bykov, Yu A.; Krastelev, E. G.; Sedin, A. A.; Feduschak, V. F.

2017-05-01

A low-inductance module of a high-current capacitive energy storage with an operating voltage of 40 kV is developed. The design of the module is based on the application of capacitive sections of the industrial condenser IK50-3. The module includes two capacitors of 0.35 μF each, one common low-jitter triggered gas switch and 2 groups of output cables of 4 from each capacitor. A bus bars topology developed for the switch and cables connections provides a small total inductance of the discharge circuit, for the module with the output cables KVIM of 0.5 m long, it is lower than 40 nH. The set of 10 modules is now used for driving the 20 stages linear transformer for a fast charging of the pulse forming line of the high-current nanosecond accelerator. A design of the module and the results of tests of a single module and a set of 10 are presented.

Retrieval of water vapor mixing ratios from a laser-based sensor

NASA Technical Reports Server (NTRS)

Tucker, George F.

1995-01-01

Langley Research Center has developed a novel external path sensor which monitors water vapor along an optical path between an airplane window and reflective material on the plane's engine. An infrared tunable diode laser is wavelength modulated across a water vapor absorption line at a frequency f. The 2f and DC signals are measured by a detector mounted adjacent to the laser. The 2f/DC ratio depends on the amount of wavelength modulation, the water vapor absorption line being observed, and the temperature, pressure, and water vapor content of the atmosphere. The present work concerns efforts to quantify the contributions of these factors and to derive a method for extracting the water vapor mixing ratio from the measurements. A 3 m cell was fabricated in order to perform laboratory tests of the sensor. Measurements of 2f/DC were made for a series of pressures and modulation amplitudes. During my 1994 faculty fellowship, a computer program was created which allowed 2f/DC to be calculated for any combination of the variables which effect it. This code was used to generate 2f/DC values for the conditions measured in the laboratory. The experimental and theoretical values agreed to within a few percent. As a result, the laser modulation amplitude can now be set in the field by comparing the response of the instrument to the calculated response as a function of modulation amplitude. Once the validity of the computer code was established, it was used to investigate possible candidate absorption lines. 2f/DC values were calculated for pressures, temperatures, and water vapor mixing ratios expected to be encountered in future missions. The results have been incorporated into a database which will be used to select the best line for a particular mission. The database will also be used to select a retrieval technique. For examples under some circumstances there is little temperature dependence in 2f/DC so temperature can be neglected. In other cases, there is a dependence with temperature for a particular pressure, requiring a more complicated retrieval algorithm. Future experimental work is necessary to test agreement with the theoretical values over a range of temperatures and mixing ratios. Additionally, retrieval algorithms for forthcoming missions must be incorporated into the software package which controls the instrument.

Ion Channel Modulators in Cystic Fibrosis.

PubMed

Gentzsch, Martina; Mall, Marcus A

2018-05-08

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains one of the most common life-shortening genetic diseases affecting the lung and other organs. CFTR functions as a cAMP-dependent anion channel that transports chloride and bicarbonate across epithelial surfaces and disruption of these ion transport processes plays a central role in the pathogenesis of CF. These findings provided the rationale for pharmacological modulation of ion transport, either by targeting mutant CFTR or alternative ion channels that can compensate for CFTR dysfunction, as a promising therapeutic approach. High throughput screening has supported the development of CFTR modulator compounds. CFTR correctors are designed to improve defective protein processing, trafficking and cell surface expression, whereas potentiators increase the activity of mutant CFTR at the cell surface. The approval of the first potentiator ivacaftor for the treatment of patients with specific CFTR mutations and, more recently the corrector lumacaftor in combination with ivacaftor for patients homozygous for the common F508del mutation, were major breakthroughs on the path to causal therapies for all patients with CF. In this review, we focus on recent developments and remaining challenges of CFTR-directed therapies, as well as modulators of other ion channels such as alternative chloride channels and the epithelial sodium channel (ENaC) as additional targets in CF lung disease. Further, we discuss how patient-derived precision medicine models may aid the translation of emerging next generation ion channel modulators from the laboratory to the clinic and tailor their use for optimal therapeutic benefits in individual patients with CF. Copyright © 2018. Published by Elsevier Inc.

Modulation of chorus intensity by ULF waves deep in the inner magnetosphere

DOE PAGES

Xia, Zhiyang; Chen, Lunjin; Dai, Lei; ...

2016-09-05

Previous studies have shown that chorus wave intensity can be modulated by Pc4-Pc5 compressional ULF waves. In this paper, we present Van Allen Probes observation of ULF wave modulating chorus wave intensity, which occurred deep in the magnetosphere. The ULF wave shows fundamental poloidal mode signature and mirror mode compressional nature. The observed ULF wave can modulate not only the chorus wave intensity but also the distribution of both protons and electrons. Linear growth rate analysis shows consistence with observed chorus intensity variation at low frequency (f <~ 0.3f ce), but cannot account for the observed higher-frequency chorus waves, includingmore » the upper band chorus waves. This suggests the chorus waves at higher-frequency ranges require nonlinear mechanisms. Finally, in addition, we use combined observations of Radiation Belt Storm Probes (RBSP) A and B to verify that the ULF wave event is spatially local and does not last long.« less

Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development.

PubMed

Wu, Kun; Ding, Jin; Chen, Cheng; Sun, Wen; Ning, Bei-Fang; Wen, Wen; Huang, Lei; Han, Tao; Yang, Wen; Wang, Chao; Li, Zhong; Wu, Meng-Chao; Feng, Gen-Sheng; Xie, Wei-Fen; Wang, Hong-Yang

2012-12-01

Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the mechanism underlying the progression from cirrhosis to HCC remains unclear. Herein we report the concurrent increase of liver progenitor cells (LPCs) and transforming growth factor-β (TGF-β) in diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis and cirrhotic livers of HCC patients. Using several experimental approaches, including 2-acetylaminofluorene/partial hepatectomy (2-AAF/PHx) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-elicited murine liver regeneration, we found that activation of LPCs in the absence of TGF-β induction was insufficient to trigger hepatocarcinogenesis. Moreover, a small fraction of LPCs was detected to coexpress tumor initiating cell (T-IC) markers during rat hepatocarcinogenesis and in human HCCs, and TGF-β levels were positively correlated with T-IC marker expression, which indicates a role of TGF-β in T-IC generation. Rat pluripotent LPC-like WB-F344 cells were exposed to low doses of TGF-β for 18 weeks imitating the enhanced TGF-β expression in cirrhotic liver. Interestingly, long-term treatment of TGF-β on WB-F344 cells impaired their LPC potential but granted them T-IC properties including expression of T-IC markers, increased self-renewal capacity, stronger chemoresistance, and tumorigenicity in NOD-SCID mice. Hyperactivation of Akt but not Notch, signal transducer and activator of transcription 3 (STAT3), or mammalian target of rapamycin (mTOR) was detected in TGF-β-treated WB-F344 cells. Introduction of the dominant-negative mutant of Akt significantly attenuated T-IC properties of those transformed WB-F344 cells, indicating Akt was required in TGF-β-mediated-generation of hepatic T-ICs. We further demonstrate that TGF-β-induced Akt activation and LPC transformation was mediated by microRNA-216a-modulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) suppression. Hepatoma-initiating cells may derive from hepatic progenitor cells exposed to chronic and constant TGF-β stimulation in cirrhotic liver, and pharmaceutical inhibition of microRNA-216a/PTEN/Akt signaling could be a novel strategy for HCC prevention and therapy targeting hepatic T-ICs. Copyright © 2012 American Association for the Study of Liver Diseases.

47 CFR 2.1509 - Environmental and duration tests.

Code of Federal Regulations, 2011 CFR

2011-10-01

... above tests are to be performed on the same test unit. The tests in § 2.1509 (f) through (i) may be run... modulation characteristic tests in § 2.1513 of this part. Step (3) Perform the spectral tests in § 2.1515 of... extent possible for this test. (f) Float free and activation test. This test is required only for Class A...

Pulsewidth Modulated Speed Control of Brushless DC Motors.

DTIC Science & Technology

1984-09-01

sped acca - racy of the motoc is defined as tne difference Letweer the maximum and mir.imum motor speed divided by the commai. =e/ s~eed. TABLE I Motor...TO = .OOC C L N I5 THE SYvSTEM ELECTRICAL TIME CONSTANT lN = INCIC/RES F6 (1.c/FREcj D C/100. lIME =Ph 71ME2 l .CiFJREQ PMs C C EO IS THE BACK EtMF C...iu-8.2 J WR ITE (b , -0 I rI M 50 FGRM AT 11 ) t’I1N: 0,Fl 0 3,v ItM : a F10..3) WRITE (6t CC) IAV,IRMS 100 f -.FM tT 1 Xj IAV = ’ ,F 8.4,, v I11RMS F6

MARES

NASA Image and Video Library

2012-12-30

View of the Muscle Atrophy Research and Exercise System (MARES),in the Columbus Module (COL1F3). MARES will carry out research on musculoskeletal,bio-mechanical,and neuromuscular human physiology. Photo was taken during Expedition 34.

Apollo 12 Mission image - Astronaut Alan L. Bean,lunar module pilot,and two U.S. spacecraft

NASA Image and Video Library

1969-11-20

AS12-48-7136 (20 Nov. 1969) --- Astronaut Charles Conrad Jr., commander, examines the unmanned Surveyor 3 spacecraft during the second Apollo 12 extravehicular activity (EVA). In the background is the lunar module, parked where the crew had landed it in the Ocean of Storms only 600 feet from Surveyor 3. This series of pictures documents the only occasion wherein Apollo astronauts landed near or had hands-on contact with another spacecraft which had arrived on the moon's surface well ahead of them. This picture was taken by astronaut Alan L. Bean, lunar module pilot. The television camera and several other pieces were taken from Surveyor 3 and brought back to Earth for scientific examination. Surveyor 3 soft-landed on the moon on April 19, 1967. Astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) in lunar orbit while astronauts Conrad and Bean descended in the LM to explore the moon. Photo credit: NASA

Single-arc volumetric-modulated arc therapy (sVMAT) as adjuvant treatment for gastric cancer: Dosimetric comparisons with three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT)

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

Wang, Xin; Li, Guangjun; Zhang, Yingjie

2013-01-01

To compare the dosimetric differences between the single-arc volumetric-modulated arc therapy (sVMAT), 3-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT) techniques in treatment planning for gastric cancer as adjuvant radiotherapy. Twelve patients were retrospectively analyzed. In each patient's case, the parameters were compared based on the dose-volume histogram (DVH) of the sVMAT, 3D-CRT, and IMRT plans, respectively. Three techniques showed similar target dose coverage. The maximum and mean doses of the target were significantly higher in the sVMAT plans than that in 3D-CRT plans and in the 3D-CRT/IMRT plans, respectively, but these differences were clinically acceptable. The IMRT and sVMATmore » plans successfully achieved better target dose conformity, reduced the V{sub 20/30}, and mean dose of the left kidney, as well as the V{sub 20/30} of the liver, compared with the 3D-CRT plans. And the sVMAT technique reduced the V{sub 20} of the liver much significantly. Although the maximum dose of the spinal cord were much higher in the IMRT and sVMAT plans, respectively (mean 36.4 vs 39.5 and 40.6 Gy), these data were still under the constraints. Not much difference was found in the analysis of the parameters of the right kidney, intestine, and heart. The IMRT and sVMAT plans achieved similar dose distribution to the target, but superior to the 3D-CRT plans, in adjuvant radiotherapy for gastric cancer. The sVMAT technique improved the dose sparings of the left kidney and liver, compared with the 3D-CRT technique, but showed few dosimetric advantages over the IMRT technique. Studies are warranted to evaluate the clinical benefits of the VMAT treatment for patients with gastric cancer after surgery in the future.« less

Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect

PubMed Central

Greineder, Colin F.; Brenza, Jacob B.; Carnemolla, Ronald; Zaitsev, Sergei; Hood, Elizabeth D.; Pan, Daniel C.; Ding, Bi-Sen; Esmon, Charles T.; Chacko, Ann Marie; Muzykantov, Vladimir R.

2015-01-01

Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood–tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to partner enzymatically to generate enhanced biologic effect. Based on the recent discovery that paired antibodies directed to adjacent epitopes of platelet endothelial cell adhesion molecule (PECAM)-1 stimulate each other’s binding, we fused single-chain fragments (scFv) of paired anti-mouse PECAM-1 antibodies to recombinant murine thrombomodulin (TM) and endothelial protein C receptor (EPCR), endothelial membrane proteins that partner in activation of protein C (PC). scFv/TM and scFv/EPCR bound to mouse endothelial PECAM-1 with high affinity (EC50 1.5 and 3.8 nM, respectively), and codelivery induced a 5-fold increase in PC activation not seen when TM and EPCR are anchored to distinct cell adhesion molecules. In a mouse model of acute lung injury, dual targeting reduces both the expression of lung inflammatory markers and trans-endothelial protein leak by as much as 40%, as compared to either agent alone. These findings provide proof of principle for endothelial dual targeting, an approach with numerous potential biomedical applications.—Greineder, C. F., Brenza, J. B., Carnemolla, R., Zaitsev, S., Hood, E. D., Pan, D. C., Ding, B.-S., Esmon, C. T., Chacko, A. M., Muzykantov, V. R. Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect. PMID:25953848

Reverberation impairs brainstem temporal representations of voiced vowel sounds: challenging “periodicity-tagged” segregation of competing speech in rooms

PubMed Central

Sayles, Mark; Stasiak, Arkadiusz; Winter, Ian M.

2015-01-01

The auditory system typically processes information from concurrently active sound sources (e.g., two voices speaking at once), in the presence of multiple delayed, attenuated and distorted sound-wave reflections (reverberation). Brainstem circuits help segregate these complex acoustic mixtures into “auditory objects.” Psychophysical studies demonstrate a strong interaction between reverberation and fundamental-frequency (F0) modulation, leading to impaired segregation of competing vowels when segregation is on the basis of F0 differences. Neurophysiological studies of complex-sound segregation have concentrated on sounds with steady F0s, in anechoic environments. However, F0 modulation and reverberation are quasi-ubiquitous. We examine the ability of 129 single units in the ventral cochlear nucleus (VCN) of the anesthetized guinea pig to segregate the concurrent synthetic vowel sounds /a/ and /i/, based on temporal discharge patterns under closed-field conditions. We address the effects of added real-room reverberation, F0 modulation, and the interaction of these two factors, on brainstem neural segregation of voiced speech sounds. A firing-rate representation of single-vowels' spectral envelopes is robust to the combination of F0 modulation and reverberation: local firing-rate maxima and minima across the tonotopic array code vowel-formant structure. However, single-vowel F0-related periodicity information in shuffled inter-spike interval distributions is significantly degraded in the combined presence of reverberation and F0 modulation. Hence, segregation of double-vowels' spectral energy into two streams (corresponding to the two vowels), on the basis of temporal discharge patterns, is impaired by reverberation; specifically when F0 is modulated. All unit types (primary-like, chopper, onset) are similarly affected. These results offer neurophysiological insights to perceptual organization of complex acoustic scenes under realistically challenging listening conditions. PMID:25628545

Identification of the Downstream Promoter Targets of Smad Tumor Suppressors in Human Breast Cancer Cells

DTIC Science & Technology

2004-10-01

signaling mediator Smad2, Smad3 and Smad4 which form oligomeric complexes and migrate into nucleus to function as transcription factors to modulate... Smad3 and Smad4. 2. Identification of the downstream promoter targets of Smad3 or Smad4 in breast cancer cells. 3. Identify Smad4 regulated downstream...Development of a novel chromatin immunoprecipitation assay (CHIPS) using a TAP-TAG system to isolate in vivo binding targets of Smad3 and Smad4

Hindcasting of Equatorial Spread F Using Seasonal Empirical Models

NASA Astrophysics Data System (ADS)

Aswathy, R. P.; Manju, G.

2018-02-01

The role of gravity waves in modulating equatorial spread F (ESF) day-to-day variability is investigated using ionosonde data at Trivandrum (geographic coordinates, 8.5°N, 77°E; mean geomagnetic latitude -0.3°N) a magnetic equatorial location. A novel empirical model that incorporates the combined effects of electrodynamics and gravity waves in modulating ESF occurrence during autumnal equinox season was presented by Aswathy and Manju (2017). In the present study, the height variations of the requisite gravity wave seed perturbations for ESF are examined for the vernal equinoxes, summer solstices, and winter solstices of different years. Subsequently, the empirical model, incorporating the electrodynamical effects and the gravity wave modulation, valid for each of the seasons is developed. Accordingly, for each season, the threshold curve may be demarcated provided the solar flux index (F10.7) is known. The empirical models are validated using the data for high, moderate, and low solar activity years corresponding to each season. In the next stage, this model is to be fine tuned to facilitate the prediction of ESF well before its onset.

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors.

PubMed

Mejías-Luque, R; Lindén, S K; Garrido, M; Tye, H; Najdovska, M; Jenkins, B J; Iglesias, M; Ernst, M; de Bolós, C

2010-03-25

Infection of gastric mucosa by Helicobacter pylori induces an inflammatory response with increased levels of proinflammatory cytokines. Among them, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 induce the activation of signaling pathways that regulate genes expression, such as MUC2 and MUC4 intestinal mucins ectopically detected in gastric tumors. This study evaluated if the predominant inflammatory cell type correlates with MUC2 and MUC4 expression in human intestinal gastric tumors (n=78). In addition, we analyzed the regulatory effects of the associated inflammatory signaling pathways on their expression in gastric cancer cell lines, and in a mouse model with hyperactivated STAT3 signaling pathway. Tumors with predominant lymphoplasmocytic infiltrate (chronic inflammation), presented higher levels of MUC2 and were more differentiated than tumors with predominant polymorphonuclear infiltrate (acute inflammation). These differences can be attributed to specific cytokines, because TNF-alpha and IL-1beta induced MUC2 but no MUC4 expression in gastric cancer cell lines. The two groups of tumors expressed similar levels of MUC4 that correlated with the expression of STAT3 transcription factor, implicated in the activation of genes through the IL-6 pathway. In gastric tissues from gp130(+/+), gp130(Y757F/Y757F) and gp130(Y757F/Y757F) Stat3(-/+) mice, Muc2 was not detected, whereas Muc4 was found in the gastric tumors developed in the gp130(Y757F/Y757F) mice, with hyperactivated STAT3. These data indicate that the signaling pathways associated with the inflammatory response can modulate the expression of MUC2 and MUC4 intestinal mucin genes, in human and mouse gastric tumors.

Haptically Guided Grasping. fMRI Shows Right-Hemisphere Parietal Stimulus Encoding, and Bilateral Dorso-Ventral Parietal Gradients of Object- and Action-Related Processing during Grasp Execution

PubMed Central

Marangon, Mattia; Kubiak, Agnieszka; Króliczak, Gregory

2016-01-01

The neural bases of haptically-guided grasp planning and execution are largely unknown, especially for stimuli having no visual representations. Therefore, we used functional magnetic resonance imaging (fMRI) to monitor brain activity during haptic exploration of novel 3D complex objects, subsequent grasp planning, and the execution of the pre-planned grasps. Haptic object exploration, involving extraction of shape, orientation, and length of the to-be-grasped targets, was associated with the fronto-parietal, temporo-occipital, and insular cortex activity. Yet, only the anterior divisions of the posterior parietal cortex (PPC) of the right hemisphere were significantly more engaged in exploration of complex objects (vs. simple control disks). None of these regions were re-recruited during the planning phase. Even more surprisingly, the left-hemisphere intraparietal, temporal, and occipital areas that were significantly invoked for grasp planning did not show sensitivity to object features. Finally, grasp execution, involving the re-recruitment of the critical right-hemisphere PPC clusters, was also significantly associated with two kinds of bilateral parieto-frontal processes. The first represents transformations of grasp-relevant target features and is linked to the dorso-dorsal (lateral and medial) parieto-frontal networks. The second monitors grasp kinematics and belongs to the ventro-dorsal networks. Indeed, signal modulations associated with these distinct functions follow dorso-ventral gradients, with left aIPS showing significant sensitivity to both target features and the characteristics of the required grasp. Thus, our results from the haptic domain are consistent with the notion that the parietal processing for action guidance reflects primarily transformations from object-related to effector-related coding, and these mechanisms are rather independent of sensory input modality. PMID:26779002

Haptically Guided Grasping. fMRI Shows Right-Hemisphere Parietal Stimulus Encoding, and Bilateral Dorso-Ventral Parietal Gradients of Object- and Action-Related Processing during Grasp Execution.

PubMed

Marangon, Mattia; Kubiak, Agnieszka; Króliczak, Gregory

2015-01-01

The neural bases of haptically-guided grasp planning and execution are largely unknown, especially for stimuli having no visual representations. Therefore, we used functional magnetic resonance imaging (fMRI) to monitor brain activity during haptic exploration of novel 3D complex objects, subsequent grasp planning, and the execution of the pre-planned grasps. Haptic object exploration, involving extraction of shape, orientation, and length of the to-be-grasped targets, was associated with the fronto-parietal, temporo-occipital, and insular cortex activity. Yet, only the anterior divisions of the posterior parietal cortex (PPC) of the right hemisphere were significantly more engaged in exploration of complex objects (vs. simple control disks). None of these regions were re-recruited during the planning phase. Even more surprisingly, the left-hemisphere intraparietal, temporal, and occipital areas that were significantly invoked for grasp planning did not show sensitivity to object features. Finally, grasp execution, involving the re-recruitment of the critical right-hemisphere PPC clusters, was also significantly associated with two kinds of bilateral parieto-frontal processes. The first represents transformations of grasp-relevant target features and is linked to the dorso-dorsal (lateral and medial) parieto-frontal networks. The second monitors grasp kinematics and belongs to the ventro-dorsal networks. Indeed, signal modulations associated with these distinct functions follow dorso-ventral gradients, with left aIPS showing significant sensitivity to both target features and the characteristics of the required grasp. Thus, our results from the haptic domain are consistent with the notion that the parietal processing for action guidance reflects primarily transformations from object-related to effector-related coding, and these mechanisms are rather independent of sensory input modality.

Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome.

PubMed

Garcia, S S; Blackledge, M S; Michalek, S; Su, L; Ptacek, T; Eipers, P; Morrow, C; Lefkowitz, E J; Melander, C; Wu, H

2017-07-01

Dental caries is a costly and prevalent disease characterized by the demineralization of the tooth's enamel. Disease outcome is influenced by host factors, dietary intake, cariogenic bacteria, and other microbes. The cariogenic bacterial species Streptococcus mutans metabolizes sucrose to initiate biofilm formation on the tooth surface and consequently produces lactic acid to degrade the tooth's enamel. Persistence of S. mutans biofilms in the oral cavity can lead to tooth decay. To date, no anticaries therapies that specifically target S. mutans biofilms but do not disturb the overall oral microbiome are available. We screened a library of 2-aminoimidazole antibiofilm compounds with a biofilm dispersion assay and identified a small molecule that specifically targets S. mutans biofilms. At 5 µM, the small molecule annotated 3F1 dispersed 50% of the established S. mutans biofilm but did not disperse biofilms formed by the commensal species Streptococcus sanguinis or Streptococcus gordonii. 3F1 dispersed S. mutans biofilms independently of biofilm-related factors such as antigen I/II and glucosyltransferases. 3F1 treatment effectively prevented dental caries by controlling S. mutans in a rat caries model without perturbing the oral microbiota. Our study demonstrates that selective targeting of S. mutans biofilms by 3F1 was able to effectively reduce dental caries in vivo without affecting the overall oral microbiota shaped by the intake of dietary sugars, suggesting that the pathogenic biofilm-specific treatment is a viable strategy for disease prevention.

Audio-vocal responses of vocal fundamental frequency and formant during sustained vowel vocalizations in different noises.

PubMed

Lee, Shao-Hsuan; Hsiao, Tzu-Yu; Lee, Guo-She

2015-06-01

Sustained vocalizations of vowels [a], [i], and syllable [mə] were collected in twenty normal-hearing individuals. On vocalizations, five conditions of different audio-vocal feedback were introduced separately to the speakers including no masking, wearing supra-aural headphones only, speech-noise masking, high-pass noise masking, and broad-band-noise masking. Power spectral analysis of vocal fundamental frequency (F0) was used to evaluate the modulations of F0 and linear-predictive-coding was used to acquire first two formants. The results showed that while the formant frequencies were not significantly shifted, low-frequency modulations (<3 Hz) of F0 significantly increased with reduced audio-vocal feedback across speech sounds and were significantly correlated with auditory awareness of speakers' own voices. For sustained speech production, the motor speech controls on F0 may depend on a feedback mechanism while articulation should rely more on a feedforward mechanism. Power spectral analysis of F0 might be applied to evaluate audio-vocal control for various hearing and neurological disorders in the future. Copyright © 2015 Elsevier B.V. All rights reserved.

Motor demand-dependent activation of ipsilateral motor cortex.

PubMed

Buetefisch, Cathrin M; Revill, Kate Pirog; Shuster, Linda; Hines, Benjamin; Parsons, Michael

2014-08-15

The role of ipsilateral primary motor cortex (M1) in hand motor control during complex task performance remains controversial. Bilateral M1 activation is inconsistently observed in functional (f)MRI studies of unilateral hand performance. Two factors limit the interpretation of these data. As the motor tasks differ qualitatively in these studies, it is conceivable that M1 contributions differ with the demand on skillfulness. Second, most studies lack the verification of a strictly unilateral execution of the motor task during the acquisition of imaging data. Here, we use fMRI to determine whether ipsilateral M1 activity depends on the demand for precision in a pointing task where precision varied quantitatively while movement trajectories remained equal. Thirteen healthy participants used an MRI-compatible joystick to point to targets of four different sizes in a block design. A clustered acquisition technique allowed simultaneous fMRI/EMG data collection and confirmed that movements were strictly unilateral. Accuracy of performance increased with target size. Overall, the pointing task revealed activation in contralateral and ipsilateral M1, extending into contralateral somatosensory and parietal areas. Target size-dependent activation differences were found in ipsilateral M1 extending into the temporal/parietal junction, where activation increased with increasing demand on accuracy. The results suggest that ipsilateral M1 is active during the execution of a unilateral motor task and that its activity is modulated by the demand on precision. Copyright © 2014 the American Physiological Society.

Effect of modulating field on photoreflectance simulated by electroreflectance

NASA Astrophysics Data System (ADS)

Chiou, S. J.; Sung, Y. G.; Wang, D. P.; Huang, K. F.; Huang, T. C.; Chu, A. K.

1999-04-01

Photoreflectance (PR) of surface-intrinsic-n+ (s-i-n+) type doped GaAs has been simulated by electroreflectance (ER). The simulated spectra of the s-i-n+ sample have exhibited many Franz-Keldysh oscillations, which enable the electric field (F) to be determined. It is known that F's determined from PR are subjected to photovoltaic effect and the measured F is close to Fbi-δF/2 when the modulating field, δF≪Fbi, where Fbi is the built-in field of the sample and δF is the modulating field. In this work, we have investigated the relation between the measured F and δF not only for the region where δF≪Fbi holds, but also for a whole range of δF. In order to determine the magnitude of δF, we have used ER to simulate PR, that is, the measurements of ER under a forward bias, which is set to be equal to δF/2.

SU-F-T-205: Effectiveness of Robust Treatment Planning to Account for Inter- Fractional Variation in Intensity Modulated Proton Therapy for Head Neck Cancer

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

Li, X; Zhang, J; Qin, A

2016-06-15

Purpose: To evaluate the potential benefits of robust optimization in intensity modulated proton therapy(IMPT) treatment planning to account for inter-fractional variation for Head Neck Cancer(HNC). Methods: One patient with bilateral HNC previous treated at our institution was used in this study. Ten daily CBCTs were selected. The CT numbers of the CBCTs were corrected by mapping the CT numbers from simulation CT via Deformable Image Registration. The planning target volumes(PTVs) were defined by a 3mm expansion from clinical target volumes(CTVs). The prescription was 70Gy, 54Gy to CTV1, CTV2, and PTV1, PTV2 for robust optimized(RO) and conventionally optimized(CO) plans respectively. Bothmore » techniques were generated by RayStation with the same beam angles: two anterior oblique and two posterior oblique angles. The similar dose constraints were used to achieve 99% of CTV1 received 100% prescription dose while kept the hotspots less than 110% of the prescription. In order to evaluate the dosimetric result through the course of treatment, the contours were deformed from simulation CT to daily CBCTs, modified, and approved by a radiation oncologist. The initial plan on the simulation CT was re-replayed on the daily CBCTs followed the bony alignment. The target coverage was evaluated using the daily doses and the cumulative dose. Results: Eight of 10 daily deliveries with using RO plan achieved at least 95% prescription dose to CTV1 and CTV2, while still kept maximum hotspot less than 112% of prescription compared with only one of 10 for the CO plan to achieve the same standards. For the cumulative doses, the target coverage for both RO and CO plans was quite similar, which was due to the compensation of cold and hot spots. Conclusion: Robust optimization can be effectively applied to compensate for target dose deficit caused by inter-fractional target geometric variation in IMPT treatment planning.« less

Catalysis-Enhancement via Rotary Fluctuation of F1-ATPase

PubMed Central

Watanabe, Rikiya; Hayashi, Kumiko; Ueno, Hiroshi; Noji, Hiroyuki

2013-01-01

Protein conformational fluctuations modulate the catalytic powers of enzymes. The frequency of conformational fluctuations may modulate the catalytic rate at individual reaction steps. In this study, we modulated the rotary fluctuation frequency of F1-ATPase (F1) by attaching probes with different viscous drag coefficients at the rotary shaft of F1. Individual rotation pauses of F1 between rotary steps correspond to the waiting state of a certain elementary reaction step of ATP hydrolysis. This allows us to investigate the impact of the frequency modulation of the rotary fluctuation on the rate of the individual reaction steps by measuring the duration of rotation pauses. Although phosphate release was significantly decelerated, the ATP-binding and hydrolysis steps were less sensitive or insensitive to the viscous drag coefficient of the probe. Brownian dynamics simulation based on a model similar to the Sumi-Marcus theory reproduced the experimental results, providing a theoretical framework for the role of rotational fluctuation in F1 rate enhancement. PMID:24268150

MR angiogenesis imaging with Robo4- vs. αVβ3-targeted nanoparticles in a B16/F10 mouse melanoma model

PubMed Central

Boles, Kent S.; Schmieder, Anne H.; Koch, Alexander W.; Carano, Richard A. D.; Wu, Yan; Caruthers, Shelton D.; Tong, Raymond K.; Stawicki, Scott; Hu, Grace; Scott, Michael J.; Zhang, Huiying; Reynolds, Benton A.; Wickline, Samuel A.; Lanza, Gregory M.

2010-01-01

The primary objective of this study was to utilize MR molecular imaging to compare the 3-dimensional spatial distribution of Robo4 and αVβ3-integrin as biosignatures of angiogenesis, in a rapidly growing, syngeneic tumor. B16-F10 melanoma-bearing mice were imaged with magnetic resonance (MR; 3.0 T) 11 d postimplantation before and after intravenous administration of either Robo4- or αVβ3-targeted paramagnetic nanoparticles. The percentage of MR signal-enhanced voxels throughout the tumor volume was low and increased in animals receiving αVβ3- and Robo4-targeted nanoparticles. Neovascular signal enhancement was predominantly associated with the tumor periphery (i.e., outer 50% of volume). Microscopic examination of tumors coexposed to the Robo4- and αVβ3-targeted nanoparticles corroborated the MR angiogenesis mapping results and further revealed that Robo4 expression generally colocalized with αVβ3-integrin. Robo4- and αVβ3-targeted nanoparticles were compared to irrelevant or nontargeted control groups in all modalities. These results suggest that αVβ3-integrin and Robo4 are useful biomarkers for noninvasive MR molecular imaging in syngeneic mouse tumors, but αVβ3-integrin expression was more detectable by MR at 3.0 T than Robo4. Noninvasive, neovascular assessments of the MR signal of Robo4, particularly combined with αVβ3-integrin expression, may help define tumor character prior to and following cancer therapy.—Boles, K. S., Schmieder, A. H., Koch, A. W., Carano, R. A. D., Wu, Y., Caruthers, S. D., Tong, R. K., Stawicki, S., Hu, G., Scott, M. J., Zhang, H., Reynolds, B. A., Wickline, S. A., and Lanza, G. M. MR angiogenesis imaging with Robo4- vs. αVβ3-targeted nanoparticles in a B16/F10 mouse melanoma model. PMID:20585027

DETECTOR FOR MODULATED AND UNMODULATED SIGNALS

DOEpatents

Patterson, H.H.; Webber, G.H.

1959-08-25

An r-f signal-detecting device is described, which is embodied in a compact coaxial circuit principally comprising a detecting crystal diode and a modulating crystal diode connected in parallel. Incoming modulated r-f signals are demodulated by the detecting crystal diode to furnish an audio input to an audio amplifier. The detecting diode will not, however, produce an audio signal from an unmodulated r-f signal. In order that unmodulated signals may be detected, such incoming signals have a locally produced audio signal superimposed on them at the modulating crystal diode and then the"induced or artificially modulated" signal is reflected toward the detecting diode which in the process of demodulation produces an audio signal for the audio amplifier.

Formant-frequency variation and its effects on across-formant grouping in speech perception.

PubMed

Roberts, Brian; Summers, Robert J; Bailey, Peter J

2013-01-01

How speech is separated perceptually from other speech remains poorly understood. In a series of experiments, perceptual organisation was probed by presenting three-formant (F1+F2+F3) analogues of target sentences dichotically, together with a competitor for F2 (F2C), or for F2+F3, which listeners must reject to optimise recognition. To control for energetic masking, the competitor was always presented in the opposite ear to the corresponding target formant(s). Sine-wave speech was used initially, and different versions of F2C were derived from F2 using separate manipulations of its amplitude and frequency contours. F2Cs with time-varying frequency contours were highly effective competitors, whatever their amplitude characteristics, whereas constant-frequency F2Cs were ineffective. Subsequent studies used synthetic-formant speech to explore the effects of manipulating the rate and depth of formant-frequency change in the competitor. Competitor efficacy was not tuned to the rate of formant-frequency variation in the target sentences; rather, the reduction in intelligibility increased with competitor rate relative to the rate for the target sentences. Therefore, differences in speech rate may not be a useful cue for separating the speech of concurrent talkers. Effects of competitors whose depth of formant-frequency variation was scaled by a range of factors were explored using competitors derived either by inverting the frequency contour of F2 about its geometric mean (plausibly speech-like pattern) or by using a regular and arbitrary frequency contour (triangle wave, not plausibly speech-like) matched to the average rate and depth of variation for the inverted F2C. Competitor efficacy depended on the overall depth of frequency variation, not depth relative to that for the other formants. Furthermore, the triangle-wave competitors were as effective as their more speech-like counterparts. Overall, the results suggest that formant-frequency variation is critical for the across-frequency grouping of formants but that this grouping does not depend on speech-specific constraints.

Not all attention orienting is created equal: recognition memory is enhanced when attention orienting involves distractor suppression.

PubMed

Markant, Julie; Worden, Michael S; Amso, Dima

2015-04-01

Learning through visual exploration often requires orienting of attention to meaningful information in a cluttered world. Previous work has shown that attention modulates visual cortex activity, with enhanced activity for attended targets and suppressed activity for competing inputs, thus enhancing the visual experience. Here we examined the idea that learning may be engaged differentially with variations in attention orienting mechanisms that drive eye movements during visual search and exploration. We hypothesized that attention orienting mechanisms that engaged suppression of a previously attended location would boost memory encoding of the currently attended target objects to a greater extent than those that involve target enhancement alone. To test this hypothesis we capitalized on the classic spatial cueing task and the inhibition of return (IOR) mechanism (Posner, 1980; Posner, Rafal, & Choate, 1985) to demonstrate that object images encoded in the context of concurrent suppression at a previously attended location were encoded more effectively and remembered better than those encoded without concurrent suppression. Furthermore, fMRI analyses revealed that this memory benefit was driven by attention modulation of visual cortex activity, as increased suppression of the previously attended location in visual cortex during target object encoding predicted better subsequent recognition memory performance. These results suggest that not all attention orienting impacts learning and memory equally. Copyright © 2015 Elsevier Inc. All rights reserved.

Perceived differences in social status between speaker and listener affect the speaker's vocal characteristics

PubMed Central

Mileva, Viktoria R.; Little, Anthony C.; Roberts, S. Craig

2017-01-01

Non-verbal behaviours, including voice characteristics during speech, are an important way to communicate social status. Research suggests that individuals can obtain high social status through dominance (using force and intimidation) or through prestige (by being knowledgeable and skilful). However, little is known regarding differences in the vocal behaviour of men and women in response to dominant and prestigious individuals. Here, we tested within-subject differences in vocal parameters of interviewees during simulated job interviews with dominant, prestigious, and neutral employers (targets), while responding to questions which were classified as introductory, personal, and interpersonal. We found that vocal modulations were apparent between responses to the neutral and high-status targets, with participants, especially those who perceived themselves as low in dominance, increasing fundamental frequency (F0) in response to the dominant and prestigious targets relative to the neutral target. Self-perceived prestige, however, was less related to contextual vocal modulations than self-perceived dominance. Finally, we found that differences in the context of the interview questions participants were asked to respond to (introductory, personal, interpersonal), also affected their vocal parameters, being more prominent in responses to personal and interpersonal questions. Overall, our results suggest that people adjust their vocal parameters according to the perceived social status of the listener as well as their own self-perceived social status. PMID:28614413

Measurement of the Structure Function Ratio $$F^{\\eta}_2$$ /$$ F^p_2$$ in Muon - Nucleon Scattering at Low $x$ and $$Q^{2}$$

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

Spentzouris, Panagiotis

1994-12-01

The ratio of the neutron to proton structure functions,more » $$F^{\\eta}_2$$ / $$F^p_2$$, from scattering of 470 GeV muons on liquid hydrogen and deuterium targets, is measured at very small-x and $Q^2$ , using the Fermilab E665 spectrometer. The results presented cover the region 0.000004 < x < 0.3 and $Q^2$ > 0.001 $GeV^2$ , three orders of magnitude lower in z than previous fixed-target experiments, and with higher average Q2 in the overlap region....« less

CstF-64 and 3'-UTR cis-element determine Star-PAP specificity for target mRNA selection by excluding PAPα.

PubMed

Kandala, Divya T; Mohan, Nimmy; A, Vivekanand; A P, Sudheesh; G, Reshmi; Laishram, Rakesh S

2016-01-29

Almost all eukaryotic mRNAs have a poly (A) tail at the 3'-end. Canonical PAPs (PAPα/γ) polyadenylate nuclear pre-mRNAs. The recent identification of the non-canonical Star-PAP revealed specificity of nuclear PAPs for pre-mRNAs, yet the mechanism how Star-PAP selects mRNA targets is still elusive. Moreover, how Star-PAP target mRNAs having canonical AAUAAA signal are not regulated by PAPα is unclear. We investigate specificity mechanisms of Star-PAP that selects pre-mRNA targets for polyadenylation. Star-PAP assembles distinct 3'-end processing complex and controls pre-mRNAs independent of PAPα. We identified a Star-PAP recognition nucleotide motif and showed that suboptimal DSE on Star-PAP target pre-mRNA 3'-UTRs inhibit CstF-64 binding, thus preventing PAPα recruitment onto it. Altering 3'-UTR cis-elements on a Star-PAP target pre-mRNA can switch the regulatory PAP from Star-PAP to PAPα. Our results suggest a mechanism of poly (A) site selection that has potential implication on the regulation of alternative polyadenylation. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

CstF-64 and 3′-UTR cis-element determine Star-PAP specificity for target mRNA selection by excluding PAPα

PubMed Central

Kandala, Divya T.; Mohan, Nimmy; A, Vivekanand; AP, Sudheesh; G, Reshmi; Laishram, Rakesh S.

2016-01-01

Almost all eukaryotic mRNAs have a poly (A) tail at the 3′-end. Canonical PAPs (PAPα/γ) polyadenylate nuclear pre-mRNAs. The recent identification of the non-canonical Star-PAP revealed specificity of nuclear PAPs for pre-mRNAs, yet the mechanism how Star-PAP selects mRNA targets is still elusive. Moreover, how Star-PAP target mRNAs having canonical AAUAAA signal are not regulated by PAPα is unclear. We investigate specificity mechanisms of Star-PAP that selects pre-mRNA targets for polyadenylation. Star-PAP assembles distinct 3′-end processing complex and controls pre-mRNAs independent of PAPα. We identified a Star-PAP recognition nucleotide motif and showed that suboptimal DSE on Star-PAP target pre-mRNA 3′-UTRs inhibit CstF-64 binding, thus preventing PAPα recruitment onto it. Altering 3′-UTR cis-elements on a Star-PAP target pre-mRNA can switch the regulatory PAP from Star-PAP to PAPα. Our results suggest a mechanism of poly (A) site selection that has potential implication on the regulation of alternative polyadenylation. PMID:26496945

Retrospective evaluation of dosimetric quality for prostate carcinomas treated with 3D conformal, intensity modulated and volumetric modulated arc radiotherapy

PubMed Central

Crowe, Scott B; Kairn, Tanya; Middlebrook, Nigel; Hill, Brendan; Christie, David R H; Knight, Richard T; Kenny, John; Langton, Christian M; Trapp, Jamie V

2013-01-01

Introduction This study examines and compares the dosimetric quality of radiotherapy treatment plans for prostate carcinoma across a cohort of 163 patients treated across five centres: 83 treated with three-dimensional conformal radiotherapy (3DCRT), 33 treated with intensity modulated radiotherapy (IMRT) and 47 treated with volumetric modulated arc therapy (VMAT). Methods Treatment plan quality was evaluated in terms of target dose homogeneity and organs at risk (OAR), through the use of a set of dose metrics. These included the mean, maximum and minimum doses; the homogeneity and conformity indices for the target volumes; and a selection of dose coverage values that were relevant to each OAR. Statistical significance was evaluated using two-tailed Welch's T-tests. The Monte Carlo DICOM ToolKit software was adapted to permit the evaluation of dose metrics from DICOM data exported from a commercial radiotherapy treatment planning system. Results The 3DCRT treatment plans offered greater planning target volume dose homogeneity than the other two treatment modalities. The IMRT and VMAT plans offered greater dose reduction in the OAR: with increased compliance with recommended OAR dose constraints, compared to conventional 3DCRT treatments. When compared to each other, IMRT and VMAT did not provide significantly different treatment plan quality for like-sized tumour volumes. Conclusions This study indicates that IMRT and VMAT have provided similar dosimetric quality, which is superior to the dosimetric quality achieved with 3DCRT. PMID:26229621

SU-F-T-520: Dosimetric Comparison of Radiation Treatment Plans for Whole Breast Irradiation Between 3D Conformal in Prone and Supine Positions Vs. VMAT and IMRT in Supine Positions

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

Bejarano Buele, A; Parsai, E

Purpose: The target volume for Whole Breast Irradiation (WBI) is dictated by location of tumor mass, breast tissue distribution, and involvement of lymph nodes. Dose coverage and Organs at Risk (OARs) sparing can be difficult to achieve in patients with unfavorable thoracic geometries. For these cases, inverse-planned and 3D-conformal prone treatments can be alternatives to traditional supine 3D-conformal plans. A dosimetric comparison can determine which of these techniques achieve optimal target coverage while sparing OARs. Methods: This study included simulation datasets for 8 patients, 5 of whom were simulated in both supine and prone positions. Positioning devices included breast boardsmore » and Vaclok bags for the supine position, and prone breast boards for the prone position. WBI 3-D conformal plans were created for patients simulated in both positions. Additional VMAT and IMRT WBI plans were made for all patients in the supine position. Results: Prone and supine 3D conformal plans had comparable PTV coverage. Prone 3D conformal plans received a significant 50% decrease to V20, V10, V5 and V30% for the ipsilateral lung in contrast to the supine plans. The heart also experienced a 10% decrease in maximum dose in the prone position, and V20, V10, V5 and V2 had significantly lower values than the supine plan. Supine IMRT and VMAT breast plans obtained comparable PTV coverage. The heart experienced a 10% decrease in maximum dose with inverse modulated plans when compared to the supine 3D conformal plan, while V20, V10, V5 and V2 showed higher values with inverse modulated plans than with supine 3D conformal plans. Conclusion: Prone 3D-conformal, and supine inverse planned treatments were generally superior in sparing OARs to supine plans with comparable PTV coverage. IMRT and VMAT plans offer sparing of OARs from high dose regions with an increase of irradiated volume in the low dose regions.« less

Stereotactic multibeam radiation therapy system in a PACS environment

NASA Astrophysics Data System (ADS)

Fresne, Francoise; Le Gall, G.; Barillot, Christian; Gibaud, Bernard; Manens, Jean-Pierre; Toumoulin, Christine; Lemoine, Didier; Chenal, C.; Scarabin, Jean-Marie

1991-05-01

A Multibeam radiation therapy treatment is a non-invasive technique devoted to treat a lesion within the cerebral medium by focusing photon-beams on the same target from a high number of entrance points. We present here a computer assisted dosimetric planning procedure which includes: (1) an analysis module to define the target volume by using 2D and 3D displays, (2) a planing module to issue a treatment strategy including the dosimetric simulations and (3) a treatment module setting up the parameters to order the robotized treatment system (i.e. chair- framework, radiation unit machine). Another important feature of this system is its connection to the PACS system SIRENE settled in the University hospital of Rennes which makes possible the archiving and the communication of the multimodal images (CT, MRI, Angiography) used by this application. The corporate use of stereotactic methods and the multimodality imagery ensures spatial coherence and makes the target definition and the cognition of the structures environment more accurate. The dosimetric planning suited to the spatial reference (i.e. the stereotactic frame) guarantees an optimal distribution of the dose computed by an original 3D volumetric algorithm. The robotic approach of the treatment stage has consisted to design a computer driven chair-framework cluster to position the target volume at the radiation unit isocenter.

Periodically Self Restoring Redundant Systems for VLSI Based Highly Reliable Design,

DTIC Science & Technology

1984-01-01

fault tolerance technique for realizing highly reliable computer systems for critical control applications . However, VL.SI technology has imposed a...operating correctly; failed critical real time control applications . n modules are discarded from the vote. the classical "static" voted redundancy...redundant modules are failure number of InterconnecttIon3. This results In f aree. However, for applications requiring higm modular complexity because

Velocity modulation spectroscopy of molecular ions II: The millimeter/submillimeter-wave spectrum of TiF + ( X3Φr)

NASA Astrophysics Data System (ADS)

Halfen, D. T.; Ziurys, L. M.

2006-11-01

The pure rotational spectrum of the molecular ion TiF + in its 3Φr ground state has been measured in the range 327-542 GHz using millimeter-wave direct absorption techniques combined with velocity modulation spectroscopy. TiF + was made in an AC discharge from a mixture of TiCl 4, F 2 in He, and argon. Ten transitions of this ion were recorded. In every transition, fluorine hyperfine interactions, as well as the fine structure splittings, were resolved. The fine structure pattern was found to be regular with almost equal spacing in frequency between the three spin components, in contrast to TiCl +, which is perturbed in the ground state. The data were fit with a case ( a) Hamiltonian and rotational, fine structure, and hyperfine constants were determined. The bond length established for TiF +, r0 = 1.7775 Å, was found to be shorter than that of TiF, r0 = 1.8342 Å—also established from mm-wave data. The hyperfine parameters determined are consistent with a δ1π1 electron configuration with the electrons primarily located on the titanium nucleus. The nuclear spin-orbit constant a indicates that the unpaired electrons are closer to the fluorine nucleus in TiF + relative to TiF, as expected with the decrease in bond length for the ion. The shorter bond distance is thought to arise from increased charge on the titanium nucleus as a result of a Ti 2+F - configuration. A similar decrease in bond length was found for TiCl + relative to TiCl.

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

PubMed Central

Sun, Tao; Zhang, Yongzhi; Power, Chanikarn; Alexander, Phillip M.; Sutton, Jonathan T.; Aryal, Muna; Vykhodtseva, Natalia; Miller, Eric L.; McDannold, Nathan J.

2017-01-01

Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies. PMID:29133392

[Comparison of planning quality and delivery efficiency between volumetric modulated arc therapy and dynamic intensity modulated radiation therapy for nasopharyngeal carcinoma with more than 4 prescribed dose levels].

PubMed

Jia, Pengfei; Xu, Jun; Zhou, Xiaoxi; Chen, Jian; Tang, Lemin

2017-12-01

The aim of this study is to compare the planning quality and delivery efficiency between dynamic intensity modulated radiation therapy (d-IMRT) and dual arc volumetric modulated arc therapy (VMAT) systematically for nasopharyngeal carcinoma (NPC) patients with multi-prescribed dose levels, and to analyze the correlations between target volumes and plan qualities. A total of 20 patients of NPC with 4-5 prescribed dose levels to achieve simultaneous integrated boost (SIB) treated by sliding window d-IMRT in our department from 2014 to 2015 were re-planned with dual arc VMAT. All optimization objectives for each VMAT plan were as the same as the corresponding d-IMRT plan. The dose parameters for targets and organ at risk (OAR), the delivery time and monitor units (MU) in two sets of plans were compared respectively. The treatment accuracy was tested by three dimensional dose validation system. Finally, the correlations between the difference of planning quality and the volume of targets were discussed. The conform indexes (CIs) of planning target volumes (PTVs) in VMAT plans were obviously high than those in d-IMRT plans ( P < 0.05), but no significant correlations between the difference of CIs and the volume of targets were discovered ( P > 0.05). The target coverage and heterogeneity indexes (HIs) of PTV 1 and PGTV nd and PTV 3 in two sets of plans were consistent. The doses of PTV 2 decreased and HIs were worse in VMAT plans. VMAT could provide better spinal cord and brainstem sparing, but increase mean dose of parotids. The average number of MUs and delivery time for d-IMRT were 3.32 and 2.19 times of that for VMAT. The γ-index (3 mm, 3%) analysis for each plans was more than 97% in COMPASS ® measurement for quality assurance (QA). The results show that target dose coverages in d-IMRT and VMAT plans are similar for NPC with multi-prescribed dose levels. VMAT could improve the the CIs of targets, but reduce the dose to the target volume in neck except for PGTV nd . The biggest advantages of VMAT over d-IMRT are delivery efficiency and QA.

SCFAtPP2-B11 modulates ABA signaling by facilitating SnRK2.3 degradation in Arabidopsis thaliana

PubMed Central

Ren, Ziyin; Zhi, Liya; Yao, Bin; Su, Chao; Liu, Liu; Li, Xia

2017-01-01

The phytohormone abscisic acid (ABA) is an essential part of the plant response to abiotic stressors such as drought. Upon the perception of ABA, pyrabactin resistance (PYR)/PYR1-like (PYL)/regulatory components of ABA receptor (RCAR) proteins interact with co-receptor protein phosphatase type 2Cs to permit activation Snf1-related protein kinase2 (SnRK2) kinases, which switch on ABA signaling by phosphorylating various target proteins. Thus, SnRK2 kinases are central regulators of ABA signaling. However, the mechanisms that regulate SnRK2 degradation remain elusive. Here, we show that SnRK2.3 is degradated by 26S proteasome system and ABA promotes its degradation. We found that SnRK2.3 interacts with AtPP2-B11 directly. AtPP2-B11 is an F-box protein that is part of a SKP1/Cullin/F-box E3 ubiquitin ligase complex that negatively regulates plant responses to ABA by specifically promoting the degradation of SnRK2.3. AtPP2-B11 was induced by ABA, and the knockdown of AtPP2-B11 expression markedly increased the ABA sensitivity of plants during seed germination and postgerminative development. Overexpression of AtPP2-B11 does not affect ABA sensitivity, but inhibits the ABA hypersensitive phenotypes of SnRK2.3 overexpression lines. These results reveal a novel mechanism through which AtPP2-B11 specifically degrades SnRK2.3 to attenuate ABA signaling and the abiotic stress response in Arabidopsis. PMID:28787436

Validation of measurement‐guided 3D VMAT dose reconstruction on a heterogeneous anthropomorphic phantom

PubMed Central

Opp, Daniel; Nelms, Benjamin E.; Zhang, Geoffrey; Stevens, Craig

2013-01-01

3DVH software (Sun Nuclear Corp., Melbourne, FL) is capable of generating a volumetric patient VMAT dose by applying a volumetric perturbation algorithm based on comparing measurement‐guided dose reconstruction and TPS‐calculated dose to a cylindrical phantom. The primary purpose of this paper is to validate this dose reconstruction on an anthropomorphic heterogeneous thoracic phantom by direct comparison to independent measurements. The dosimetric insert to the phantom is novel, and thus the secondary goal is to demonstrate how it can be used for the hidden target end‐to‐end testing of VMAT treatments in lung. A dosimetric insert contains a 4 cm diameter unit‐density spherical target located inside the right lung (0.21g/cm3 density). It has 26 slots arranged in two orthogonal directions, milled to hold optically stimulated luminescent dosimeters (OSLDs). Dose profiles in three cardinal orthogonal directions were obtained for five VMAT plans with varying degrees of modulation. After appropriate OSLD corrections were applied, 3DVH measurement‐guided VMAT dose reconstruction agreed 100% with the measurements in the unit density target sphere at 3%/3 mm level (composite analysis) for all profile points for the four less‐modulated VMAT plans, and for 96% of the points in the highly modulated C‐shape plan (from TG‐119). For this latter plan, while 3DVH shows acceptable agreement with independent measurements in the unit density target, in the lung disagreement with experiment is relatively high for both the TPS calculation and 3DVH reconstruction. For the four plans excluding the C‐shape, 3%/3mm overall composite analysis passing rates for 3DVH against independent measurement ranged from 93% to 100%. The C‐shape plan was deliberately chosen as a stress test of the algorithm. The dosimetric spatial alignment hidden target test demonstrated the average distance to agreement between the measured and TPS profiles in the steep dose gradient area at the edge of the 2 cm target to be 1.0±0.7,0.3±0.3, and 0.3±0.3mm for the IEC X, Y, and Z directions, respectively. PACS number: 87.55Qr PMID:23835381

A Prostate Fossa Contouring Instructional Module: Implementation and Evaluation.

PubMed

Gunther, Jillian R; Liauw, Stanley L; Choi, Seungtaek; Mohamed, Abdallah S R; Thaker, Nikhil G; Fuller, Clifton D; Stepaniak, Christopher J; Das, Prajnan; Golden, Daniel W

2016-07-01

Radiation oncology trainees frequently learn to contour through clinical experience and lectures. A hands-on contouring module was developed to teach delineation of the postoperative prostate clinical target volume (CTV) and improve contouring accuracy. Medical students independently contoured a prostate fossa CTV before and after receiving educational materials and live instruction detailing the RTOG approach to contouring this CTV. Metrics for volume overlap and surface distance (Dice similarity coefficient, Hausdorff distance (HD), and mean distance) determined discordance between student and consensus contours. An evaluation assessed perception of session efficacy (1 = "not at all" to 5 = "extremely"; reported as median[interquartile range]). Non-parametric statistical tests were used. Twenty-four students at two institutions completed the module, and 21 completed the evaluation (88% response). The content was rated as "quite" important (4[3.5-5]). The module improved comfort contouring a prostate fossa (pre 1[1-2] vs. post 4[3-4], p<.01), ability to find references (pre 2[1-3] vs. post 4[3.5-4], p<0.01), knowledge of CT prostate/pelvis anatomy (pre 2[1.5-3] vs. post 3[3-4], p<.01), and ability to use contouring software tools (pre 2[2-3.5] vs. post 3[3-4], p=.01). After intervention, mean DSC increased (0.29 to 0.68, p<0.01) and HD and mean distance both decreased, respectively (42.8 to 30.0, p<.01; 11.5 to 1.9, p<.01). A hands-on module to teach CTV delineation to medical students was developed and implemented. Student and expert contours exhibited near "excellent agreement" (as defined in the literature) after intervention. Additional modules to teach target delineation to all educational levels can be developed using this model. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Routine {sup 18}F{sup -} production with 180 {mu}A to 200 {mu}A target beam current on a GE PETtrace 800 cyclotron

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

Eberl, S.; Eriksson, T.; Svedberg, O.

2012-12-19

Through upgrades and enhancements, which are now standard on current PETtrace 800 cyclotrons, a GE PETtrace cyclotron installed in 2002 has demonstrated reliable routine [{sup 18}F]FDG production at total target beam currents of 180 {mu}A without detriment to saturation and [{sup 18}F]FDG yields. Routine production at 200 {mu}A has been achieved and its evaluation is continuing. Self-shielded target using W/Cu alloy for the target body afforded a reduction in dose rate from the Havar foils by a factor of {approx} 8-10, reducing dose from the targets and need for removing targets during maintenance. The main activation product in the shieldmore » is {sup 187}W (T1/2 24 h). The {sup 60}Co ((T1/2 5.3 y) activation is about 250 times less at 24 h post EOB and is not considered a major issue despite its long half-life.« less

Routine 18F- production with 180 μA to 200 μA target beam current on a GE PETtrace 800 cyclotron

NASA Astrophysics Data System (ADS)

Eberl, S.; Eriksson, T.; Svedberg, O.; Norling, J.; Henderson, D.; Lam, P.; Bourdier, T.; Fulham, M.

2012-12-01

Through upgrades and enhancements, which are now standard on current PETtrace 800 cyclotrons, a GE PETtrace cyclotron installed in 2002 has demonstrated reliable routine [18F]FDG production at total target beam currents of 180 μA without detriment to saturation and [18F]FDG yields. Routine production at 200 μA has been achieved and its evaluation is continuing. Self-shielded target using W/Cu alloy for the target body afforded a reduction in dose rate from the Havar foils by a factor of ˜ 8-10, reducing dose from the targets and need for removing targets during maintenance. The main activation product in the shield is 187W (T1/2 24 h). The 60Co ((T1/2 5.3 y) activation is about 250 times less at 24 h post EOB and is not considered a major issue despite its long half-life.

Effects of dipotassium-trioxohydroxytetrafluorotriborate, K2[B3O3F4OH], on cell viability and gene expression of common human cancer drug targets in a melanoma cell line.

PubMed

Pojskic, Lejla; Haveric, Sanin; Lojo-Kadric, Naida; Hadzic, Maida; Haveric, Anja; Galic, Zoran; Galic, Borivoj; Vullo, Daniela; Supuran, Claudiu T; Milos, Mladen

2016-12-01

Recently it was found that dipotassium-trioxohydroxytetrafluorotriborate, K2(B3O3F4OH), is a potent and highly specific inhibitor of precancerous cell processes. We conducted gene expression profiling of human melanoma cells before and after treatment with two concentrations (0.1 and 1 mM) of this boron inorganic derivative in order to assess its effects on deregulation of genes associated with tumor pathways. Parallel trypan blue exclusion assay was performed to assess the cytotoxicity effects of this chemical. Treatment with K2(B3O3F4OH) induced a significant decrease of cell viability in melanoma cellline at both tested concentrations. Furthermore, these treatments caused deregulation of more than 30 genes known as common anti-tumor drug targets. IGF-1 and hTERT were found to be significantly downregulated and this result may imply potential use of K2(B3O3F4OH) as an inhibitor or human telomerase and insulin-like growth factor 1, both of which are associated with various tumor pathways.

The effects of orientation and attention during surround suppression of small image features: A 7 Tesla fMRI study.

PubMed

Schallmo, Michael-Paul; Grant, Andrea N; Burton, Philip C; Olman, Cheryl A

2016-08-01

Although V1 responses are driven primarily by elements within a neuron's receptive field, which subtends about 1° visual angle in parafoveal regions, previous work has shown that localized fMRI responses to visual elements reflect not only local feature encoding but also long-range pattern attributes. However, separating the response to an image feature from the response to the surrounding stimulus and studying the interactions between these two responses demands both spatial precision and signal independence, which may be challenging to attain with fMRI. The present study used 7 Tesla fMRI with 1.2-mm resolution to measure the interactions between small sinusoidal grating patches (targets) at 3° eccentricity and surrounds of various sizes and orientations to test the conditions under which localized, context-dependent fMRI responses could be predicted from either psychophysical or electrophysiological data. Targets were presented at 8%, 16%, and 32% contrast while manipulating (a) spatial extent of parallel (strongly suppressive) or orthogonal (weakly suppressive) surrounds, (b) locus of attention, (c) stimulus onset asynchrony between target and surround, and (d) blocked versus event-related design. In all experiments, the V1 fMRI signal was lower when target stimuli were flanked by parallel versus orthogonal context. Attention amplified fMRI responses to all stimuli but did not show a selective effect on central target responses or a measurable effect on orientation-dependent surround suppression. Suppression of the V1 fMRI response by parallel surrounds was stronger than predicted from psychophysics but showed a better match to previous electrophysiological reports.

High-fidelity phase and amplitude control of phase-only computer generated holograms using conjugate gradient minimisation.

PubMed

Bowman, D; Harte, T L; Chardonnet, V; De Groot, C; Denny, S J; Le Goc, G; Anderson, M; Ireland, P; Cassettari, D; Bruce, G D

2017-05-15

We demonstrate simultaneous control of both the phase and amplitude of light using a conjugate gradient minimisation-based hologram calculation technique and a single phase-only spatial light modulator (SLM). A cost function, which incorporates the inner product of the light field with a chosen target field within a defined measure region, is efficiently minimised to create high fidelity patterns in the Fourier plane of the SLM. A fidelity of F = 0.999997 is achieved for a pattern resembling an LG10 mode with a calculated light-usage efficiency of 41.5%. Possible applications of our method in optical trapping and ultracold atoms are presented and we show uncorrected experimental realisation of our patterns with F = 0.97 and 7.8% light efficiency.

A new three-dimensional conformal radiotherapy (3DCRT) technique for large breast and/or high body mass index patients: evaluation of a novel fields assessment aimed to reduce extra-target-tissue irradiation.

PubMed

Gerardina, Stimato; Edy, Ippolito; Sonia, Silipigni; Cristina, Di Venanzio; Carla Germana, Rinaldi; Diego, Gaudino; Michele, Fiore; Lucio, Trodella; Maria, D'Angelillo Rolando; Sara, Ramella

2016-09-01

To develop an alternative three-dimensional treatment plan with standardized fields class solution for whole-breast radiotherapy in patients with large/pendulous breast and/or high body mass index (BMI). Two treatment plans [tangential fields and standardized five-fields technique (S5F)] for a total dose of 50 Gy/25 fractions were generated for patients with large breasts [planning target volume (PTV) >1000 cm(3) and/or BMI >25 kg m(-2)], supine positioned. S5F plans consist of two wedged tangential beams, anteroposterior: 20° for the right breast and 340° for the left breast, and posteroanterior: 181° for the right breast and 179° for the left breast. A field in field in medial-lateral beam and additional fields were added to reduce hot spot areas and extra-target-tissue irradiation and to improve dose distribution. The percentage of PTV receiving 95% of the prescribed dose (PTV V95%), percentage of PTV receiving 105% of the prescribed dose (PTV V105%), maximal dose to PTV (PTV Dmax), homogeneity index (HI) and conformity index were recorded. V10%, V20%, V105% and V107% of a "proper" normal tissue structure (body-PTV healthy tissue) were recorded. Statistical analyses were performed using SYSTAT v.12.0 (SPSS, Chicago, IL). In 38 patients included, S5F improved HI (8.4 vs 10.1; p ≤ 0.001) and significantly reduced PTV Dmax and PTV V105%. The extra-target-tissue irradiation was significantly reduced using S5F for V105% (cm(3)) and V107% (cm(3)) with a very high difference in tissue irradiation (46.6 vs 3.0 cm(3), p ≤ 0.001 for V105% and 12.2 vs 0.0 cm(3), p ≤ 0.001 for V107% for tangential field and S5F plans, respectively). Only a slight increase in low-dose extra-target-tissue irradiation (V10%) was observed (2.2719 vs 1.8261 cm(3), p = 0.002). The S5F technique in patients with large breast or high BMI increases HI and decreases hot spots in extra-target-tissues and can therefore be easily implemented in breast cancer radiotherapy. The treatment planning strategy proposed in this study has several advantages: (a) it is extremely reliable as the standard supine positioning is used; (b) the standardized class solution allows for widespread use; (c) time and cost of treatment are not increased; and (d) it can be used for both large breasted and obese patients not compliant to different treatment positioning.

Layer-Specific fMRI Reflects Different Neuronal Computations at Different Depths in Human V1

PubMed Central

Olman, Cheryl A.; Harel, Noam; Feinberg, David A.; He, Sheng; Zhang, Peng; Ugurbil, Kamil; Yacoub, Essa

2012-01-01

Recent work has established that cerebral blood flow is regulated at a spatial scale that can be resolved by high field fMRI to show cortical columns in humans. While cortical columns represent a cluster of neurons with similar response properties (spanning from the pial surface to the white matter), important information regarding neuronal interactions and computational processes is also contained within a single column, distributed across the six cortical lamina. A basic understanding of underlying neuronal circuitry or computations may be revealed through investigations of the distribution of neural responses at different cortical depths. In this study, we used T2-weighted imaging with 0.7 mm (isotropic) resolution to measure fMRI responses at different depths in the gray matter while human subjects observed images with either recognizable or scrambled (physically impossible) objects. Intact and scrambled images were partially occluded, resulting in clusters of activity distributed across primary visual cortex. A subset of the identified clusters of voxels showed a preference for scrambled objects over intact; in these clusters, the fMRI response in middle layers was stronger during the presentation of scrambled objects than during the presentation of intact objects. A second experiment, using stimuli targeted at either the magnocellular or the parvocellular visual pathway, shows that laminar profiles in response to parvocellular-targeted stimuli peak in more superficial layers. These findings provide new evidence for the differential sensitivity of high-field fMRI to modulations of the neural responses at different cortical depths. PMID:22448223

Targeting Signal Transducers and Activators of Transcription-3 (STAT3) as a Novel Strategy in Sensitizing Breast Cancer to EGFR-Targeted Therapy

DTIC Science & Technology

2009-06-01

Osman, F. The human glutathione S-transferase P1 ( GSTP1 ) gene is transactivated by cyclic AMP (cAMP) via a cAMP response element (CRE) proximal to the...transcription start site. Chem-Biol. Interactions 133, 320-321, 2001. 4. Lo, H.-W. and Ali-Osman, F. Cyclic AMP mediated GSTP1 gene activation in...tumor cells involves the interaction of activated CREB-1 with the GSTP1 CRE: a novel mechanism of cellular GSTP1 gene regulation. Journal of Cellular

Optical properties of BaY2F8:Ce3+

NASA Astrophysics Data System (ADS)

Fabeni, P.; di Martino, D.; Nikl, M.; Pazzi, G. P.; Sani, E.; Toncelli, A.; Tonelli, M.; Vedda, A.

2005-01-01

The optical properties of Ce3+-doped BaY2F8 crystals were investigated under selective laser excitation and X-ray irradiation. In both cases, the emission spectrum is dominated by the characteristic doublet transition from the lowest energy level of the 5d configuration to the spin-orbit split 2F ground state of Ce3+. Excitation bands at 4.1, 5.0, 5.9 and 6.2 eV, due to transitions between 4f and split 5d levels were observed. The emission time decay was satisfactorily analyzed by a single exponential component, characterized by a decay time of approximately 28 ns at 10 K and slightly increasing with temperature. A monotonic temperature quenching of the photo-luminescence intensity was observed; on the other hand, the temperature dependence of radio-luminescence intensity is modulated by the presence of shallow traps competing with Ce3+ ions in carrier trapping during irradiation.

Breaking down the barriers: fMRI applications in pain, analgesia and analgesics

PubMed Central

Borsook, David; Becerra, Lino R

2006-01-01

This review summarizes functional magnetic resonance imaging (fMRI) findings that have informed our current understanding of pain, analgesia and related phenomena, and discusses the potential role of fMRI in improved therapeutic approaches to pain. It is divided into 3 main sections: (1) fMRI studies of acute and chronic pain. Physiological studies of pain have found numerous regions of the brain to be involved in the interpretation of the 'pain experience'; studies in chronic pain conditions have identified a significant CNS component; and fMRI studies of surrogate models of chronic pain are also being used to further this understanding. (2) fMRI studies of endogenous pain processing including placebo, empathy, attention or cognitive modulation of pain. (3) The use of fMRI to evaluate the effects of analgesics on brain function in acute and chronic pain. fMRI has already provided novel insights into the neurobiology of pain. These insights should significantly advance therapeutic approaches to chronic pain. PMID:16982005

The light ion pulsed power induction accelerator for ETF

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

Mazarakis, M.G.; Olson, R.E.; Olson, C.L.

1994-12-31

Our Engineering Test Facility (ETF) driver concept is based on HERMES III and RHEPP technologies. Actually, it is a scaled-down version of the LMF design incorporating repetition rate capabilities of up to 10 Hz CW. The preconceptual design presented here provides 200-TW peak power to the ETF target during 10 ns, equal to 2-MJ total ion beam energy. Linear inductive voltage addition driving a self-magnetically insulated transmission line (MITL) is utilized to generate the 36-MV peak voltage needed for lithium ion beams. The {approximately} 3-MA ion current is achieved by utilizing many accelerating modules in parallel. Since the current permore » module is relatively modest ({approximately}300 kA), two-stage or one-stage extraction diodes can be utilized for the generation of singly charged lithium ions. The accelerating modules are arranged symmetrically around the fusion chamber in order to provide uniform irradiation onto the ETF target. In addition, the modules are fired in a programmed sequence in order to generate the optimum power pulse shape onto the target. This design utilizes RHEPP accelerator modules as the principal power source.« less

Regulation of miR394 in Response to Fusarium oxysporum f. sp. cepae (FOC) Infection in Garlic (Allium sativum L)

PubMed Central

Chand, Subodh K.; Nanda, Satyabrata; Joshi, Raj K.

2016-01-01

MicroRNAs (miRNAs) are a class of post-transcriptional regulators that negatively regulate gene expression through target mRNA cleavage or translational inhibition and play important roles in plant development and stress response. In the present study, six conserved miRNAs from garlic (Allium sativum L.) were analyzed to identify differentially expressed miRNAs in response to Fusarium oxysporum f. sp. cepae (FOC) infection. Stem-loop RT-PCR revealed that miR394 is significantly induced in garlic seedlings post-treatment with FOC for 72 h. The induction of miR394 expression during FOC infection was restricted to the basal stem plate tissue, the primary site of infection. Garlic miR394 was also upregulated by exogenous application of jasmonic acid. Two putative targets of miR394 encoding F-box domain and cytochrome P450 (CYP450) family proteins were predicted and verified using 5′ RLM-RACE (RNA ligase mediated rapid amplification of cDNA ends) assay. Quantitative RT-PCR showed that the transcript levels of the predicted targets were significantly reduced in garlic plants exposed to FOC. When garlic cultivars with variable sensitivity to FOC were exposed to the pathogen, an upregulation of miR394 and down regulation of the targets were observed in both varieties. However, the expression pattern was delayed in the resistant genotypes. These results suggest that miR394 functions in negative modulation of FOC resistance and the difference in timing and levels of expression in variable genotypes could be examined as markers for selection of FOC resistant garlic cultivars. PMID:26973694

MAP18 regulates the direction of pollen tube growth in Arabidopsis by modulating F-actin organization.

PubMed

Zhu, Lei; Zhang, Yan; Kang, Erfang; Xu, Qiangyi; Wang, Miaoying; Rui, Yue; Liu, Baoquan; Yuan, Ming; Fu, Ying

2013-03-01

For fertilization to occur in plants, the pollen tube must be guided to enter the ovule via the micropyle. Previous reports have implicated actin filaments, actin binding proteins, and the tip-focused calcium gradient as key contributors to polar growth of pollen tubes; however, the regulation of directional pollen tube growth is largely unknown. We reported previously that Arabidopsis thaliana MICROTUBULE-ASSOCIATED PROTEIN18 (MAP18) contributes to directional cell growth and cortical microtubule organization. The preferential expression of MAP18 in pollen and in pollen tubes suggests that MAP18 also may function in pollen tube growth. In this study, we demonstrate that MAP18 functions in pollen tubes by influencing actin organization, rather than microtubule assembly. In vitro biochemical results indicate that MAP18 exhibits Ca(2+)-dependent filamentous (F)-actin-severing activity. Abnormal expression of MAP18 in map18 and MAP18 OX plants was associated with disorganization of the actin cytoskeleton in the tube apex, resulting in aberrant pollen tube growth patterns and morphologies, inaccurate micropyle targeting, and fewer fertilization events. Experiments with MAP18 mutants created by site-directed mutagenesis suggest that F-actin-severing activity is essential to the effects of MAP18 on pollen tube growth direction. Our study demonstrates that in Arabidopsis, MAP18 guides the direction of pollen tube growth by modulating actin filaments.

Laser frequency stabilization and shifting by using modulation transfer spectroscopy

NASA Astrophysics Data System (ADS)

Cheng, Bing; Wang, Zhao-Ying; Wu, Bin; Xu, Ao-Peng; Wang, Qi-Yu; Xu, Yun-Fei; Lin, Qiang

2014-10-01

The stabilizing and shifting of laser frequency are very important for the interaction between the laser and atoms. The modulation transfer spectroscopy for the 87Rb atom with D2 line transition F = 2 → F' = 3 is used for stabilizing and shifting the frequency of the external cavity grating feedback diode laser. The resonant phase modulator with electro—optical effect is used to generate frequency sideband to lock the laser frequency. In the locking scheme, circularly polarized pump- and probe-beams are used. By optimizing the temperature of the vapor, the pump- and probe-beam intensity, the laser linewidth of 280 kHz is obtained. Furthermore, the magnetic field generated by a solenoid is added into the system. Therefore the system can achieve the frequency locking at any point in a range of hundreds of megahertz frequency shifting with very low power loss.

Low-noise magnetometer based on inductance modulation in high-critical-temperature superconductor coil

NASA Astrophysics Data System (ADS)

Enpuku, Keiji; Matsuo, Masaaki; Yoshida, Yujiro; Yamashita, Shigeya; Sasayama, Teruyoshi; Yoshida, Takashi

2018-06-01

We developed a magnetometer based on inductance modulation of a coil made from a high-critical-temperature superconducting material. The coil inductance was modulated over time via a modulation current applied to a magnetic wire that was inserted into the coil. The magnetic field was then converted into a signal voltage using this time-dependent inductance. The relationship between magnetometer performance and the modulation current conditions was studied. Under appropriate conditions, the magnetometer had responsivity of 885 V/T. The magnetic field noise was 1.3 pT/Hz1/2 in the white noise region and 5.6 pT/Hz1/2 at f = 1 Hz.

Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues

PubMed Central

Tulloch, Lindsay B.; Menzies, Stefanie K.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Zacharova, Marija K.; Florence, Gordon J.

2017-01-01

Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3, a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1, to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model. PMID:28873407

18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase.

PubMed

Horti, Andrew G; Wang, Yuchuan; Minn, Il; Lan, Xi; Wang, Jian; Koehler, Raymond C; Alkayed, Nabil J; Dannals, Robert F; Pomper, Martin G

2016-11-01

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which are generated in the brain to couple neuronal activity and cerebral blood flow in normal and pathologic states. Altered regulation of sEH was observed previously in various neuropathologic disorders including vascular dementia and stroke. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6- 18 F-fluoronicotinamide ( 18 F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. 18 F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18 F-FNDP was measured using an sEH inhibitor screening assay kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pretreatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in 3 baboons, with regional tracer binding quantified using distribution volume. The metabolism of 18 F-FNDP in baboons was assessed using high-performance liquid chromatography. 18 F-FNDP (inhibition binding affinity constant, 1.73 nM) was prepared in 1 step in a radiochemical yield of 14% ± 7%, specific radioactivity in the range of 888-3,774 GBq/μmol, and a radiochemical purity greater than 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice, regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2% injected dose per gram of tissue at peak uptake. Blockade of 80%-90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH knock-out mice. PET baboon brain distribution paralleled that seen in mouse, with a marked blockade (95%) noted in all regions indicating sEH-mediated uptake of 18 F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma. 18 F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18 F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18 F-FNDP is a promising PET radiotracer likely to be useful for understanding the role of sEH in a variety of conditions affecting the central nervous system. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Intensity-Modulated Radiotherapy for Craniospinal Irradiation: Target Volume Considerations, Dose Constraints, and Competing Risks

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

Parker, William; Filion, Edith; Roberge, David

2007-09-01

Purpose: To report the results of an analysis of dose received to tissues and organs outside the target volume, in the setting of spinal axis irradiation for the treatment of medulloblastoma, using three treatment techniques. Methods and Materials: Treatment plans (total dose, 23.4 Gy) for a standard two-dimensional (2D) technique, a three-dimensional (3D) technique using a 3D imaging-based target volume, and an intensity-modulated radiotherapy (IMRT) technique, were compared for 3 patients in terms of dose-volume statistics for target coverage, as well as organ at risk (OAR) and overall tissue sparing. Results: Planning target volume coverage and dose homogeneity was superiormore » for the IMRT plans for V{sub 95%} (IMRT, 100%; 3D, 96%; 2D, 98%) and V{sub 107%} (IMRT, 3%; 3D, 38%; 2D, 37%). In terms of OAR sparing, the IMRT plan was better for all organs and whole-body contour when comparing V{sub 10Gy}, V{sub 15Gy}, and V{sub 20Gy}. The 3D plan was superior for V{sub 5Gy} and below. For the heart and liver in particular, the IMRT plans provided considerable sparing in terms of V{sub 10Gy} and above. In terms of the integral dose, the IMRT plans were superior for liver (IMRT, 21.9 J; 3D, 28.6 J; 2D, 38.6 J) and heart (IMRT, 9 J; 3D, 14.1J; 2D, 19.4 J), the 3D plan for the body contour (IMRT, 349 J; 3D, 337 J; 2D, 555 J). Conclusions: Intensity-modulated radiotherapy is a valid treatment option for spinal axis irradiation. We have shown that IMRT results in sparing of organs at risk without a significant increase in integral dose.« less

Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

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

Duprez, Frederic, E-mail: frederic.duprez@ugent.be; De Neve, Wilfried; De Gersem, Werner

Purpose: To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer. Methods and Materials: Each patient's treatment used three separate treatment plans: fractions 1-10 used a DPBN ([{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography [{sup 18}F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment {sup 18}F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a {sup 18}F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gymore » to the high-dose clinical target volume (CTV{sub highdose}) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled. Results: All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second {sup 18}F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV{sub highdose} (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV{sub highdose} and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I. Conclusion: To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible.« less

Left prefrontal cortex control of novel occurrences during recollection: a psychopharmacological study using scopolamine and event-related fMRI.

PubMed

Bozzali, M; MacPherson, S E; Dolan, R J; Shallice, T

2006-10-15

Recollection and familiarity represent two processes involved in episodic memory retrieval. We investigated how scopolamine (an antagonist of acetylcholine muscarinic receptors) influenced brain activity during memory retrieval, using a paradigm that separated recollection and familiarity. Eighteen healthy volunteers were recruited in a randomized, placebo-controlled, double-blind design using event-related fMRI. Participants were required to perform a verbal recognition memory task within the scanner, either under placebo or scopolamine conditions. Depending on the subcondition, participants were required to make a simple recognition decision (old/new items) or base their decision on more specific information related to prior experience (target/non-target/new items). We show a drug modulation in left prefrontal and perirhinal cortex during recollection. Such an effect was specifically driven by novelty and showed an inverse correlation with accuracy performance. Additionally, we show a direct correlation between drug-related signal change in left prefrontal and perirhinal cortices. We discuss the findings in terms of acetylcholine mediation of the familiarity/novelty signal through perirhinal cortex and the control of the relative signal strength through prefrontal cortex.

Online education improves pediatric residents' understanding of atopic dermatitis.

PubMed

Craddock, Megan F; Blondin, Heather M; Youssef, Molly J; Tollefson, Megha M; Hill, Lauren F; Hanson, Janice L; Bruckner, Anna L

2018-01-01

Pediatricians manage skin conditions such as atopic dermatitis (AD) but report that their dermatologic training is inadequate. Online modules may enhance medical education when sufficient didactic or clinical teaching experiences are lacking. We assessed whether an online module about AD improved pediatric residents' knowledge and changed their clinical management of AD. Target and control cohorts of pediatric residents from two institutions were recruited. Target subjects took a 30-question test about AD early in their residency, reviewed the online module, and repeated the test 6 months and 1 year later. The control subjects, who had 1 year of clinical experience but had not reviewed the online module, also took the test. The mean percentage of correct answers was calculated and compared using two-sided, two-sample independent t tests and repeated-measures analysis of variance. For a subset of participants, clinical documentation from AD encounters was reviewed and 13 practice behaviors were compared using the Fisher exact test. Twenty-five subjects in the target cohort and 29 subjects in the control cohort completed the study. The target cohort improved from 18.0 ± 3.2 to 23.4 ± 3.4 correctly answered questions over 1 year (P < .001). This final value was greater than that of the control cohort (20.7 ± 4.5; P = .01). Meaningful differences in practice behaviors were not seen. Pediatric residents who reviewed an online module about AD demonstrated statistically significant improvement in disease-specific knowledge over time and had statistically significantly higher scores than controls. Online dermatology education may effectively supplement traditional clinical teaching. © 2017 Wiley Periodicals, Inc.

Phenyl derivative of pyranocoumarin precludes Fusarium oxysporum f.sp. Lycopersici infection in Lycopersicon esculentum via induction of enzymes of the phenylpropanoid pathway.

PubMed

Sangeetha, S; Sarada, D V L

2015-01-01

Binding of phenyl derivative of pyranocoumarin (PDP) modulated activity of fungal endopolygalacturonase in silico. Induced fit docking study of PDP with endopolygalacturonase (1HG8) showed a bifurcated hydrogen bond interaction with the protein at Lys 244 with a docking score of -3.6 and glide energy of -37.30 kcal/mol. Docking with endopolygalacturonase II (1CZF) resulted hydrogen bond formation with Lys 258 with a docking score of -2.3 and glide energy of -30.42 kcal/mol. It was hypothesized that this modulation favors accumulation of cell wall fragments (oligogalacturonides) which act as elicitors of plant defense responses. In order to prove the same, in vivo studies were carried out using a formulation developed from PDP (PDP 5EC) on greenhouse grown Lycopersicon esculentum L. The formulation was effective at different concentrations in reduction of seed infection, improvement of vigor and control of Fusarium oxysporum f.sp. lycopersici infection in L. esculentum. At a concentration of 2 %, PDP 5EC significant reduction in seed infection (95.83 %), improvement in seed vigor (64.31 %) and control of F. oxysporum f.sp. lycopersici infection (96.15 %) were observed. Further application of PDP 5EC to L. esculentum challenged with F. oxysporum f.sp. lycopersici significantly increased the activity of enzymes of the phenylpropanoid pathway, namely, peroxidase (PO), polyphenol oxidase (PPO), phenylalanine ammonia lyase (PAL), and enhanced the total phenolic content when compared to the control.

High-temperature molten salt thermal energy storage systems

NASA Technical Reports Server (NTRS)

Petri, R. J.; Claar, T. D.; Tison, R. R.; Marianowski, L. G.

1980-01-01

The results of comparative screening studies of candidate molten carbonate salts as phase change materials (PCM) for advanced solar thermal energy storage applications at 540 to 870 C (1004 to 1600 F) and steam Rankine electric generation at 400 to 540 C (752 to 1004 F) are presented. Alkali carbonates are attractive as latent heat storage materials because of their relatively high storage capacity and thermal conductivity, low corrosivity, moderate cost, and safe and simple handling requirements. Salts were tested in 0.1 kWhr lab scale modules and evaluated on the basis of discharge heat flux, solidification temperature range, thermal cycling stability, and compatibility with containment materials. The feasibility of using a distributed network of high conductivity material to increase the heat flux through the layer of solidified salt was evaluated. The thermal performance of an 8 kWhr thermal energy storage (TES) module containing LiKCO3 remained very stable throughout 5650 hours and 130 charge/discharge cycles at 480 to 535 C (896 to 995 F). A TES utilization concept of an electrical generation peaking subsystem composed of a multistage condensing steam turbine and a TES subsystem with a separate power conversion loop was defined. Conceptual designs for a 100 MW sub e TES peaking system providing steam at 316 C, 427 C, and 454 C (600 F, 800 F, and 850 F) at 3.79 million Pa (550 psia) were developed and evaluated. Areas requiring further investigation have also been identified.

Orientation-specific contextual modulation of the fMRI BOLD response to luminance and chromatic gratings in human visual cortex.

PubMed

McDonald, J Scott; Seymour, Kiley J; Schira, Mark M; Spehar, Branka; Clifford, Colin W G

2009-05-01

The responses of orientation-selective neurons in primate visual cortex can be profoundly affected by the presence and orientation of stimuli falling outside the classical receptive field. Our perception of the orientation of a line or grating also depends upon the context in which it is presented. For example, the perceived orientation of a grating embedded in a surround tends to be repelled from the predominant orientation of the surround. Here, we used fMRI to investigate the basis of orientation-specific surround effects in five functionally-defined regions of visual cortex: V1, V2, V3, V3A/LO1 and hV4. Test stimuli were luminance-modulated and isoluminant gratings that produced responses similar in magnitude. Less BOLD activation was evident in response to gratings with parallel versus orthogonal surrounds across all the regions of visual cortex investigated. When an isoluminant test grating was surrounded by a luminance-modulated inducer, the degree of orientation-specific contextual modulation was no larger for extrastriate areas than for V1, suggesting that the observed effects might originate entirely in V1. However, more orientation-specific modulation was evident in extrastriate cortex when both test and inducer were luminance-modulated gratings than when the test was isoluminant; this difference was significant in area V3. We suggest that the pattern of results in extrastriate cortex may reflect a refinement of the orientation-selectivity of surround suppression specific to the colour of the surround or, alternatively, processes underlying the segmentation of test and inducer by spatial phase or orientation when no colour cue is available.

Robustness of the Voluntary Breath-Hold Approach for the Treatment of Peripheral Lung Tumors Using Hypofractionated Pencil Beam Scanning Proton Therapy

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

Dueck, Jenny, E-mail: jenny.dueck@psi.ch; Center for Proton Therapy, Paul Scherrer Institut, Villigen PSI; Niels Bohr Institute, University of Copenhagen, Copenhagen

Purpose: The safe clinical implementation of pencil beam scanning (PBS) proton therapy for lung tumors is complicated by the delivery uncertainties caused by breathing motion. The purpose of this feasibility study was to investigate whether a voluntary breath-hold technique could limit the delivery uncertainties resulting from interfractional motion. Methods and Materials: Data from 15 patients with peripheral lung tumors previously treated with stereotactic radiation therapy were included in this study. The patients had 1 computed tomographic (CT) scan in voluntary breath-hold acquired before treatment and 3 scans during the treatment course. PBS proton treatment plans with 2 fields (2F) andmore » 3 fields (3F), respectively, were calculated based on the planning CT scan and subsequently recalculated on the 3 repeated CT scans. Recalculated plans were considered robust if the V{sub 95%} (volume receiving ≥95% of the prescribed dose) of the gross target volume (GTV) was within 5% of what was expected from the planning CT data throughout the simulated treatment. Results: A total of 14/15 simulated treatments for both 2F and 3F met the robustness criteria. Reduced V{sub 95%} was associated with baseline shifts (2F, P=.056; 3F, P=.008) and tumor size (2F, P=.025; 3F, P=.025). Smaller tumors with large baseline shifts were also at risk for reduced V{sub 95%} (interaction term baseline/size: 2F, P=.005; 3F, P=.002). Conclusions: The breath-hold approach is a realistic clinical option for treating lung tumors with PBS proton therapy. Potential risk factors for reduced V{sub 95%} are small targets in combination with large baseline shifts. On the basis of these results, the baseline shift of the tumor should be monitored (eg, through image guided therapy), and appropriate measures should be taken accordingly. The intrafractional motion needs to be investigated to confirm that the breath-hold approach is robust.« less

In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment

PubMed Central

van Dam, Peter A.; van Dam, Pieter-Jan H. H.; Rolfo, Christian; Giallombardo, Marco; van Berckelaer, Christophe; Trinh, Xuan Bich; Altintas, Sevilay; Huizing, Manon; Papadimitriou, Kostas; Tjalma, Wiebren A. A.; van Laere, Steven

2016-01-01

An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability. PMID:26701206

111In-BnDTPA-F3: an Auger electron-emitting radiotherapeutic agent that targets nucleolin.

PubMed

Cornelissen, Bart; Waller, Andrew; Target, Carol; Kersemans, Veerle; Smart, Sean; Vallis, Katherine A

2012-02-20

The F3 peptide (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK), a fragment of the human high mobility group protein 2, binds nucleolin. Nucleolin is expressed in the nuclei of normal cells but is also expressed on the membrane of some cancer cells. The goal was to investigate the use of 111In-labeled F3 peptide for Auger electron-targeted radiotherapy. F3 was labeled with fluorescein isothiocyanate (FITC) for confocal microscopy and conjugated to p-SCN-benzyl-diethylenetriaminepentaacetic acid (BnDTPA) for labeling with 111In to form 111In-BnDTPA-F3. MDA-MB-231-H2N (231-H2N) human breast cancer cells were exposed to 111In-BnDTPA-F3 and used in cell fractionation, γH2AX immunostaining (a marker of DNA double-strand breaks), and clonogenic assays. In vivo, biodistribution studies of 111In-BnDTPA-F3 were performed in 231-H2N xenograft-bearing mice. In tumor growth delay studies, 111In-BnDTPA-F3 (3 μg, 6 MBq/μg) was administered intravenously to 231-H2N xenograft-bearing mice once weekly for 3 weeks. Membrane-binding of FITC-F3 was observed in 231-H2N cells, and there was co-localization of FITC-F3 with nucleolin in the nuclei. After exposure of 231-H2N cells to 111In-BnDTPA-F3 for 2 h, 1.7% of 111In added to the medium was membrane-bound. Of the bound 111In, 15% was internalized, and of this, 37% was localized in the nucleus. Exposure of 231-H2N cells to 111In-BnDTPA-F3 (1 μM, 6 MBq/μg) resulted in a dose-dependent increase in γH2AX foci and in a significant reduction of clonogenic survival compared to untreated cells or cells exposed to unlabeled BnDTPA-F3 (46 ± 4.1%, 100 ± 1.8%, and 132 ± 7.7%, respectively). In vivo, tumor uptake of 111In-BnDTPA-F3 (3 μg, 6 MBq/μg) at 3-h post-injection was 1% of the injected dose per gram (%ID/g), and muscle uptake was 0.5%ID/g. In tumor growth delay studies, tumor growth rate was reduced 19-fold compared to untreated or unlabeled BnDTPA-F3-treated mice (p = 0.023). 111In-BnDTPA-F3 is internalized into 231-H2N cells and translocates to the nucleus. 111In-BnDTPA-F3 has a potent cytotoxic effect in vitro and an anti-tumor effect in mice bearing 231-H2N xenografts despite modest total tumor accumulation.

111In-BnDTPA-F3: an Auger electron-emitting radiotherapeutic agent that targets nucleolin

PubMed Central

2012-01-01

Introduction The F3 peptide (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK), a fragment of the human high mobility group protein 2, binds nucleolin. Nucleolin is expressed in the nuclei of normal cells but is also expressed on the membrane of some cancer cells. The goal was to investigate the use of 111In-labeled F3 peptide for Auger electron-targeted radiotherapy. Methods F3 was labeled with fluorescein isothiocyanate (FITC) for confocal microscopy and conjugated to p-SCN-benzyl-diethylenetriaminepentaacetic acid (BnDTPA) for labeling with 111In to form 111In-BnDTPA-F3. MDA-MB-231-H2N (231-H2N) human breast cancer cells were exposed to 111In-BnDTPA-F3 and used in cell fractionation, γH2AX immunostaining (a marker of DNA double-strand breaks), and clonogenic assays. In vivo, biodistribution studies of 111In-BnDTPA-F3 were performed in 231-H2N xenograft-bearing mice. In tumor growth delay studies, 111In-BnDTPA-F3 (3 μg, 6 MBq/μg) was administered intravenously to 231-H2N xenograft-bearing mice once weekly for 3 weeks. Results Membrane-binding of FITC-F3 was observed in 231-H2N cells, and there was co-localization of FITC-F3 with nucleolin in the nuclei. After exposure of 231-H2N cells to 111In-BnDTPA-F3 for 2 h, 1.7% of 111In added to the medium was membrane-bound. Of the bound 111In, 15% was internalized, and of this, 37% was localized in the nucleus. Exposure of 231-H2N cells to 111In-BnDTPA-F3 (1 μM, 6 MBq/μg) resulted in a dose-dependent increase in γH2AX foci and in a significant reduction of clonogenic survival compared to untreated cells or cells exposed to unlabeled BnDTPA-F3 (46 ± 4.1%, 100 ± 1.8%, and 132 ± 7.7%, respectively). In vivo, tumor uptake of 111In-BnDTPA-F3 (3 μg, 6 MBq/μg) at 3-h post-injection was 1% of the injected dose per gram (%ID/g), and muscle uptake was 0.5%ID/g. In tumor growth delay studies, tumor growth rate was reduced 19-fold compared to untreated or unlabeled BnDTPA-F3-treated mice (p = 0.023). Conclusion 111In-BnDTPA-F3 is internalized into 231-H2N cells and translocates to the nucleus. 111In-BnDTPA-F3 has a potent cytotoxic effect in vitro and an anti-tumor effect in mice bearing 231-H2N xenografts despite modest total tumor accumulation. PMID:22348532

Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins.

PubMed

Song, Albert S; Poor, Taylor A; Abriata, Luciano A; Jardetzky, Theodore S; Dal Peraro, Matteo; Lamb, Robert A

2016-07-05

Parainfluenza virus 5 (PIV5) is an enveloped, single-stranded, negative-sense RNA virus of the Paramyxoviridae family. PIV5 fusion and entry are mediated by the coordinated action of the receptor-binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F). Upon triggering by HN, F undergoes an irreversible ATP- and pH-independent conformational change, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. Previous studies have highlighted key conformational changes in the F-protein refolding pathway, but a detailed understanding of prefusion F-protein metastability remains elusive. Here, using two previously described F-protein mutations (S443D or P22L), we examine the capacity to modulate PIV5 F stability and the mechanisms by which these point mutants act. The S443D mutation destabilizes prefusion F proteins by disrupting a hydrogen bond network at the base of the F-protein globular head. The introduction of a P22L mutation robustly rescues destabilized F proteins through a local hydrophobic interaction between the N-terminal helix and a hydrophobic pocket. Prefusion stabilization conferred by a P22L-homologous mutation is demonstrated in the F protein of Newcastle disease virus, a paramyxovirus of a different genus, suggesting a conserved stabilizing structural element within the paramyxovirus family. Taken together, the available data suggest that movement of the N-terminal helix is a necessary early step for paramyxovirus F-protein refolding and presents a novel target for structure-based drug design.

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation.

PubMed

Zhou, Zhengyuan; Vaidyanathan, Ganesan; McDougald, Darryl; Kang, Choong Mo; Balyasnikova, Irina; Devoogdt, Nick; Ta, Angeline N; McNaughton, Brian R; Zalutsky, Michael R

2017-12-01

Our previous studies with F-18-labeled anti-HER2 single-domain antibodies (sdAbs) utilized 5F7, which binds to the same epitope on HER2 as trastuzumab, complicating its use for positron emission tomography (PET) imaging of patients undergoing trastuzumab therapy. On the other hand, sdAb 2Rs15d binds to a different epitope on HER2 and thus might be a preferable vector for imaging in these patients. The aim of this study was to evaluate the tumor targeting of F-18 -labeled 2Rs15d in HER2-expressing breast carcinoma cells and xenografts. sdAb 2Rs15d was labeled with the residualizing labels N-succinimidyl 3-((4-(4-[ 18 F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([ 18 F]RL-I) and N-succinimidyl 4-guanidinomethyl-3-[ 125 I]iodobenzoate ([ 125 I]SGMIB), and the purity and HER2-specific binding affinity and immunoreactivity were assessed after labeling. The biodistribution of I-125- and F-18-labeled 2Rs15d was determined in SCID mice bearing subcutaneous BT474M1 xenografts. MicroPET/x-ray computed tomograph (CT) imaging of [ 18 F]RL-I-2Rs15d was performed in this model and compared to that of nonspecific sdAb [ 18 F]RL-I-R3B23. MicroPET/CT imaging was also done in an intracranial HER2-positive breast cancer brain metastasis model after administration of 2Rs15d-, 5F7-, and R3B23-[ 18 F]RL-I conjugates. [ 18 F]RL-I was conjugated to 2Rs15d in 40.8 ± 9.1 % yield and with a radiochemical purity of 97-100 %. Its immunoreactive fraction (IRF) and affinity for HER2-specific binding were 79.2 ± 5.4 % and 7.1 ± 0.4 nM, respectively. [ 125 I]SGMIB was conjugated to 2Rs15d in 58.4 ± 8.2 % yield and with a radiochemical purity of 95-99 %; its IRF and affinity for HER2-specific binding were 79.0 ± 12.9 % and 4.5 ± 0.8 nM, respectively. Internalized radioactivity in BT474M1 cells in vitro for [ 18 F]RL-I-2Rs15d was 43.7 ± 3.6, 36.5 ± 2.6, and 21.7 ± 1.2 % of initially bound radioactivity at 1, 2, and 4 h, respectively, and was similar to that seen for [ 125 I]SGMIB-2Rs15d. Uptake of [ 18 F]RL-I-2Rs15d in subcutaneous xenografts was 16-20 %ID/g over 1-3 h. Subcutaneous tumor could be clearly delineated by microPET/CT imaging with [ 18 F]RL-I-2Rs15d but not with [ 18 F]RL-I-R3B23. Intracranial breast cancer brain metastases could be visualized after intravenous administration of both [ 18 F]RL-I-2Rs15d and [ 18 F]RL-I-5F7. Although radiolabeled 2Rs15d conjugates exhibited lower tumor cell retention both in vitro and in vivo than that observed previously for 5F7, given that it binds to a different epitope on HER2 from those targeted by the clinically utilized HER2-targeted therapeutic antibodies trastuzumab and pertuzumab, F-18-labeled 2Rs15d has potential for assessing HER2 status by PET imaging after trastuzumab and/or pertuzumab therapy.

Bubble Memory Module.

DTIC Science & Technology

1980-12-01

I AD-A093 642 ROCKWELL INTERNATIONAL ANAHEIM CA AUOEISSTAE-T F/S V/2 I BU13LE MEMORY MODULE. (U) DEC 80 0 0 BOHNING. F J BECKER NASI -14174...Cde under Contract NASI -14174 Dist’m/o National Aeronautics and Space Administration Scientific and Technical Information BranchA 1980 J Approvod ior...9/ BUBBLE M MORY MODULE.(U) DEC 80 0 BHNING, F J BECKER NASI -14174 NCLASSIFIED CB-569/201 NASA-CR-3380 ML22-fllfllf ll l ff mmlmmmmm.l®fmmM EEmmEI

Effects of fundamental frequency and vocal-tract length cues on sentence segregation by listeners with hearing loss

PubMed Central

Mackersie, Carol L.; Dewey, James; Guthrie, Lesli A.

2011-01-01

The purpose was to determine the effect of hearing loss on the ability to separate competing talkers using talker differences in fundamental frequency (F0) and apparent vocal-tract length (VTL). Performance of 13 adults with hearing loss and 6 adults with normal hearing was measured using the Coordinate Response Measure. For listeners with hearing loss, the speech was amplified and filtered according to the NAL-RP hearing aid prescription. Target-to-competition ratios varied from 0 to 9 dB. The target sentence was randomly assigned to the higher or lower values of F0 or VTL on each trial. Performance improved for F0 differences up to 9 and 6 semitones for people with normal hearing and hearing loss, respectively, but only when the target talker had the higher F0. Recognition for the lower F0 target improved when trial-to-trial uncertainty was removed (9-semitone condition). Scores improved with increasing differences in VTL for the normal-hearing group. On average, hearing-impaired listeners did not benefit from VTL cues, but substantial inter-subject variability was observed. The amount of benefit from VTL cues was related to the average hearing loss in the 1–3-kHz region when the target talker had the shorter VTL. PMID:21877813

PET Imaging of Macrophage Mannose Receptor-Expressing Macrophages in Tumor Stroma Using 18F-Radiolabeled Camelid Single-Domain Antibody Fragments.

PubMed

Blykers, Anneleen; Schoonooghe, Steve; Xavier, Catarina; D'hoe, Kevin; Laoui, Damya; D'Huyvetter, Matthias; Vaneycken, Ilse; Cleeren, Frederik; Bormans, Guy; Heemskerk, Johannes; Raes, Geert; De Baetselier, Patrick; Lahoutte, Tony; Devoogdt, Nick; Van Ginderachter, Jo A; Caveliers, Vicky

2015-08-01

Tumor-associated macrophages constitute a major component of the stroma of solid tumors, encompassing distinct subpopulations with different characteristics and functions. We aimed to identify M2-oriented tumor-supporting macrophages within the tumor microenvironment as indicators of cancer progression and prognosis, using PET imaging. This can be realized by designing (18)F-labeled camelid single-domain antibody fragments (sdAbs) specifically targeting the macrophage mannose receptor (MMR), which has been identified as an important biomarker on this cell population. Cross-reactive anti-MMR sdAbs were generated after immunization of an alpaca with the extracellular domains of both human and mouse MMR. The lead binder was chosen on the basis of comparisons of binding affinity and in vivo pharmacokinetics. The PET tracer (18)F-fluorobenzoate (FB)-anti-MMR sdAb was developed using the prosthetic group N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB), and its biodistribution, tumor-targeting potential, and specificity in terms of macrophage and MMR targeting were evaluated in mouse tumor models. Four sdAbs were selected after affinity screening, but only 2 were found to be cross-reactive for human and mouse MMR. The lead anti-MMR 3.49 sdAb, bearing an affinity of 12 and 1.8 nM for mouse and human MMR, respectively, was chosen for its favorable in vivo biodistribution profile and tumor-targeting capacity. (18)F-FB-anti-MMR 3.49 sdAb was synthesized with a 5%-10% radiochemical yield using an automated and optimized protocol. In vivo biodistribution analyses showed fast clearance via the kidneys and retention in MMR-expressing organs and tumor. The kidney retention of the fluorinated sdAb was 20-fold lower than a (99m)Tc-labeled counterpart. Compared with MMR- and C-C chemokine receptor 2-deficient mice, significantly higher uptake was observed in tumors grown in wild-type mice, demonstrating the specificity of the (18)F tracer for MMR and macrophages, respectively. Anti-MMR 3.49 was denoted as the lead cross-reactive MMR-targeting sdAb. (18)F radiosynthesis was optimized, providing an optimal probe for PET imaging of the tumor-promoting macrophage subpopulation in the tumor stroma. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Rho GTPase activity modulates paramyxovirus fusion protein-mediated cell-cell fusion

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

Schowalter, Rachel M.; Wurth, Mark A.; Aguilar, Hector C.

2006-07-05

The paramyxovirus fusion protein (F) promotes fusion of the viral envelope with the plasma membrane of target cells as well as cell-cell fusion. The plasma membrane is closely associated with the actin cytoskeleton, but the role of actin dynamics in paramyxovirus F-mediated membrane fusion is unclear. We examined cell-cell fusion promoted by two different paramyxovirus F proteins in three cell types in the presence of constitutively active Rho family GTPases, major cellular coordinators of actin dynamics. Reporter gene and syncytia assays demonstrated that expression of either Rac1{sup V12} or Cdc42{sup V12} could increase cell-cell fusion promoted by the Hendra ormore » SV5 glycoproteins, though the effect was dependent on the cell type expressing the viral glycoproteins. In contrast, RhoA{sup L63} decreased cell-cell fusion promoted by Hendra glycoproteins but had little affect on SV5 F-mediated fusion. Also, data suggested that GTPase activation in the viral glycoprotein-containing cell was primarily responsible for changes in fusion. Additionally, we found that activated Cdc42 promoted nuclear rearrangement in syncytia.« less

HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

PubMed Central

Stadhouders, Ralph; Aktuna, Suleyman; Thongjuea, Supat; Aghajanirefah, Ali; Pourfarzad, Farzin; van IJcken, Wilfred; Lenhard, Boris; Rooks, Helen; Best, Steve; Menzel, Stephan; Grosveld, Frank; Thein, Swee Lay; Soler, Eric

2014-01-01

Genetic studies have identified common variants within the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q that are associated with elevated fetal hemoglobin (HbF) levels and alterations of other clinically important human erythroid traits. It is unclear how these noncoding sequence variants affect multiple erythrocyte characteristics. Here, we determined that several HBS1L-MYB intergenic variants affect regulatory elements that are occupied by key erythroid transcription factors within this region. These elements interact with MYB, a critical regulator of erythroid development and HbF levels. We found that several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting long-range interactions with MYB and MYB expression levels. These data provide a functional explanation for the genetic association of HBS1L-MYB intergenic polymorphisms with human erythroid traits and HbF levels. Our results further designate MYB as a target for therapeutic induction of HbF to ameliorate sickle cell and β-thalassemia disease severity. PMID:24614105

A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease.

PubMed

Pule, Gift D; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S; Wonkam, Ambroise

2015-10-01

To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. Systematic review. Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.

Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma.

PubMed

Maugeri, Marco; Barbagallo, Davide; Barbagallo, Cristina; Banelli, Barbara; Di Mauro, Stefania; Purrello, Francesco; Magro, Gaetano; Ragusa, Marco; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

2016-12-13

Neuroblastoma is the most common human extracranial solid tumor during infancy. Involvement of several miRNAs in its pathogenesis has been ascertained. Interestingly, most of their encoding genes reside in hypermethylated genomic regions: thus, their tumor suppressor function is normally disallowed in these tumors. To date, the therapeutic role of the demethylating agent 5'-Aza-2 deoxycytidine (5'-AZA) and its effects on miRNAome modulation in neuroblastoma have not been satisfactorily explored. Starting from a high-throughput expression profiling of 754 miRNAs and based on a proper selection, we focused on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p as candidate miRNAs for our analysis. They resulted downregulated in four neuroblastoma cell lines with respect to normal adrenal gland. MiRNAs 29a-3p and 34b-3p also resulted downregulated in vivo in a murine neuroblastoma progression model. Unlike the amount of methylation of their encoding gene promoters, all these miRNAs were significantly overexpressed following treatment with 5'-AZA. Transfection with candidate miRNAs mimics significantly decreased neuroblastoma cells proliferation rate. A lower expression of miR-181c was significantly associated to a worse overall survival in a public dataset of 498 neuroblastoma samples (http://r2.amc.nl). Our data strongly suggest that CDK6, DNMT3A, DNMT3B are targets of miR-29a-3p, while CCNE2 and E2F3 are targets of miR-34b-3p. Based on all these data, we propose that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are disallowed tumor suppressor genes in neuroblastoma and suggest them as new therapeutic targets in neuroblastoma.

Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma

PubMed Central

Di Mauro, Stefania; Purrello, Francesco; Magro, Gaetano; Ragusa, Marco; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

2016-01-01

Neuroblastoma is the most common human extracranial solid tumor during infancy. Involvement of several miRNAs in its pathogenesis has been ascertained. Interestingly, most of their encoding genes reside in hypermethylated genomic regions: thus, their tumor suppressor function is normally disallowed in these tumors. To date, the therapeutic role of the demethylating agent 5′-Aza-2 deoxycytidine (5'-AZA) and its effects on miRNAome modulation in neuroblastoma have not been satisfactorily explored. Starting from a high-throughput expression profiling of 754 miRNAs and based on a proper selection, we focused on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p as candidate miRNAs for our analysis. They resulted downregulated in four neuroblastoma cell lines with respect to normal adrenal gland. MiRNAs 29a-3p and 34b-3p also resulted downregulated in vivo in a murine neuroblastoma progression model. Unlike the amount of methylation of their encoding gene promoters, all these miRNAs were significantly overexpressed following treatment with 5′-AZA. Transfection with candidate miRNAs mimics significantly decreased neuroblastoma cells proliferation rate. A lower expression of miR-181c was significantly associated to a worse overall survival in a public dataset of 498 neuroblastoma samples (http://r2.amc.nl). Our data strongly suggest that CDK6, DNMT3A, DNMT3B are targets of miR-29a-3p, while CCNE2 and E2F3 are targets of miR-34b-3p. Based on all these data, we propose that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are disallowed tumor suppressor genes in neuroblastoma and suggest them as new therapeutic targets in neuroblastoma. PMID:27829219

Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics

PubMed Central

de Waal, Luc; Lewis, Timothy A.; Rees, Matthew G.; Tsherniak, Aviad; Wu, Xiaoyun; Choi, Peter S.; Gechijian, Lara; Hartigan, Christina; Faloon, Patrick W.; Hickey, Mark J.; Tolliday, Nicola; Carr, Steven A.; Clemons, Paul A.; Munoz, Benito; Wagner, Bridget K.; Shamji, Alykhan F.; Koehler, Angela N.; Schenone, Monica; Burgin, Alex B.; Schreiber, Stuart L.; Greulich, Heidi; Meyerson, Matthew

2015-01-01

High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery. PMID:26656089

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate.

PubMed

Aikawa, Katsuji; Asano, Moriteru; Ono, Koji; Habuka, Noriyuki; Yano, Jason; Wilson, Keith; Fujita, Hisashi; Kandori, Hitoshi; Hara, Takahito; Morimoto, Megumi; Santou, Takashi; Yamaoka, Masuo; Nakayama, Masaharu; Hasuoka, Atsushi

2017-07-01

We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterization of the Caenorhabditis elegans G protein-coupled serotonin receptors.

PubMed

Carre-Pierrat, Maïté; Baillie, David; Johnsen, Robert; Hyde, Rhonda; Hart, Anne; Granger, Laure; Ségalat, Laurent

2006-12-01

Serotonin (5-HT) regulates a wide range of behaviors in Caenorhabditis elegans, including egg laying, male mating, locomotion and pharyngeal pumping. So far, four serotonin receptors have been described in the nematode C. elegans, three of which are G protein-coupled receptors (GPCR), (SER-1, SER-4 and SER-7), and one is an ion channel (MOD-1). By searching the C. elegans genome for additional 5-HT GPCR genes, we identified five further genes which encode putative 5-HT receptors, based on sequence similarities to 5-HT receptors from other species. Using loss-of-function mutants and RNAi, we performed a systematic study of the role of the eight GPCR genes in serotonin-modulated behaviors of C. elegans (F59C12.2, Y22D7AR.13, K02F2.6, C09B7.1, M03F4.3, F16D3.7, T02E9.3, C24A8.1). We also examined their expression patterns. Finally, we tested whether the most likely candidate receptors were able to modulate adenylate cyclase activity in transfected cells in a 5-HT-dependent manner. This paper is the first comprehensive study of G protein-coupled serotonin receptors of C. elegans. It provides a direct comparison of the expression patterns and functional roles for 5-HT receptors in C. elegans.

Evasion of adaptive immunity by HIV through the action of host APOBEC3G/F enzymes.

PubMed

Grant, Michael; Larijani, Mani

2017-09-12

APOBEC3G (A3G) and APOBEC3F (A3F) are DNA-mutating enzymes expressed in T cells, dendritic cells and macrophages. A3G/F have been considered innate immune host factors, based on reports that they lethally mutate the HIV genome in vitro. In vivo, A3G/F effectiveness is limited by viral proteins, entrapment in inactive complexes and filtration of mutations during viral life cycle. We hypothesized that the impact of sub-lethal A3G/F action could extend beyond the realm of innate immunity confined to the cytoplasm of infected cells. We measured recognition of wild type and A3G/F-mutated epitopes by cytotoxic T lymphocytes (CTL) from HIV-infected individuals and found that A3G/F-induced mutations overwhelmingly diminished CTL recognition of HIV peptides, in a human histocompatibility-linked leukocyte antigen (HLA)-dependent manner. Furthermore, we found corresponding enrichment of A3G/F-favored motifs in CTL epitope-encoding sequences within the HIV genome. These findings illustrate that A3G/F-mediated mutations mediate immune evasion by HIV in vivo. Therefore, we suggest that vaccine strategies target T cell or antibody epitopes that are not poised for mutation into escape variants by A3G/F action.

Communication via Chalkboard and on Paper. TLA-100.00 (F.U.F.).

ERIC Educational Resources Information Center

Hardison, Margaret J.

The purpose of this cluster of learning modules is to increase the teacher intern's understanding and skills with regard to his role as a communicator. The cluster contains three modules: (a) objectives for teaching handwriting, (b) methodology of manuscript writing, and (c) practice teaching of manuscript handwriting. Each module contains a…

Parametric Amplification Protocol for Frequency-Modulated Magnetic Resonance Force Microscopy Signals

NASA Astrophysics Data System (ADS)

Harrell, Lee; Moore, Eric; Lee, Sanggap; Hickman, Steven; Marohn, John

2011-03-01

We present data and theoretical signal and noise calculations for a protocol using parametric amplification to evade the inherent tradeoff between signal and detector frequency noise in force-gradient magnetic resonance force microscopy signals, which are manifested as a modulated frequency shift of a high- Q microcantilever. Substrate-induced frequency noise has a 1 / f frequency dependence, while detector noise exhibits an f2 dependence on modulation frequency f . Modulation of sample spins at a frequency that minimizes these two contributions typically results in a surface frequency noise power an order of magnitude or more above the thermal limit and may prove incompatible with sample spin relaxation times as well. We show that the frequency modulated force-gradient signal can be used to excite the fundamental resonant mode of the cantilever, resulting in an audio frequency amplitude signal that is readily detected with a low-noise fiber optic interferometer. This technique allows us to modulate the force-gradient signal at a sufficiently high frequency so that substrate-induced frequency noise is evaded without subjecting the signal to the normal f2 detector noise of conventional demodulation.

Apollo 12 Mission image - Lunar surface near lunar module

NASA Image and Video Library

1969-11-19

AS12-47-6949 (19-20 Nov. 1969) --- A photograph of the Apollo 12 lunar landing site taken during the extravehicular activity (EVA) of astronauts Charles Conrad Jr., commander; and Alan L. Bean, lunar module pilot. The Apollo 12 Lunar Module (LM) is on the left. Barely visible in the center of the picture, in the shadows on the farside of the crater, is the Surveyor 3 spacecraft. The two spacecraft are about 600 feet apart. Conrad and Bean walked over to Surveyor 3 during their second EVA. The television camera and several other pieces were taken from Surveyor 3 and brought back to Earth for scientific examination. Astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) in lunar orbit, while astronauts Conrad and Bean descended in the LM to explore the moon. The considerable glare in the picture is caused by the position of the sun. The Apollo tool carrier is the object next to the LM footpad.

Evaluation of volumetric modulated arc therapy for cranial radiosurgery using multiple noncoplanar arcs

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

Audet, Chantal; Poffenbarger, Brett A.; Chang, Pauling

2011-11-15

Purpose: To evaluate a commercial volumetric modulated arc therapy (VMAT), using multiple noncoplanar arcs, for linac-based cranial radiosurgery, as well as evaluate the combined accuracy of the VMAT dose calculations and delivery. Methods: Twelve patients with cranial lesions of variable size (0.1-29 cc) and two multiple metastases patients were planned (Eclipse RapidArc AAA algorithm, v8.6.15) using VMAT (1-6 noncoplanar arcs), dynamic conformal arc (DCA, {approx}4 arcs), and IMRT (nine static fields). All plans were evaluated according to a conformity index (CI), healthy brain tissue doses and volumes, and the dose to organs at risk. A 2D dose distribution was measuredmore » (Varian Novalis Tx, HD120 MLC, 1000 MU/min, 6 MV beam) for the {approx}4 arc VMAT treatment plans using calibrated film dosimetry. Results: The CI (0-1 best) average for all plans was best for {approx}4 noncoplanar arc VMAT at 0.86 compared with {approx}0.78 for IMRT and a single arc VMAT and 0.68 for DCA. The volumes of healthy brain receiving 50% of the prescribed target coverage dose or more (V{sub 50%}) were lowest for the four arc VMAT [RA(4)] and DCA plans. The average ratio of the V{sub 50%} for the other plans to the RA(4) V{sub 50%} were 1.9 for a single noncoplanar arc VMAT [RA(1nc)], 1.4 for single full coplanar arc VMAT [RA(1f)] and 1.3 for IMRT. The V{sub 50%} improved significantly for single isocenter multiple metastases plan when two noncoplanar VMAT arcs were added to a full single coplanar one. The maximum dose to 5 cc of the outer 1 cm rim of healthy brain which one may want to keep below nonconsequential doses of 300-400 cGy, was 2-3 times greater for IMRT, RA(1nc) and RA(1f) plans compared with the multiple noncoplanar arc DCA and RA(4) techniques. Organs at risk near (0-4 mm) to targets were best spared by (i) single noncoplanar arcs when the targets are lateral to the organ at risk and (ii) by skewed nonvertical planes of IMRT fields when the targets are not lateral to the organ at risk. The highest dose gradient observed between an organ at risk and a target at the edge of a VMAT arc plane or plane of IMRT fields was 17%/mm. The average absolute percent difference between the measured and calculated central axis dose for all the VMAT plans was 3.6 {+-} 2.2%. The measured perpendicular profile widths and shifts were on average within 0.5 mm of planned values. The average total MUs for VMAT plans was double the DCA average and similar to the IMRT average. Conclusions: For the aforementioned planning and delivery system and cranial lesions greater than 7 mm in diameter, multiple noncoplanar arc VMAT consistently provides accurate and high quality cranial radiosurgery dose distributions with low doses to healthy brain tissue and high dose conformity to the target. These qualities may make multiple noncoplanar arc VMAT suitable for a greater range of prescription doses or larger and more irregular lesions. For smaller and/or rounder lesions there are other clinically acceptable treatment techniques that may involve fewer couch angles or arcs and reduce treatment times.« less

Design of a small molecule against an oncogenic noncoding RNA.

PubMed

Velagapudi, Sai Pradeep; Cameron, Michael D; Haga, Christopher L; Rosenberg, Laura H; Lafitte, Marie; Duckett, Derek R; Phinney, Donald G; Disney, Matthew D

2016-05-24

The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif-small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm.

Impact of infrasound on the human cochlea.

PubMed

Hensel, Johannes; Scholz, Günther; Hurttig, Ulrike; Mrowinski, Dieter; Janssen, Thomas

2007-11-01

Low-frequency tones were reported to modulate the amplitude of distortion product otoacoustic emissions (DPOAEs) indicating periodic changes of the operating point of the cochlear amplifier. The present study investigates potential differences between infrasound and low-frequency sounds in their ability to modulate human DPOAEs. DPOAEs were recorded in 12 normally hearing subjects in the presence of a biasing tone with f(B)=6Hz and a level L(B)=130dB SPL. Primary frequencies were fixed at f(1)=1.6 and f(2)=2.0kHz with fixed levels L(1)=51 and L(2)=30dB SPL. A new measure, the modulation index (MI), was devised to characterise the degree of DPOAE modulation. In subsequent measurements with biasing tones of f(B) = 12, 24 and 50Hz, L(B) was adjusted to maintain the MI as obtained individually at 6Hz. Modulation patterns lagged with increasing f(B). The necessary L(B) decreased by 12dB/octave with increasing f(B) and ran almost parallel to the published infrasound detection threshold. No signs of an abrupt change in transmission into the cochlea were found between infra- and low-frequency sounds. The results show clearly that infrasound enters the inner ear, and can alter cochlear processing.

Mandarin-Speaking Children's Speech Recognition: Developmental Changes in the Influences of Semantic Context and F0 Contours.

PubMed

Zhou, Hong; Li, Yu; Liang, Meng; Guan, Connie Qun; Zhang, Linjun; Shu, Hua; Zhang, Yang

2017-01-01

The goal of this developmental speech perception study was to assess whether and how age group modulated the influences of high-level semantic context and low-level fundamental frequency ( F 0 ) contours on the recognition of Mandarin speech by elementary and middle-school-aged children in quiet and interference backgrounds. The results revealed different patterns for semantic and F 0 information. One the one hand, age group modulated significantly the use of F 0 contours, indicating that elementary school children relied more on natural F 0 contours than middle school children during Mandarin speech recognition. On the other hand, there was no significant modulation effect of age group on semantic context, indicating that children of both age groups used semantic context to assist speech recognition to a similar extent. Furthermore, the significant modulation effect of age group on the interaction between F 0 contours and semantic context revealed that younger children could not make better use of semantic context in recognizing speech with flat F 0 contours compared with natural F 0 contours, while older children could benefit from semantic context even when natural F 0 contours were altered, thus confirming the important role of F 0 contours in Mandarin speech recognition by elementary school children. The developmental changes in the effects of high-level semantic and low-level F 0 information on speech recognition might reflect the differences in auditory and cognitive resources associated with processing of the two types of information in speech perception.

Combined hairpin-antisense compositions and methods for modulating expression

DOEpatents

Shanklin, John; Nguyen, Tam

2014-08-05

A nucleotide construct comprising a nucleotide sequence that forms a stem and a loop, wherein the loop comprises a nucleotide sequence that modulates expression of a target, wherein the stem comprises a nucleotide sequence that modulates expression of a target, and wherein the target modulated by the nucleotide sequence in the loop and the target modulated by the nucleotide sequence in the stem may be the same or different. Vectors, methods of regulating target expression, methods of providing a cell, and methods of treating conditions comprising the nucleotide sequence are also disclosed.

Combined hairpin-antisense compositions and methods for modulating expression

DOEpatents

Shanklin, John; Nguyen, Tam Huu

2015-11-24

A nucleotide construct comprising a nucleotide sequence that forms a stem and a loop, wherein the loop comprises a nucleotide sequence that modulates expression of a target, wherein the stem comprises a nucleotide sequence that modulates expression of a target, and wherein the target modulated by the nucleotide sequence in the loop and the target modulated by the nucleotide sequence in the stem may be the same or different. Vectors, methods of regulating target expression, methods of providing a cell, and methods of treating conditions comprising the nucleotide sequence are also disclosed.

Backward masked fearful faces enhance contralateral occipital cortical activity for visual targets within the spotlight of attention

PubMed Central

Reinke, Karen S.; LaMontagne, Pamela J.; Habib, Reza

2011-01-01

Spatial attention has been argued to be adaptive by enhancing the processing of visual stimuli within the ‘spotlight of attention’. We previously reported that crude threat cues (backward masked fearful faces) facilitate spatial attention through a network of brain regions consisting of the amygdala, anterior cingulate and contralateral visual cortex. However, results from previous functional magnetic resonance imaging (fMRI) dot-probe studies have been inconclusive regarding a fearful face-elicited contralateral modulation of visual targets. Here, we tested the hypothesis that the capture of spatial attention by crude threat cues would facilitate processing of subsequently presented visual stimuli within the masked fearful face-elicited ‘spotlight of attention’ in the contralateral visual cortex. Participants performed a backward masked fearful face dot-probe task while brain activity was measured with fMRI. Masked fearful face left visual field trials enhanced activity for spatially congruent targets in the right superior occipital gyrus, fusiform gyrus and lateral occipital complex, while masked fearful face right visual field trials enhanced activity in the left middle occipital gyrus. These data indicate that crude threat elicited spatial attention enhances the processing of subsequent visual stimuli in contralateral occipital cortex, which may occur by lowering neural activation thresholds in this retinotopic location. PMID:20702500

Long-term memory biases auditory spatial attention.

PubMed

Zimmermann, Jacqueline F; Moscovitch, Morris; Alain, Claude

2017-10-01

Long-term memory (LTM) has been shown to bias attention to a previously learned visual target location. Here, we examined whether memory-predicted spatial location can facilitate the detection of a faint pure tone target embedded in real world audio clips (e.g., soundtrack of a restaurant). During an initial familiarization task, participants heard audio clips, some of which included a lateralized target (p = 50%). On each trial participants indicated whether the target was presented from the left, right, or was absent. Following a 1 hr retention interval, participants were presented with the same audio clips, which now all included a target. In Experiment 1, participants showed memory-based gains in response time and d'. Experiment 2 showed that temporal expectations modulate attention, with greater memory-guided attention effects on performance when temporal context was reinstated from learning (i.e., when timing of the target within audio clips was not changed from initially learned timing). Experiment 3 showed that while conscious recall of target locations was modulated by exposure to target-context associations during learning (i.e., better recall with higher number of learning blocks), the influence of LTM associations on spatial attention was not reduced (i.e., number of learning blocks did not affect memory-guided attention). Both Experiments 2 and 3 showed gains in performance related to target-context associations, even for associations that were not explicitly remembered. Together, these findings indicate that memory for audio clips is acquired quickly and is surprisingly robust; both implicit and explicit LTM for the location of a faint target tone modulated auditory spatial attention. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Plug-and-play modules for flexible radiosynthesis

PubMed Central

Herman, Henry; Flores, Graciela; Quinn, Kevin; Eddings, Mark; Olma, Sebastian; Moore, Melissa D.; Ding, Huijiang; Bobinski, Krzysztof P.; Wang, Mingwei; Williams, Dirk; Wiliams, Darin; Shen, Clifton Kwang-Fu; Phelps, Michael E.; van Dam, R. Michael

2015-01-01

We present a plug-and-play radiosynthesis platform and accompanying computer software based on modular subunits that can easily and flexibly be configured to implement a diverse range of radiosynthesis protocols. Modules were developed that perform: (i) reagent storage and delivery, (ii) evaporations and sealed reactions, and (iii) cartridge-based purifications. The reaction module incorporates a simple robotic mechanism that removes tubing from the vessel and replaces it with a stopper prior to sealed reactions, enabling the system to withstand high pressures and thus provide tremendous flexibility in choice of solvents and temperatures. Any number of modules can rapidly be connected together using only a few fluidic connections to implement a particular synthesis, and the resulting system is controlled in a semi-automated fashion by a single software interface. Radiosyntheses of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), 1-[18F]fluoro-4-nitrobenzene ([18F]FNB), and 2′-deoxy-2′-[18F]fluoro-1-β-D-arabinofuranosyl cytosine (D-[18F]FAC) were performed to validate the system and demonstrate its versatility. PMID:23702795

Electronic sputtering of LiF, CaF2, LaF3 and UF4 with 197 MeV Au ions. Is the stoichiometry of atom emission preserved?

NASA Astrophysics Data System (ADS)

Toulemonde, M.; Assmann, W.; Muller, D.; Trautmann, C.

2017-09-01

Sputtering experiments with swift heavy ions in the electronic energy loss regime were performed by using the catcher technique in combination with elastic recoil detection analysis. Four different fluoride targets, LiF, CaF2, LaF3 and UF4 were irradiated in the electronic energy loss regime using 197 MeV Au ions. The angular distribution of particles sputtered from the surface of freshly cleaved LiF and CaF2 single crystals is composed of a broad cosine distribution superimposed by a jet-like peak that appears perpendicular to the surface independent of the angle of beam incidence. For LiF, the particle emission in the entire angular distribution (jet plus broad cosine component) is stoichiometric, whereas for CaF2 the ratio of the sputtered F to Ca particles is at large angles by a factor of two smaller than the stoichiometry of the crystal. For single crystalline LaF3 no jet component is observed and the angular distribution is non-stoichiometric with the number of sputtered F particles being slightly larger than the number of sputtered La particles. In the case of UF4, the target was polycrystalline and had a much rougher surface compared to cleaved crystals. This destroys the appearance of a possible jet component leading to a broad angular distribution. The ratio of sputtered U atoms compared to F atoms is in the order of 1-2, i.e. the number of collected particles on the catcher is also non-stoichiometric. Such unlike behavior of particles sputtered from different fluoride crystals creates new questions.

Fructose 1,6-Bisphosphate Aldolase, a Novel Immunogenic Surface Protein on Listeria Species

PubMed Central

Conceição, Fabricio Rochedo; Hust, Michael; Mendonça, Karla Sequeira; Moreira, Ângela Nunes; França, Rodrigo Correa; da Silva, Wladimir Padilha; Aleixo, José Antonio G.

2016-01-01

Listeria monocytogenes is a ubiquitous food-borne pathogen, and its presence in food or production facilities highlights the importance of surveillance. Increased understanding of the surface exposed antigens on Listeria would provide potential diagnostic and therapeutic targets. In the present work, using mass spectrometry and genetic cloning, we show that fructose-1,6-bisphosphate aldolase (FBA) class II in Listeria species is the antigen target of the previously described mAb-3F8. Western and dot blot assays confirmed that the mAb-3F8 could distinguish all tested Listeria species from close-related bacteria. Localization studies indicated that FBA is present in every fraction of Listeria cells, including supernatant and the cell wall, setting Listeria spp. as one of the few bacteria described to have this protein on their cell surface. Epitope mapping using ORFeome display and a peptide membrane revealed a 14-amino acid peptide as the potential mAb-3F8 epitope. The target epitope in FBA allowed distinguishing Listeria spp. from closely-related bacteria, and was identified as part of the active site in the dimeric enzyme. However, its function in cell surface seems not to be host cell adhesion-related. Western and dot blot assays further demonstrated that mAb-3F8 together with anti-InlA mAb-2D12 could differentiate pathogenic from non-pathogenic Listeria isolated from artificially contaminated cheese. In summary, we report FBA as a novel immunogenic surface target useful for the detection of Listeria genus. PMID:27489951

Fructose 1,6-Bisphosphate Aldolase, a Novel Immunogenic Surface Protein on Listeria Species.

PubMed

Mendonça, Marcelo; Moreira, Gustavo Marçal Schmidt Garcia; Conceição, Fabricio Rochedo; Hust, Michael; Mendonça, Karla Sequeira; Moreira, Ângela Nunes; França, Rodrigo Correa; da Silva, Wladimir Padilha; Bhunia, Arun K; Aleixo, José Antonio G

2016-01-01

Listeria monocytogenes is a ubiquitous food-borne pathogen, and its presence in food or production facilities highlights the importance of surveillance. Increased understanding of the surface exposed antigens on Listeria would provide potential diagnostic and therapeutic targets. In the present work, using mass spectrometry and genetic cloning, we show that fructose-1,6-bisphosphate aldolase (FBA) class II in Listeria species is the antigen target of the previously described mAb-3F8. Western and dot blot assays confirmed that the mAb-3F8 could distinguish all tested Listeria species from close-related bacteria. Localization studies indicated that FBA is present in every fraction of Listeria cells, including supernatant and the cell wall, setting Listeria spp. as one of the few bacteria described to have this protein on their cell surface. Epitope mapping using ORFeome display and a peptide membrane revealed a 14-amino acid peptide as the potential mAb-3F8 epitope. The target epitope in FBA allowed distinguishing Listeria spp. from closely-related bacteria, and was identified as part of the active site in the dimeric enzyme. However, its function in cell surface seems not to be host cell adhesion-related. Western and dot blot assays further demonstrated that mAb-3F8 together with anti-InlA mAb-2D12 could differentiate pathogenic from non-pathogenic Listeria isolated from artificially contaminated cheese. In summary, we report FBA as a novel immunogenic surface target useful for the detection of Listeria genus.

Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use.

PubMed

Taurisano, Paolo; Antonucci, Linda A; Fazio, Leonardo; Rampino, Antonio; Romano, Raffaella; Porcelli, Annamaria; Masellis, Rita; Colizzi, Marco; Quarto, Tiziana; Torretta, Silvia; Di Giorgio, Annabella; Pergola, Giulio; Bertolino, Alessandro; Blasi, Giuseppe

2016-08-01

The CB1 cannabinoid receptor is targeted in the brain by endocannabinoids under physiological conditions as well as by delta9-tetrahydrocannabinol under cannabis use. Furthermore, its signaling appears to affect brain cognitive processing. Recent findings highlight a crucial role of cyclooxygenase-2 (COX-2) in the mechanism of intraneuronal CB1 signaling transduction, while others indicate that two single nucleotide polymorphisms (SNPs) (rs1406977 and rs20417) modulate expression of CB1 (CNR1) and COX-2 (PTGS2) coding genes, respectively. Here, our aim was to use fMRI to investigate in healthy humans whether these SNPs interact in modulating prefrontal activity during working memory processing and if this modulation is linked with cannabis use. We recruited 242 healthy subjects genotyped for CNR1 rs1406977 and PTGS2 rs20417 that performed the N-back working memory task during fMRI and were interviewed using the Cannabis Experience Questionnaire (CEQ). We found that the interaction between CNR1 rs1406977 and PTGS2 rs20417 is associated with dorsolateral prefrontal cortex (DLPFC) activity such that specific genotype configurations (CNR1 C carriers/PTGS2 C carriers and CNR1 TT/PTGS2 GG) predict lower cortical response versus others in spite of similar behavioral accuracy. Furthermore, DLPFC activity in the cluster associated with the CNR1 by PTGS2 interaction was negatively correlated with behavioral efficiency and positively correlated with frequency of cannabis use in cannabis users. These results suggest that a genetically modulated balancing of signaling within the CB1-COX-2 pathway may reflect on more or less efficient patterns of prefrontal activity during working memory. Frequency of cannabis use may be a factor for further modulation of CNR1/PTGS2-mediated cortical processing associated with this cognitive process. Copyright © 2016 Elsevier Ltd. All rights reserved.

76 FR 17789 - Fisheries of the Northeastern United States; Atlantic Bluefish Fishery; 2011 Atlantic Bluefish...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-31

... allowable 2011 harvest levels and other management measures to achieve the target fishing mortality rate (F... regulations that specify the process for setting the annual TAL and target F to more clearly reflect the... established that the long-term target F is 90 percent of F MSY (F MSY = 0.19, therefore F target = 90 percent...

Detection of Brain Reorganization in Pediatric Multiple Sclerosis Using Functional MRI

DTIC Science & Technology

2015-10-01

accomplish this, we apply comparative assessments of fMRI mappings of language, memory , and motor function, and performance on clinical neurocognitive...community at a target rate of 13 volunteers per quarter period; acquire fMRI data for language, memory , and visual-motor functions (months 3-12). c...consensus fMRI activation maps for language, memory , and visual-motor tasks (months 8-12). f) Subtask 1f. Prepare publication to disseminate our

Proteolytic regulation of metabolic enzymes by E3 ubiquitin ligase complexes: lessons from yeast.

PubMed

Nakatsukasa, Kunio; Okumura, Fumihiko; Kamura, Takumi

2015-01-01

Eukaryotic organisms use diverse mechanisms to control metabolic rates in response to changes in the internal and/or external environment. Fine metabolic control is a highly responsive, energy-saving process that is mediated by allosteric inhibition/activation and/or reversible modification of preexisting metabolic enzymes. In contrast, coarse metabolic control is a relatively long-term and expensive process that involves modulating the level of metabolic enzymes. Coarse metabolic control can be achieved through the degradation of metabolic enzymes by the ubiquitin-proteasome system (UPS), in which substrates are specifically ubiquitinated by an E3 ubiquitin ligase and targeted for proteasomal degradation. Here, we review select multi-protein E3 ligase complexes that directly regulate metabolic enzymes in Saccharomyces cerevisiae. The first part of the review focuses on the endoplasmic reticulum (ER) membrane-associated Hrd1 and Doa10 E3 ligase complexes. In addition to their primary roles in the ER-associated degradation pathway that eliminates misfolded proteins, recent quantitative proteomic analyses identified native substrates of Hrd1 and Doa10 in the sterol synthesis pathway. The second part focuses on the SCF (Skp1-Cul1-F-box protein) complex, an abundant prototypical multi-protein E3 ligase complex. While the best-known roles of the SCF complex are in the regulation of the cell cycle and transcription, accumulating evidence indicates that the SCF complex also modulates carbon metabolism pathways. The increasing number of metabolic enzymes whose stability is directly regulated by the UPS underscores the importance of the proteolytic regulation of metabolic processes for the acclimation of cells to environmental changes.

Advanced EMU electrochemically regenerable CO2 and moisture absorber module breadboard

NASA Technical Reports Server (NTRS)

Lee, M. C.; Sudar, M.; Chang, B. J.

1988-01-01

The applicability of the Electrochemically Regenerable Carbon Dioxide and Moisture Absorption Technology to the advanced extravehicular mobility unit was demonstrated by designing, fabricating, and testing a breadboard Absorber Module and an Electrochemical Regenerator. Test results indicated that the absorber module meets or exceeds the carbon dioxide removal requirements specified for the design and can meet the moisture removal requirement when proper cooling is provided. CO2 concentration in the vent gas stream was reduced from 0.52 to 0.027 kPa (3.9 to 0.20 mm Hg) for the full five hour test period. Vent gas dew point was reduced from inlet values of 294 K (69 F) to 278 K (41 F) at the outlet. The regeneration of expended absorbent was achieved by the electrochemical method employed in the testing. An absorbent bed using microporous hydrophobic membrane sheets with circulating absorbent is shown to be the best approach to the design of an Absorber Module based on sizing and performance. Absorber Module safety design, comparison of various absorbents and their characteristics, moisture absorption and cooling study and subsystem design and operation time-lining study were also performed.

Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives

NASA Astrophysics Data System (ADS)

War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

2017-02-01

The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues.

Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives.

PubMed

War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

2017-02-15

The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues. Copyright © 2016 Elsevier B.V. All rights reserved.

A proteomic screen reveals the mitochondrial outer membrane protein Mdm34p as an essential target of the F-box protein Mdm30p.

PubMed

Ota, Kazuhisa; Kito, Keiji; Okada, Satoshi; Ito, Takashi

2008-10-01

Ubiquitination plays various critical roles in eukaryotic cellular regulation and is mediated by a cascade of enzymes including ubiquitin protein ligase (E3). The Skp1-Cullin-F-box protein complex comprises the largest E3 family, in each member of which a unique F-box protein binds its targets to define substrate specificity. Although genome sequencing uncovers a growing number of F-box proteins, most of them have remained as "orphans" because of the difficulties in identification of their substrates. To address this issue, we tested a quantitative proteomic approach by combining the stable isotope labeling by amino acids in cell culture (SILAC), parallel affinity purification (PAP) that we had developed for efficient enrichment of ubiquitinated proteins, and mass spectrometry (MS). We applied this SILAC-PAP-MS approach to compare ubiquitinated proteins between yeast cells with and without over-expressed Mdm30p, an F-box protein implicated in mitochondrial morphology. Consequently, we identified the mitochondrial outer membrane protein Mdm34p as a target of Mdm30p. Furthermore, we found that mitochondrial defects induced by deletion of MDM30 are not only recapitulated by a mutant Mdm34p defective in interaction with Mdm30p but alleviated by ubiquitination-mimicking forms of Mdm34p. These results indicate that Mdm34p is a physiologically important target of Mdm30p.

Carrier envelope offset frequency detection and stabilization of a diode-pumped mode-locked Ti:sapphire laser.

PubMed

Gürel, Kutan; Wittwer, Valentin J; Hakobyan, Sargis; Schilt, Stéphane; Südmeyer, Thomas

2017-03-15

We demonstrate the first diode-pumped Ti:sapphire laser frequency comb. It is pumped by two green laser diodes with a total pump power of 3 W. The Ti:sapphire laser generates 250 mW of average output power in 61-fs pulses at a repetition rate of 216 MHz. We generated an octave-spanning supercontinuum spectrum in a photonic-crystal fiber and detected the carrier envelope offset (CEO) frequency in a standard f-to-2f interferometer setup. We stabilized the CEO-frequency through direct current modulation of one of the green pump diodes with a feedback bandwidth of 55 kHz limited by the pump diode driver used in this experiment. We achieved a reduction of the CEO phase noise power spectral density by 140 dB at 1 Hz offset frequency. An advantage of diode pumping is the ability for high-bandwidth modulation of the pump power via direct current modulation. After this experiment, we studied the modulation capabilities and noise properties of green pump laser diodes with improved driver electronics. The current-to-output-power modulation transfer function shows a bandwidth larger than 1 MHz, which should be sufficient to fully exploit the modulation bandwidth of the Ti:sapphire gain for CEO stabilization in future experiments.

The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway.

PubMed

Pinz, Sophia; Unser, Samy; Brueggemann, Susanne; Besl, Elisabeth; Al-Rifai, Nafisah; Petkes, Hermina; Amslinger, Sabine; Rascle, Anne

2014-01-01

Signal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for malignant transformation. We describe here the identification of the synthetic chalcone α-Br-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) as a novel JAK/STAT inhibitor. Using the non-transformed IL-3-dependent B cell line Ba/F3 and its oncogenic derivative Ba/F3-1*6 expressing constitutively activated STAT5, we show that α-Br-TMC targets the JAK/STAT pathway at multiple levels, inhibiting both JAK2 and STAT5 phosphorylation. Moreover, α-Br-TMC alters the mobility of STAT5A/B proteins in SDS-PAGE, indicating a change in their post-translational modification state. These alterations correlate with a decreased association of STAT5 and RNA polymerase II with STAT5 target genes in chromatin immunoprecipitation assays. Interestingly, expression of STAT5 target genes such as Cis and c-Myc was differentially regulated by α-Br-TMC in normal and cancer cells. While both genes were inhibited in IL-3-stimulated Ba/F3 cells, expression of the oncogene c-Myc was down-regulated and that of the tumor suppressor gene Cis was up-regulated in transformed Ba/F3-1*6 cells. The synthetic chalcone α-Br-TMC might therefore represent a promising novel anticancer agent for therapeutic intervention in STAT5-associated malignancies.

SGR9, a RING type E3 ligase, modulates amyloplast dynamics important for gravity sensing.

NASA Astrophysics Data System (ADS)

Morita, Miyo T.; Nakamura, Moritaka; Tasaka, Masao

Gravitropism is triggered when the directional change of gravity is sensed in the specific cells, called statocytes. In higher plants, statocytes contain sinking heavier amyloplasts which are particular plastids accumulating starch granules. The displacement of amyloplasts within the statocytes is thought to be the initial event of gravity perception. We have demonstrated that endodermal cells are most likely to be the statocytes in Arabidop-sis shoots. Live cell imaging of the endodermal cell of stem has shown that most amyloplasts are sediment to the direction of gravity but they are not static. Several amyloplasts move dynamically in an actin filament (F-actin) dependent manner. In the presence of actin poly-merization inhibitor, all amyloplasts become static and sediment to the direction of gravity. In addition, stems treated with the inhibitor can exhibit gravitropism. These results suggest that F-actin-dependent dynamic movement of amyloplasts is not essential for gravity sensing. sgr (shoot gravitropism) 9 mutant exhibits greatly reduced shoot gravitropism. In endodermal cells of sgr9, dynamic amyloplast movement was predominantly observed and amyloplasts did not sediment to the direction of gravity. Interestingly, inhibition of actin polymerization re-stored both gravitropism and amyloplast sedimentation in sgr9. The SGR9 encodes a novel RING finger protein, which is localized to amyloplasts in endodermal cells. SGR9 showed ubiq-uitin E3 ligase activity in vitro. Together with live cell imaging of amyloplasts and F-actin, our data suggest that SGR9 modulate interaction between amyloplasts and F-actin on amylo-plasts. SGR9 positively act on amyloplasts sedimentation, probably by releasing amyloplasts from F-actin. SGR9 that is localized to amyloplast, possibly degrades unknown substrates by its E3 ligase activity, and this might promote release of amyloplasts from F-actin.

Processing of targets in smooth or apparent motion along the vertical in the human brain: an fMRI study.

PubMed

Maffei, Vincenzo; Macaluso, Emiliano; Indovina, Iole; Orban, Guy; Lacquaniti, Francesco

2010-01-01

Neural substrates for processing constant speed visual motion have been extensively studied. Less is known about the brain activity patterns when the target speed changes continuously, for instance under the influence of gravity. Using functional MRI (fMRI), here we compared brain responses to accelerating/decelerating targets with the responses to constant speed targets. The target could move along the vertical under gravity (1g), under reversed gravity (-1g), or at constant speed (0g). In the first experiment, subjects observed targets moving in smooth motion and responded to a GO signal delivered at a random time after target arrival. As expected, we found that the timing of the motor responses did not depend significantly on the specific motion law. Therefore brain activity in the contrast between different motion laws was not related to motor timing responses. Average BOLD signals were significantly greater for 1g targets than either 0g or -1g targets in a distributed network including bilateral insulae, left lingual gyrus, and brain stem. Moreover, in these regions, the mean activity decreased monotonically from 1g to 0g and to -1g. In the second experiment, subjects intercepted 1g, 0g, and -1g targets either in smooth motion (RM) or in long-range apparent motion (LAM). We found that the sites in the right insula and left lingual gyrus, which were selectively engaged by 1g targets in the first experiment, were also significantly more active during 1g trials than during -1g trials both in RM and LAM. The activity in 0g trials was again intermediate between that in 1g trials and that in -1g trials. Therefore in these regions the global activity modulation with the law of vertical motion appears to hold for both RM and LAM. Instead, a region in the inferior parietal lobule showed a preference for visual gravitational motion only in LAM but not RM.

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

PubMed Central

Salem, Heba F; Ahmed, Sayed M; Hassaballah, Ashraf E; Omar, Mahmoud M

2015-01-01

Background The blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain. Methods Glutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency. Results The size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than −65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824. Conclusion Overall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new therapeutic option for the treatment of the brain infections. PMID:26229435

Short-term selection for high and low ethanol intake yields differential sensitivity to ethanol's motivational effects and anxiety-like responses in adolescent Wistar rats.

PubMed

Fernández, Macarena Soledad; Báez, Bárbara; Bordón, Ana; Espinosa, Laura; Martínez, Eliana; Pautassi, Ricardo Marcos

2017-10-03

Alcohol use disorders are modulated by genetic factors, but the identification of specific genes and their concomitant biological changes that are associated with a higher risk for these disorders has proven difficult. Alterations in the sensitivity to the motivational effects of ethanol may be one way by which genes modulate the initiation and escalation of ethanol intake. Rats and mice have been selectively bred for high and low ethanol consumption during adulthood. However, selective breeding programs for ethanol intake have not focused on adolescence. This phase of development is associated with the initiation and escalation of ethanol intake and characterized by an increase in the sensitivity to ethanol's appetitive effects and a decrease in the sensitivity to ethanol's aversive effects compared with adulthood. The present study performed short-term behavioral selection to select rat lines that diverge in the expression of ethanol drinking during adolescence. A progenitor nucleus of Wistar rats (F 0 ) and filial generation 1 (F 1 ), F 2 , and F 3 adolescent rats were derived from parents that were selected for high (STDRHI) and low (STDRLO) ethanol consumption during adolescence and were tested for ethanol intake and responsivity to ethanol's motivational effects. STDRHI rats exhibited significantly greater ethanol intake and preference than STDRLO rats. Compared with STDRLO rats, STDRHI F 2 and F 3 rats exhibited a blunted response to ethanol in the conditioned taste aversion test. F 2 and F 3 STDRHI rats but not STDRLO rats exhibited ethanol-induced motor stimulation. STDRHI rats exhibited avoidance of the white compartment of the light-dark box, a reduction of locomotion, and a reduction of saccharin consumption, suggesting an anxiety-prone phenotype. The results suggest that the genetic risk for enhanced ethanol intake during adolescence is associated with lower sensitivity to the aversive effects of ethanol, heightened reactivity to ethanol's stimulating effects, and enhanced innate anxiety. Copyright © 2017 Elsevier Inc. All rights reserved.

High-bandwidth scanned-wavelength-modulation spectroscopy sensors for temperature and H2O in a rotating detonation engine

NASA Astrophysics Data System (ADS)

Goldenstein, Christopher S.; Almodóvar, Christopher A.; Jeffries, Jay B.; Hanson, Ronald K.; Brophy, Christopher M.

2014-10-01

The design and use of two-color tunable diode laser (TDL) absorption sensors for measurements of temperature and H2O in a rotating detonation engine (RDE) are presented. Both sensors used first-harmonic-normalized scanned-wavelength-modulation spectroscopy with second-harmonic detection (scanned-WMS-2f/1f) to account for non-absorbing transmission losses and emission encountered in the harsh combustion environment. One sensor used two near-infrared (NIR) TDLs near 1391.7 nm and 1469.3 nm that were modulated at 225 kHz and 285 kHz, respectively, and sinusoidally scanned across the peak of their respective H2O absorption transitions to provide a measurement rate of 50 kHz and a detection limit in the RDE of 0.2% H2O by mole. The other sensor used two mid-infrared (MIR) TDLs near 2551 nm and 2482 nm that were modulated at 90 kHz and 112 kHz, respectively, and sinusoidally scanned across the peak of their respective H2O transitions to provide a measurement rate of 10 kHz and a detection limit in the RDE of 0.02% H2O by mole. Four H2O absorption transitions with different lower-state energies were used to assess the homogeneity of temperature in the measurement plane. Experimentally derived spectroscopic parameters that enable temperature and H2O sensing to within 1.5-3.5% of known values are reported. The sensor design enabling the high-bandwidth scanned-WMS-2f/1f measurements is presented. The two sensors were deployed across two orthogonal and coplanar lines-of-sight (LOS) located in the throat of a converging-diverging nozzle at the RDE combustor exit. Measurements in the non-premixed H2-fueled RDE indicate that the temperature and H2O oscillate at the detonation frequency (≈3.25 kHz) and that production of H2O is a weak function of global equivalence ratio.

Processes of interaction of laser radiation with porous transparent materials during their ablation

NASA Astrophysics Data System (ADS)

Osipov, V. V.; Lisenkov, V. V.; Platonov, V. V.; Tikhonov, E. V.

2018-03-01

The effect of ytterbium fibre laser radiation with λ = 1.07 μm on the pressed micropowders of transparent oxides and fluorides (CaF2, Y2O3, Al2O3, YSZ, etc.) having low absorption coefficients is theoretically studied. Using the numerical modelling, it is established that the radiation scattering in the medium of particles 0.5–4.6 μm in diameter leads to the concentration of radiation in the local regions of the medium, with the intensity level exceeding the intensity of the incident radiation (0.46 MW cm-2) by many times. It is shown that with the growth of the refractive index n of the material from 1.38 (MgF2) to 2.12 (YSZ) the intensity of radiation in the region of the strongest local maximum increases from 3.8 to 31 MW cm-2. In our opinion, this factor can be dominant in determining the possibility of achieving the ablation of such a medium by means of the radiation having an intensity of no greater than 1 MW cm-2. This hypothesis is experimentally checked by the example of preparing a nanopowder of CaF2 (n = 1.43) and 1% Nd : Y2O3 (n = 1.91) by evaporating the pressed target with the porosity 50% by the continuous-wave radiation of the ytterbium fibre laser with the power 600 W and the intensity 0.4 MW cm-2. Inside the CaF2 target, the scattered radiation intensity is smaller than the optical breakdown threshold, and the target is not evaporated. Under the same conditions, the target made of higher-melting 1% Nd : Y2O3 evaporates well, and the efficiency of the nanopowder production amounts to 23 g h-1.

SU-F-T-349: Dosimetric Comparison of Three Different Simultaneous Integrated Boost Irradiation Techniques for Multiple Brain Metastases: Intensity-Modulatedradiotherapy, Hybrid Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy

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

Lin, X; Sun, T; Yin, Y

Purpose: To study the dosimetric impact of intensity-modulated radiotherapy (IMRT), hybrid intensity-modulated radiotherapy (h-IMRT) and volumetric modulated arc therapy(VMAT) for whole-brain radiotherapy (WBRT) with simultaneous integrated boost in patients with multiple brain metastases. Methods: Ten patients with multiple brain metastases were included in this analysis. The prescribed dose was 45 Gy to the whole brain (PTVWBRT) and 55 Gy to individual brain metastases (PTVboost) delivered simultaneously in 25 fractions. Three treatment techniques were designed: the 7 equal spaced fields IMRT plan, hybrid IMRT plan and VMAT with two 358°arcs. In hybrid IMRT plan, two fields(90°and 270°) were planned to themore » whole brain. This was used as a base dose plan. Then 5 fields IMRT plan was optimized based on the two fields plan. The dose distribution in the target, the dose to the organs at risk and total MU in three techniques were compared. Results: For the target dose, conformity and homogeneity in PTV, no statistically differences were observed in the three techniques. For the maximum dose in bilateral lens and the mean dose in bilateral eyes, IMRT and h-IMRT plans showed the highest and lowest value respectively. No statistically significant differences were observed in the dose of optic nerve and brainstem. For the monitor units, IMRT and VMAT plans showed the highest and lowest value respectively. Conclusion: For WBRT with simultaneous integrated boost in patients with multiple brain metastases, hybrid IMRT could reduce the doses to lens and eyes. It is feasible for patients with brain metastases.« less

Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis

PubMed Central

Rady, Brian; Chen, Yanmei; Vaca, Pilar; Wang, Qian; Wang, Yong; Salmon, Patrick; Oberholzer, José

2013-01-01

The mechanisms that control proliferation, or lack thereof, in adult human β cells are poorly understood. Controlled induction of proliferation could dramatically expand the clinical application of islet cell transplantation and represents an important component of regenerative approaches to a functional cure of diabetes. Adult human β cells are particularly resistant to common proliferative targets and often dedifferentiate during proliferation. Here we show that expression of the transcription factor E2F3 has a role in regulating β-cell quiescence and proliferation. We found human islets have virtually no expression of the pro-proliferative G1/S transcription factors E2F1–3, but an abundance of inhibitory E2Fs 4–6. In proliferative human insulinomas, inhibitory E2Fs were absent, while E2F3 is expressed. Using this pattern as a “roadmap” for proliferation, we demonstrated that ectopic expression of nuclear E2F3 induced significant expansion of insulin-positive cells in both rat and human islets. These cells did not undergo apoptosis and retained their glucose-responsive insulin secretion, showing the ability to reverse diabetes in mice. Our results suggest that E2F4–6 may help maintain quiescence in human β cells and identify E2F3 as a novel target to induce proliferation of functional β cells. Refinement of this approach may increase the islets available for cell-based therapies and research and could provide important cues for understanding in vivo proliferation of β cells. PMID:23907129

Optimizing cardiovascular gene therapy: increased vascular gene transfer with modified adenoviral vectors.

PubMed

Kibbe, M R; Murdock, A; Wickham, T; Lizonova, A; Kovesdi, I; Nie, S; Shears, L; Billiar, T R; Tzeng, E

2000-02-01

Adenovirus is widely used as a vector for gene transfer to the vasculature. However, the efficiency of these vectors can be limited by ineffective viral-target cell interactions. Viral attachment, which largely determines adenoviral tropism, is mediated through binding of the adenoviral fiber coat protein to the Coxsackievirus and adenovirus receptor, while internalization follows binding of the adenoviral RGD motif to alpha(v)-integrin receptors. Modifications of the fiber coat protein sequence have been successful for targeting the adenovirus to more prevalent receptors in the vasculature, including heparan sulfate-containing receptors and alpha(v)-integrin receptors. Modified adenoviral vectors targeted to receptors more prevalent in the vasculature result in an increased transfer efficiency of the virus in vitro and in vivo even in the presence of clinically relevant doses of heparin. We tested 2 modified E1- and E3-deleted Ad5 type adenoviral vectors containing the beta-galactosidase gene. AdZ.F(pK7) contains multiple positively charged lysines in the fiber coat protein that target the adenovirus to heparan sulfate receptors, while AdZ.F(RGD) contains an RGD integrin-binding sequence in the fiber coat protein that allows binding to alpha(v)-integrin receptors. The gene transfer efficiency of these modified viruses was compared in rat aortic smooth muscle cells in vitro and in an in vivo porcine model of balloon-induced arterial injury. Because of the use of heparin during most vascular surgical procedures and the concern that heparin might interfere with the binding of AdZ.F(pK7) to heparan sulfate receptors, the effect of heparin on the in vitro and in vivo transfer efficiency of these 2 modified adenoviruses was evaluated. In vitro infection of rat aortic smooth muscle cells with AdZ.F(pK7) and AdZ.F(RGD) resulted in significantly higher levels of beta-galactosidase expression compared with the unmodified adenovirus (mean +/- SEM, 1766.3 +/- 89.1 and 44.8 +/- 3.4 vs 10.1 +/- 0.7 mU per milligram of protein; P<.001). Following heparin administration, the gene transfer efficiency achieved with AdZ.F(pK7) diminished slightly in a concentration-dependent manner. However, the transfer efficiency was still greater than with the unmodified virus (mean +/- SEM, 1342.3 +/- 101.8 vs 4.8 +/- 0.4 mU per milligram of protein; P<.001). In vivo, following injury to the pig iliac artery with a 4F Fogarty balloon catheter, we found that AdZ.F(pK7) transduced the artery approximately 35-fold more efficiently than AdZ.F and 3-fold more efficiently than AdZ.F(RGD) following the administration of intravenous heparin, 100 U/kg body weight, and heparinized saline irrigation. Modifications of the adenovirus that lead to receptor targeting resulted in significantly improved gene transfer efficiencies. These improvements in transfer efficiencies observed with the modified vectors decreased slightly in the presence of heparin. However, AdZ.F(pK7) was still superior to AdZ.F(RGD) and AdZ.F despite heparin administration. These data demonstrate that modifications of adenoviral vectors that enhance binding to heparan sulfate receptors significantly improve gene transfer efficiency even in the presence of heparin and suggest an approach to optimize gene transfer into blood vessels.

Non-invasive identification of stable rotors and focal sources for human atrial fibrillation: mechanistic classification of atrial fibrillation from the electrocardiogram.

PubMed

Jones, Aled R; Krummen, David E; Narayan, Sanjiv M

2013-09-01

To develop electrocardiogram (ECG) tools to quantify the number of sources for atrial fibrillation (AF), i.e. spatially stable rotors and focal impulses, and whether they lie in right or left atrium. Intracardiac mapping has recently shown that paroxysmal and persistent AF is sustained by rotors or focal sources that are stable in location and thus targets for limited ablation [focal impulse and rotor modulation (FIRM)] to eliminate AF. Importantly, the numbers and locations of concurrent sources determine both the complexity of AF and the approach for ablation. In 36 AF patients (n = 29 persistent, 63 ± 9 years) in the CONventional ablation with or without Focal Impulse and Rotor Modulation (CONFIRM) trial, we developed phase lock (PL) to quantify spatial repeatability of ECG 'F-waves' between leads over time. Phase lock spectrally quantifies the angle θ between F-wave voltages in planes formed by ECG leads I, aVF, and V1 at successive points in time. We compared PL with ECG spectral dominant frequency (DF) and organizational index (OI) to characterize stable rotors and focal sources validated by intracardiac FIRM mapping. Focal impulse and rotor modulation ablation alone at ≤3 sources acutely terminated and rendered AF non-inducible or substantially slowed AF in 31 of 36 patients. Receiver operating characteristics of PL for this endpoint had area under the curve (AUC) = 0.72, and the optimum cut-point (PL = 0.09) had 74% sensitivity, 92% positive predictive value (PPV). Receiver operating characteristics areas for OI and DF were 0.50 and 0.58, respectively. Left (n = 28) or right (n = 3) atrial sources were localized by PL with AUC = 0.85, sensitivity 100%, PPV 30%, and negative predictive value 100%. Spectral DF provided AUC = 0.79. Notably, PL did not comigrate with diagnosis of paroxysmal or persistent AF (P = NS), unlike ECG DF. The novel metric of ECG PL identifies patients with fewer (≤3) or greater numbers of stable rotors/focal sources for AF, validated by intracardiac FIRM mapping, and localized them to right or left atria. These data open the possibility of using 12-lead ECG analyses to classify AF mechanistically and plan procedures for right- or left-sided FIRM ablation.

[18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes.

PubMed

Würschmidt, Florian; Petersen, Cordula; Wahl, Andreas; Dahle, Jörg; Kretschmer, Matthias

2011-05-01

At present there is no consensus on irradiation treatment volumes for intermediate to high-risk primary cancers or recurrent disease. Conventional imaging modalities, such as CT, MRI and transrectal ultrasound, are considered suboptimal for treatment decisions. Choline-PET/CT might be considered as the imaging modality in radiooncology to select and delineate clinical target volumes extending the prostate gland or prostate fossa. In conjunction with intensity modulated radiotherapy (IMRT) and imaged guided radiotherapy (IGRT), it might offer the opportunity of dose escalation to selected sites while avoiding unnecessary irradiation of healthy tissues. Twenty-six patients with primary (n = 7) or recurrent (n = 19) prostate cancer received Choline-PET/CT planned 3D conformal or intensity modulated radiotherapy. The median age of the patients was 65 yrs (range 45 to 78 yrs). PET/CT-scans with F18-fluoroethylcholine (FEC) were performed on a combined PET/CT-scanner equipped for radiation therapy planning. The majority of patients had intermediate to high risk prostate cancer. All patients received 3D conformal or intensity modulated and imaged guided radiotherapy with megavoltage cone beam CT. The median dose to primary tumours was 75.6 Gy and to FEC-positive recurrent lymph nodal sites 66,6 Gy. The median follow-up time was 28.8 months. The mean SUV(max) in primary cancer was 5,97 in the prostate gland and 3,2 in pelvic lymph nodes. Patients with recurrent cancer had a mean SUV(max) of 4,38. Two patients had negative PET/CT scans. At 28 months the overall survival rate is 94%. Biochemical relapse free survival is 83% for primary cancer and 49% for recurrent tumours. Distant disease free survival is 100% and 75% for primary and recurrent cancer, respectively. Acute normal tissue toxicity was mild in 85% and moderate (grade 2) in 15%. No or mild late side effects were observed in the majority of patients (84%). One patient had a severe bladder shrinkage (grade 4) after a previous treatment with TUR of the prostate and seed implantation. FEC-PET/CT planning could be helpful in dose escalation to lymph nodal sites of prostate cancer.

Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling.

PubMed

Fetoni, A R; Paciello, F; Mezzogori, D; Rolesi, R; Eramo, S L M; Paludetti, G; Troiani, D

2015-11-17

In oncology, an emerging paradigm emphasises molecularly targeted approaches for cancer prevention and therapy and the use of adjuvant chemotherapeutics to overcome cisplatin limitations. Owing to their safe use, some polyphenols, such as curcumin, modulate important pathways or molecular targets in cancers. This paper focuses on curcumin as an adjuvant molecule to cisplatin by analysing its potential implications on the molecular targets, signal transducer and activator of transcription 3 (STAT3) and NF-E2 p45-related factor 2 (Nrf-2), in tumour progression and cisplatin resistance in vitro and the adverse effect ototoxicity in vivo. The effects of curcumin and/or cisplatin treatment have been evaluated in head and neck squamous cell carcinoma as well as in a rat model of cisplatin-induced ototoxicity by using immunofluorescence, western blot, and functional and morphological analysis. This study demonstrates that curcumin attenuates all stages of tumour progression (survival, proliferation) and, by targeting pSTAT3 and Nrf-2 signalling pathways, provides chemosensitisation to cisplatin in vitro and protection from its ototoxic adverse effects in vivo. These results indicate that curcumin can be used as an efficient adjuvant to cisplatin cancer therapy. This treatment strategy in head and neck cancer could mediate cisplatin chemoresistance by modulating therapeutic targets (STAT3 and Nrf2) and, at the same time, reduce cisplatin-related ototoxic adverse effects.

Scientific and Engineering Studies, Compiled 1989. Signal Processing Studies

DTIC Science & Technology

1989-01-01

Version W(t,f) . . . . . .......... 25 3 W(t,f) for Real Waveform s(t) ............... 25 4 Contour of WDF (72) at l/e Relative Level . . . . . . . . . 30...spectral level , (189) B Passband of filter H, figure 8 Duration of weighting v, figure 8 LFM Linear Frequency Modulation sgn(x) 1 for x > 0, -1 for x...figure 4. the area of thl parir( Iua level ellipse is 1/2 In the t.f Vifne Wher this area i *, rlt IVe! bl ty e peak height of ?[, the product Is . *ýich

Search time critically depends on irrelevant subset size in visual search.

PubMed

Benjamins, Jeroen S; Hooge, Ignace T C; van Elst, Jacco C; Wertheim, Alexander H; Verstraten, Frans A J

2009-02-01

In order for our visual system to deal with the massive amount of sensory input, some of this input is discarded, while other parts are processed [Wolfe, J. M. (1994). Guided search 2.0: a revised model of visual search. Psychonomic Bulletin and Review, 1, 202-238]. From the visual search literature it is unclear how well one set of items can be selected that differs in only one feature from target (a 1F set), while another set of items can be ignored that differs in two features from target (a 2F set). We systematically varied the percentage of 2F non-targets to determine the contribution of these non-targets to search behaviour. Increasing the percentage 2F non-targets, that have to be ignored, was expected to result in increasingly faster search, since it decreases the size of 1F set that has to be searched. Observers searched large displays for a target in the 1F set with a variable percentage of 2F non-targets. Interestingly, when the search displays contained 5% 2F non-targets, the search time was longer compared to the search time in other conditions. This effect of 2F non-targets on performance was independent of set size. An inspection of the saccades revealed that saccade target selection did not contribute to the longer search times in displays with 5% 2F non-targets. Occurrence of longer search times in displays containing 5% 2F non-targets might be attributed to covert processes related to visual analysis of the fixated part of the display. Apparently, visual search performance critically depends on the percentage of irrelevant 2F non-targets.

LASER APPLICATIONS AND OTHER TOPICS IN QUANTUM ELECTRONICS: Picosecond laser with active mode locking and calcium lithium niobium gallium disordered Nd3+-activated garnet

NASA Astrophysics Data System (ADS)

Basiev, Tasoltan T.; Grudinin, A. B.; Karasik, Aleksandr Ya; Senatorov, A. K.; Sobol, A. A.; Fedorov, V. V.; Shubochkin, R. L.

1994-01-01

A laser was constructed in which the active medium was a crystal of calcium lithium niobium gallium garnet activated with Nd3+ ions. An acoustooptic modulator made of an LiNbO3 crystal and a passive LiF switch with F2 colour centres were used in this laser. The combination of active mode locking and Q switching made it possible to generate laser pulses of 10-15 ps duration at the wavelength λ = 1061.2 nm with a peak power of about 15 MW.

Development of Liquid Crystal Spatial Light Modulators for mid-IR Radiation, Addressed by Visible Radiation

DTIC Science & Technology

2002-10-01

POTENTIAL ENERGY DISTRIBUTION, % Further tables contain the frequencies of the most intense oscillations and the impact to the potential energy of atoms...0.96 µm diode pumping) 2F5/2 2F7/2 3H4 -23- In the Fig.3.1 is shown the working scheme of the active medium Yb- Pr:YLF(BYF). Energy , absorbed by... absorbed energy – 1 J, laser transition cross-section – σ = 2x10-21 cm2 [17]. Fig.3.4. Dependence of gain increment (kL) upon ytterbium concentration in

Radio Frequency Magneto-Optical Trapping of CaF with High Density.

PubMed

Anderegg, Loïc; Augenbraun, Benjamin L; Chae, Eunmi; Hemmerling, Boerge; Hutzler, Nicholas R; Ravi, Aakash; Collopy, Alejandra; Ye, Jun; Ketterle, Wolfgang; Doyle, John M

2017-09-08

We demonstrate significantly improved magneto-optical trapping of molecules using a very slow cryogenic beam source and either rf modulated or dc magnetic fields. The rf magneto-optical trap (MOT) confines 1.0(3)×10^{5} CaF molecules at a density of 7(3)×10^{6}  cm^{-3}, which is an order of magnitude greater than previous molecular MOTs. Near Doppler-limited temperatures of 340(20)  μK are attained. The achieved density enables future work to directly load optical tweezers and create optical arrays for quantum simulation.

A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT)

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

Ding, Xuanfeng; Dionisi, Francesco; Tang, Shikui

With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as wellmore » as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients’ average CT. All the plans delivered 50.4 Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V{sub 18} {sub Gy}), stomach (mean and V{sub 20} {sub Gy}), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V{sub 18} {sub Gy}), liver (mean dose), total bowel (V{sub 20} {sub Gy} and mean dose), and small bowel (V{sub 15} {sub Gy} absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose escalation and combining with radiosensitizing chemotherapy.« less

Desflurane usage during anesthesia with and without N2O using FLOW-i Automatic Gas Control with three different wash-in speeds.

PubMed

De Medts, Robrecht; Carette, Rik; De Wolf, Andre M; Hendrickx, Jan F A

2017-06-09

AGC ® (Automatic Gas Control) is the FLOW-i's automated low flow tool (Maquet, Solna, Sweden) that target controls the inspired O 2 (F I O 2 ) and end-expired desflurane concentration (F A des) while (by design) exponentially decreasing fresh gas flow (FGF) during wash-in to a maintenance default FGF of 300 mL min -1 . It also offers a choice of wash-in speeds for the inhaled agents. We examined AGC performance and hypothesized that the use of lower wash-in speeds and N 2 O both reduce desflurane usage (Vdes). After obtaining IRB approval and patient consent, 78 ASA I-II patients undergoing abdominal surgery were randomly assigned to 1 of 6 groups (n = 13 each), depending on carrier gas (O 2 /air or O 2 /N 2 O) and wash-in speed (AGC speed 2, 4, or 6) of desflurane, resulting in groups air/2, air/4, air/6, N 2 O/2, N 2 O/4, and N 2 O/6. The target for F I O 2 was set at 35%, while the F A des target was selected so that the AGC displayed 1.3 MAC (corrected for the additive affect of N 2 O if used). AGC was activated upon starting mechanical ventilation. Varvel's criteria were used to describe performance of achieving the targets. Patient demographics, end-expired N 2 O concentration, MAC, FGF, and Vdes were compared using ANOVA. Data are presented as mean ± standard deviation, except for Varvel's criteria (median ± quartiles). Patient demographics did not differ among the groups. Median performance error was -2-0% for F I O 2 and -3-1% for F A des; median absolute performance error was 1-2% for F I O 2 and 0-3% for F A des. MAC increased faster in N 2 O groups, but total MAC decreased 0.1-0.25 MAC below that in the O 2 /air groups after 60 min. The effect of wash-in speed on Vdes faded over time. N 2 O decreased Vdes by 62%. AGC performance for O 2 and desflurane targeting is excellent. After 1 h, the wash-in speeds tested are unlikely to affect desflurane usage. N 2 O usage decreases Vdes proportionally with its reduction in F A tdes.

Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium

PubMed Central

Shuvaev, Vladimir V.; Christofidou-Solomidou, Melpo; Scherpereel, Arnaud; Simone, Eric; Arguiri, Evguenia; Tliba, Samira; Pick, Jeremy; Kennel, Stephen; Albelda, Steven M.; Muzykantov, Vladimir R.

2007-01-01

Vascular drug targeting may improve therapies, yet a thorough understanding of the factors that regulate effects of drugs directed to the endothelium is needed to translate this approach into the clinical domain. To define factors modulating the efficacy and effects of endothelial targeting, we used a model enzyme (glucose oxidase, GOX) coupled with monoclonal antibodies (anti-TM34 or anti-TM201) to distinct epitopes of thrombomodulin, a surface determinant enriched in the pulmonary endothelium. GOX delivery results in conversion of glucose and oxygen into H2O2 leading to lung damage, a clear physiologic endpoint. Results of in vivo studies in mice showed that the efficiency of cargo delivery and its effect are influenced by a number of factors including: 1) The level of pulmonary uptake of the targeting antibody (anti-TM201 was more efficient than anti-TM34); 2) The amount of an active drug delivered to the target; 3) The amount of target antigen on the endothelium (animals with suppressed TM levels showed less targeting); and, 4) The substrate availability for the enzyme cargo in the target tissue (hyperoxia augmented GOX-induced injury). Therefore, both activity of the conjugates and biological factors control targeting and effects of enzymatic cargo. Understanding the nature of such “modulating biological factors” will hopefully allow optimization and ultimately applications of drug targeting for “individualized” pharmacotherapy. PMID:17270308

Taking "The Math You Need When You Need It" Modules Beyond Introductory Geology Courses

NASA Astrophysics Data System (ADS)

Baer, E. M.; Wenner, J. M.; Burn, H. E.

2012-12-01

"The Math You Need, When You Need It" (TMYN) modules are finding use well beyond the courses for which they were originally written. However, faculty survey responses indicate that the modules are used in similar ways, suggesting that the overall design of the modules is effective. TMYN modules are online resources designed to help students develop quantitative skills in conjunction with introductory geology courses. Since 2010, 29 faculty members at 26 institutions used these asynchronous resources at in 68 different courses nationwide, impacting about 3000 students. After each use of the modules, instructors responded to a survey about their use of the modules and the impact on each course and student cohort. Of the 29 instructors, 16 responded with a total of 36 implementations, a 52% response rate. Survey responses indicate use of TMYN modules in classes well beyond their original design. The modules were originally designed for students in introductory geology classes, especially those targeted at non-geoscience majors. Sixty-nine percent (22/32) of TMYN courses included introductory geology courses such as Physical Geology, Earth System Science and Environmental Geology. The remainder of courses included multiple uses in oceanography and meteorology courses and more specialized geoscience courses such as geomorphology, structural geology and hydrology. Surveys suggest that only 63% of courses that used TMYN (20/32) were targeted to students in general education courses. Nine percent (3/32) of courses were targeted to STEM majors and 19% (6/32) were specifically targeted to geoscience majors, including upper-level courses. Despite the wide variety of institutions, instructors, classes, and student educational goals, faculty incorporated the modules into their curriculum in as originally designed, indicating that the overall design of the modules is effective. Twenty-two respondents indicate that modules were assigned immediately prior to using a skill in the classroom (either in lab exercises or a lecture period). Almost all instructors employed pre- and posttests to gauge learning. More than ¾ of survey respondents introduced the modules within the first week of class. In all but one instance, students were instructed to complete an online quiz immediately after working through the online modules and most (77%) designed these post-module quizzes as formative assessments allowing at least 3 attempts. The grades on these modules contributed to students' grades but were relatively low stakes with 88% reporting that the modules contributed to less than 10% of a student's course grade. Given the use beyond the introductory geology classroom and the similarity of the use of these modules in a wide variety of courses, it appears that the design of the modules is sound. However, previous studies have indicated that mathematical skills are not easily transferred (e.g. Bassok. and Holyoak, 1989) suggesting the adaptation of the modules for use outside the geosciences.

High-sensitivity in situ QCLAS-based ammonia concentration sensor for high-temperature applications

NASA Astrophysics Data System (ADS)

Peng, W. Y.; Sur, R.; Strand, C. L.; Spearrin, R. M.; Jeffries, J. B.; Hanson, R. K.

2016-07-01

A novel quantum cascade laser (QCL) absorption sensor is presented for high-sensitivity in situ measurements of ammonia (hbox {NH}_3) in high-temperature environments, using scanned wavelength modulation spectroscopy (WMS) with first-harmonic-normalized second-harmonic detection (scanned WMS-2 f/1 f) to neutralize the effect of non-absorption losses in the harsh environment. The sensor utilized the sQ(9,9) transition of the fundamental symmetric stretch band of hbox {NH}_3 at 10.39 {\\upmu }hbox {m} and was sinusoidally modulated at 10 kHz and scanned across the peak of the absorption feature at 50 Hz, leading to a detection bandwidth of 100 Hz. A novel technique was used to select an optimal WMS modulation depth parameter that reduced the sensor's sensitivity to spectral interference from hbox {H}_2hbox {O} and hbox {CO}_2 without significantly sacrificing signal-to-noise ratio. The sensor performance was validated by measuring known concentrations of hbox {NH}_3 in a flowing gas cell. The sensor was then demonstrated in a laboratory-scale methane-air burner seeded with hbox {NH}_3, achieving a demonstrated detection limit of 2.8 ± 0.26 ppm hbox {NH}_3 by mole at a path length of 179 cm, equivalence ratio of 0.6, pressure of 1 atm, and temperatures of up to 600 K.

Modulated-alignment dual-axis (MAD) confocal microscopy for deep optical sectioning in tissues

PubMed Central

Leigh, Steven Y.; Chen, Ye; Liu, Jonathan T.C.

2014-01-01

A strategy is presented to enable optical-sectioning microscopy with improved contrast and imaging depth using low-power (0.5 - 1 mW) diode laser illumination. This technology combines the inherent strengths of focal-modulation microscopy and dual-axis confocal (DAC) microscopy for rejecting out-of-focus and multiply scattered background light in tissues. The DAC architecture is unique in that it utilizes an intersecting pair of illumination and collection beams to improve the spatial-filtering and optical-sectioning performance of confocal microscopy while focal modulation selectively ‘labels’ in-focus signals via amplitude modulation. Simulations indicate that modulating the spatial alignment of dual-axis beams at a frequency f generates signals from the focal volume of the microscope that are modulated at 2f with minimal modulation of background signals, thus providing nearly an order-of-magnitude improvement in optical-sectioning contrast compared to DAC microscopy alone. Experiments show that 2f lock-in detection enhances contrast and imaging depth within scattering phantoms and fresh tissues. PMID:24940534

SU-F-T-648: Sharpening Dose Fall-Off Via Beam Number Enhancements For Stereotactic Brain Radiosurgery

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

Chiu, J; Braunstein, S; McDermott, M

Purpose: Sharp dose fall-off is the hallmark of brain radiosurgery to deliver a high dose of radiation to the target while minimizing dose to normal brain tissue. In this study, we developed a technique for the purpose of enhancing the peripheral dose gradient by magnifying the total number of beams focused toward each isocenter via patient head tilt and simultaneous beam intensity modulations. Methods: Computer scripting for the proposed beam number enhancement (BNE) technique was developed. The technique was tested and then implemented on a clinical treatment planning system for a dedicated brain radiosurgical system (GK Perfexion, Elekta Oncology). Tomore » study technical feasibility and dosimetric advantages of the technique, we compared treatment planning quality and delivery efficiency for 20 radiosurgical cases previously treated at our institution. These cases included relatively complex treatments such as acoustic schwannoma, meningioma, brain metastasis and mesial temporal lobe epilepsy. Results: The BNE treatment plans were found to produce nearly identical target volume coverage (absolute value < 0.5%, P > 0.2) and dose conformity (BNE CI= 1.41±0.15 versus 1.41±0.20, P>0.9) as the original treatment plans. The total beam-on time for theBNE treatment plans were comparable (within 1.0 min or 1.8%) with those of the original treatment plans for all the cases. However, BNE treatment plans significantly improved the mean gradient index (BNE GI = 2.9±0.3 versus original GI =3.0±0.3 p<0.0001) and low-level isodose volumes, e.g. 20-50% prescribed isodose volumes, by 2.0% to 5.0% (p<0.02). Furthermore, with 4 to 5-fold increase in the total number of beams, the GI decreased by as much as 20% or 0.5 in absolute values. Conclusion: BNE via head tilt and simultaneous beam intensity modulation is an effective and efficient technique that physically sharpens the peripheral dose gradient for brain radiosurgery.« less

Working memory load-dependent spatio-temporal activity of single-trial P3 response detected with an adaptive wavelet denoiser.

PubMed

Zhang, Qiushi; Yang, Xueqian; Yao, Li; Zhao, Xiaojie

2017-03-27

Working memory (WM) refers to the holding and manipulation of information during cognitive tasks. Its underlying neural mechanisms have been explored through both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Trial-by-trial coupling of simultaneously collected EEG and fMRI signals has become an important and promising approach to study the spatio-temporal dynamics of such cognitive processes. Previous studies have demonstrated a modulation effect of the WM load on both the BOLD response in certain brain areas and the amplitude of P3. However, much remains to be explored regarding the WM load-dependent relationship between the amplitude of ERP components and cortical activities, and the low signal-to-noise ratio (SNR) of the EEG signal still poses a challenge to performing single-trial analyses. In this paper, we investigated the spatio-temporal activities of P3 during an n-back verbal WM task by introducing an adaptive wavelet denoiser into the extraction of single-trial P3 features and using general linear model (GLM) to integrate simultaneously collected EEG and fMRI data. Our results replicated the modulation effect of the WM load on the P3 amplitude. Additionally, the activation of single-trial P3 amplitudes was detected in multiple brain regions, including the insula, the cuneus, the lingual gyrus (LG), and the middle occipital gyrus (MOG). Moreover, we found significant correlations between P3 features and behavioral performance. These findings suggest that the single-trial integration of simultaneous EEG and fMRI signals may provide new insights into classical cognitive functions. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

BMI not WHR modulates BOLD fMRI responses in a sub-cortical reward network when participants judge the attractiveness of human female bodies.

PubMed

Holliday, Ian E; Longe, Olivia A; Thai, N Jade; Hancock, Peter J B; Tovée, Martin J

2011-01-01

In perceptual terms, the human body is a complex 3d shape which has to be interpreted by the observer to judge its attractiveness. Both body mass and shape have been suggested as strong predictors of female attractiveness. Normally body mass and shape co-vary, and it is difficult to differentiate their separate effects. A recent study suggested that altering body mass does not modulate activity in the reward mechanisms of the brain, but shape does. However, using computer generated female body-shaped greyscale images, based on a Principal Component Analysis of female bodies, we were able to construct images which covary with real female body mass (indexed with BMI) and not with body shape (indexed with WHR), and vice versa. Twelve observers (6 male and 6 female) rated these images for attractiveness during an fMRI study. The attractiveness ratings were correlated with changes in BMI and not WHR. Our primary fMRI results demonstrated that in addition to activation in higher visual areas (such as the extrastriate body area), changing BMI also modulated activity in the caudate nucleus, and other parts of the brain reward system. This shows that BMI, not WHR, modulates reward mechanisms in the brain and we infer that this may have important implications for judgements of ideal body size in eating disordered individuals.

BMI Not WHR Modulates BOLD fMRI Responses in a Sub-Cortical Reward Network When Participants Judge the Attractiveness of Human Female Bodies

PubMed Central

Holliday, Ian E.; Longe, Olivia A.; Thai, N. Jade; Hancock, Peter J. B.; Tovée, Martin J.

2011-01-01

In perceptual terms, the human body is a complex 3d shape which has to be interpreted by the observer to judge its attractiveness. Both body mass and shape have been suggested as strong predictors of female attractiveness. Normally body mass and shape co-vary, and it is difficult to differentiate their separate effects. A recent study suggested that altering body mass does not modulate activity in the reward mechanisms of the brain, but shape does. However, using computer generated female body-shaped greyscale images, based on a Principal Component Analysis of female bodies, we were able to construct images which covary with real female body mass (indexed with BMI) and not with body shape (indexed with WHR), and vice versa. Twelve observers (6 male and 6 female) rated these images for attractiveness during an fMRI study. The attractiveness ratings were correlated with changes in BMI and not WHR. Our primary fMRI results demonstrated that in addition to activation in higher visual areas (such as the extrastriate body area), changing BMI also modulated activity in the caudate nucleus, and other parts of the brain reward system. This shows that BMI, not WHR, modulates reward mechanisms in the brain and we infer that this may have important implications for judgements of ideal body size in eating disordered individuals. PMID:22102883

Wavelength-independent constant period spin-echo modulated small angle neutron scattering

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

Sales, Morten, E-mail: lsp260@alumni.ku.dk; Plomp, Jeroen; Bouwman, Wim

2016-06-15

Spin-Echo Modulated Small Angle Neutron Scattering (SEMSANS) in Time-of-Flight (ToF) mode has been shown to be a promising technique for measuring (very) small angle neutron scattering (SANS) signals and performing quantitative Dark-Field Imaging (DFI), i.e., SANS with 2D spatial resolution. However, the wavelength dependence of the modulation period in the ToF spin-echo mode has so far limited the useful modulation periods to those resolvable with the limited spatial resolution of the detectors available. Here we present our results of an approach to keep the period of the induced modulation constant for the wavelengths utilised in ToF. This is achieved bymore » ramping the magnetic fields in the coils responsible for creating the spatially modulated beam in synchronisation with the neutron pulse, thus keeping the modulation period constant for all wavelengths. Such a setup enables the decoupling of the spatial detector resolution from the resolution of the modulation period by the use of slits or gratings in analogy to the approach in grating-based neutron DFI.« less

Neural Substrates of Auditory Emotion Recognition Deficits in Schizophrenia.

PubMed

Kantrowitz, Joshua T; Hoptman, Matthew J; Leitman, David I; Moreno-Ortega, Marta; Lehrfeld, Jonathan M; Dias, Elisa; Sehatpour, Pejman; Laukka, Petri; Silipo, Gail; Javitt, Daniel C

2015-11-04

Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal ("prosodic") features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and rsfMRI was assessed in the subset who performed all assessments (14 patients, 21 controls). As predicted, patients showed robust reductions in MMN across FM stimulus type (p = 0.005), particularly to modulations in F0M, along with impairments in AER and FM tone discrimination. MMN source analysis indicated dipoles in both auditory cortex and anterior insula, whereas rsfMRI analyses showed reduced auditory-insula connectivity. MMN to FM tones and functional connectivity together accounted for ∼50% of the variance in AER performance across individuals. These findings demonstrate that impaired preattentive processing of tonal information and reduced auditory-insula connectivity are critical determinants of social cognitive dysfunction in schizophrenia, and thus represent key targets for future research and clinical intervention. Schizophrenia patients show deficits in the ability to infer emotion based upon tone of voice [auditory emotion recognition (AER)] that drive impairments in social cognition and global functional outcome. This study evaluated neural substrates of impaired AER in schizophrenia using a combined event-related potential/resting-state fMRI approach. Patients showed impaired mismatch negativity response to emotionally relevant frequency modulated tones along with impaired functional connectivity between auditory and medial temporal (anterior insula) cortex. These deficits contributed in parallel to impaired AER and accounted for ∼50% of variance in AER performance. Overall, these findings demonstrate the importance of both auditory-level dysfunction and impaired auditory/insula connectivity in the pathophysiology of social cognitive dysfunction in schizophrenia. Copyright © 2015 the authors 0270-6474/15/3514910-13$15.00/0.

Recent QCD Results from NuTeV/CCFR Collaboration

NASA Astrophysics Data System (ADS)

Adams, T.; Alton, A.; Arroyo, C. G.; Avvakumov, S.; de Barbaro, L.; de Barbaro, P.; Bazarko, A. O.; Bernstein, R. H.; Bodek, A.; Bolton, T.; Brau, J.; Buchholz, D.; Budd, H.; Bugel, L.; Conrad, J. M.; Drucker, R. B.; Formaggio, J. A.; Frey, R.; Goldman, J.; Goncharov, M.; Harris, D. A.; Johnson, R. A.; Kim, J. H.; King, B. J.; Kinnel, T.; Koutsoliotas, S.; Lamm, M. J.; Marsh, W.; Mason, D.; McFarland, K. S.; McNulty, C.; Mishra, S. R.; Naples, D.; Nienaber, P.; Romosan, A.; Sakumoto, W. K.; Schellman, H. M.; Sculli, F. J.; Seligman, W. G.; Shaevitz, M. H.; Smith, W. H.; Spentzouris, P.; Stern, E. G.; Tamminga, B. M.; Vakili, M.; Vaitaitis, A.; Wu, V.; Yang, U. K.; Yu, J.; Zeller, G. P.

2000-06-01

Fermilab experiments CCFR and its successor NuTeV study nucleon structure through deep inelastic scattering of neutrino beams off an iron target. We report on the most recent CCFR measurement of the νN differential cross section and resulting structure functions ΔxF 3 = xF ν3 - xF overlineν3, and R long = {σ L}/{σ T}, in the framework of massive charm quark. ΔxF3 in sensitive to strange and charm content of the nucleon. NuTeV's preliminary direct measurement of the strange sea, from dimuon charged-current production, and nucleon charm content probed by neutral-current νN interaction, are also presented.

Properties of an entropy-based signal receiver with an application to ultrasonic molecular imaging.

PubMed

Hughes, M S; McCarthy, J E; Marsh, J N; Arbeit, J M; Neumann, R G; Fuhrhop, R W; Wallace, K D; Znidersic, D R; Maurizi, B N; Baldwin, S L; Lanza, G M; Wickline, S A

2007-06-01

Qualitative and quantitative properties of the finite part, H(f), of the Shannon entropy of a continuous waveform f(t) in the continuum limit are derived in order to illuminate its use for waveform characterization. Simple upper and lower bounds on H(f), based on features of f(t), are defined. Quantitative criteria for a priori estimation of the average-case variation of H(f) and log E(f), where E(f) is the signal energy of f(t) are also derived. These provide relative sensitivity estimates that could be used to prospectively choose optimal imaging strategies in real-time ultrasonic imaging machines, where system bandwidth is often pushed to its limits. To demonstrate the utility of these sensitivity relations for this application, a study designed to assess the feasibility of identification of angiogenic neovasculature targeted with perfluorocarbon nanoparticles that specifically bind to alpha(v)beta3-integrin expression in tumors was performed. The outcome of this study agrees with the prospective sensitivity estimates that were used for the two receivers. Moreover, these data demonstrate the ability of entropy-based signal receivers when used in conjunction with targeted nanoparticles to elucidate the presence of alpha(v)beta3 integrins in primordial neovasculature, particularly in acoustically unfavorable environments.

Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer.

PubMed

Hao, Huai-Xiang; Jiang, Xiaomo; Cong, Feng

2016-06-08

Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area. Membrane E3 ligase ZNRF3 and RNF43 are critical negative feedback regulators of the Wnt pathway, which function through promoting ubiquitination and degradation of Wnt receptors. R-spondin proteins (RSPO1-4) serve as natural antagonists of ZNRF3/RNF43. To maintain strong and sustained Wnt/β-catenin signaling, cancers need to overcome ZNRF3/RNF43-mediated feedback inhibition. Indeed, mutations of RNF43/ZNRF3 and recurrent translocations of RSPO2/RSPO3 have recently been identified in various cancers. Significantly, genetic alterations in RNF43/ZNRF3/RSPO2/RSPO3 have shown promise as predictive biomarkers in pre-clinical models for the efficacy of upstream Wnt inhibitors. In this review, we will discuss the biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module, and their value as biomarkers to identify Wnt-addicted tumors.

Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer

PubMed Central

Hao, Huai-Xiang; Jiang, Xiaomo; Cong, Feng

2016-01-01

Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area. Membrane E3 ligase ZNRF3 and RNF43 are critical negative feedback regulators of the Wnt pathway, which function through promoting ubiquitination and degradation of Wnt receptors. R-spondin proteins (RSPO1-4) serve as natural antagonists of ZNRF3/RNF43. To maintain strong and sustained Wnt/β-catenin signaling, cancers need to overcome ZNRF3/RNF43-mediated feedback inhibition. Indeed, mutations of RNF43/ZNRF3 and recurrent translocations of RSPO2/RSPO3 have recently been identified in various cancers. Significantly, genetic alterations in RNF43/ZNRF3/RSPO2/RSPO3 have shown promise as predictive biomarkers in pre-clinical models for the efficacy of upstream Wnt inhibitors. In this review, we will discuss the biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module, and their value as biomarkers to identify Wnt-addicted tumors. PMID:27338477

150 {mu}A 18F{sup -} target and beam port upgrade for the IBA 18/9 cyclotron

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

Stokely, M. H.; Peeples, J. L.; Poorman, M. C.

2012-12-19

A high power ({approx}3 kW) target platform has been developed for the IBA 18/9 cyclotron. New designs for the airlock, collimator and target subsystems have been fabricated and deployed. The primary project goal is reliable commercial production of 18F{sup -} at 150 {mu}A or greater, while secondary goals include improving serviceability and extending service intervals relative to OEM systems. Reliable operation in a production environment has been observed at beam currents up to 140 {mu}A. Challenges include ion source lifetime and localized peaking in the beam intensity distribution.

Development of an irradiation method with lateral modulation of SOBP width using a cone-type filter for carbon ion beams.

PubMed

Ishizaki, Azusa; Ishii, Keizo; Kanematsu, Nobuyuki; Kanai, Tatsuaki; Yonai, Shunsuke; Kase, Yuki; Takei, Yuka; Komori, Masataka

2009-06-01

Passive irradiation methods deliver an extra dose to normal tissues upstream of the target tumor, while in dynamic irradiation methods, interplay effects between dynamic beam delivery and target motion induced by breathing or respiration distort the dose distributions. To solve the problems of those two irradiation methods, the authors have developed a new method that laterally modulates the spread-out Bragg peak (SOBP) width. By reducing scanning in the depth direction, they expect to reduce the interplay effects. They have examined this new irradiation method experimentally. In this system, they used a cone-type filter that consisted of 400 cones in a grid of 20 cones by 20 cones. There were five kinds of cones with different SOBP widths arranged on the frame two dimensionally to realize lateral SOBP modulation. To reduce the number of steps of cones, they used a wheel-type filter to make minipeaks. The scanning intensity was modulated for each SOBP width with a pair of scanning magnets. In this experiment, a stepwise dose distribution and spherical dose distribution of 60 mm in diameter were formed. The nonflatness of the stepwise dose distribution was 5.7% and that of the spherical dose distribution was 3.8%. A 2 mm misalignment of the cone-type filter resulted in a nonflatness of more than 5%. Lateral SOBP modulation with a cone-type filter and a scanned carbon ion beam successfully formed conformal dose distribution with nonflatness of 3.8% for the spherical case. The cone-type filter had to be set to within 1 mm accuracy to maintain nonflatness within 5%. This method will be useful to treat targets moving during breathing and targets in proximity to important organs.

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

Li, Guodong; Department of Abdominal Surgery, Cancer treatment center, Fourth Affiliated Hospital of Harbin Medical University, Harbin; Lin, Wenwei

Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor and serves as a key regulator to maintain health of the liver and intestine. Bile acids are endogenous ligands of FXR, and there are increasing efforts to identify FXR modulators to serve as biological probes and/or pharmaceutical agents. Natural FXR ligands isolated from plants may serve as models to synthesize novel FXR modulators. In this study, we demonstrated that epigallocatechin-3-gallate (EGCG), a major tea catechin, specifically and dose-dependently activates FXR. In addition, EGCG induced FXR target gene expression in vitro. Surprisingly, in a co-activator (SRC2) recruitment assay, we found that EGCGmore » does not recruit SRC2 to FXR, but it dose-dependently inhibits recruitment of SRC2 to FXR (IC{sub 50}, 1 μM) by GW6064, which is a potent FXR synthetic ligand. In addition, EGCG suppressed FXR target gene expression induced by either GW4064 or chenodeoxycholic acid in vitro. Furthermore, wild-type and FXR knockout mice treated with an acute dose of EGCG had induced mRNA expression in a subset of FXR target genes in the intestine but not in the liver. In conclusion, EGCG is a unique modulator of FXR in the intestine and may serve as an important model for future development of FXR modulators. -- Highlights: ► Epigallocatechin-3-gallate (EGCG) is a unique farnesoid X receptor (FXR) modulator. ► EGCG activates FXR by itself, but inhibits FXR transactivation by other agonists. ► Low concentration of EGCG activates FXR in mouse intestine but not liver. ► EGCG activates FXR to induce a subset of FXR target genes in mouse intestine.« less

First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms.

PubMed

Borgegard, Tomas; Juréus, Anders; Olsson, Fredrik; Rosqvist, Susanne; Sabirsh, Alan; Rotticci, Didier; Paulsen, Kim; Klintenberg, Rebecka; Yan, Hongmei; Waldman, Magnus; Stromberg, Kia; Nord, Johan; Johansson, Jonas; Regner, Anna; Parpal, Santiago; Malinowsky, David; Radesater, Ann-Cathrin; Li, Tingsheng; Singh, Rajeshwar; Eriksson, Hakan; Lundkvist, Johan

2012-04-06

γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.