[Target chemotherapy of intestinal nematode infection in area with low endemicity].

PubMed

Zhang, Tao; Shen, Yi-ping; Liu, Ying; Yang, Wei-ping; Shao, Jing-ou; Ju, Shao-you; Dong, Kai; Xu, Ju-ling; Jiang, Ji-min

2002-01-01

To evaluate the control measures for intestinal nematodiasis in endemic area with low prevalence and intensity of infection. Target chemotherapy was carried out in high-risk population based on the epidemiological characteristics such as age and clinical findings. Albendazole and mebendazole were administered each 200 mg once daily every year for 3 or 5 years. Saturated brine floatation and Kato-Katz thick smear techniques were used for stool examination to evaluate the efficacy of treatment. Two hundred residents from each of the three investigation villages were selected for target chemotherapy once a year for three years. The prevalence of intestinal nematodes decreased from 6.2% in 1995 to 5.4% in 1996 and 3.2% in 1997, and remained at 2.3% after three years in 2000. One control village where only primary school students were treated once a year for 5 years, the prevalence of Ascaris and Trichuris infection also decreased from 1.4% and 4.2% in 1995 to 0.9% and 1.4% in 2000, respectively. The target chemotherapy on the predisposed population to hookworm infection showed that the prevalence in the population above 41 years old was declined from 19.4% to 10.9%. The target chemotherapy is an economical and effective approach for the control of intestinal nematode infection in endemic area with low prevalence and intensity of infection.

PDE4 as a target for cognition enhancement

PubMed Central

Richter, Wito; Menniti, Frank S.; Zhang, Han-Ting; Conti, Marco

2014-01-01

Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors. PMID:23883342

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

Hagland, Hanne R.; Nilsson, Linn I.H.; Burri, Lena

Highlights: Black-Right-Pointing-Pointer We investigated mechanisms of mitochondrial regulation in rat hepatocytes. Black-Right-Pointing-Pointer Tetradecylthioacetic acid (TTA) was employed to activate mitochondrial oxidation. Black-Right-Pointing-Pointer Mitochondrial biogenesis and respiration were induced. Black-Right-Pointing-Pointer It was confirmed that PPAR target genes were induced. Black-Right-Pointing-Pointer The mechanism involved activation mTOR. -- Abstract: The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects,more » and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPAR{alpha}-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.« less

Comparison of autogenous cancellous bone grafting and extracorporeal shock wave therapy on osteotomy healing in the tibial tuberosity advancement procedure in dogs. Radiographic densitometric evaluation.

PubMed

Barnes, K; Lanz, O; Werre, S; Clapp, K; Gilley, R

2015-01-01

To compare optical values in the osteotomy gap created after a tibial tuberosity advancement (TTA) treated with autogenous cancellous bone graft, extracorporeal shock wave therapy, a combination of autogenous cancellous bone graft and extracorporeal shock wave therapy, and absence of both autogenous cancellous bone graft and extracorporeal shock wave therapy using densitometry. Dogs that were presented for surgical repair of a cranial cruciate ligament rupture were randomly assigned to one of four groups: TTA with autogenous cancellous bone graft (TTA-G), TTA with autogenous cancellous bone graft and extracorporeal shock wave therapy (TTA-GS), TTA with extracorporeal shock wave therapy (TTA-S), and TTA with no additional therapy (TTA-O). Mediolateral radiographs at zero, four and eight weeks after surgery were evaluated to compare healing of the osteotomy gap via densitometry. An analysis of variance was used to compare the densitometric values between groups. At four weeks after surgery, a significant difference in osteotomy gap density was noted between TTA-GS (8.4 millimetres of aluminium equivalent [mmAleq]) and TTA-S (6.1 mmAleq), and between TTA-GS (8.4 mmAleq) and TTA-O (6.4 mmAleq). There were no significant differences noted between any groups at the eight week re-evaluation. There were no significant differences in the osteotomy gap density at eight weeks after surgery regardless of the treatment modality used. The combination of autogenous cancellous bone graft and extracorporeal shock wave therapy may lead to increased radiographic density of the osteotomy gap in the first four weeks after surgery. Densitometry using an aluminium step wedge is a feasible method for comparison of bone density after TTA in dogs.

Interactive target tracking for persistent wide-area surveillance

NASA Astrophysics Data System (ADS)

Ersoy, Ilker; Palaniappan, Kannappan; Seetharaman, Guna S.; Rao, Raghuveer M.

2012-06-01

Persistent aerial surveillance is an emerging technology that can provide continuous, wide-area coverage from an aircraft-based multiple-camera system. Tracking targets in these data sets is challenging for vision algorithms due to large data (several terabytes), very low frame rate, changing viewpoint, strong parallax and other imperfections due to registration and projection. Providing an interactive system for automated target tracking also has additional challenges that require online algorithms that are seamlessly integrated with interactive visualization tools to assist the user. We developed an algorithm that overcomes these challenges and demonstrated it on data obtained from a wide-area imaging platform.

A facile access to new diazepines derivatives: Spectral characterization and crystal structures of 7-(thiophene-2-yl)-5-(trifluoromethyl)-2,3-dihydro-1H-1,4-diazepine and 2-thiophene-4-trifluoromethyl-1,5-benzodiazepine

NASA Astrophysics Data System (ADS)

Ahumada, Guillermo; Carrillo, David; Manzur, Carolina; Fuentealba, Mauricio; Roisnel, Thierry; Hamon, Jean-René

2016-12-01

The one-pot double condensation reaction of 2-thenoyltrifluoroacetone (2-TTA) with ethylendiamine or o-phenylenediamine, in a 2:1 stoichiometric molar ratio, leads to the formation of 7-(thiophene-2-yl)-5-(trifluoromethyl)-2,3-dihydro-1H-1,4-diazepine 2 and 2-thiophene-4-trifluoromethyl-1,5-benzodiazepine 3, that were isolated in 56 and 53% yields, respectively. The bis(trifluoroacetamide)ethylene derivative 1 was also isolated in 32% yield as a side-product in the reaction of 2-TTA and ethylenediamine. Compounds 1-3 were fully characterized by elemental analysis, FT-IR and multinuclear (1H, 13C and 19F) NMR spectroscopy. In addition, their molecular identities and geometries have been authenticated by single-crystal X-ray diffraction analysis. The spectroscopic and structural data confirm that the 1,4-diazepine 2 and the 1,5-benzodiazepine 3 exist in the imine-enamine and diimine tautomeric forms, respectively, both in solution and in the solid-state.

OPS MCC level B/C formulation requirements: Area targets and space volumes processor

NASA Technical Reports Server (NTRS)

Bishop, M. J., Jr.

1979-01-01

The level B/C mathematical specifications for the area targets and space volumes processor (ATSVP) are described. The processor is designed to compute the acquisition-of-signal (AOS) and loss-of-signal (LOS) times for area targets and space volumes. The characteristics of the area targets and space volumes are given. The mathematical equations necessary to determine whether the spacecraft lies within the area target or space volume are given. These equations provide a detailed model of the target geometry. A semianalytical technique for predicting the AOS and LOS time periods is disucssed. This technique was designed to bound the actual visibility period using a simplified target geometry model and unperturbed orbital motion. Functional overview of the ATSVP is presented and it's detailed logic flow is described.

12 CFR 952.4 - Targeted Community Lending Plan

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Targeted Community Lending Plan 952.4 Section... SHEET ITEMS COMMUNITY INVESTMENT CASH ADVANCE PROGRAMS § 952.4 Targeted Community Lending Plan Each Bank shall develop and adopt an annual Targeted Community Lending Plan pursuant to § 944.6 of this chapter...

100-N Area Decision Unit Target Analyte List Development for Soil

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

Ovink, R.

2012-09-18

This report documents the process used to identify source area target analytes in support of the 100-N Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

Target surface area effects on hot electron dynamics from high intensity laser–plasma interactions

DOE PAGES

Zulick, C.; Raymond, A.; McKelvey, A.; ...

2016-06-15

Reduced surface area targets were studied using an ultra-high intensity femtosecond laser in order to determine the effect of electron sheath field confinement on electron dynamics. X-ray emission due to energetic electrons was imaged using a K α imaging crystal. Electrons were observed to travel along the surface of wire targets, and were slowed mainly by the induced fields. Targets with reduced surface areas were correlated with increased hot electron densities and proton energies. Furthermore, Hybrid Vlasov–Fokker–Planck simulations demonstrated increased electric sheath field strength in reduced surface area targets.

7 CFR 916.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 916.4 Section 916.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Regulating Handling Definitions § 916.4 Production area. Production area means the State of California. ...

7 CFR 922.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 922.4 Section 922.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... IN WASHINGTON Order Regulating Handling Definitions § 922.4 Production area. Production area means...

7 CFR 953.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 953.4 Section 953.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... STATES Order Regulating Handling Definitions § 953.4 Production area. Production area means and includes...

7 CFR 923.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 923.4 Section 923.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... COUNTIES IN WASHINGTON Order Regulating Handling Definitions § 923.4 Production area. Production area means...

7 CFR 946.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 946.4 Section 946.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Order Regulating Handling Definitions § 946.4 Production area. Production area means all territory...

7 CFR 966.4 - Production area and regulated area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area and regulated area. 966.4 Section 966.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE TOMATOES...

7 CFR 959.4 - Production area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Production area. 959.4 Section 959.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Regulating Handling Definitions § 959.4 Production area. Production area means the counties of Val Verde...

7 CFR 947.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 947.4 Section 947.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Definitions § 947.4 Production area. Production area means and includes Modoc and Siskiyou Counties in the...

7 CFR 959.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 959.4 Section 959.4 Agriculture... and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE ONIONS GROWN IN SOUTH TEXAS Order Regulating Handling Definitions § 959.4 Production area. Production area means the counties of Val Verde...

Geothermal Target Areas in Colorado as Identified by Remote Sensing Techniques

DOE Data Explorer

Khalid Hussein

2012-02-01

This layer contains the areas identified as targets of potential geothermal activity. The Criteria used to identify the target areas include: hot/warm surface exposures modeled from ASTER/Landsat satellite imagery and geological characteristics, alteration mineral commonly associated with hot springs (clays, Si, and FeOx) modeled from ASTER and Landsat data, Colorado Geological Survey (CGS) known thermal hot springs/wells and heat-flow data points, Colorado deep-seated fault zones, weakened basement identified from isostatic gravity data, and Colorado sedimentary and topographic characteristics.

Triplet-triplet annihilation in highly efficient fluorescent organic light-emitting diodes: current state and future outlook.

PubMed

Kondakov, Denis Y

2015-06-28

range of current densities producing near-maximum TTA electroluminescence are the areas where future improvements would be most beneficial. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

pH-sensitive fluorescent sensors based on europium(III) complexes.

PubMed

Zhang, Xiaolin; Jiao, Yang; Jing, Xu; Wu, Hongmei; He, Guangjie; Duan, Chunying

2011-03-21

New europium(III) complexes Eu(TTA)(2)-DSQ and Eu(TTA)(3)-DR1 were designed and synthesized as new fluorescent pH probes (where HDSQ = 5-(dimethylamino)-N-(4-(2-((8-hydroxyquinolin-2-yl)methylene)hydrazinecarbonyl)phenyl)naphthalene-1-sulfonamide, DR1 = N(1)-(4-(dimethylamino)benzylidene)-N(2)-(rhodamine-6G) lactamethylene-diamine and TTA = thiophentrifluoroacetone). Eu(TTA)(2)-DSQ exhibited high sensitivity in monitoring pH changes in neutral aqueous solution with negligible background fluorescence. Eu(TTA)(3)-DR1 comprised a green light emitting Rhodamine 6G fluorophore and a Eu(III) moiety as the origin of red light. These pH-sensitive emitter components have pK(a) values of 5.0 and 7.2 respectively, and exhibit isolated protonated steps within one molecule. Luminescence titrations demonstrate that Eu(TTA)(3)-DR1 was able to detect pH values at both near neutral pH and acidic pH ranges, and was also able to detect pH in both cultured cells and in vivo.

7 CFR 924.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 924.4 Section 924.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Production area. Production area means the Counties of Okanogan, Chelan, Kittitas, Yakima, and Klickitat in...

7 CFR 945.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 945.4 Section 945.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Production area. Production area means all territory included within Malheur County, Oregon, and the counties...

Targeting Plasmodium PI(4)K to eliminate malaria.

PubMed

McNamara, Case W; Lee, Marcus Cs; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Simon, Oliver; Yeung, Bryan Ks; Chatterjee, Arnab K; McCormack, Susan L; Manary, Micah J; Zeeman, Anne-Marie; Dechering, Koen J; Kumar, Tr Santha; Henrich, Philipp P; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L; Fischli, Christoph; Nagle, Advait; Rottmann, Matthias; Plouffe, David M; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C; Kocken, Clemens Hm; Glynne, Richard J; Bodenreider, Christophe; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A

2013-12-12

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Targeting Plasmodium PI(4)K to eliminate malaria

NASA Astrophysics Data System (ADS)

McNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.

2013-12-01

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

AN EARLY STAGE IN THE PLANT RECOLONIZATION OF A NUCLEAR TARGET AREA

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

Rickard, W.H.; Shields, L.M.

1963-01-01

Vegetational analyses were conducted three years postdetonation in a nuclear target area in a Grayia spinosa-Lycium andersonii community in Yucca Fiat, Nevada. Annual plants dominated the early stage of recolonization and were quantitatively more abundant in the disturbed areas than in an adjacent undisturbed shrub community. Ment zelia albicaulis and Chaenactis steviodes occurred in both disturbed and undisturbed areas, however; Mentzelia was more abundant in disturbed areas while Chaenactis was more abundant in the undisturbed community. Salsola kali was confined to disturbed areas while Phacelia vallismortae was more often encountered in the undisturbed community. The plant recolonization of a mechanicallymore » disturbed area was quantitatively and qualitatively more like that of the interior zone of the nuclear target area than less disturbed habitats. These data support a conclusion that soil displacement presents a more rigorous habitat for plant recolonization than disturbances created by the wider ranging destructive components of a nuclear detonation. (auth)« less

The effects of figure/ground, perceived area, and target saliency on the luminosity threshold.

PubMed

Bonato, F; Cataliotti, J

2000-02-01

Observers adjusted the luminance of a target region until it began to appear self-luminous, or glowing. In Experiment 1, the target was either a face-shaped region (figure) or a non-face-shaped region (ground) of identical area that appeared to be the face's background. In Experiment 2, the target was a square or a trapezoid of identical area that appeared as a tilted rectangle. In Experiment 3, the target was a square surrounded by square, circular, or diamond-shaped elements. Targets that (1) were perceived as figures, (2) were phenomenally small in area, or (3) did not group well with other elements in the array because of shape appeared self-luminous at significantly lower luminance levels. These results indicate that like lightness perception, the luminosity threshold is influenced by perceptual organization and is not based on low-level retinal processes alone.

7 CFR 906.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 906.4 Section 906.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... RIO GRANDE VALLEY IN TEXAS Order Regulating Handling Definitions § 906.4 Production area. Production...

7 CFR 958.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 958.4 Section 958.4 Agriculture... and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE ONIONS GROWN IN CERTAIN DESIGNATED COUNTIES IN IDAHO, AND MALHEUR COUNTY, OREGON Order Regulating Handling Definitions § 958.4 Production area...

32 CFR 1602.4 - Area office.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Area office. 1602.4 Section 1602.4 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM DEFINITIONS § 1602.4 Area office. The Selective Service Office which is responsible for all administrative and operational support...

Identification of clinical target areas in the brainstem of prion‐infected mice

PubMed Central

Mirabile, Ilaria; Jat, Parmjit S.; Brandner, Sebastian

2015-01-01

Aims While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas. Method We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset). Results We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre‐Bötzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem. Conclusions Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre‐Bötzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt–Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases. PMID:25311251

33 CFR 334.120 - Delaware Bay off Milford Neck; naval aircraft bombing target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Delaware Bay off Milford Neck; naval aircraft bombing target area. 334.120 Section 334.120 Navigation and Navigable Waters CORPS OF....120 Delaware Bay off Milford Neck; naval aircraft bombing target area. (a) The danger zone. A circular...

33 CFR 334.120 - Delaware Bay off Milford Neck; naval aircraft bombing target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Delaware Bay off Milford Neck; naval aircraft bombing target area. 334.120 Section 334.120 Navigation and Navigable Waters CORPS OF....120 Delaware Bay off Milford Neck; naval aircraft bombing target area. (a) The danger zone. A circular...

Philippine protected areas are not meeting the biodiversity coverage and management effectiveness requirements of Aichi Target 11.

PubMed

Mallari, Neil Aldrin D; Collar, Nigel J; McGowan, Philip J K; Marsden, Stuart J

2016-04-01

Aichi Target 11 of the Convention on Biological Diversity urges, inter alia, that nations protect at least 17 % of their land, and that protection is effective and targets areas of importance for biodiversity. Five years before reporting on Aichi targets is due, we assessed the Philippines' current protected area system for biodiversity coverage, appropriateness of management regimes and capacity to deliver protection. Although protected estate already covers 11 % of the Philippines' land area, 64 % of its key biodiversity areas (KBAs) remain unprotected. Few protected areas have appropriate management and governance infrastructures, funding streams, management plans and capacity, and a serious mismatch exists between protected area land zonation regimes and conservation needs of key species. For the Philippines to meet the biodiversity coverage and management effectiveness elements of Aichi Target 11, protected area and KBA boundaries should be aligned, management systems reformed to pursue biodiversity-led targets and effective management capacity created.

EphB4 as a therapeutic target in mesothelioma

PubMed Central

2013-01-01

Background Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. Methods We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. Results EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. Conclusion EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted. PMID:23721559

Time to Appendectomy and Risk of Complicated Appendicitis and Adverse Outcomes in Children.

PubMed

Serres, Stephanie K; Cameron, Danielle B; Glass, Charity C; Graham, Dionne A; Zurakowski, David; Karki, Mahima; Anandalwar, Seema P; Rangel, Shawn J

2017-08-01

Management of appendicitis as an urgent rather than emergency procedure has become an increasingly common practice in children. Controversy remains as to whether this practice is associated with increased risk of complicated appendicitis and adverse events. To examine the association between time to appendectomy (TTA) and risk of complicated appendicitis and postoperative complications. In this retrospective cohort study using the Pediatric National Surgical Quality Improvement Program appendectomy pilot database, 2429 children younger than 18 years who underwent appendectomy within 24 hours of presentation at 23 children's hospitals from January 1, 2013, through December 31, 2014, were studied. The main exposure was TTA, defined as the time from emergency department presentation to appendectomy. Patients were further categorized into early and late TTA groups based on whether their TTA was shorter or longer than their hospital's median TTA. Exposures were defined in this manner to compare rates of complicated appendicitis within a time frame sensitive to each hospital's existing infrastructure and diagnostic practices. The primary outcome was complicated appendicitis documented at operation. The association between treatment delay and complicated appendicitis was examined across all hospitals by using TTA as a continuous variable and at the level of individual hospitals by using TTA as a categorical variable comparing outcomes between late and early TTA groups. Secondary outcomes included length of stay (LOS) and postoperative complications (incisional and organ space infections, percutaneous drainage procedures, unplanned reoperation, and hospital revisits). Of the 6767 patients who met the inclusion criteria, 2429 were included in the analysis (median age, 10 years; interquartile range, 8-13 years; 1467 [60.4%] male). Median hospital TTA was 7.4 hours (range, 5.0-19.2 hours), and 574 patients (23.6%) were diagnosed with complicated appendicitis (range, 5

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false San Pablo Bay, Calif.; target... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a..., Mare Island Naval Shipyard, Vallejo, California, will conduct target practice in the area at intervals...

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false San Pablo Bay, Calif.; target... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a..., Mare Island Naval Shipyard, Vallejo, California, will conduct target practice in the area at intervals...

Protease-Activated Receptor 4 (PAR4): A Promising Target for Antiplatelet Therapy.

PubMed

Rwibasira Rudinga, Gamariel; Khan, Ghulam Jilany; Kong, Yi

2018-02-14

Cardiovascular diseases (CVDs) are currently among the leading causes of death worldwide. Platelet aggregation is a key cellular component of arterial thrombi and major cause of CVDs. Protease-activated receptors (PARs), including PAR1, PAR2, PAR3 and PAR4, fall within a subfamily of seven-transmembrane G-protein-coupled receptors (GPCR). Human platelets express PAR1 and PAR4, which contribute to the signaling transduction processes. In association with CVDs, PAR4 not only contributes to platelet activation but also is a modulator of cellular responses that serve as hallmarks of inflammation. Although several antiplatelet drugs are available on the market, they have many side effects that limit their use. Emerging evidence shows that PAR4 targeting is a safer strategy for preventing thrombosis and consequently may improve the overall cardiac safety profile. Our present review summarizes the PAR4 structural characteristics, activation mechanism, role in the pathophysiology of diseases and understanding the association of PAR4 targeting for improved cardiac protection. Conclusively, this review highlights the importance of PAR4 antagonists and its potential utility in different CVDs.

3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation.

PubMed

Sethi, Pallavi; Jyoti, Amar; Swindell, Elden P; Chan, Ryan; Langner, Ulrich W; Feddock, Jonathan M; Nagarajan, Radhakrishnan; O'Halloran, Thomas V; Upreti, Meenakshi

2015-11-01

An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies. Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration.

PubMed

Kukreja, L; Shahidehpour, R; Kim, G; Keegan, J; Sadleir, K R; Russell, T; Csernansky, J; Mesulam, M; Vassar, R J; Wang, L; Dong, H; Geula, C

2018-05-28

Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) employing tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43 which is placed downstream of the tetracycline response element (TRE). The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in post-weaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3 and loss of neurons. The atrophy associated with tTA expression was rescuable by tetracycline analog, doxycycline in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration and behavioral deficits in FTLD. SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing

Impact of 4D image quality on the accuracy of target definition.

PubMed

Nielsen, Tine Bjørn; Hansen, Christian Rønn; Westberg, Jonas; Hansen, Olfred; Brink, Carsten

2016-03-01

Delineation accuracy of target shape and position depends on the image quality. This study investigates whether the image quality on standard 4D systems has an influence comparable to the overall delineation uncertainty. A moving lung target was imaged using a dynamic thorax phantom on three different 4D computed tomography (CT) systems and a 4D cone beam CT (CBCT) system using pre-defined clinical scanning protocols. Peak-to-peak motion and target volume were registered using rigid registration and automatic delineation, respectively. A spatial distribution of the imaging uncertainty was calculated as the distance deviation between the imaged target and the true target shape. The measured motions were smaller than actual motions. There were volume differences of the imaged target between respiration phases. Imaging uncertainties of >0.4 cm were measured in the motion direction which showed that there was a large distortion of the imaged target shape. Imaging uncertainties of standard 4D systems are of similar size as typical GTV-CTV expansions (0.5-1 cm) and contribute considerably to the target definition uncertainty. Optimising and validating 4D systems is recommended in order to obtain the most optimal imaged target shape.

78 FR 35612 - Agency Information Collection Activities; Comment Request; Targeted Teacher Shortage Areas...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-13

... address the targeted teacher deferment provision of the Higher Education Act of 1965, as amended. The... DEPARTMENT OF EDUCATION [Docket No. ED-2013-ICCD-0076] Agency Information Collection Activities; Comment Request; Targeted Teacher Shortage Areas Nationwide Listing AGENCY: Office of Postsecondary...

7 CFR 948.4 - Area.

Code of Federal Regulations, 2010 CFR

2010-01-01

..., Huerfano, Las Animas, Mineral, Archuleta, in the State of Colorado, and all counties in said State, south... Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE IRISH POTATOES GROWN IN COLORADO Order Regulating Handling Definitions § 948.4 Area. Area means any of the subdivisions of the State of Colorado as...

7 CFR 989.4 - Area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Area. 989.4 Section 989.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN IN...

7 CFR 989.4 - Area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Area. 989.4 Section 989.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN IN...

7 CFR 989.4 - Area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Area. 989.4 Section 989.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN IN...

7 CFR 989.4 - Area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Area. 989.4 Section 989.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN IN...

7 CFR 989.4 - Area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Area. 989.4 Section 989.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN IN...

7 CFR 993.4 - Area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Area. 993.4 Section 993.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA Order...

7 CFR 993.4 - Area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Area. 993.4 Section 993.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA Order...

7 CFR 993.4 - Area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Area. 993.4 Section 993.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA Order...

7 CFR 993.4 - Area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Area. 993.4 Section 993.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA Order...

7 CFR 993.4 - Area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Area. 993.4 Section 993.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA Order...

Area 4 has layer IV in adult primates

PubMed Central

García-Cabezas, Miguel Ángel; Barbas, Helen

2014-01-01

There are opposing views about the status of layer IV in primary motor cortex (area 4). Cajal described a layer IV in area 4 of adult humans. In contrast, Brodmann found layer IV in development but not in adult primates and called area 4 ‘agranular’. We addressed this issue in rhesus monkeys using the neural marker SMI-32, which labels neurons in lower layer III and upper V, but not in layer IV. SMI-32 delineated a central unlabeled cortical stripe in area 4 that corresponds to layer IV, which was populated with small interneurons also found in layer IV in ‘granular’ areas (such as area 46). We distinguished layer IV interneurons from projection neurons in the layers above and below using cellular criteria. The commonly used term ‘agranular’ for area 4 is also used for the phylogenetically ancient limbic cortices, confusing areas that differ markedly in laminar structure. This issue pertains to the systematic variation in the architecture across cortices, traced from limbic cortices through areas with increasingly more elaborate laminar structure. The principle of systematic variation can be used to predict laminar patterns of connections across cortical systems. This principle places area 4 and agranular anterior cingulate cortices at opposite poles of the graded laminar differentiation of motor cortices. The status of layer IV in area 4 thus pertains to core organizational features of the cortex, its connections and evolution. PMID:24735460

Decoding Target Distance and Saccade Amplitude from Population Activity in the Macaque Lateral Intraparietal Area (LIP)

PubMed Central

Bremmer, Frank; Kaminiarz, Andre; Klingenhoefer, Steffen; Churan, Jan

2016-01-01

Primates perform saccadic eye movements in order to bring the image of an interesting target onto the fovea. Compared to stationary targets, saccades toward moving targets are computationally more demanding since the oculomotor system must use speed and direction information about the target as well as knowledge about its own processing latency to program an adequate, predictive saccade vector. In monkeys, different brain regions have been implicated in the control of voluntary saccades, among them the lateral intraparietal area (LIP). Here we asked, if activity in area LIP reflects the distance between fovea and saccade target, or the amplitude of an upcoming saccade, or both. We recorded single unit activity in area LIP of two macaque monkeys. First, we determined for each neuron its preferred saccade direction. Then, monkeys performed visually guided saccades along the preferred direction toward either stationary or moving targets in pseudo-randomized order. LIP population activity allowed to decode both, the distance between fovea and saccade target as well as the size of an upcoming saccade. Previous work has shown comparable results for saccade direction (Graf and Andersen, 2014a,b). Hence, LIP population activity allows to predict any two-dimensional saccade vector. Functional equivalents of macaque area LIP have been identified in humans. Accordingly, our results provide further support for the concept of activity from area LIP as neural basis for the control of an oculomotor brain-machine interface. PMID:27630547

Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.

PubMed

Eng, M S; Kaur, J; Prasmickaite, L; Engesæter, B Ø; Weyergang, A; Skarpen, E; Berg, K; Rosenblum, M G; Mælandsmo, G M; Høgset, A; Ferrone, S; Selbo, P K

2018-05-16

Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.

Target Surface Area Effects on Hot Electron Dynamics from High Intensity Laser-Plasma Interactions

DTIC Science & Technology

2016-08-19

New J. Phys. 18 (2016) 063020 doi:10.1088/1367-2630/18/6/063020 PAPER Target surface area effects on hot electron dynamics from high intensity laser ...Science, University ofMichigan, AnnArbor,MI 48109-2099, USA E-mail: czulick@umich.edu Keywords: laser -plasma,mass-limited, fast electrons, sheath...field Abstract Reduced surface area targets were studied using an ultra-high intensity femtosecond laser in order to determine the effect of electron

A strontium-90 sequestrant for first-aid treatment of radiation emergency.

PubMed

Haratake, Mamoru; Hatanaka, Eisuke; Fuchigami, Takeshi; Akashi, Makoto; Nakayama, Morio

2012-01-01

In this study, hydrophilic porous polymer beads with phosphonic acid groups (PGMA-EGDMA-TTA-MP) were synthesized, and assessed as a radioactive strontium-90 sequestrant for the treatment of the radiation emergency. Strontium ions were rapidly absorbed into the blood from the gastrointestinal (GI) tract after oral administration to rats, and distributed to the target organ, i.e., bones. Over 40% of the administered strontium was absorbed into the blood, while the remainder was discharged in the feces within 48 h after the administration. When the PGMA-EGDMA-TTA-MP beads were administered to rats subsequent to the strontium solution, the strontium had accumulated less in the femur. Consequently, the oral administration of the PGMA-EGDMA-TTA-MP beads was effective in suppressing the absorption of strontium from the GI tract.

Urban-area extraction from polarimetric SAR image using combination of target decomposition and orientation angle

NASA Astrophysics Data System (ADS)

Zou, Bin; Lu, Da; Wu, Zhilu; Qiao, Zhijun G.

2016-05-01

The results of model-based target decomposition are the main features used to discriminate urban and non-urban area in polarimetric synthetic aperture radar (PolSAR) application. Traditional urban-area extraction methods based on modelbased target decomposition usually misclassified ground-trunk structure as urban-area or misclassified rotated urbanarea as forest. This paper introduces another feature named orientation angle to improve urban-area extraction scheme for the accurate mapping in urban by PolSAR image. The proposed method takes randomness of orientation angle into account for restriction of urban area first and, subsequently, implements rotation angle to improve results that oriented urban areas are recognized as double-bounce objects from volume scattering. ESAR L-band PolSAR data of the Oberpfaffenhofen Test Site Area was used to validate the proposed algorithm.

Endoscopic Endonasal Transsphenoidal Approach

PubMed Central

Cappabianca, Paolo; Alfieri, Alessandra; Colao, Annamaria; Ferone, Diego; Lombardi, Gaetano; de Divitiis, Enrico

1999-01-01

The outcome of endoscopic endonasal transsphenoidal surgery in 10 patients with pituitary adenomas was compared with that of traditional transnasal transsphenoidal approach (TTA) in 20 subjects. Among the 10 individuals subjected to “pure endoscopy,” 2 had a microadenoma, 1 an intrasellar macroadenoma, 4 had a macroadenoma with suprasellar expansion, 2 had a macroadenoma with supra-parasellar expansion, and 1 a residual tumor; 5 had acromegaly and 5 had a nonfunctioning adenoma (NFA). Among the patients subjected to TTA, 4 had a microadenoma, 2 had an intrasellar macroadenoma, 6 had a macroadenoma with suprasellar expansion, 4 had a macroadenoma with supra-parasellar expansion, and 4 had a residual tumor; 9 patients had acromegaly, 1 hyperprolactinemia, 1 Cushing's disease, and 9 a NFA. At the macroscopic evaluation, tumor removal was total (100%) after endoscopy in 9 patients and after TTA in 14 patients. Six months after surgery, magnetic resonance imaging (MRI) confirmed the total tumor removal in 21 of 23 patients (91.3%). Circulating growth hormone (GH) and insulin-like growth factor-I (IGF-I) significantly decreased 6 months after surgery in all 14 acromegalic patients: normalization of plasma IGF-I levels was obtained in 4 of 5 patients after the endoscopic procedure and in 4 of 9 patients after TTA. Before surgery, pituitary hormone deficiency was present in 14 out of 30 patients: pituitary function improved in 4 patients, remaining unchanged in the other 10 patients. Visual field defects were present before surgery in 4 patients, and improved in all. Early surgical results in the group of 10 patients who underwent endoscopic pituitary tumor removal were at least equivalent to those of standard TTA, with excellent postoperative course. Postsurgical hospital stay was significantly shorter (3.1 ± 0.4 vs. 6.2 ± 0.3 days, p < 0.001) after endoscopy as compared to TTA. ImagesFigure 1Figure 2 PMID:17171126

Magnetic Field Effects on Triplet-Triplet Annihilation in Solutions: Modulation of Visible/NIR Luminescence.

PubMed

Mani, Tomoyasu; Vinogradov, Sergei A

2013-08-06

Photon upconversion based on sensitized triplet-triplet annihilation (TTA) presents interest for such areas as photovoltaics and imaging. Usually energy upconversion is observed as p -type delayed fluorescence from molecules whose triplet states are populated via energy transfer from a suitable triplet donor, followed by TTA. Magnetic field effects (MFE) on delayed fluorescence in molecular crystals are well known; however, there exist only a few examples of MFE on TTA in solutions, and all of them are limited to UV-emitting materials. Here we present MFE on TTA-mediated visible and near infrared (NIR) emission, sensitized by far-red absorbing metalloporphyrins in solutions at room temperature. In addition to visible delayed fluorescence from annihilator, we also observed NIR emission from the sensitizer, occurring as a result of triplet-triplet energy transfer back from annihilator, termed "delayed phosphorescence". This emission also exhibits MFE, but opposite in sign to the annihilator fluorescence.

Fe3O4 Nanoparticles in Targeted Drug/Gene Delivery Systems

PubMed Central

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-01-01

Fe3O4 nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe3O4 NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe3O4 NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe3O4 NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe3O4 NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe3O4 NPs targeting drug/gene delivery systems. PMID:29473914

4. TEST AREA 1120 OVERVIEW, TEST AREA 1115 IN MIDDLE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. TEST AREA 1-120 OVERVIEW, TEST AREA 1-115 IN MIDDLE DISTANCE, AND TEST AREA 1-110 IN FAR DISTANCE AT EXTREME LEFT. ROGERS DRY LAKE AND THE HANGARS AT MAIN BASE ARE VISIBLE IN THE FAR RIGHT DISTANCE. TEST STANDS 2-A AND 1-A ARE NEAREST THE CAMERA. Looking west southwest. - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Leuhman Ridge near Highways 58 & 395, Boron, Kern County, CA

33 CFR 334.60 - Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Harbor, Mass.; naval aircraft bombing target area. 334.60 Section 334.60 Navigation and Navigable Waters... REGULATIONS § 334.60 Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area. (a... bombing target hulk James Longstreet in Cape Cod Bay at latitude 41°49′46″, longitude 70°02′54″. (b) The...

33 CFR 334.60 - Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Harbor, Mass.; naval aircraft bombing target area. 334.60 Section 334.60 Navigation and Navigable Waters... REGULATIONS § 334.60 Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area. (a... bombing target hulk James Longstreet in Cape Cod Bay at latitude 41°49′46″, longitude 70°02′54″. (b) The...

Mesophotic depths as refuge areas for fishery-targeted species on coral reefs

NASA Astrophysics Data System (ADS)

Lindfield, Steven J.; Harvey, Euan S.; Halford, Andrew R.; McIlwain, Jennifer L.

2016-03-01

Coral reefs are subjected to unprecedented levels of disturbance with population growth and climate change combining to reduce standing coral cover and stocks of reef fishes. Most of the damage is concentrated in shallow waters (<30 m deep) where humans can comfortably operate and where physical disturbances are most disruptive to marine organisms. Yet coral reefs can extend to depths exceeding 100 m, potentially offering refuge from the threats facing shallower reefs. We deployed baited remote underwater stereo-video systems (stereo-BRUVs) at depths of 10-90 m around the southern Mariana Islands to investigate whether fish species targeted by fishing in the shallows may be accruing benefits from being at depth. We show that biomass, abundance and species richness of fishery-targeted species increased from shallow reef areas to a depth of 60 m, whereas at greater depths, a lack of live coral habitat corresponded to lower numbers of fish. The majority of targeted species were found to have distributions that ranged from shallow depths (10 m) to depths of at least 70 m, emphasising that habitat, not depth, is the limiting factor in their vertical distribution. While the gradient of abundance and biomass versus depth was steepest for predatory species, the first species usually targeted by fishing, we also found that fishery-targeted herbivores prevailed in similar biomass and species richness to 60 m. Compared to shallow marine protected areas, there was clearly greater biomass of fishery-targeted species accrued in mesophotic depths. Particularly some species typically harvested by depth-limited fishing methods (e.g., spearfishing), such as the endangered humphead wrasse Cheilinus undulatus, were found in greater abundance on deeper reefs. We conclude that mesophotic depths provide essential fish habitat and refuge for fishery-targeted species, representing crucial zones for fishery management and research into the resilience of disturbed coral reef ecosystems.

Ground target geolocation based on digital elevation model for airborne wide-area reconnaissance system

NASA Astrophysics Data System (ADS)

Qiao, Chuan; Ding, Yalin; Xu, Yongsen; Xiu, Jihong

2018-01-01

To obtain the geographical position of the ground target accurately, a geolocation algorithm based on the digital elevation model (DEM) is developed for an airborne wide-area reconnaissance system. According to the platform position and attitude information measured by the airborne position and orientation system and the gimbal angles information from the encoder, the line-of-sight pointing vector in the Earth-centered Earth-fixed coordinate frame is solved by the homogeneous coordinate transformation. The target longitude and latitude can be solved with the elliptical Earth model and the global DEM. The influences of the systematic error and measurement error on ground target geolocation calculation accuracy are analyzed by the Monte Carlo method. The simulation results show that this algorithm can improve the geolocation accuracy of ground target in rough terrain area obviously. The geolocation accuracy of moving ground target can be improved by moving average filtering (MAF). The validity of the geolocation algorithm is verified by the flight test in which the plane flies at a geodetic height of 15,000 m and the outer gimbal angle is <47°. The geolocation root mean square error of the target trajectory is <45 and <7 m after MAF.

33 CFR 334.1460 - Atlantic Ocean and Vieques Sound, in vicinity of Culebra Island; bombing and gunnery target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., in vicinity of Culebra Island; bombing and gunnery target area. 334.1460 Section 334.1460 Navigation...; bombing and gunnery target area. (a) The danger zone. From Punta Resaca on the north coast of Culebra at... danger zone is subject to use as a target area for bombing and gunnery practice. It will be open to...

33 CFR 334.1460 - Atlantic Ocean and Vieques Sound, in vicinity of Culebra Island; bombing and gunnery target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., in vicinity of Culebra Island; bombing and gunnery target area. 334.1460 Section 334.1460 Navigation...; bombing and gunnery target area. (a) The danger zone. From Punta Resaca on the north coast of Culebra at... danger zone is subject to use as a target area for bombing and gunnery practice. It will be open to...

Evaluation of plasma membrane calcium/calmodulin-dependent ATPase isoform 4 as a potential target for fertility control.

PubMed

Cartwright, Elizabeth J; Neyses, Ludwig

2010-01-01

The array of contraceptives currently available is clearly inadequate and does not meet consumer demands since it is estimated that up to a quarter of all pregnancies worldwide are unintended. There is, therefore, an overwhelming global need to develop new effective, safe, ideally non-hormonal contraceptives for both male and female use. The contraceptive field, unlike other areas such as cancer, has a dearth of new targets. We have addressed this issue and propose that isoform 4 of the plasma membrane calcium ATPase is a potentially exciting novel target for fertility control. The plasma membrane calcium ATPase is a ubiquitously expressed calcium pump whose primary function in the majority of cells is to extrude calcium to the extracellular milieu. Two isoforms of this gene family, PMCA1 and PMCA4, are expressed in spermatozoa, with PMCA4 being the predominant isoform. Although this gene is ubiquitously expressed, its function is highly tissue-specific. Genetic deletion of PMCA4, in PMCA4 knockout mice, led to 100% infertility specifically in the male mutant mice due to a selective defect in sperm motility. It is important to note that the gene deletion did not affect normal mating characteristics in these mice. This phenotype was mimicked in wild-type sperm treated with the non-specific PMCA inhibitor 5-(and 6-) carboxyeosin diacetate succinimidyl ester; a proof-of-principle that inhibition of PMCA4 has potential importance in the control of fertility. This review outlines the potential for PMCA4 to be a novel target for fertility control by acting to inhibit sperm motility. It will outline the characteristics that make this target drugable and will describe methodologies to identify and validate novel inhibitors of this target.

33 CFR 334.10 - Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. 334.10 Section 334.10 Navigation and Navigable Waters CORPS... REGULATIONS § 334.10 Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. (a) The danger...

33 CFR 334.10 - Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. 334.10 Section 334.10 Navigation and Navigable Waters CORPS... REGULATIONS § 334.10 Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. (a) The danger...

33 CFR 334.10 - Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. 334.10 Section 334.10 Navigation and Navigable Waters CORPS... REGULATIONS § 334.10 Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. (a) The danger...

33 CFR 334.10 - Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. 334.10 Section 334.10 Navigation and Navigable Waters CORPS... REGULATIONS § 334.10 Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. (a) The danger...

Measuring the extent and effectiveness of protected areas as an indicator for meeting global biodiversity targets

PubMed Central

Chape, S; Harrison, J; Spalding, M; Lysenko, I

2005-01-01

There are now over 100 000 protected areas worldwide, covering over 12% of the Earth's land surface. These areas represent one of the most significant human resource use allocations on the planet. The importance of protected areas is reflected in their widely accepted role as an indicator for global targets and environmental assessments. However, measuring the number and extent of protected areas only provides a unidimensional indicator of political commitment to biodiversity conservation. Data on the geographic location and spatial extent of protected areas will not provide information on a key determinant for meeting global biodiversity targets: ‘effectiveness’ in conserving biodiversity. Although tools are being devised to assess management effectiveness, there is no globally accepted metric. Nevertheless, the numerical, spatial and geographic attributes of protected areas can be further enhanced by investigation of the biodiversity coverage of these protected areas, using species, habitats or biogeographic classifications. This paper reviews the current global extent of protected areas in terms of geopolitical and habitat coverage, and considers their value as a global indicator of conservation action or response. The paper discusses the role of the World Database on Protected Areas and collection and quality control issues, and identifies areas for improvement, including how conservation effectiveness indicators may be included in the database to improve the value of protected areas data as an indicator for meeting global biodiversity targets. PMID:15814356

7 CFR 920.4 - Production area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Production area. 920.4 Section 920.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE KIWIFRUIT GROWN IN CALIFORNIA...

7 CFR 920.4 - Production area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Production area. 920.4 Section 920.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE KIWIFRUIT GROWN IN CALIFORNIA...

7 CFR 920.4 - Production area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Production area. 920.4 Section 920.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE KIWIFRUIT GROWN IN CALIFORNIA...

7 CFR 920.4 - Production area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Production area. 920.4 Section 920.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE KIWIFRUIT GROWN IN CALIFORNIA...

7 CFR 929.4 - Production area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Production area. 929.4 Section 929.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE CRANBERRIES GROWN IN STATES OF...

7 CFR 929.4 - Production area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Production area. 929.4 Section 929.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE CRANBERRIES GROWN IN STATES OF...

7 CFR 929.4 - Production area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Production area. 929.4 Section 929.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE CRANBERRIES GROWN IN STATES OF...

7 CFR 929.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 929.4 Section 929.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE CRANBERRIES GROWN IN STATES OF...

7 CFR 929.4 - Production area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Production area. 929.4 Section 929.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE CRANBERRIES GROWN IN STATES OF...

7 CFR 955.4 - Production area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Production area. 955.4 Section 955.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE VIDALIA ONIONS GROWN IN GEORGIA...

7 CFR 955.4 - Production area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Production area. 955.4 Section 955.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE VIDALIA ONIONS GROWN IN GEORGIA...

7 CFR 955.4 - Production area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Production area. 955.4 Section 955.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE VIDALIA ONIONS GROWN IN GEORGIA...

7 CFR 955.4 - Production area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Production area. 955.4 Section 955.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE VIDALIA ONIONS GROWN IN GEORGIA...

7 CFR 920.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 920.4 Section 920.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE KIWIFRUIT GROWN IN CALIFORNIA...

7 CFR 945.4 - Production area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Production area. 945.4 Section 945.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE IRISH POTATOES GROWN IN CERTAIN...

7 CFR 945.4 - Production area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Production area. 945.4 Section 945.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE IRISH POTATOES GROWN IN CERTAIN...

33 CFR 334.200 - Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U...

Code of Federal Regulations, 2011 CFR

2011-07-01

... Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River... Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U.S. Naval Air...) The regulations. (i) Through navigation of surface craft outside the target areas will be permitted at...

7 CFR 915.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 915.4 Section 915.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE AVOCADOS GROWN IN SOUTH FLORIDA Order...

7 CFR 956.4 - Production area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Production area. 956.4 Section 956.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE SWEET ONIONS GROWN IN THE WALLA WALLA...

7 CFR 956.4 - Production area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Production area. 956.4 Section 956.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE SWEET ONIONS GROWN IN THE WALLA WALLA...

7 CFR 956.4 - Production area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Production area. 956.4 Section 956.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE SWEET ONIONS GROWN IN THE WALLA WALLA...

7 CFR 956.4 - Production area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Production area. 956.4 Section 956.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE SWEET ONIONS GROWN IN THE WALLA WALLA...

7 CFR 956.4 - Production area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Production area. 956.4 Section 956.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE SWEET ONIONS GROWN IN THE WALLA WALLA...

7 CFR 915.4 - Production area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Production area. 915.4 Section 915.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE AVOCADOS GROWN IN SOUTH FLORIDA Order...

7 CFR 915.4 - Production area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Production area. 915.4 Section 915.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE AVOCADOS GROWN IN SOUTH FLORIDA Order...

7 CFR 915.4 - Production area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Production area. 915.4 Section 915.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE AVOCADOS GROWN IN SOUTH FLORIDA Order...

7 CFR 915.4 - Production area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Production area. 915.4 Section 915.4 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE AVOCADOS GROWN IN SOUTH FLORIDA Order...

Intracellular CXCR4+ cell targeting with T22-empowered protein-only nanoparticles

PubMed Central

Unzueta, Ugutz; Céspedes, María Virtudes; Ferrer-Miralles, Neus; Casanova, Isolda; Cedano, Juan; Corchero, José Luis; Domingo-Espín, Joan; Villaverde, Antonio; Mangues, Ramón; Vázquez, Esther

2012-01-01

Background Cell-targeting peptides or proteins are appealing tools in nanomedicine and innovative medicines because they increase the local drug concentration and reduce potential side effects. CXC chemokine receptor 4 (CXCR4) is a cell surface marker associated with several severe human pathologies, including colorectal cancer, for which intracellular targeting agents are currently missing. Results Four different peptides that bind CXCR4 were tested for their ability to internalize a green fluorescent protein-based reporter nanoparticle into CXCR4+ cells. Among them, only the 18 mer peptide T22, an engineered segment derivative of polyphemusin II from the horseshoe crab, efficiently penetrated target cells via a rapid, receptor-specific endosomal route. This resulted in accumulation of the reporter nanoparticle in a fully fluorescent and stable form in the perinuclear region of the target cells, without toxicity either in cell culture or in an in vivo model of metastatic colorectal cancer. Conclusion Given the urgent demand for targeting agents in the research, diagnosis, and treatment of CXCR4-linked diseases, including colorectal cancer and human immunodeficiency virus infection, T22 appears to be a promising tag for the intracellular delivery of protein drugs, nanoparticles, and imaging agents. PMID:22923991

Time-Tag Generation Script

NASA Technical Reports Server (NTRS)

Jackson, Dan E.

2010-01-01

Time-Tag Generation Script (TTaGS) is an application program, written in the AWK scripting language, for generating commands for aiming one Ku-band antenna and two S-band antennas for communicating with spacecraft. TTaGS saves between 2 and 4 person-hours per every 24 hours by automating the repetitious process of building between 150 and 180 antenna-control commands. TTaGS reads a text database of communication satellite schedules and a text database of satellite rise and set times and cross-references items in the two databases. It then compares the scheduled start and stop with the geometric rise and set to compute the times to execute antenna control commands. While so doing, TTaGS determines whether to generate commands for guidance, navigation, and control computers to tell them which satellites to track. To help prevent Ku-band irradiation of the Earth, TTaGS accepts input from the user about horizon tolerance and accordingly restricts activation and effects deactivation of the transmitter. TTaGS can be modified easily to enable tracking of additional satellites and for such other tasks as reading Sun-rise/set tables to generate commands to point the solar photovoltaic arrays of the International Space Station at the Sun.

Targeting the impact of agri-environmental policy - Future scenarios in two less favoured areas in Portugal.

PubMed

Jones, Nadia; Fleskens, Luuk; Stroosnijder, Leo

2016-10-01

Targeting agri-environmental measures (AEM) improves their effectiveness in the delivery of public goods, provided the necessary coordination with other incentives. In less favoured areas (LFA) measures focusing on the conservation of extensive farming contribute to sustainable land management in these areas. In this paper we investigate the implementation of a possible AEM supporting the improvement of permanent pastures coordinated with the extensive livestock and single farm payments actually in place. Through applying a spatially-explicit mixed integer optimisation model we simulate future land use scenarios for two less favoured areas in Portugal (Centro and Alentejo) considering two policy scenarios: a 'targeted AEM', and a 'non-targeted AEM'. We then compare the results with a 'basic policy' option (reflecting a situation without AEM). This is done with regard to landscape-scale effects on the reduction of fire hazard and erosion risk, as well as effects on farm income. The results show that an AEM for permanent pastures would be more cost-effective for erosion and fire hazard mitigation if implemented within a spatially targeted framework. However when cost-effectiveness is assessed with other indicators (e.g. net farm income and share of grazing livestock) 'non-targeted AEM' implementation delivers the best outcome in Alentejo. In Centro the implementation of an AEM involves important losses of income compared to the 'basic policy'. 'Targeted AEM' tends to favour farms in very marginal conditions, i.e. targeting is demonstrated to perform best in landscapes where spatial heterogeneity is higher. The results also show the risk of farm abandonment in the two studied less favoured areas: in all three scenarios more than 30% of arable land is deemed to be abandoned. Copyright © 2016 Elsevier Ltd. All rights reserved.

Transcriptome-wide targets of alternative splicing by RBM4 and possible role in cancer.

PubMed

Markus, M Andrea; Yang, Yee Hwa J; Morris, Brian J

2016-04-01

This study determined transcriptome-wide targets of the splicing factor RBM4 using Affymetrix GeneChip(®) Human Exon 1.0 ST Arrays and HeLa cells treated with RBM4-specific siRNA. This revealed 238 transcripts that were targeted for alternative splicing. Cross-linking and immunoprecipitation experiments identified 945 RBM4 targets in mouse HEK293 cells, 39% of which were ascribed to "alternative splicing" by in silico pathway analysis. Mouse embryonic stem cells transfected with Rbm4 siRNA hairpins exhibited reduced colony numbers and size consistent with involvement of RBM4 in cell proliferation. RBM4 cDNA probing of a cancer cDNA array involving 18 different tumor types from 13 different tissues and matching normal tissue found overexpression of RBM4 mRNA (p<0.01) in cervical, breast, lung, colon, ovarian and rectal cancers. Many RBM4 targets we identified have been implicated in these cancers. In conclusion, our findings reveal transcriptome-wide targets of RBM4 and point to potential cancer-related targets and mechanisms that may involve RBM4. Copyright © 2016 Elsevier Inc. All rights reserved.

Increased hepatic mitochondrial FA oxidation reduces plasma and liver TG levels and is associated with regulation of UCPs and APOC-III in rats

PubMed Central

Lindquist, Carine; Bjørndal, Bodil; Rossmann, Christine Renate; Tusubira, Deusdedit; Svardal, Asbjørn; Røsland, Gro Vatne; Tronstad, Karl Johan; Hallström, Seth; Berge, Rolf Kristian

2017-01-01

Hepatic mitochondrial function, APOC-III, and LPL are potential targets for triglyceride (TG)-lowering drugs. After 3 weeks of dietary treatment with the compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), the hepatic mitochondrial FA oxidation increased more than 5-fold in male Wistar rats. Gene expression analysis in liver showed significant downregulation of APOC-III and upregulation of LPL and the VLDL receptor. This led to lower hepatic (53%) and plasma (73%) TG levels. Concomitantly, liver-specific biomarkers related to mitochondrial biogenesis and function (mitochondrial DNA, citrate synthase activity, and cytochrome c and TFAM gene expression) were elevated. Interestingly, 1-triple TTA lowered plasma acetylcarnitine levels, whereas the concentration of β-hydroxybutyrate was increased. The hepatic energy state was reduced in 1-triple TTA-treated rats, as reflected by increased AMP/ATP and decreased ATP/ADP ratios, whereas the energy state remained unchanged in muscle and heart. The 1-triple TTA administration induced gene expression of uncoupling protein (UCP)2 and UCP3 in liver. In conclusion, the 1-triple TTA-mediated clearance of blood TG may result from lowered APOC-III production, increased hepatic LPL gene expression, mitochondrial FA oxidation, and (re)uptake of VLDL facilitating drainage of FAs to the liver for β-oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2 and UCP3 mediate a moderate degree of mitochondrial uncoupling should be considered. PMID:28473603

The area centralis in the chicken retina contains efferent target amacrine cells

PubMed Central

Weller, Cynthia; Lindstrom, Sarah H.; De Grip, Willem J.; Wilson, Martin

2012-01-01

The retinas of birds receive a substantial efferent, or centrifugal, input from a midbrain nucleus. The function of this input is presently unclear but previous work in the pigeon has shown that efferent input is excluded from the area centralis, suggesting that the functions of the area centralis and the efferent system are incompatible. Using an antibody specific to rods, we have identified the area centralis in another species, the chicken, and mapped the distribution of the unique amacrine cells that are the postsynaptic partners of efferent fibers. Efferent target amacrine cells are found within the chicken area centralis and their density is continuous across the border of the area centralis. In contrast to the pigeon retina then, we conclude that the chicken area centralis receives efferent input. We suggest that the difference between the 2 species is attributable to the presence of a fovea within the area centralis of the pigeon and its absence from that of the chicken. PMID:19296862

Large area thermal target board: An improvement to environmental effects and system parameters characterization

NASA Astrophysics Data System (ADS)

Watkins, Wendell R.; Bean, Brent L.; Munding, Peter D.

1994-06-01

Recent field tests have provided excellent opportunities to use a new characterization tool associated with the Mobile Imaging Spectroscopy Laboratory (MISL) of the Battlefield Environment Directorate, formerly the U.S. Army Atmospheric Sciences Laboratory. The MISL large area (1.8 by 1.8 m, uniform temperature, thermal target) was used for characterization and isolation of phenomena which impact target contrast. By viewing the target board from closeup and distant ranges simultaneously with the MISL thermal imagers, the inherent scene content could be calibrated and the degrading effects of atmospheric propagation could be isolated. The target board is equipped with several spatial frequency bar patterns, but only the largest 3.5-cycle full area bar pattern was used for the distant range of 1.6 km. The quantities measured with the target board include the inherent background change, the contrast transmission, and the atmospheric modulation transfer function. The MISL target board has a unique design which makes it lightweight with near perfect transition between the hot and cold portions of the bar pattern. The heated portion of the target is an elongated rectangular even which is tilted back at a 30 deg angle to form a 1.8 by 1.8 m square when viewed from the front. The cold bars we positioned in front of the heated oven surface and can be oriented in either the vertical or horizontal direction. The oven is mounted on a lightweight trailer for one- or two-man positioning. An attached metal and canvas structure is used to shield the entire target from both solar loading and cooling winds. The target board has a thin aluminum sheet front surface which is insulated from the oven's heating structure.

West wall, display area (room 101), view 4 of 4: ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

West wall, display area (room 101), view 4 of 4: northwest corner, with D.M. logistics office below (room 137), and D.O./D.D.O. offices above. Lower stairs lead to entry shown in view 13 - March Air Force Base, Strategic Air Command, Combat Operations Center, 5220 Riverside Drive, Moreno Valley, Riverside County, CA

Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

DTIC Science & Technology

2016-10-01

Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

COS LP4 FUV Target Acquisition Enabling and Verification

NASA Astrophysics Data System (ADS)

Penton, Steven V.

2016-10-01

This LP4 program is designed to verify the ability of the LV0058/LV0059 COS FSW to place an isolated point source at the center of the PSA, using FUV dispersed light target acquisition (TA) for COS (LP4-TA-COS). Tests will be performed for all 3 FUV TA modes (ACQ/SEARCH, ACQ/PEAKD, and ACQ/PEAKXD). It is sufficient to test ACQ/SEARCH and ACQ/PEAKD with only one grating, but all three FUV gratings need to be tested for the new (as of LV0054) ACQ/PEAKXD with NUM_POS>1 (also known internally, and in the spt files, as OPMODE=ACQ/PEAKD(XD) at the Fourth Lifetime Position (LP4). This program is modeled after the LP2 and LP3 versions of this program; 12797 and 13636.This program has specific visits to test each portion of the FUV spectroscopic TA process. Visits 01-05 will use the target AV18, while Visit 06 will observe (WD1657+343). Both targets are visible year round. For the LP4 enabling, several improvements to APT, the ground system, and the flight software (FSW) have greatly simplified the enabling process. There are now no non-standard exposures, or special commanding, in this program.Specifically; 1) We now use the LIFETIME-POS = LP4 functionality in APT & FSW to specify the LP. The old procedure of using LIFETIME-POS ="ALTERNATE" has been removed. FUV LPs are now called out by number (e.g., LP4). 2) We will be using the new NUM_POS > 1 PEAKXD algorithm at LP4 due to large geometric distortions (GD) at the "Y" detector positions of LP4. FUVA is particularly affected by GD rendering the old PEAKXD algorithm unable to center a target to the required XD accuracy at LP4. 3) Numerous FSW Patchable constants that were essential for PEAKXD operations at previous LPs are no longer required. These are the WCA-to-PSA offsets and XD plate-scales. Like PEAKD, the NUM_POS > 1 PEAKXD requires no patchable constant updates. At previous LPs, numerous updates to the patchable constants were required, this is not necessary for LP4 TA enabling.Prior to the submission of this

Statistical methods for identifying and bounding a UXO target area or minefield

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

McKinstry, Craig A.; Pulsipher, Brent A.; Gilbert, Richard O.

2003-09-18

The sampling unit for minefield or UXO area characterization is typically represented by a geographical block or transect swath that lends itself to characterization by geophysical instrumentation such as mobile sensor arrays. New spatially based statistical survey methods and tools, more appropriate for these unique sampling units have been developed and implemented at PNNL (Visual Sample Plan software, ver. 2.0) with support from the US Department of Defense. Though originally developed to support UXO detection and removal efforts, these tools may also be used in current form or adapted to support demining efforts and aid in the development of newmore » sensors and detection technologies by explicitly incorporating both sampling and detection error in performance assessments. These tools may be used to (1) determine transect designs for detecting and bounding target areas of critical size, shape, and density of detectable items of interest with a specified confidence probability, (2) evaluate the probability that target areas of a specified size, shape and density have not been missed by a systematic or meandering transect survey, and (3) support post-removal verification by calculating the number of transects required to achieve a specified confidence probability that no UXO or mines have been missed.« less

A forced-convection gas target for the production of [11C]CH4.

PubMed

Uittenbosch, T; Buckley, K; Ruth, T; Martinez, D M; Hoehr, C

2018-06-15

A forced-convection gas target for the production of [ 11 C]CH 4 on a 13 MeV cyclotron was constructed and tested. A small fan was incorporated into the back of the target, which mixes the target gas during irradiation. The effect of the forced convection alone on the target operation and the [ 11 C]CH 4 yield was measured. Forced convection improved the target yield by up to 16 ± 4%. In addition, improvement in heat transfer of up to 70% was observed to be a function of fan speed. Operating with forced convection allowed delivery of 21% higher beam currents while still staying in the acceptable pressure rise during irradiation, providing a 25 ± 7% greater yield. Copyright © 2018 Elsevier Ltd. All rights reserved.

Co-Targeting HER2 and EphB4 Pathways

DTIC Science & Technology

2013-09-01

soluble EphB4 decoy receptor that efficiently blocks EphB4/EphB2 signaling. A phase I study for solid tumors using this agent given intravenously...June 2013 3 . DATES COVERED 4. TITLE AND SUBTITLE Co-Targeting HER2 and EphB4 Pathways 5a. CONTRACT NUMBER W81XWH-11-1-0471 5b. GRANT...13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple receptor pathways allow for redundancy in growth pathways that are dysregulated in cancer and lead to

Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

PubMed

Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

2016-07-05

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

Generation of Parametric Equivalent-Area Targets for Design of Low-Boom Supersonic Concepts

NASA Technical Reports Server (NTRS)

Li, Wu; Shields, Elwood

2011-01-01

A tool with an Excel visual interface is developed to generate equivalent-area (A(sub e)) targets that satisfy the volume constraints for a low-boom supersonic configuration. The new parametric Ae target explorer allows users to interactively study the tradeoffs between the aircraft volume constraints and the low-boom characteristics (e.g., loudness) of the ground signature. Moreover, numerical optimization can be used to generate the optimal A(sub e) target for given A(sub e) volume constraints. A case study is used to demonstrate how a generated low-boom Ae target can be matched by a supersonic configuration that includes a fuselage, wing, nacelle, pylon, aft pod, horizontal tail, and vertical tail. The low-boom configuration is verified by sonic-boom analysis with an off-body pressure distribution at three body lengths below the configuration

Co-Targeting HER2 and EphB4 Pathways

DTIC Science & Technology

2013-07-01

progress has been made toward the clinic. An IND has been obtained for sEphbB4- HSA, an albumin stabilized soluble EphB4 decoy receptor that efficiently...for activated HER2/HER family receptors , angiogenic markers (EphrinB2, EphB1,2,3,4,6, VEGF, VEGFR-1, 2, 3 and PDGFR), vessel density, signal...ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE 3 . DATES COVERED 4. TITLE AND SUBTITLE Co-Targeting HER2 and EphB4 Pathways 5a. CONTRACT NUMBER 5b

Mineral target areas in Nevada from geological analysis of LANDSAT-1 imagery

NASA Technical Reports Server (NTRS)

Abdel-Gawad, M.; Tubbesing, L.

1975-01-01

Geological analysis of LANDSAT-1 Scene MSS 1053-17540 suggests that certain known mineral districts in east-central Nevada frequently occur near faults or at faults or lineament intersections and areas of complex deformation and flexures. Seventeen (17) areas of analogous characteristics were identified as favorable targets for mineral exploration. During reconnaissance field trips eleven areas were visited. In three areas evidence was found of mining and/or prospecting not known before the field trips. In four areas favorable structural and alteration features were observed which call for more detailed field studies. In one of the four areas limonitic iron oxide samples were found in the regolith of a brecciated dolomite ridge. This area contains quartz veins, granitic and volcanic rocks and lies near the intersection of two linear fault structures identified in the LANDSAT-1 imagery. Semiquantitative spectroscopic analysis of selected portions of the samples showed abnormal contents of arsenic, molybdenum, copper, lead, zinc, and silver. These limonitic samples found were not in situ and further field studies are required to assess their source and significance.

Retrospective Analysis of Dose Titration and Serum Testosterone Level Assessments in Patients Treated With Topical Testosterone.

PubMed

Muram, David; Kaltenboeck, Anna; Boytsov, Natalie; Hayes-Larson, Eleanor; Ivanova, Jasmina; Birnbaum, Howard G; Swindle, Ralph

2015-11-01

Patterns of care following topical testosterone agent (TTA) initiation are poorly understood. This study aimed to characterize care following TTA initiation and compare results between patients with and without a serum testosterone (T) assay within 30 days before and including TTA initiation. Adult men (N=4,146) initiating TTAs from January 1, 2011, to March 31, 2012, were identified from a commercially insured database. Patients were included if they initiated at recommended starting dose (RSD) and had ≥12 and ≥6 months of continuous eligibility preinitiation (baseline) and postinitiation (study period), respectively. Patients were stratified by preinitiation T assay. Maintenance dose attainment month was determined using unadjusted generalized estimating equations regression to compare dose relative to RSD month by month. Outcomes included maintenance dose attainment month, time to stopping of index TTA refills or a claim for nonindex testosterone replacement therapy (TRT), and proportion of patients with study period T assay or diagnosis of hypogonadism (HG) or another low testosterone condition, and were compared using chi-square and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. Maintenance dose was attained in Month 4 postinitiation, at 115.2% of RSD. Approximately 46% of patients had a preinitiation T assay; these men were more likely to receive a diagnosis of HG or another low testosterone condition, to have a follow-up T assay, to continue treatment by filling a nonindex TRT, and less likely to stop refilling treatment with their index TTA. Differences in care following TTA initiation suggest that preinitiation T assays (i.e., guideline-based care) may be helpful in ensuring treatment benefits. © The Author(s) 2014.

33 CFR 334.200 - Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U...

Code of Federal Regulations, 2010 CFR

2010-07-01

... damage caused by projectiles, bombs, missiles, or Naval or Coast Guard vessels to fishing structures or... and bombs will be dropped at frequent intervals in the target areas. Hooper and Hannibal target areas...

Enhancing teen pregnancy prevention in local communities: capacity building using the interactive systems framework.

PubMed

Duffy, Jennifer L; Prince, Mary Severson; Johnson, Erin E; Alton, Forrest L; Flynn, Shannon; Faye, Amy Mattison; Padgett, Polly Edwards; Rollison, Chris; Becker, Dana; Hinzey, Angela L

2012-12-01

Getting To Outcomes (GTO), an innovative framework for planning, implementing, evaluating, and sustaining interventions has been shown to be effective in helping community-based organizations (CBOs) introduce science-based approaches into their prevention work. However, the Interactive Systems Framework (ISF) suggests that adopting innovations like GTO requires a significant amount of capacity building through training and technical assistance (T/TA). In this study, 11 CBOs and three schools in South Carolina entered into a 3 year program of intense and proactive T/TA based on the ISF to learn how to apply an adaptation of GTO (Promoting Science-Based Approaches-Getting To Outcomes, PSBA-GTO) to their teen pregnancy prevention programs. Using semi-structured interviews, the partnering organizations were assessed at three points in time, pre-T/TA, 12 months, and post T/TA (30 months) for their performance of the steps of GTO in their work. The seven organizations which participated in T/TA until the end of the project received an average of 76 h of TA and 112 h of training per organization. Interview results showed increased performance of all 10 steps of PSBA-GTO by these organizations when conducting their teen pregnancy programs. These results suggest targeted and proactive T/TA can successfully bridge the gap between research and practice by using a three part delivery system, as prescribed in the ISF, which relies on an intermediary prevention support system to ensure accurate and effective translation of research to the everyday work of community-based practitioners.

Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4 ▿ †

PubMed Central

Li, Pingxin; Yao, Hongjie; Zhang, Zhiqiang; Li, Ming; Luo, Yuan; Thompson, Paul R.; Gilmour, David S.; Wang, Yanming

2008-01-01

Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression. PMID:18505818

How Do Vision and Hearing Impact Pedestrian Time-to-Arrival Judgments?

PubMed Central

Roper, JulieAnne M.; Hassan, Shirin E.

2014-01-01

Purpose To determine how accurate normally-sighted male and female pedestrians were at making time-to-arrival (TTA) judgments of approaching vehicles when using just their hearing or both their hearing and vision. Methods Ten male and 14 female subjects with confirmed normal vision and hearing estimated the TTA of approaching vehicles along an unsignalized street under two sensory conditions: (i) using both habitual vision and hearing; and (ii) using habitual hearing only. All subjects estimated how long the approaching vehicle would take to reach them (ie the TTA). The actual TTA of vehicles was also measured using custom made sensors. The error in TTA judgments for each subject under each sensory condition was calculated as the difference between the actual and estimated TTA. A secondary timing experiment was also conducted to adjust each subject’s TTA judgments for their “internal metronome”. Results Error in TTA judgments changed significantly as a function of both the actual TTA (p<0.0001) and sensory condition (p<0.0001). While no main effect for gender was found (p=0.19), the way the TTA judgments varied within each sensory condition for each gender was different (p<0.0001). Females tended to be as accurate under either condition (p≥0.01) with the exception of TTA judgments made when the actual TTA was two seconds or less and eight seconds or longer, during which the vision and hearing condition was more accurate (p≤0.002). Males made more accurate TTA judgments under the hearing only condition for actual TTA values five seconds or less (p<0.0001), after which there were no significant differences between the two conditions (p≥0.01). Conclusions Our data suggests that males and females use visual and auditory information differently when making TTA judgments. While the sensory condition did not affect the females’ accuracy in judgments, males initially tended to be more accurate when using their hearing only. PMID:24509543

MicroRNA-650 targets ING4 to promote gastric cancer tumorigenicity

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

Zhang, XueLi, E-mail: zhangxueli.200010@yahoo.com.cn; Zhu, WeiYing; Zhang, JiFa

2010-04-30

MicroRNAs (miRNAs) are non-coding RNAs that regulate the expression of target mRNAs. Altered expression of specific miRNAs in human gastric cancer progression has been reported; however, the role of miR-650 in gastric cancer is poorly understood. In this study, we show that miR-650 is involved in lymphatic and distant metastasis in human gastric cancer, and we find that ectopic expression of miR-650 promotes tumorigenesis and proliferation of gastric cancer cells. A luciferase reporter assay demonstrates that Inhibitor of Growth 4 (ING4) is a direct target of miR-650. Collectively, our study demonstrates that over-expression of miR-650 in gastric cancer may promotemore » proliferation and growth of cancer cells, at least partially through directly targeting ING4. These findings help clarify the molecular mechanisms involved in gastric carcinogenesis and indicate that miR-650 modulation may be a bona fide miRNA-based treatment of gastric cancer.« less

Protocol for Reducing Time to Antibiotics in Pediatric Patients Presenting to an Emergency Department With Fever and Neutropenia: Efficacy and Barriers.

PubMed

Cohen, Clay; King, Amber; Lin, Chee Paul; Friedman, Gregory K; Monroe, Kathy; Kutny, Matthew

2016-11-01

Patients with febrile neutropenia are at high risk of morbidity and mortality from infectious causes. Decreasing time to antibiotic (TTA) administration is associated with improved patient outcomes. We sought to reduce TTA for children presenting to the emergency department with fever and neutropenia. In a prospective cohort study with historical comparison, TTA administration was evaluated in patients with neutropenia presenting to the Children's of Alabama Emergency Department. A protocol was established to reduce delays in antibiotic administration and increase the percentage of patients who receive treatment within 60 minutes of presentation. One hundred pre-protocol patient visits between August 2010 and December 2011 were evaluated and 153 post-protocol visits were evaluated between August 2012 and September 2013. We reviewed individual cases to determine barriers to rapid antibiotic administration. Antibiotics were administered in 96.9 ± 57.8 minutes in the pre-protocol patient group, and only 35% of patients received antibiotics within 60 minutes of presentation and 70% received antibiotics within 120 minutes. After implementation of the protocol, TTA for neutropenic patients was decreased to 64.3 ± 28.4 minutes (P < 0.0001) with 51.4% receiving antibiotics within 60 minutes and 93.2% within 120 minutes. Implementing a standard approach to patients at risk for neutropenia decreased TTA. There are numerous challenges in providing timely antibiotics to children with febrile neutropenia. Identified delays included venous access (time to effect of topical anesthetics, and difficulty obtaining access), physicians waiting on laboratory results, and antibiotic availability.

Major complications of tibial tuberosity advancement in 1613 dogs.

PubMed

Costa, Mario; Craig, Diane; Cambridge, Tony; Sebestyen, Peter; Su, Yuhua; Fahie, Maria A

2017-05-01

To report major postoperative complications in 1613 dogs with tibial tuberosity advancement (TTA). Retrospective case series. Dogs (n = 1613) with cranial cruciate ligament deficiency treated with TTA. Medical records of TTAs performed between December 2007-2013 were reviewed for age, sex, weight, contralateral stifle surgery, surgical approach, duration of preoperative lameness, presence of meniscal damage, concurrent patellar luxation and simultaneous bilateral TTA. Major postoperative complications were defined as surgical site infection (SSI) (superficial, deep, or organ/space), implant failure, fracture, patellar luxation, and meniscal tear. Major complications were recorded in 13.4% of cases. Superficial SSI (incisional irritation) was diagnosed in 6.9% cases, requiring only antimicrobial therapy. Other complications included postliminary medial meniscal tear (2% incidence), deep SSI (incisional dehiscence, 1.1%), implant failure (1%), patellar luxation (1.2%), fracture (0.9%), and organ/space SSI (septic arthritis, 0.4%). Dogs with normal menisci were less likely to develop postliminary meniscal tears if the medial meniscus was released at the time of TTA (P < .0001). No association was detected between recorded parameters and complications, although dogs >8 years old approached significance (P = .05) in terms of predisposition to major complications. Major complications after TTA are uncommon, even in dogs with concurrent patellar luxation or bilateral simultaneous procedures. In spite of its morbidity, medial meniscal release may prevent postliminary meniscal tears. © 2017 The American College of Veterinary Surgeons.

33 CFR 334.1470 - Caribbean Sea and Vieques Sound, in vicinity of Eastern Vieques; bombing and gunnery target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Caribbean Sea and Vieques Sound, in vicinity of Eastern Vieques; bombing and gunnery target area. 334.1470 Section 334.1470 Navigation...; bombing and gunnery target area. (a) The danger zone. From Punta Conejo on the south coast of Vieques at...

33 CFR 334.1470 - Caribbean Sea and Vieques Sound, in vicinity of Eastern Vieques; bombing and gunnery target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Caribbean Sea and Vieques Sound, in vicinity of Eastern Vieques; bombing and gunnery target area. 334.1470 Section 334.1470 Navigation...; bombing and gunnery target area. (a) The danger zone. From Punta Conejo on the south coast of Vieques at...

Development and In Vitro Characterization of a Gemcitabine-loaded MUC4-targeted Immunoliposome Against Pancreatic Ductal Adenocarcinoma.

PubMed

Urey, Carlos; Hilmersson, Katarzyma Said; Andersson, Bodil; Ansari, Daniel; Andersson, Roland

2017-11-01

Pancreatic Ductal adeno-carcinoma (PDAC) is a devastating disease. Gemcitabine is the standard chemotherapeutic agent against PDAC but has only limited effectiveness. The aim of the study was to develop and study the targeting affinity and in vitro antiproliferative effect of a MUC4-targeted gemcitabine-loaded immuno-liposome for treatment of PDAC. Gemcitabine-loaded immunoliposomes were developed by grafting anti-MUC4 antibodies to the liposomal surface. Targeting affinity was compared in vitro between immunoliposomes and non-targeted liposomes and anti-proliferative effect was compared in vitro between free drug, non-targeted liposomal gemcitabine and MUC4-targeted immunoliposomal gemcitabine on a MUC4-positive pancreatic cancer cell line, Capan-1. Development of a MUC4-targeted immunoliposome was confirmed and characterized by immunoblots and size characterization. The MUC4-targeted immunoliposome showed a significantly higher targeting affinity compared to the non-targeted liposomes and also showed an improved antiproliferative effect compared to free and non-targeted liposomal drug. Successful development and characterization of a MUC4-targeted immunoliposome shows promising results for a targeted treatment and improved retention of gemcitabine for treatment of PDAC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

CXCR4 in breast cancer: oncogenic role and therapeutic targeting

PubMed Central

Xu, Chao; Zhao, Hong; Chen, Haitao; Yao, Qinghua

2015-01-01

Chemokines are 8–12 kDa peptides that function as chemoattractant cytokines and are involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled seven-span transmembrane receptors. Chemokines play a fundamental role in the regulation of a variety of cellular, physiological, and developmental processes. Their aberrant expression can lead to a variety of human diseases including cancer. C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12). CXCR4 belongs to the superfamily of the seven transmembrane domain heterotrimeric G protein-coupled receptors and is functionally expressed on the cell surface of various types of cancer cells. CXCR4 also plays a role in the cell proliferation and migration of these cells. Recently, CXCR4 has been reported to play an important role in cell survival, proliferation, migration, as well as metastasis of several cancers including breast cancer. This review is mainly focused on the current knowledge of the oncogenic role and potential drugs that target CXCR4 in breast cancer. Additionally, CXCR4 proangiogenic molecular mechanisms will be reviewed. Strict biunivocal binding affinity and activation of CXCR4/CXCL12 complex make CXCR4 a unique molecular target for prevention and treatment of breast cancer. PMID:26356032

Effects of nandrolone decanoate on time to consolidation of bone defects resulting from osteotomy for tibial tuberosity advancement.

PubMed

Marques, Danilo R C; Marques, Danilo; Ibanez, Jose F; Freitas, Itallo B; Hespanha, Ana C; Monteiro, Juliana F; Eggert, Mayara; Becker, Amanda

2017-09-12

Experimental study. The aim of this study was to evaluate the effect of nandrolone decanoate (ND) on the time taken for bone consolidation in dogs undergoing tibial tuberosity advancement surgery (TTA). Seventeen dogs that underwent TTA surgery were randomly divided into two groups: group C (TTA; 9 stifles), and group TTA+ND (TTA and systemic administration of ND; 8 stifles). Three observers (two radiologists and an orthopaedic surgeon), assessed bone consolidation by visual inspection of serial radiographs at intervals of 21 days following surgery. There were no differences in median weight and age between groups, nor between the medians of the variables right and left stifle. Only weight and age values were normally distributed. The other variables, right and left stifle and time to consolidation, showed non-normal distribution. Meniscal injury was present in all animals in group C and all animals in group TTA+ND. There was a significant difference between time to consolidation in groups C and TTA+ND (p <0.05). One animal in the group TTA+ND showed increased libido. Kappa agreement among observers on radiographs was 0.87. Administration of ND reduces time to bone consolidation in dogs undergoing TTA.

The Human Adenovirus Type 5 E4orf4 Protein Targets Two Phosphatase Regulators of the Hippo Signaling Pathway

PubMed Central

Mui, Melissa Z.; Zhou, Yiwang; Blanchette, Paola; Chughtai, Naila; Knight, Jennifer F.; Gruosso, Tina; Papadakis, Andreas I.; Huang, Sidong; Park, Morag; Gingras, Anne-Claude

2015-01-01

ABSTRACT When expressed alone at high levels, the human adenovirus E4orf4 protein exhibits tumor cell-specific p53-independent toxicity. A major E4orf4 target is the B55 class of PP2A regulatory subunits, and we have shown recently that binding of E4orf4 inhibits PP2AB55 phosphatase activity in a dose-dependent fashion by preventing access of substrates (M. Z. Mui et al., PLoS Pathog 9:e1003742, 2013, http://dx.doi.org/10.1371/journal.ppat.1003742). While interaction with B55 subunits is essential for toxicity, E4orf4 mutants exist that, despite binding B55 at high levels, are defective in cell killing, suggesting that other essential targets exist. In an attempt to identify additional targets, we undertook a proteomics approach to characterize E4orf4-interacting proteins. Our findings indicated that, in addition to PP2AB55 subunits, ASPP-PP1 complex subunits were found among the major E4orf4-binding species. Both the PP2A and ASPP-PP1 phosphatases are known to positively regulate effectors of the Hippo signaling pathway, which controls the expression of cell growth/survival genes by dephosphorylating the YAP transcriptional coactivator. We find here that expression of E4orf4 results in hyperphosphorylation of YAP, suggesting that Hippo signaling is affected by E4orf4 interactions with PP2AB55 and/or ASPP-PP1 phosphatases. Furthermore, knockdown of YAP1 expression was seen to enhance E4orf4 killing, again consistent with a link between E4orf4 toxicity and inhibition of the Hippo pathway. This effect may in fact contribute to the cancer cell specificity of E4orf4 toxicity, as many human cancer cells rely heavily on the Hippo pathway for their enhanced proliferation. IMPORTANCE The human adenovirus E4orf4 protein has been known for some time to induce tumor cell-specific death when expressed at high levels; thus, knowledge of its mode of action could be of importance for development of new cancer therapies. Although the B55 form of the phosphatase PP2A has long been

Effect of tibial tuberosity advancement on femorotibial contact mechanics and stifle kinematics.

PubMed

Kim, Stanley E; Pozzi, Antonio; Banks, Scott A; Conrad, Bryan P; Lewis, Daniel D

2009-01-01

Objective- To evaluate the effects of tibial tuberosity advancement (TTA) on femorotibial contact mechanics and 3-dimensional kinematics in cranial cruciate ligament (CrCL)-deficient stifles of dogs. Study Design- In vitro biomechanical study. Animals- Unpaired pelvic limbs from 8 dogs, weighing 28-35 kg. Methods- Digital pressure sensors placed subjacent to the menisci were used to measure femorotibial contact force, contact area, peak and mean contact pressure, and peak pressure location with the limb under an axial load of 30% body weight and a stifle angle of 135 degrees . Three-dimensional static poses of the stifle were obtained using a Microscribe digitizing arm. Each specimen was tested under normal, CrCL-deficient, and TTA-treated conditions. Repeated measures analysis of variance with a Tukey post hoc test (P<.05) was used for statistical comparison. Results- Significant disturbances to all measured contact mechanic parameters were evident after CrCL transection, which corresponded to marked cranial tibial subluxation and internal tibial rotation in the CrCL-deficient stifle. No significant differences in any contact mechanic and kinematic parameters were detected between normal and TTA-treated stifles. Conclusion- TTA eliminates craniocaudal stifle instability during simulated weight-bearing and concurrently restores femorotibial contact mechanics to normal. Clinical Relevance- TTA may mitigate the progression of stifle osteoarthritis in dogs afflicted with CrCL insufficiency by eliminating cranial tibial thrust while preserving the normal orientation of the proximal tibial articulating surface.

A method for deriving a 4D-interpolated balanced planning target for mobile tumor radiotherapy.

PubMed

Roland, Teboh; Hales, Russell; McNutt, Todd; Wong, John; Simari, Patricio; Tryggestad, Erik

2012-01-01

Tumor control and normal tissue toxicity are strongly correlated to the tumor and normal tissue volumes receiving high prescribed dose levels in the course of radiotherapy. Planning target definition is, therefore, crucial to ensure favorable clinical outcomes. This is especially important for stereotactic body radiation therapy of lung cancers, characterized by high fractional doses and steep dose gradients. The shift in recent years from population-based to patient-specific treatment margins, as facilitated by the emergence of 4D medical imaging capabilities, is a major improvement. The commonly used motion-encompassing, or internal-target volume (ITV), target definition approach provides a high likelihood of coverage for the mobile tumor but inevitably exposes healthy tissue to high prescribed dose levels. The goal of this work was to generate an interpolated balanced planning target that takes into account both tumor coverage and normal tissue sparing from high prescribed dose levels, thereby improving on the ITV approach. For each 4DCT dataset, 4D deformable image registration was used to derive two bounding targets, namely, a 4D-intersection and a 4D-composite target which minimized normal tissue exposure to high prescribed dose levels and maximized tumor coverage, respectively. Through definition of an "effective overlap volume histogram" the authors derived an "interpolated balanced planning target" intended to balance normal tissue sparing from prescribed doses with tumor coverage. To demonstrate the dosimetric efficacy of the interpolated balanced planning target, the authors performed 4D treatment planning based on deformable image registration of 4D-CT data for five previously treated lung cancer patients. Two 4D plans were generated per patient, one based on the interpolated balanced planning target and the other based on the conventional ITV target. Plans were compared for tumor coverage and the degree of normal tissue sparing resulting from the new

GEANT4 simulation of cyclotron radioisotope production in a solid target.

PubMed

Poignant, F; Penfold, S; Asp, J; Takhar, P; Jackson, P

2016-05-01

The use of radioisotopes in nuclear medicine is essential for diagnosing and treating cancer. The optimization of their production is a key factor in maximizing the production yield and minimizing the associated costs. An efficient approach to this problem is the use of Monte Carlo simulations prior to experimentation. By predicting isotopes yields, one can study the isotope of interest expected activity for different energy ranges. One can also study the target contamination with other radioisotopes, especially undesired radioisotopes of the wanted chemical element which are difficult to separate from the irradiated target and might result in increasing the dose when delivering the radiopharmaceutical product to the patient. The aim of this work is to build and validate a Monte Carlo simulation platform using the GEANT4 toolkit to model the solid target system of the South Australian Health and Medical Research Institute (SAHMRI) GE Healthcare PETtrace cyclotron. It includes a GEANT4 Graphical User Interface (GUI) where the user can modify simulation parameters such as the energy, shape and current of the proton beam, the target geometry and material, the foil geometry and material and the time of irradiation. The paper describes the simulation and presents a comparison of simulated and experimental/theoretical yields for various nuclear reactions on an enriched nickel 64 target using the GEANT4 physics model QGSP_BIC_AllHP, a model recently developed to evaluate with high precision the interaction of protons with energies below 200MeV available in Geant4 version 10.1. The simulation yield of the (64)Ni(p,n)(64)Cu reaction was found to be 7.67±0.074 mCi·μA(-1) for a target energy range of 9-12MeV. Szelecsenyi et al. (1993) gives a theoretical yield of 6.71mCi·μA(-1) and an experimental yield of 6.38mCi·μA(-1). The (64)Ni(p,n)(64)Cu cross section obtained with the simulation was also verified against the yield predicted from the nuclear database TENDL and

Abnormal temperature dependent behaviors of intersystem crossing and triplet-triplet annihilation in organic planar heterojunction devices

NASA Astrophysics Data System (ADS)

Xiang, Jie; Chen, Yingbing; Yuan, De; Jia, Weiyao; Zhang, Qiaoming; Xiong, Zuhong

2016-09-01

Anomalous temperature dependent magneto-electroluminescence was observed at low and high magnetic field strength from organic planar heterojunction devices incorporated common phosphorescent host materials of N,N'-dicarbazolyl-3,5-benzene (mCP) or 4,4'-N,N'-dicarbazole-biphenyl (CBP) as an emissive layer. We found that intersystem crossing became stronger with decreasing temperature and that triplet-triplet annihilation (TTA) occurred at room temperature but ceased at low temperature. Analyses of the electroluminescence spectra of these devices and their temperature dependences indicated that the population of exciplex states increased at low temperature, which caused the abnormal behavior of intersystem crossing. Additionally, long lifetime of the excitons within mCP or CBP layer may allow TTA to occur at room temperature, while the reduced population of excitons at low temperature may account for the disappearance of TTA even though the excitons had increased lifetime.

Summary of Synoptic Meteorological Observations. Indonesian Coastal Marine Areas. Volume 1. Area 1 - Southeast Sumatra. Area 2 - Christmas Island. Area 3 - Sunda Strait. Area 4 - Northwest Java Sea. Area 5 - Bangka Island Northwest. Area 6 - Natuna Island. Area 7 - Sarawak

DTIC Science & Technology

1975-04-01

AD/ A -006 923 SUMMARY OF SYNOPTIC METEOROLOGICAL OBSERVATIONS. INDONESIAN COASTAL MARINE AREAS. VOLUME I. AREA 1 - SOUTHEAST SUMATRA. AREA 2...Weather Service Command Washington, D. C. April 1975 ;V, A DISTRIBUTED BY: Nausm Tsciulca Iufennls Suvm• U. S. DEPARTMENT OF COMMERCE 2 z z 0 0 ~ > o CI2LI...00 4 bO >~ d) cn q 00 ca (n~ -0E 4) fl) U C 0 E CD o :Cu -V 0. Cau . .t $4 Cu a X k) 04. " # Cu c.. - u 0- u c0 E Q =E 0 ca- 1 ca 4).,u 04$ = a )E ==r

Inverse Design of Low-Boom Supersonic Concepts Using Reversed Equivalent-Area Targets

NASA Technical Reports Server (NTRS)

Li, Wu; Rallabhand, Sriam

2011-01-01

A promising path for developing a low-boom configuration is a multifidelity approach that (1) starts from a low-fidelity low-boom design, (2) refines the low-fidelity design with computational fluid dynamics (CFD) equivalent-area (Ae) analysis, and (3) improves the design with sonic-boom analysis by using CFD off-body pressure distributions. The focus of this paper is on the third step of this approach, in which the design is improved with sonic-boom analysis through the use of CFD calculations. A new inverse design process for off-body pressure tailoring is formulated and demonstrated with a low-boom supersonic configuration that was developed by using the mixed-fidelity design method with CFD Ae analysis. The new inverse design process uses the reverse propagation of the pressure distribution (dp/p) from a mid-field location to a near-field location, converts the near-field dp/p into an equivalent-area distribution, generates a low-boom target for the reversed equivalent area (Ae,r) of the configuration, and modifies the configuration to minimize the differences between the configuration s Ae,r and the low-boom target. The new inverse design process is used to modify a supersonic demonstrator concept for a cruise Mach number of 1.6 and a cruise weight of 30,000 lb. The modified configuration has a fully shaped ground signature that has a perceived loudness (PLdB) value of 78.5, while the original configuration has a partially shaped aft signature with a PLdB of 82.3.

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2012 CFR

2012-07-01

... practice area, Mare Island Naval Shipyard, Vallejo. 334.1160 Section 334.1160 Navigation and Navigable... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a) The danger zone. A sector in San Pablo Bay adjacent to the westerly shore of Mare Island with a radius...

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2013 CFR

2013-07-01

... practice area, Mare Island Naval Shipyard, Vallejo. 334.1160 Section 334.1160 Navigation and Navigable... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a) The danger zone. A sector in San Pablo Bay adjacent to the westerly shore of Mare Island with a radius...

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2014 CFR

2014-07-01

... practice area, Mare Island Naval Shipyard, Vallejo. 334.1160 Section 334.1160 Navigation and Navigable... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a) The danger zone. A sector in San Pablo Bay adjacent to the westerly shore of Mare Island with a radius...

Efficacy of a two-tiered trauma team activation protocol in a Norwegian trauma centre.

PubMed

Rehn, M; Lossius, H M; Tjosevik, K E; Vetrhus, M; Østebø, O; Eken, T

2012-02-01

A registry-based analysis revealed imprecise informal one-tiered trauma team activation (TTA) in a primary trauma centre. A two-tiered TTA protocol was introduced and analysed to examine its impact on triage precision and resource utilization. Interhospital transfers and patients admitted by non-healthcare personnel were excluded. Undertriage was defined as the fraction of major trauma victims (New Injury Severity Score over 15) admitted without TTA. Overtriage was the fraction of TTA without major trauma. Of 1812 patients, 768 had major trauma. Overall undertriage was reduced from 28·4 to 19·1 per cent (P < 0·001) after system revision. Overall overtriage increased from 61·5 to 71·6 per cent, whereas the mean number of skilled hours spent per overtriaged patient was reduced from 6·5 to 3·5 (P < 0·001) and the number of skilled hours spent per major trauma victim was reduced from 7·4 to 7·1 (P < 0·001). Increasing age increased risk for undertriage and decreased risk for overtriage. Falls increased risk for undertriage and decreased risk for overtriage, whereas motor vehicle-related accidents showed the opposite effects. Patients triaged to a prehospital response involving an anaesthetist had less chance of both undertriage and overtriage. A two-tiered TTA protocol was associated with reduced undertriage and increased overtriage, while trauma team resource consumption was reduced. NCT00876564 (http://www.clinicaltrials.gov). Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

33 CFR 334.200 - Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U...

Code of Federal Regulations, 2013 CFR

2013-07-01

... Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River... Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River, Maryland, danger zones. (a) Aerial firing range—(1) The danger zone. The waters...

33 CFR 334.200 - Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U...

Code of Federal Regulations, 2012 CFR

2012-07-01

... Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River... Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River, Maryland, danger zones. (a) Aerial firing range—(1) The danger zone. The waters...

33 CFR 334.200 - Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U...

Code of Federal Regulations, 2014 CFR

2014-07-01

... Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River... Chesapeake Bay, Point Lookout to Cedar Point; aerial and surface firing range and target area, U.S. Naval Air Station, Patuxent River, Maryland, danger zones. (a) Aerial firing range—(1) The danger zone. The waters...

EMICORON: A multi-targeting G4 ligand with a promising preclinical profile.

PubMed

Porru, Manuela; Zizza, Pasquale; Franceschin, Marco; Leonetti, Carlo; Biroccio, Annamaria

2017-05-01

During the last decade, guanine G-rich sequences folding into G-quadruplex (G4) structures have received a lot of attention and their biological role is now a matter of large debate. Rising amounts of experimental evidence have validated several G-rich motifs as molecular targets in cancer treatment. Despite that an increasing number of small molecules has been reported to possess excellent G4 stabilizing properties, none of them has progressed through the drug-development pipeline due to their poor drug-like properties. In this context, the identification of G4 ligands with more favorable pharmacological properties and with a well-defined target activity could be fruitful for anticancer therapy application. This manuscript outlines the current state of knowledge regarding EMICORON, a G4-interactive molecule structurally and biologically similar, on the one side, to coronene and, on the other side, to a bay-monosubstituted perylene. Overall this work evidences that EMICORON, a new promising G4 ligand, possesses a marked antitumoral activity both standing alone and in combination with chemotherapeutics. Moreover, EMICORON represents a good example of multimodal class of antitumoral drug, able to simultaneously affect multiple targets participating in several distinct signaling pathways, thus simplifying the treatment modalities and improving the selectivity against cancer cells. Due to the importance of G4 forming sequences in crucial biological processes participating in tumor progression, their successful targeting with small molecules could represent a very important innovation in the development of effective therapeutic strategies against cancer. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2016 Elsevier B.V. All rights reserved.

Temporal triangular alopecia and a review of 52 past cases.

PubMed

Yamazaki, Masashi; Irisawa, Ryokichi; Tsuboi, Ryoji

2010-04-01

Temporal triangular alopecia (TTA) is a circumscribed, non-cicatricial form of alopecia confined to the frontotemporal region. The patient, a 15-year-old boy, was noticed at birth to have an alopecial area, sized 1.5 cm x 2.5 cm, in the right temporal region. Microscopic examination revealed miniaturized hair follicles accompanied by differentiated sebaceous glands. We have provided a synopsis of the past 52 cases. Of the 53 cases of TTA including our case, more than half (55.8%) were detected in childhood between the ages of 2 and 9 years, while 36.5% were detected at birth and only 3.8% (only two cases) in adulthood. There were three familial cases. Several congenital diseases were associated with the condition, for example, phakomatosis pigmentovascularis, Down syndrome and Dandy-Walker malformation. This information suggests that TTA can be recognized as a hamartomatous mosaic disease.

48 CFR 970.1504-4 - Special cost or pricing areas.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Special cost or pricing areas. 970.1504-4 Section 970.1504-4 Federal Acquisition Regulations System DEPARTMENT OF ENERGY AGENCY... cost or pricing areas. ...

Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis

PubMed Central

Srivastava, Rajneesh; Aslam, Muhammad; Kalluri, Sudhakar Reddy; Schirmer, Lucas; Buck, Dorothea; Tackenberg, Björn; Rothhammer, Veit; Chan, Andrew; Gold, Ralf; Berthele, Achim; Bennett, Jeffrey L.; Korn, Thomas; Hemmer, Bernhard

2016-01-01

BACKGROUND Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. METHODS We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. CONCLUSIONS KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.) PMID:22784115

33 CFR 334.10 - Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Gulf of Maine off Seal Island... REGULATIONS § 334.10 Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. (a) The danger zone. A circular area with a radius of 1.5 nautical miles, having its center just easterly of Seal...

Monitoring liver macrophages using nanobodies targeting Vsig4: concanavalin A induced acute hepatitis as paradigm.

PubMed

Zheng, Fang; Devoogdt, Nick; Sparkes, Amanda; Morias, Yannick; Abels, Chloé; Stijlemans, Benoit; Lahoutte, Tony; Muyldermans, Serge; De Baetselier, Patrick; Schoonooghe, Steve; Beschin, Alain; Raes, Geert

2015-02-01

Kupffer cells (KCs) are liver resident macrophages which are important for tissue homeostasis and have been implicated in immunogenic, tolerogenic and pathogenic immune reactions depending on the insult. These cells and the biomarkers they express thus represent interesting in vivo sensors for monitoring liver inflammation. In the current study, we explored whether KCs can be monitored non-invasively using single-photon-emission computed tomography (SPECT) with (99m)Tc labeled nanobodies (Nbs) targeting selected biomarkers. Nbs targeting V-set and immunoglobulin domain-containing 4 (Vsig4) or macrophage mannose receptor (MMR) accumulated in the liver of untreated mice. The liver targeting of anti-Vsig4 Nbs, but not anti-MMR Nbs, was blunted upon depletion of macrophages, highlighting specificity of anti-Vsig4 Nbs for liver macrophage imaging. Ex vivo flow cytometry and immunohistochemistry analysis confirmed that anti-Vsig4 Nbs specifically targeted KCs but no other cell types in the liver. Upon induction of acute hepatitis using concanavalin A (ConA), down-regulation of the in vivo imaging signal obtained using anti-Vsig4 Nbs reflected reduction in KC numbers and transient modulation of Vsig4 expression on KCs. Overall, these results indicate that Nbs targeting Vsig4 as molecular imaging biomarker enable non-invasive monitoring of KCs during hepatic inflammation. Copyright © 2014 Elsevier GmbH. All rights reserved.

Europium (III) Organic Complexes in Porous Boron Nitride Microfibers: Efficient Hybrid Luminescent Material

NASA Astrophysics Data System (ADS)

Lin, Jing; Feng, Congcong; He, Xin; Wang, Weijia; Fang, Yi; Liu, Zhenya; Li, Jie; Tang, Chengchun; Huang, Yang

2016-09-01

We report the design and synthesis of a novel kind of organic-inorganic hybrid material via the incorporation of europium (III) β-diketonate complexes (Eu(TTA)3, TTA = 2-thenoyltrifluoroacetone) into one-dimensional (1D) porous boron nitride (BN) microfibers. The developed Eu(TTA)3@BN hybrid composites with typical 1D fibrous morphology exhibit bright visible red-light emission on UV illumination. The confinement of Eu(TTA)3 within pores of BN microfibers not only decreases the aggregation-caused quenching in solid Eu(TTA)3, but also improves their thermal stabilities. Moreover, The strong interactions between Eu(TTA)3 and porous BN matrix result in an interesting energy transfer process from BN host to TTA ligand and TTA ligand to Eu3+ ions, leading to the remarkable increase of red emission. The synthetic approach should be a very promising strategy which can be easily expanded to other hybrid luminescent materials based on porous BN.

Europium (III) Organic Complexes in Porous Boron Nitride Microfibers: Efficient Hybrid Luminescent Material

PubMed Central

Lin, Jing; Feng, Congcong; He, Xin; Wang, Weijia; Fang, Yi; Liu, Zhenya; Li, Jie; Tang, Chengchun; Huang, Yang

2016-01-01

We report the design and synthesis of a novel kind of organic-inorganic hybrid material via the incorporation of europium (III) β-diketonate complexes (Eu(TTA)3, TTA = 2-thenoyltrifluoroacetone) into one-dimensional (1D) porous boron nitride (BN) microfibers. The developed Eu(TTA)3@BN hybrid composites with typical 1D fibrous morphology exhibit bright visible red-light emission on UV illumination. The confinement of Eu(TTA)3 within pores of BN microfibers not only decreases the aggregation-caused quenching in solid Eu(TTA)3, but also improves their thermal stabilities. Moreover, The strong interactions between Eu(TTA)3 and porous BN matrix result in an interesting energy transfer process from BN host to TTA ligand and TTA ligand to Eu3+ ions, leading to the remarkable increase of red emission. The synthetic approach should be a very promising strategy which can be easily expanded to other hybrid luminescent materials based on porous BN. PMID:27687246

SU-E-J-192: Verification of 4D-MRI Internal Target Volume Using Cine MRI

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

Lafata, K; Czito, B; Palta, M

Purpose: To investigate the accuracy of 4D-MRI in determining the Internal Target Volume (ITV) used in radiation oncology treatment planning of liver cancers. Cine MRI is used as the standard baseline in establishing the feasibility and accuracy of 4D-MRI tumor motion within the liver. Methods: IRB approval was obtained for this retrospective study. Analysis was performed on MR images from four patients receiving external beam radiation therapy for liver cancer at our institution. Eligible patients received both Cine and 4D-MRI scans before treatment. Cine images were acquired sagittally in real time at a slice bisecting the tumor, while 4D imagesmore » were acquired volumetrically. Cine MR DICOM headers were manipulated such that each respiratory frame was assigned a unique slice location. This approach permitted the treatment planning system (Eclipse, Varian Medical Systems) to recognize a complete respiratory cycle as a “volume”, where the gross tumor was contoured temporally. Software was developed to calculate the union of all frame contours in the structure set, resulting in the corresponding plane of the ITV projecting through the middle of the tumor, defined as the Internal Target Area (ITA). This was repeated for 4D-MRI, at the corresponding slice location, allowing a direct comparison of ITAs obtained from each modality. Results: Four patients have been analyzed. ITAs contoured from 4D-MRI correlate with contours from Cine MRI. The mean error of 4D values relative to Cine values is 7.67 +/− 2.55 %. No single ITA contoured from 4D-MRI demonstrated more than 10.5 % error compared to its Cine MRI counterpart. Conclusion: Motion management is a significant aspect of treatment planning within dynamic environments such as the liver, where diaphragmatic and cardiac activity influence plan accuracy. This small pilot study suggests that 4D-MRI based ITA measurements agree with Cine MRI based measurements, an important step towards clinical implementation

Effect of cranial cruciate ligament deficiency, tibial plateau leveling osteotomy, and tibial tuberosity advancement on contact mechanics and alignment of the stifle in flexion.

PubMed

Kim, Stanley E; Pozzi, Antonio; Banks, Scott A; Conrad, Bryan P; Lewis, Daniel D

2010-04-01

To assess contact mechanics and 3-dimensional (3-D) joint alignment in cranial cruciate ligament (CCL)-deficient stifles before and after tibial plateau leveling osteotomy (TPLO) and tibial tuberosity advancement (TTA) with the stifle in 90 degrees of flexion. In vitro biomechanical study. Cadaveric pelvic limb pairs (n=8) from dogs weighing 28-35 kg. Contralateral limbs were assigned to receive TPLO or TTA. Digital pressure sensors were used to measure femorotibial contact area, peak and mean contact pressure, and peak pressure location with the limb under a load of 30% body weight and stifle flexion angle of 90 degrees . 3-D poses were obtained using a Microscribe digitizer. Specimens were tested under normal, CCL deficient, and treatment conditions. Significant disturbances in alignment were not observed after CCL transection, although medial contact area was 10% smaller than normal (P=.003). There were no significant differences in contact mechanics or alignment between normal and TTA conditions; TPLO induced 6 degrees varus angulation (P<.001), 26% decrease in lateral peak pressure (P=.027), and 18% increase in medial mean pressure (P=.008) when compared with normal. Cranial tibial subluxation is nominal in CCL-deficient stifles loaded in flexion. Stifle alignment and contact mechanics are not altered by TTA, whereas TPLO causes mild varus and a subsequent increase in medial compartment loading. Cranial tibial subluxation of CCL-deficient stifles may not occur during postures that load the stifle in flexion. The significance of minor changes in loading patterns after TPLO is unknown.

Computerized pediatric telephone triage and advice programs at children's hospitals: operating and financial characteristics.

PubMed

Melzer, S M; Poole, S R

1999-08-01

To describe the operating characteristics, financial performance, and perceived value of computerized children's hospital-based telephone triage and advice (TTA) programs. A written survey of all 32 children's hospital-based TTA programs in the United States that used the same proprietary pediatric TTA software product for at least 6 months. The expense, revenues, and perceived value of children's hospital-based TTA programs. Of 30 programs (94%) responding, 27 (90%) were eligible for the study and reported on their experience with nearly 1.3 million TTA calls over a 12-month period. Programs provided pediatric TTA services for 1560 physicians, serving an average of 82 physicians (range, 10-340 physicians) and answering 38880 calls (range, 8500-140000 calls) annually. The mean call duration was 11.3 minutes and the estimated mean total expense per call was $12.45. Of programs charging fees for TTA services, 16 (59%) used a per-call fee and 7 (26%) used a monthly service fee. All respondents indicated that fees did not cover all associated costs. Telephone triage and advice programs, when examined on a stand-alone basis, were all operating with annual deficits (mean, $447000; median, $325000; range, $74000-$1.3 million), supported by the sponsoring children's hospitals and their companion programs. Using a 3-point Likert scale, the TTA program managers rated the value of the TTA program very highly as a mechanism for marketing to physicians (2.85) and increasing physician (2.92) and patient (2.80) satisfaction. Children's hospital-based TTA programs operate at substantial financial deficits. Ongoing support of these programs may derive from the perception that they are a valuable mechanism for marketing and increase patient and physician satisfaction. Children's hospitals should develop strategies to ensure the long-term financial viability of TTA programs or they may have to discontinue these services.

Measurement of the distribution of radiation in the area surrounding the target mass using optically stimulated luminescence technique.

PubMed

Tanır, A Güneş; Yedek, Hatice; Koç, Kemal; Bölükdemir, M Hicabi

2017-01-01

The scattered doses received by the area surrounding the target that has been subjected to x-rays were investigated. Two experiments were carried out: 1- Al 2 O 3 : C was used as dosimeter and the luminescence counts was measured using both the RisØ TL/OSL system and an ion chamber. 2- BeO aliquots were used and the counts were read using the IBEOX/OSL system. According to the results, the doses absorbed by the area surrounding the target are significantly amount. Copyright © 2016 Elsevier Ltd. All rights reserved.

Theta EEG source localization using LORETA in partial epilepsy patients with and without medication.

PubMed

Clemens, B; Bessenyei, M; Fekete, I; Puskás, S; Kondákor, I; Tóth, M; Hollódy, K

2010-06-01

To investigate and localize the sources of spontaneous, scalp-recorded theta activity in patients with partial epilepsy (PE). Nine patients with beginning, untreated PE (Group 1), 31 patients with already treated PE (Group 2), and 14 healthy persons were investigated by means of spectral analysis and LORETA, low resolution electromagnetic tomography (1 Hz very narrow band analysis, age-adjusted, Z-scored values). The frequency of main interest was 4-8 Hz. Group analysis: Group 1 displayed bilateral theta maxima in the temporal theta area (TTA), parietal theta area (PTA), and frontal theta area (FTA). In Group 2, theta activity increased all over the scalp as compared to the normative mean (Z=0) and also to Group 1. Maximum activity was found in the TTA, PTA, and FTA. However, in the PTA and FTA the centers of the abnormality shifted towards the medial cortex. Individual analysis: all the patients showed preferential activation (maximum Z-values) within one of the three theta areas. EEG activity in the theta band is increased in anatomically meaningful patterns in PE patients, which differs from the anatomical distribution of theta in healthy persons. The findings contribute to our understanding of the sources of theta rhythms and the pathophysiology of PE. Copyright 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

75 FR 53969 - Office of Community Services: Notice To Award an Expansion Supplement

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-02

... related to job creation and new initiatives that target careers in energy efficiency and other...; and (3) collects, develops, and disseminates resources related to job creation and careers related to... through professional consultations and peer assistance sessions; and online toolkit(s). The T/TA CAP will...

Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality

PubMed Central

Beauparlant, David; Rusert, Peter; Magnus, Carsten; Weber, Jacqueline; Uhr, Therese; Clapham, Paul R.; Metzner, Karin J.

2017-01-01

A hallmark of HIV-1 infection is the continuously declining number of the virus’ predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur. PMID:28264054

NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

PubMed Central

Yu, Jun-lan; Chen, Tian-tian; Zhou, Chen; Lian, Fu-lin; Tang, Xu-long; Wen, Yi; Shen, Jing-kang; Xu, Ye-chun; Xiong, Bing; Zhang, Nai-xia

2016-01-01

Aim: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. Methods: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. Results: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8–10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100–260 μmol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. Conclusion: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors. PMID:27238211

Developing a novel therapeutic strategy targeting Kallikrein-4 to inhibit prostate cancer growth and metastasis

DTIC Science & Technology

Kallikrein-related peptidase 4 (KLK4) is a rational therapeutic target for prostate cancer (PCa) as it is up-regulated in both localised and bone ...in PCa homing to bone . We therefore hypothesize that blockade of KLK4 activity will inhibit PCa growth and prevent metastasis to secondary sites like... bone . This project aims to develop a novel therapeutic strategy targeting KLK4 specifically in PCa. KLK4 siRNA is incorporated into a novel polymeric

Changes in Extremely Hot Summers over the Global Land Area under Various Warming Targets.

PubMed

Wang, Lei; Huang, Jianbin; Luo, Yong; Yao, Yao; Zhao, Zongci

2015-01-01

Summer temperature extremes over the global land area were investigated by comparing 26 models of the fifth phase of the Coupled Model Intercomparison Project (CMIP5) with observations from the Goddard Institute for Space Studies (GISS) and the Climate Research Unit (CRU). Monthly data of the observations and models were averaged for each season, and statistics were calculated for individual models before averaging them to obtain ensemble means. The summers with temperature anomalies (relative to 1951-1980) exceeding 3σ (σ is based on the local internal variability) are defined as "extremely hot". The models well reproduced the statistical characteristics evolution, and partly captured the spatial distributions of historical summer temperature extremes. If the global mean temperature increases 2°C relative to the pre-industrial level, "extremely hot" summers are projected to occur over nearly 40% of the land area (multi-model ensemble mean projection). Summers that exceed 5σ warming are projected to occur over approximately 10% of the global land area, which were rarely observed during the reference period. Scenarios reaching warming levels of 3°C to 5°C were also analyzed. After exceeding the 5°C warming target, "extremely hot" summers are projected to occur throughout the entire global land area, and summers that exceed 5σ warming would become common over 70% of the land area. In addition, the areas affected by "extremely hot" summers are expected to rapidly expand by more than 25%/°C as the global mean temperature increases by up to 3°C before slowing to less than 16%/°C as the temperature continues to increase by more than 3°C. The area that experiences summers with warming of 5σ or more above the warming target of 2°C is likely to maintain rapid expansion of greater than 17%/°C. To reduce the impacts and damage from severely hot summers, the global mean temperature increase should remain low.

Changes in Extremely Hot Summers over the Global Land Area under Various Warming Targets

PubMed Central

Wang, Lei; Huang, Jianbin; Luo, Yong; Yao, Yao; Zhao, Zongci

2015-01-01

Summer temperature extremes over the global land area were investigated by comparing 26 models of the fifth phase of the Coupled Model Intercomparison Project (CMIP5) with observations from the Goddard Institute for Space Studies (GISS) and the Climate Research Unit (CRU). Monthly data of the observations and models were averaged for each season, and statistics were calculated for individual models before averaging them to obtain ensemble means. The summers with temperature anomalies (relative to 1951–1980) exceeding 3σ (σ is based on the local internal variability) are defined as “extremely hot”. The models well reproduced the statistical characteristics evolution, and partly captured the spatial distributions of historical summer temperature extremes. If the global mean temperature increases 2°C relative to the pre-industrial level, “extremely hot” summers are projected to occur over nearly 40% of the land area (multi-model ensemble mean projection). Summers that exceed 5σ warming are projected to occur over approximately 10% of the global land area, which were rarely observed during the reference period. Scenarios reaching warming levels of 3°C to 5°C were also analyzed. After exceeding the 5°C warming target, “extremely hot” summers are projected to occur throughout the entire global land area, and summers that exceed 5σ warming would become common over 70% of the land area. In addition, the areas affected by “extremely hot” summers are expected to rapidly expand by more than 25%/°C as the global mean temperature increases by up to 3°C before slowing to less than 16%/°C as the temperature continues to increase by more than 3°C. The area that experiences summers with warming of 5σ or more above the warming target of 2°C is likely to maintain rapid expansion of greater than 17%/°C. To reduce the impacts and damage from severely hot summers, the global mean temperature increase should remain low. PMID:26090931

Molecular Validation of PACE4 as a Target in Prostate Cancer12

PubMed Central

D'Anjou, François; Routhier, Sophie; Perreault, Jean-Pierre; Latil, Alain; Bonnel, David; Fournier, Isabelle; Salzet, Michel; Day, Robert

2011-01-01

Prostate cancer remains the single most prevalent cancer in men. Standard therapies are still limited and include androgen ablation that initially causes tumor regression. However, tumor cells eventually relapse and develop into a hormone-refractory prostate cancer. One of the current challenges in this disease is to define new therapeutic targets, which have been virtually unchanged in the past 30 years. Recent studies have suggested that the family of enzymes known as the proprotein convertases (PCs) is involved in various types of cancers and their progression. The present study examined PC expression in prostate cancer and validates one PC, namely PACE4, as a target. The evidence includes the observed high expression of PACE4 in all different clinical stages of human prostate tumor tissues. Gene silencing studies targeting PACE4 in the DU145 prostate cancer cell line produced cells (cell line 4-2) with slower proliferation rates, reduced clonogenic activity, and inability to grow as xenografts in nude mice. Gene expression and proteomic profiling of the 4-2 cell line reveals an increased expression of known cancer-related genes (e.g., GJA1, CD44, IGFBP6) that are downregulated in prostate cancer. Similarly, cancer genes whose expression is decreased in the 4-2 cell line were upregulated in prostate cancer (e.g., MUC1, IL6). The direct role of PACE4 in prostate cancer is most likely through the upregulated processing of growth factors or through the aberrant processing of growth factors leading to sustained cancer progression, suggesting that PACE4 holds a central role in prostate cancer. PMID:21633671

Bipolar molecular composites: a new class of high-electron-mobility organic solids

NASA Astrophysics Data System (ADS)

Lin, Liang-Bih; Jenekhe, Samson A.; Borsenberger, Paul M.

1997-10-01

We describe high electron mobility in organic solids in the form of bipolar molecular composites of N,N'-bis(1,2-dimethylpropyl)-1,4,5,8-naphthalenetetracarboxylic diimide (NTDI) and tri-p-tolylaniine (TTA). The electron mobility in the NTDI/TTA composites is ~2 x 10 cm2/Vs, which is a factor of 4 to 6 higher than in pure NTDI and isone of the highest values reported for disordered organic solids. The field and temperature dependencies of the charge mobility can be described using the disorder formalism due to Bassler and co-workers, which provides an estimation of the energy width σ of the hopping site manifold. Analysis of the data gave σ=0.081 and 0.060 eV for the electron and hole mobilities in a NTDI/TTA composite of 0.5510.45 molar ratio. The energetic disorder for electron transport in the bipolar composites is substantially lower than for pure NTDI, which is 0.093 eV. The results suggest that the observed enhancement arises from a substantial reduction of energetic disorder in the electron transport manifold of the bipolar composites. The reduction of energetic disorder may be due to intermolecular charge transfer between NTDI and TTA. Such a charge transfer could stabilize the electron transport manifold by better charge delocalization, and consequently, less energetic disorder. Another possible reason for the observed enhanced electron mobility is the reduction of NTDI dimers that can act as carrier traps by the presence of TTA molecules in the bipolar composites. These results also suggest that bipolar composites represent a promising new class of high electron mobility organic solids.

MiR-32 promotes gastric carcinoma tumorigenesis by targeting Kruppel-like factor 4

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

Yan, Chao; Yu, Jianchun, E-mail: yu_jchpumch@163.com; Liu, Yuqin

Gastric cancer (GC) is a prevalent malignant cancer worldwide and is highly lethal because of its fast growth. Currently, the clinical therapy options for GC remain limited. MiR-32 has been reported as an oncogenic microRNA in many cancers, but its role in GC is unclear. Here, we found that miR-32 was overexpressed in GC tissues compared with adjacent normal tissue, and miR-32 was higher in GC patients' plasma compared with healthy individuals. Furthermore, we have identified miR-32 to be oncogenic, by promoting gastric cell proliferation, migration and invasion. We also identified Kruppel-like factor 4 (KLF4) as a direct target ofmore » miR-32. Knockdown of KLF4 promoted proliferation, migration and invasion of GC cells. We conclude that miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4, suggesting that the miR-32-KLF4 pathway may be useful in clinical diagnosis and therapeutics. - Highlights: • miR-32 was overexpression in GC tissues than adjacent normal tissue. • miR-32 was higher in GC patients' plasma compared with healthy people. • miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4.« less

The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer.

PubMed

Choi, Stephen Yiu Chuen; Xue, Hui; Wu, Rebecca; Fazli, Ladan; Lin, Dong; Collins, Colin C; Gleave, Martin E; Gout, Peter W; Wang, Yuzhuo

2016-06-01

The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling-directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721-33. ©2016 AACR. ©2016 American Association for Cancer Research.

Toward a Unified Theory of Visual Area V4

PubMed Central

Roe, Anna W.; Chelazzi, Leonardo; Connor, Charles E.; Conway, Bevil R.; Fujita, Ichiro; Gallant, Jack L.; Lu, Haidong; Vanduffel, Wim

2016-01-01

Visual area V4 is a midtier cortical area in the ventral visual pathway. It is crucial for visual object recognition and has been a focus of many studies on visual attention. However, there is no unifying view of V4’s role in visual processing. Neither is there an understanding of how its role in feature processing interfaces with its role in visual attention. This review captures our current knowledge of V4, largely derived from electrophysiological and imaging studies in the macaque monkey. Based on recent discovery of functionally specific domains in V4, we propose that the unifying function of V4 circuitry is to enable selective extraction of specific functional domain-based networks, whether it be by bottom-up specification of object features or by top-down attentionally driven selection. PMID:22500626

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma

PubMed Central

Ge, Yaoqi; Zhong, Yuejiao; Ji, Guozhong; Lu, Qianling; Dai, Xinyu; Guo, Zhirui; Zhang, Peng; Peng, Gang; Zhang, Kangzhen; Li, Yuntao

2018-01-01

Objective To study the characterization of Fe3O4@Au-C225 composite targeted MNPs. Methods Fe3O4@Au-C225 was prepared by the absorption method. The immunosorbent assay was used to evaluate its absorption efficiency at C225 Fc. ZETA SIZER3000 laser particle size analyzer, ultraviolet photometer and its characteristics were analyzed by VSM. the targeting effect of Fe3O4@Au-C225 composite targeted MNPs on U251 cells in vitro were detected by 7.0 Tesla Micro-MR; and subcutaneous transplanted human glioma in nude mice were performed the targeting effect in vivo after tail vein injection of Fe3O4@Au-C225 composite targeted MNPs by MRI. Results The self-prepared Fe3O4@Au composite MNPs can adsorb C225 with high efficiency of adsorption so that Fe3O4@Au-C225 composite targeted MNPs were prepared successfully. Fe3O4@Au-C225 composite targeted MNPs favorably targeted human glioma cell line U251 in vitro; Fe3O4@Au-C225 composite targeted MNPs have good targeting ability to xenografted glioma on nude mice in vivo, and can be traced by MRI. Conclusion The Fe3O4@Au-C225 composite targeted MNPs have the potential to be used as a tracer for glioma in vivo. PMID:29652919

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma.

PubMed

Ge, Yaoqi; Zhong, Yuejiao; Ji, Guozhong; Lu, Qianling; Dai, Xinyu; Guo, Zhirui; Zhang, Peng; Peng, Gang; Zhang, Kangzhen; Li, Yuntao

2018-01-01

To study the characterization of Fe3O4@Au-C225 composite targeted MNPs. Fe3O4@Au-C225 was prepared by the absorption method. The immunosorbent assay was used to evaluate its absorption efficiency at C225 Fc. ZETA SIZER3000 laser particle size analyzer, ultraviolet photometer and its characteristics were analyzed by VSM. the targeting effect of Fe3O4@Au-C225 composite targeted MNPs on U251 cells in vitro were detected by 7.0 Tesla Micro-MR; and subcutaneous transplanted human glioma in nude mice were performed the targeting effect in vivo after tail vein injection of Fe3O4@Au-C225 composite targeted MNPs by MRI. The self-prepared Fe3O4@Au composite MNPs can adsorb C225 with high efficiency of adsorption so that Fe3O4@Au-C225 composite targeted MNPs were prepared successfully. Fe3O4@Au-C225 composite targeted MNPs favorably targeted human glioma cell line U251 in vitro; Fe3O4@Au-C225 composite targeted MNPs have good targeting ability to xenografted glioma on nude mice in vivo, and can be traced by MRI. The Fe3O4@Au-C225 composite targeted MNPs have the potential to be used as a tracer for glioma in vivo.

1,4-Dihydropyridine Derivatives: Dihydronicotinamide Analogues—Model Compounds Targeting Oxidative Stress

PubMed Central

Velena, Astrida; Zarkovic, Neven; Gall Troselj, Koraljka; Bisenieks, Egils; Krauze, Aivars; Poikans, Janis; Duburs, Gunars

2016-01-01

Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry. PMID:26881016

SEDIMENT HABITAT ASSESSMENT FOR TARGETED NEAR-COASTAL AREAS OF THE GULF OF MEXICO: A SUMMARY

EPA Science Inventory

Lewis, Michael A. In press. Sediment Habitat Assessment for Targeted Near-Coastal Areas of the Gulf of Mexico: A Summary. In: Estuarine Indicators Workshop Proceedings. CRC Press, Boca Raton, FL. 25 p. (ERL,GB 1201).

Sediment chemical and biological quality is summarized ...

Liprin-α4 as a Possible New Therapeutic Target for Pancreatic Cancer.

PubMed

Yamasaki, Akio; Nakayama, Kazunori; Imaizumi, Akira; Kawamoto, Makoto; Fujimura, Akiko; Oyama, Yasuhiro; Nagai, Shuntaro; Yanai, Kosuke; Onishi, Hideya

2017-12-01

In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated. Suppression of liprin-α4 reduced proliferation of pancreatic cancer cells both in vitro and in vivo. Inhibition of liprin-α4 also reduced invasiveness through the suppression of endothelial-mesenchymal transition. Stimulation by liprin-α4 was through phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways. Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Restraint status improves the predictive value of motor vehicle crash criteria for pediatric trauma team activation.

PubMed

Bozeman, Andrew P; Dassinger, Melvin S; Recicar, John F; Smith, Samuel D; Rettiganti, Mallikarjuna R; Nick, Todd G; Maxson, Robert T

2012-12-01

Most trauma centers incorporate mechanistic criteria (MC) into their algorithm for trauma team activation (TTA). We hypothesized that characteristics of the crash are less reliable than restraint status in predicting significant injury and the need for TTA. We identified 271 patients (age, <15 y) admitted with a diagnosis of motor vehicle crash. Mechanistic criteria and restraint status of each patient were recorded. Both MC and MC plus restraint status were evaluated as separate measures for appropriately predicting TTA based on treatment outcomes and injury scores. Improper restraint alone predicted a need for TTA with an odds ratios of 2.69 (P = .002). MC plus improper restraint predicted the need for TTA with an odds ratio of 2.52 (P = .002). In contrast, the odds ratio when using MC alone was 1.65 (P = .16). When the 5 MC were evaluated individually as predictive of TTA, ejection, death of occupant, and intrusion more than 18 inches were statistically significant. Improper restraint is an independent predictor of necessitating TTA in this single-institution study. Copyright © 2012 Elsevier Inc. All rights reserved.

Miz1, a Novel Target of ING4, Can Drive Prostate Luminal Epithelial Cell Differentiation.

PubMed

Berger, Penny L; Winn, Mary E; Miranti, Cindy K

2017-01-01

How prostate epithelial cells differentiate and how dysregulation of this process contributes to prostate tumorigenesis remain unclear. We recently identified a Myc target and chromatin reader protein, ING4, as a necessary component of human prostate luminal epithelial cell differentiation, which is often lost in primary prostate tumors. Furthermore, loss of ING4 in the context of oncogenic mutations is required for prostate tumorigenesis. Identifying the gene targets of ING4 can provide insight into how its loss disrupts differentiation and leads to prostate cancer. Using a combination of RNA-Seq, a best candidate approach, and chromatin immunoprecipitation (ChIP), we identified Miz1 as a new ING4 target. ING4 or Miz1 overexpression, shRNA knock-down, and a Myc-binding mutant were used in a human in vitro differentiation assay to assess the role of Miz1 in luminal cell differentiation. ING4 directly binds the Miz1 promoter and is required to induce Miz1 mRNA and protein expression during luminal cell differentiation. Miz1 mRNA was not induced in shING4 expressing cells or tumorigenic cells in which ING4 is not expressed. Miz1 dependency on ING4 was unique to differentiating luminal cells; Miz1 mRNA expression was not induced in basal cells. Although Miz1 is a direct target of ING4, and its overexpression can drive luminal cell differentiation, Miz1 was not required for differentiation. Miz1 is a newly identified ING4-induced target gene which can drive prostate luminal epithelial cell differentiation although it is not absolutely required. Prostate 77:49-59, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

IL-4 downregulates expression of the target receptor CD30 in neoplastic canine mast cells

PubMed Central

Bauer, K.; Hadzijusufovic, E.; Cerny-Reiterer, S.; Hoermann, G.; Reifinger, M.; Pirker, A.; Valent, P.; Willmann, M.

2018-01-01

CD30 is a novel therapeutic target in human mast cell (MC) neoplasms. In this ‘comparative oncology’ study, we examined CD30 expression and regulation in neoplastic canine MC using a panel of immunomodulatory cytokines [interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-13 and stem cell factor (SCF)] and the canine mastocytoma cell lines NI-1 and C2. Of all cytokines tested IL-4 was found to downregulate expression of CD30 in NI-1 and C2 cells. We also found that the CD30-targeting antibody-conjugate brentuximab vedotin induces growth inhibition and apoptosis in both MC lines. Next, we asked whether IL-4-induced downregulation of CD30 interferes with brentuximab vedotin-effects. Indeed, pre-incubation of NI-1 cells with IL-4 decreased responsiveness towards brentuximab vedotin. To overcome IL-4-mediated resistance, we applied drug combinations and found that brentuximab vedotin synergizes with the Kit-targeting drugs masitinib and PKC412 in inhibiting growth of NI-1 and C2 cells. In summary, CD30 is a new marker and IL-4-regulated target in neoplastic canine MC. PMID:27507155

Time-to-Antibiotic Administration as a Quality of Care Measure in Children with Febrile Neutropenia: A Survey of Pediatric Oncology Centers

PubMed Central

McCavit, Timothy L.; Winick, Naomi

2011-01-01

Time-to-antibiotic administration (TTA) has been suggested as a quality-of-care (QOC) measure for pediatric oncology patients with febrile neutropenia (FN). Unknown, however, is to what extent pediatric oncology centers utilize TTA. Therefore, we designed and administered an electronic survey (68% response rate) of programs in the Children's Oncology Group to assess TTA utilization. Nearly half of respondents track TTA. Most reported using a benchmark of less than 60 minutes from arrival. TTA is a commonly used QOC measure for pediatric FN despite an absence of studies establishing its validity and a lack of data supporting its impact on outcomes of FN. PMID:21509930

Monte carlo simulations of the n_TOF lead spallation target with the Geant4 toolkit: A benchmark study

NASA Astrophysics Data System (ADS)

Lerendegui-Marco, J.; Cortés-Giraldo, M. A.; Guerrero, C.; Quesada, J. M.; Meo, S. Lo; Massimi, C.; Barbagallo, M.; Colonna, N.; Mancussi, D.; Mingrone, F.; Sabaté-Gilarte, M.; Vannini, G.; Vlachoudis, V.; Aberle, O.; Andrzejewski, J.; Audouin, L.; Bacak, M.; Balibrea, J.; Bečvář, F.; Berthoumieux, E.; Billowes, J.; Bosnar, D.; Brown, A.; Caamaño, M.; Calviño, F.; Calviani, M.; Cano-Ott, D.; Cardella, R.; Casanovas, A.; Cerutti, F.; Chen, Y. H.; Chiaveri, E.; Cortés, G.; Cosentino, L.; Damone, L. A.; Diakaki, M.; Domingo-Pardo, C.; Dressler, R.; Dupont, E.; Durán, I.; Fernández-Domínguez, B.; Ferrari, A.; Ferreira, P.; Finocchiaro, P.; Göbel, K.; Gómez-Hornillos, M. B.; García, A. R.; Gawlik, A.; Gilardoni, S.; Glodariu, T.; Gonçalves, I. F.; González, E.; Griesmayer, E.; Gunsing, F.; Harada, H.; Heinitz, S.; Heyse, J.; Jenkins, D. G.; Jericha, E.; Käppeler, F.; Kadi, Y.; Kalamara, A.; Kavrigin, P.; Kimura, A.; Kivel, N.; Kokkoris, M.; Krtička, M.; Kurtulgil, D.; Leal-Cidoncha, E.; Lederer, C.; Leeb, H.; Lonsdale, S. J.; Macina, D.; Marganiec, J.; Martínez, T.; Masi, A.; Mastinu, P.; Mastromarco, M.; Maugeri, E. A.; Mazzone, A.; Mendoza, E.; Mengoni, A.; Milazzo, P. M.; Musumarra, A.; Negret, A.; Nolte, R.; Oprea, A.; Patronis, N.; Pavlik, A.; Perkowski, J.; Porras, I.; Praena, J.; Radeck, D.; Rauscher, T.; Reifarth, R.; Rout, P. C.; Rubbia, C.; Ryan, J. A.; Saxena, A.; Schillebeeckx, P.; Schumann, D.; Smith, A. G.; Sosnin, N. V.; Stamatopoulos, A.; Tagliente, G.; Tain, J. L.; Tarifeño-Saldivia, A.; Tassan-Got, L.; Valenta, S.; Variale, V.; Vaz, P.; Ventura, A.; Vlastou, R.; Wallner, A.; Warren, S.; Woods, P. J.; Wright, T.; Žugec, P.

2017-09-01

Monte Carlo (MC) simulations are an essential tool to determine fundamental features of a neutron beam, such as the neutron flux or the γ-ray background, that sometimes can not be measured or at least not in every position or energy range. Until recently, the most widely used MC codes in this field had been MCNPX and FLUKA. However, the Geant4 toolkit has also become a competitive code for the transport of neutrons after the development of the native Geant4 format for neutron data libraries, G4NDL. In this context, we present the Geant4 simulations of the neutron spallation target of the n_TOF facility at CERN, done with version 10.1.1 of the toolkit. The first goal was the validation of the intra-nuclear cascade models implemented in the code using, as benchmark, the characteristics of the neutron beam measured at the first experimental area (EAR1), especially the neutron flux and energy distribution, and the time distribution of neutrons of equal kinetic energy, the so-called Resolution Function. The second goal was the development of a Monte Carlo tool aimed to provide useful calculations for both the analysis and planning of the upcoming measurements at the new experimental area (EAR2) of the facility.

Assessing protected area effectiveness using surrounding (buffer) areas environmentally similar to the target area.

PubMed

Mas, Jean-François

2005-06-01

Many studies are based on the assumption that an area and its surrounding (buffer) area present similar environmental conditions and can be compared. For example, in order to assess the effectiveness of a protected area, the land use/cover changes are compared inside the park with its surroundings. However, the heterogeneity in spatial variables can bias this assessment: we have shown that most of the protected areas in Mexico present significant environmental differences between their interior and their surroundings. Therefore, a comparison that aims at assessing the effectiveness of conservation strategies, must be cautioned. In this paper, a simple method which allows the generation of a buffer area that presents similar conditions with respect to a set of environmental variables is presented. The method was used in order to assess the effectiveness of the Calakmul Biosphere Reserve, a protected area located in the south-eastern part of Mexico. The annual rate of deforestation inside the protected area, the standard buffer area (based upon distance from the protected area only) and the similar buffer area (taking into account distance along with some environmental variables) were 0.3, 1.3 and 0.6%, respectively. These results showed that the protected area was effective in preventing land clearing, but that the comparison with the standard buffer area gave an over-optimistic vision of its effectiveness.

Toxicity of the bionematicide 1,4-naphthoquinone on non-target soil organisms.

PubMed

Chelinho, S; Maleita, C M N; Francisco, R; Braga, M E M; da Cunha, M J M; Abrantes, I; de Sousa, H C; Morais, P V; Sousa, J P

2017-08-01

The main goal of the present study was to evaluate the ecotoxicological effects of 1,4-naphthoquinone (1,4-NTQ), a natural-origin compound presenting nematicidal activity, that can be obtained from walnut husk, in plants and soil invertebrates, including non-target soil nematode communities. This research was part of an ongoing project that aims to develop environmentally-friendly nematicides obtained from agricultural residues. The battery of ISO tests included emergence and growth of corn (Zea mays) and rape (Brassica napus); avoidance with the earthworm Eisenia andrei and the collembolan Folsomia candida; and reproduction with the previous species plus the enchytraeid Enchytraeus crypticus. A novel soil nematode community assay was also performed. ISO tests and nematode assays were conducted using a natural uncontaminated soil that was spiked with a range of 1,4-NTQ concentrations. Toxicity of 1,4-NTQ was found for all test-species and the most sensitive were F. candida and E. andrei. After 7 days of exposure to 1,4-NTQ, nematode abundance decreased along the concentration gradient, and a partial recovery was observed after 14 days (1,4-NTQ <48 mg kg -1 soil). The number of nematode families consistently decreased in both periods. Overall, results indicate that a 1,4-NTQ concentration of <20 mg kg -1 could be environmentally safe but preliminary data suggest that it might be ineffective for the target-nematodes, root-knot nematodes, Meloidogyne spp., and root-lesion nematodes, Pratylenchus spp. In addition, if higher dosages of 1,4-NTQ bionematicide are necessary, the potential recovery of non-target organisms under real field scenarios also needs to be assessed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Conformational Ensembles Explored Dynamically from Disordered Peptides Targeting Chemokine Receptor CXCR4

PubMed Central

Vincenzi, Marian; Costantini, Susan; Scala, Stefania; Tesauro, Diego; Accardo, Antonella; Leone, Marilisa; Colonna, Giovanni; Guillon, Jean; Portella, Luigi; Trotta, Anna Maria; Ronga, Luisa; Rossi, Filomena

2015-01-01

This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target. PMID:26030674

M13 phage peptide ZL4 exerts its targeted binding effect on schistosoma japonicum via alkaline phosphatase.

PubMed

Liu, Yan; Yang, Shenghui; Xiao, Jianhua; Yu, Liang; Chen, Li; Zou, Ju; Wang, Kegeng; Tan, Sijie; Yu, Zhengyang; Zeng, Qingren

2015-01-01

The present study was to determine the targeting effect of M13 phage peptide ZL4 (MppZL4) on Schistosoma japonicum (S.j). Mice infected with S.j were injected with MppZL4. Real-time PCR was used to detect the distribution and metabolism of MppZL4 in the livers and lungs of mice. In vivo refusion test was performed to detect the targeting of MppZL4. Western blotting was employed to determine the expression of MppZL4. Live imaging was used to detect the distribution of oligopeptide MppZL4. Immunohistochemistry was employed to determine MppZL4 location on adult S.j body surface. Gomori method was employed to detect the influence of oligopeptide MppZL4 on alkaline phosphatase activity. The distribution and metabolism of MppZL4 and M13KE are not significantly different from each other at each time point. The abundance of MppZL4 is changed as S.j migrates in mice. The targeted binding effect of MppZL4 varies at different stages. ZL4 oligopeptide targets S.j in mice. The specific binding sites of MppZL4 on S.j body are mainly located in syncytial cells. The binding sites of MppZL4 on S.j body surface might be ALP or ALP-related proteins. MppZL4 had targeted binding effect on S.j with its binding site being associated with proteins related to S.j alkaline phosphatase. S.j tegument had a specifically binding site with exogenous peptides, offering new means to explore the interactions between hosts and parasites. Additionally, MppZL4 can possibly be used as targeting molecules in worm-resistant drugs or as tracing molecules in imaging diagnosis technologies.

Grants4Targets - an innovative approach to translate ideas from basic research into novel drugs.

PubMed

Lessl, Monika; Schoepe, Stefanie; Sommer, Anette; Schneider, Martin; Asadullah, Khusru

2011-04-01

Collaborations between industry and academia are steadily gaining importance. To combine expertises Bayer Healthcare has set up a novel open innovation approach called Grants4Targets. Ideas on novel drug targets can easily be submitted to http://www.grants4targets.com. After a review process, grants are provided to perform focused experiments to further validate the proposed targets. In addition to financial support specific know-how on target validation and drug discovery is provided. Experienced scientists are nominated as project partners and, depending on the project, tools or specific models are provided. Around 280 applications have been received and 41 projects granted. According to our experience, this type of bridging fund combined with joint efforts provides a valuable tool to foster drug discovery collaborations. Copyright © 2010 Elsevier Ltd. All rights reserved.

Exploiting the benefit of S0 → T1 excitation in triplet-triplet annihilation upconversion to attain large anti-stokes shifts: tuning the triplet state lifetime of a tris(2,2'-bipyridine) osmium(ii) complex.

PubMed

Liu, Dongyi; Zhao, Yingjie; Wang, Zhijia; Xu, Kejing; Zhao, Jianzhang

2018-03-07

Os(ii) complexes are particularly interesting for triplet-triplet annihilation (TTA) upconversion, due to the strong direct S 0 → T 1 photoexcitation, as in this way, energy loss is minimized and large anti-Stokes shift can be achieved for TTA upconversion. However, Os(bpy) 3 has an intrinsic short T 1 state lifetime (56 ns), which is detrimental for the intermolecular triplet-triplet energy transfer (TTET), one of the crucial steps in TTA upconversion. In order to prolong the triplet state lifetime, we prepared an Os(ii) tris(bpy) complex with a Bodipy moiety attached, so that an extended T 1 state lifetime is achieved by excited state electronic configuration mixing or triplet state equilibrium between the coordination center-localized state ( 3 MLCT state) and Bodipy ligand-localized state ( 3 IL state). With steady-state and time-resolved transient absorption/emission spectroscopy, we proved that the 3 MLCT is slightly above the 3 IL state (by 0.05 eV), and the triplet state lifetime was prolonged by 31-fold (from 56 ns to 1.73 μs). The TTA upconversion quantum yield was increased by 4-fold as compared to that of the unsubstituted Os(ii) complex.

48 CFR 52.226-4 - Notice of Disaster or Emergency Area Set-Aside.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Emergency Area Set-Aside. 52.226-4 Section 52.226-4 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.226-4 Notice of Disaster or Emergency Area Set-Aside. As prescribed in 26.206(b), insert the following clause: Notice of Disaster or Emergency Area Set-Aside (NOV 2007) (a) Set-aside area...

48 CFR 52.226-4 - Notice of Disaster or Emergency Area Set-Aside.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Emergency Area Set-Aside. 52.226-4 Section 52.226-4 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.226-4 Notice of Disaster or Emergency Area Set-Aside. As prescribed in 26.206(b), insert the following clause: Notice of Disaster or Emergency Area Set-Aside (NOV 2007) (a) Set-aside area...

48 CFR 52.226-4 - Notice of Disaster or Emergency Area Set-Aside.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Emergency Area Set-Aside. 52.226-4 Section 52.226-4 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.226-4 Notice of Disaster or Emergency Area Set-Aside. As prescribed in 26.206(b), insert the following clause: Notice of Disaster or Emergency Area Set-Aside (NOV 2007) (a) Set-aside area...

48 CFR 52.226-4 - Notice of Disaster or Emergency Area Set-Aside.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Emergency Area Set-Aside. 52.226-4 Section 52.226-4 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.226-4 Notice of Disaster or Emergency Area Set-Aside. As prescribed in 26.206(b), insert the following clause: Notice of Disaster or Emergency Area Set-Aside (NOV 2007) (a) Set-aside area...

48 CFR 52.226-4 - Notice of Disaster or Emergency Area Set-Aside.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Emergency Area Set-Aside. 52.226-4 Section 52.226-4 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.226-4 Notice of Disaster or Emergency Area Set-Aside. As prescribed in 26.206(b), insert the following clause: Notice of Disaster or Emergency Area Set-Aside (NOV 2007) (a) Set-aside area...

Is fibroblast growth factor receptor 4 a suitable target of cancer therapy?

PubMed

Heinzle, Christine; Erdem, Zeynep; Paur, Jakob; Grasl-Kraupp, Bettina; Holzmann, Klaus; Grusch, Michael; Berger, Walter; Marian, Brigitte

2014-01-01

Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.

Is Fibroblast Growth Factor Receptor 4 a Suitable Target of Cancer Therapy?

PubMed Central

Heinzle, Christine; Erdem, Zeynep; Paur, Jakob; Grasl-Kraupp, Bettina; Holzmann, Klaus; Grusch, Michael; Berger, Walter; Marian, Brigitte

2017-01-01

Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy. PMID:23944363

Using Genetic Buffering Relationships Identified in Fission Yeast To Elucidate the Molecular Pathology of Tuberous Sclerosis

DTIC Science & Technology

2016-07-01

5’-aat tat ttt ata tgg aat gag caa gta tgt ttt atc ata att gac cag ttc att tca agg acc ttc aaa aat ata cct acg aat tcg agc tcg ttt aaa c-3’), or...oTsc13 (5’-tta aga gtt cag att tgc ttt atg tgg tta ttc tgc tga agg tcc taa ttt att gac gtt gaa aaa taa agg cca cat agc gga tcc ccg ggt taa tta a-3...and oTsc14 (5’-ata aaa aaa att aat taa tga tgg caa ggc aca atc gta atc aat ctt tta att tag gac ttt tta tat gcc ctt atg gcg aat tcg agc tcg ttt aaa c

Missing marine protected area (MPA) targets: How the push for quantity over quality undermines sustainability and social justice.

PubMed

De Santo, Elizabeth M

2013-07-30

International targets for marine protected areas (MPAs) and networks of MPAs set by the World Summit on Sustainable Development and United Nations Convention on Biological Diversity failed to meet their 2012 deadline and have been extended to 2020. Whilst targets play an important role in building momentum for conservation, they are also responsible for the recent designation of several extremely large no-take MPAs, which pose significant long-term monitoring and enforcement challenges. This paper critically examines the effectiveness of MPA targets, focusing on the underlying risks to achieving Millennium Development Goals posed by the global push for quantity versus quality of MPAs. The observations outlined in this paper have repercussions for international protected area politics with respect to (1) the science-policy interface in environmental decision-making, and (2) social justice concerns in global biodiversity conservation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effective Photothermal Chemotherapy Using Doxorubicin-Loaded Gold Nanospheres That Target EphB4 Receptors in Tumors

PubMed Central

You, Jian; Zhang, Rui; Xiong, Chiyi; Zhong, Meng; Melancon, Maritess; Gupta, Sanjay; Nick, Alpa M.; Sood, Anil K.; Li, Chun

2012-01-01

Photothermal ablation (PTA) is an emerging technique that uses near-infrared laser light-generated heat to destroy tumor cells. However, complete tumor eradication by PTA therapy alone is difficult because heterogeneous heat distribution can lead to sub-lethal thermal dose in some areas of the tumor. Successful PTA therapy requires selective delivery of photothermal conducting nanoparticles to mediate effective PTA of tumor cells, and the ability to combine PTA with other therapy modalities. Here, we synthesized multifunctional doxorubicin (DOX)-loaded hollow gold nanospheres (DOX@HAuNS) that target EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on the cell membrane of multiple tumors and angiogenic blood vessels. Increased uptake of targeted nanoparticles T-DOX@HAuNS was observed in three EphB4-positive tumors both in vitro and in vivo. In vivo release of DOX from DOX@HAuNS, triggered by near-infrared laser, was confirmed by dual radiotracer technique. Treatment with T-DOX@HAuNS followed by near-infrared laser irradiation resulted in significantly decreased tumor growth when compared to treatments with non-targeted DOX@HAuNS plus laser or HAuNS plus laser. The tumors in six of the eight mice treated with T-DOX@HAuNS plus laser regressed completely with only residual scar tissue by 22 days following injection, and none of the treatment groups experienced a loss in body weight. Together, our findings demonstrate that concerted chemo-photothermal therapy with a single nanodevice capable of mediating simultaneous PTA and local drug release may have promise as a new anticancer therapy. PMID:22865457

Electronic Warfare Systems Career Ladder, AFSC 456X1A/B.

DTIC Science & Technology

1991-04-01

En .. 𔃾- (AS L o t.. 4 - 0 L. 0 IXtC SL U41 .004- -C . W a 3 2 ) P- C XL x1. C4’ X O b .4 -J L. 0...2 Im 1m 1 AL/HRD/ID 1 1M lm/lh1 ARMY OCCUPATIONAL SURVEY BRANCH 1 CCAF/AYX 1 DEFENSE TECHNICAL INFORMATION CENTER 2 DE1 3 , USAFOMS (KEESLER AFB MS) 1...1 i HQ AFISC/DAP 2 HQ AFLC/DPMAE 3 HQ AFSC/DPAL 3 3 HQ AFSC/TTA 1 1 HQ ATC/DPAE 3 3 HQ ATC/TTOA 2 1 HQ ESC/DPTE 3 3 HQ ESC/TTA 1 1 HQ MAC/DPAT 3 3

T-type calcium channel antagonism decreases motivation for nicotine and blocks nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine.

PubMed

Uslaner, Jason M; Vardigan, Joshua D; Drott, Jason M; Uebele, Victor N; Renger, John J; Lee, Ariel; Li, Zhaoxia; Lê, A D; Hutson, Pete H

2010-10-15

Recent evidence suggests an involvement of T-type calcium channels in the effects of drugs of abuse. We examined the influence of the novel, potent, and selective T-type calcium channel antagonist [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA-A2) (.3, 1, or 3 mg/kg) on motivation for nicotine, as measured by nicotine self-administration on a progressive ratio (PR) schedule, and nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine delivery (n = 11 or 12 Long Evans rats/group). Furthermore, we examined the specificity of the TTA-A2 effects by characterizing its influence on PR responding for food (in the absence or presence of nicotine-potentiated responding), food- versus nicotine-induced cue-potentiated reinstatement for a response previously reinforced by food administration (n = 11 or 12 Wistar Hannover rats/group), and its ability to induce a conditioned place aversion. TTA-A2 dose-dependently decreased self-administration of nicotine on a PR schedule and the ability of both nicotine and a cue paired with nicotine to reinstate responding. The effects were specific for nicotine's incentive motivational properties, as TTA-A2 did not influence responding for food on a PR schedule but did attenuate the ability of nicotine to potentiate responding for food. Likewise, TTA-A2 did not alter food-induced cue-potentiated reinstatement for a response previously reinforced by food but did decrease nicotine-induced cue-potentiated reinstatement. Finally, TTA-A2 did not produce an aversive state, as indicated by a lack of ability to induce conditioned place aversion. These data suggest that T-type calcium channel antagonists have potential for alleviating nicotine addiction by selectively decreasing the incentive motivational properties of nicotine. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

A Comparison of Angular Values of the Pelvic Limb with Normal and Medial Patellar Luxation Stifles in Chihuahua Dogs Using Radiography and Computed Tomography.

PubMed

Phetkaew, Thitaporn; Kalpravidh, Marissak; Penchome, Rampaipat; Wangdee, Chalika

2018-02-01

 This article aimed to determine and compare the angular values of the pelvic limb in normal and medial patellar luxation (MPL) stifles in Chihuahuas using radiography and computed tomographic (CT) scan, to identify the relationship between pelvic limb angles and severity of MPL. In addition, radiographic and CT images were compared to determine the more suitable method of limb deformity assessment.  Sixty hindlimbs of Chihuahuas were divided into normal and grade 1, 2, 3 and 4 MPL groups. The pelvic limb angles in frontal and sagittal planes were evaluated on radiography and CT scan. Femoral and tibial torsion angles (FTA and TTA) were evaluated only by CT scan. All angles were compared among normal and MPL stifles and between radiography and CT scan.  Based on the CT scan, the mechanical lateral distal femoral angle (mLDFA), anatomical caudal proximal femoral angle (aCdPFA), and TTA were related to the severity of MPL. The mLDFA and TTA were significantly increased ( p  < 0.05) in grade 4 MPL, while the aCdPFA was significantly decreased in grade 2, 3 and 4 MPL groups. There were significant differences of many angles between radiography and CT scan.  The angles related to MPL in Chihuahuas are aLDFA, mLDFA, aCdPFA and TTA. Radiography had some limitations for evaluating pelvic limb angles. The caudocranial radiograph is recommended for the assessment of the distal femoral angles, while the craniocaudal radiograph is for the tibial angles. Schattauer GmbH Stuttgart.

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation.

PubMed

Zhou, H; Liu, Y; Zhu, R; Ding, F; Wan, Y; Li, Y; Liu, Z

2017-06-08

Krüppel-like factor 4 (KLF4, GKLF) is a zinc-finger transcription factor involved in a large variety of cellular processes, including apoptosis, cell cycle progression, as well as stem cell renewal. KLF4 is critical for cell fate decision and has an ambivalent role in tumorigenesis. Emerging data keep reminding us that KLF4 dysregulation either facilitates or impedes tumor progression, making it important to clarify the regulating network of KLF4. Like most transcription factors, KLF4 has a rather short half-life within the cell and its turnover must be carefully orchestrated by ubiquitination and ubiquitin-proteasome system. To better understand the mechanism of KLF4 ubiquitination, we performed a genome-wide screen of E3 ligase small interfering RNA library based on western blot and identified SCF-FBXO32 to be a new E3 ligase, which is responsible for KLF4 ubiquitination and degradation. The F-box domain is critical for FBXO32-dependent KLF4 ubiquitination and degradation. Furthermore, we demonstrated that FBXO32 physically interacts with the N-terminus (1-60 aa) of KLF4 via its C-terminus (228-355 aa) and directly targets KLF4 for ubiquitination and degradation. We also found out that p38 mitogen-activated protein kinase pathway may be implicated in FBXO32-mediated ubiquitination of KLF4, as p38 kinase inhibitor coincidently abrogates endogenous KLF4 ubiquitination and degradation, as well as FBXO32-dependent exogenous KLF4 ubiquitination and degradation. Finally, FBXO32 inhibits colony formation in vitro and primary tumor initiation and growth in vivo through targeting KLF4 into degradation. Our findings thus further elucidate the tumor-suppressive function of FBXO32 in breast cancer. These results expand our understanding of the posttranslational modification of KLF4 and of its role in breast cancer development and provide a potential target for diagnosis and therapeutic treatment of breast cancer.

MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*

PubMed Central

Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

2015-01-01

Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009

Closure Report for Corrective Action Unit 408: Bomblet Target Area Tonopah Test Range (TTR), Nevada, Revision 0

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

Mark Krauss

2010-09-01

This Closure Report (CR) presents information supporting the closure of Corrective Action Unit (CAU) 408: Bomblet Target Area (TTR), Tonopah Test Range, Nevada. This CR complies with the requirements of the Federal Facility Agreement and Consent Order that was agreed to by the State of Nevada; U.S. Department of Energy (DOE), Environmental Management; U.S. Department of Defense; and DOE, Legacy Management. Corrective Action Unit 408 is located at the Tonopah Test Range, Nevada, and consists of Corrective Action Site (CAS) TA-55-002-TAB2, Bomblet Target Areas. This CAS includes the following seven target areas: • Mid Target • Flightline Bomblet Location •more » Strategic Air Command (SAC) Target Location 1 • SAC Target Location 2 • South Antelope Lake • Tomahawk Location 1 • Tomahawk Location 2 The purpose of this CR is to provide documentation supporting the completed corrective actions and data confirming that the closure objectives for the CAS within CAU 408 were met. To achieve this, the following actions were performed: • Review the current site conditions, including the concentration and extent of contamination. • Implement any corrective actions necessary to protect human health and the environment. • Properly dispose of corrective action and investigation wastes. • Document Notice of Completion and closure of CAU 408 issued by the Nevada Division of Environmental Protection. From July 2009 through August 2010, closure activities were performed as set forth in the Streamlined Approach for Environmental Restoration Plan for CAU 408: Bomblet Target Area, Tonopah Test Range (TTR), Nevada. The purposes of the activities as defined during the data quality objectives process were as follows: • Identify and remove munitions of explosive concern (MEC) associated with DOE activities. • Investigate potential disposal pit locations. • Remove depleted uranium-contaminated fragments and soil. • Determine whether contaminants of concern

Exciplex-Sensitized Triplet-Triplet Annihilation in Heterojunction Organic Thin-Film.

PubMed

Lin, Bo-Yen; Easley, Connor J; Chen, Chia-Hsun; Tseng, Po-Chen; Lee, Ming-Zer; Sher, Pin-Hao; Wang, Juen-Kai; Chiu, Tien-Lung; Lin, Chi-Feng; Bardeen, Christopher J; Lee, Jiun-Haw

2017-03-29

A new concept for organic light-emitting diodes (OLEDs) is presented, which is called exciplex-sensitized triplet-triplet annihilation (ESTTA). The exciplex formed at the organic heterojunction interface of 4,4',4″-tris(N-3-methyphenyl-N-phenyl-amino) triphenylamine and 9,10-bis(2'-naphthyl) anthracene (ADN) is used to sensitize the triplet-triplet annihilation (TTA) process on the ADN molecules. This results in a turn-on voltage (2.2 V) of the blue emission from the OLED below the bandgap (2.9 eV). From the transient electroluminescence measurement, blue emission totally came from the TTA process without direct recombination on the ADN molecules. The blue singlet exciton from the TTA process can be quenched by energy transfer to the exciplex, as revealed by transient photoluminescence measurements. This can be prevented by blocking the energy transfer path and improving the radiative recombination rate of blue emission. With the insertion of the "triplet diffusion and singlet blocking (TDSB)" layer and the incorporation of the dopant material, an ESTTA-OLED with external quantum efficiency of 5.1% was achieved, which consists of yellow and blue emission coming from the exciplex and ESTTA process, respectively.

Crystal structure, molecular docking, and biological activity of the zinc complexes with 2-thenoyltrifluoroacetone and N-donor heterocyclic ligands

NASA Astrophysics Data System (ADS)

Eshaghi Malekshah, Rahime; Salehi, Mehdi; Kubicki, Maciej; Khaleghian, Ali

2017-12-01

Two novel mononuclear complexes, [Zn (TTA) (bipy)Cl] (1) and [Zn (TTA) (phen)Cl] (2) (TTA = 4,4,4-Trifluoro-1-(2-furyl)-1,3-butanedione, phen = 1,10-phenanthroline and bipy 2, 2ʹ-bipyridine), were synthesized and fully characterized by elemental analyses, 1H NMR, UV-Vis, FTIR spectroscopy, and conductivity measurements. The crystal structures of these two mono-nuclear zinc (II) complexes were determined by X-ray single-crystal diffraction. The result of X-ray diffraction analyses revealed that both complexes have distorted tetragonal-pyramid structures. In MTT cytotoxicity studies, these Zn (II) complexes exhibited antitumor activity against MCF-7 and MKN-45 cell lines. It was also found that the proliferation rate of MCF-7 and MKN-45 cells decreased after treatment with the above-mentioned complexes. In addition, the apoptosis-inducing activity was assessed by AO/EB (Acridine Orange/Ethidium bromide) staining assay and found that they have the potential to act as effective metal-based anticancer drugs. Finally, the molecular docking studies showed that complex 2 strongly binds through minor groove with DNA by relative binding energy -7.33 kcal mol-1.

Rational Design of a Lanthanide-Based Complex Featuring Different Single-Molecule Magnets.

PubMed

Pointillart, F; Guizouarn, T; Lefeuvre, B; Golhen, S; Cador, O; Ouahab, L

2015-11-16

The rational synthesis of the 2-{1-methylpyridine-N-oxide-4,5-[4,5-bis(propylthio)tetrathiafulvalenyl]-1H-benzimidazol-2-yl}pyridine ligand (L) is described. It led to the tetranuclear complex [Dy4(tta)12(L)2] (Dy-Dy2-Dy) after coordination reaction with the precursor Dy(tta)3⋅2 H2O (tta(-) = 2-thenoyltrifluoroacetonate). The X-ray structure of Dy-Dy2-Dy can be described as two terminal mononuclear units bridged by a central antiferromagnetically coupled dinuclear complex. The terminal N2O6 and central O8 environments are described as distorted square antiprisms. The ac magnetism measurements revealed a strong out-of-phase signal of the magnetic susceptibility with two distinct sets of data. The high- and low-frequency components were attributed to the two terminal mononuclear single-molecule magnets (SMMs) and the central dinuclear SMM, respectively. A magnetic hysteresis loop was detected at very low temperature. From both structural and magnetic points of view, the tetranuclear SMM Dy-Dy2-Dy is a self-assembly of two known mononuclear SMMs bridged by a known dinuclear SMM. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Impact of target area selection in 125 Iodine seed brachytherapy on locoregional recurrence in patients with non-small cell lung cancer.

PubMed

Yan, Wei-Liang; Lv, Jin-Shuang; Guan, Zhi-Yu; Wang, Li-Yang; Yang, Jing-Kui; Liang, Ji-Xiang

2017-05-01

Computed tomography (CT)-guided percutaneous implantation of 125 Iodine radioactive seeds requires the precise arrangement of seeds by tumor shape. We tested whether selecting target areas, including subclinical areas around tumors, can influence locoregional recurrence in patients with non-small cell lung cancer (NSCLC). We divided 82 patients with NSCLC into two groups. Target areas in group 1 (n = 40) were defined along tumor margins based on lung-window CT. Target areas in group 2 (n = 42) were extended by 0.5 cm in all dimensions outside tumor margins. Preoperative plans for both groups were based on a treatment plan system, which guided 125 I seed implantation. Six months later, patients underwent chest CT to evaluate treatment efficacy (per Response Evaluation Criteria in Solid Tumors version 1). We compared locoregional recurrences between the groups after a year of follow-up. We then used the treatment plan system to extend target areas for group 1 patients by 0.5 cm (defined as group 3 data) and compared these hypothetical group 3 planned seeds with the actual seed numbers used in group 1 patients. All patients successfully underwent implantation; none died during the follow-up period. Recurrence was significantly lower in group 2 than in group 1 ( P  < 0.05). Group 1 patients and group 3 data significantly differed in seed numbers ( P  < 0.01). Our results imply that extending the implantation area for 125 I seeds can decrease recurrence risk by eradicating cancerous lymph-duct blockades within the extended areas. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment.

PubMed

Scala, Stefania

2015-10-01

Evidence suggests that the CXC-chemokine receptor-4 pathway plays a role in cancer cell homing and metastasis, and thus represents a potential target for cancer therapy. The homeostatic microenvironment chemokine CXCL12 binds the CXCR4 and CXCR7 receptors, activating divergent signals on multiple pathways, such as ERK1/2, p38, SAPK/JNK, AKT, mTOR, and the Bruton tyrosine kinase (BTK). An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia. The CXCR4-CXCL12 axis regulates the hematopoietic stem cell niche--a property that has led to the approval of the CXCR4 antagonist plerixafor (AMD3100) for mobilization of hematopoietic precursors. In preclinical models, plerixafor has shown antimetastatic potential in vivo, offering proof of concept. Other antagonists are in preclinical and clinical development. Recent evidence demonstrates that inhibiting CXCR4 signaling restores sensitivity to CTLA-4 and PD-1 checkpoint inhibitors, creating a new line for investigation. Targeting the CXCR4-CXCL12 axis thus offers the possibility of affecting CXCR4-expressing primary tumor cells, modulating the immune response, or synergizing with other targeted anticancer therapies. ©2015 American Association for Cancer Research.

Comparison of the boomerang wire vascular access management system versus manual compression alone during percutaneous diagnostic and interventional cardiovascular procedures: The boomerang™ wire vascular access management trial II.

PubMed

Goswami, Nilesh J; Smalling, Ronnie G; Sinha, Shantanu; Gammon, Roger S; Ramaiah, Venkatesh G

2016-01-01

To evaluate the use of the Boomerang™ Wire as an adjunct to manual compression (MC) in patients requiring diagnostic (Dx) or interventional (Ix) percutaneous procedures. MC remains the standard of care for closure of femoral artery access sites. Adjunctive use of a device to facilitate closure, reduce time to hemostasis (TTH) and ambulation (TTA) without increasing complication rates could reduce costs and hospital resource demands. The Boomerang™ Trial was a prospective, multicenter, randomized, controlled trial comparing use of the Boomerang™ wire, (Cardiva Medical, Sunnyvale, CA) in conjunction with MC versus MC alone to achieve hemostasis in Dx and Ix patients undergoing percutaneous procedures requiring femoral artery access. Endpoints included TTH, TTA, major, and minor access-site related complications. Subjects were randomized 3:1, Boomerang versus MC. No minor or major device-related adverse events were reported. Nondevice related complication rates were 3 (0.9%) in the Boomerang arm (n = 327) and 1 (0.8%) in MC arm (n = 123). Mean TTH for Boomerang vs. MC was 11.2 ± 4.3 vs. 23.2 ± 11 min for Dx (P < 0.0001) and 13.9 ± 5.4 vs. 38.4 ± 57.3 min for Ix patients (P < 0.0001). Mean TTA for Boomerang vs. MC was 3.3 ± 3.0 vs. 4.5 ± 2.0 hr (P < 0.0001)for Dx and 5.4 ± 3.3 vs. 6.8 ± 3.2 hr (P < 0.0001) for Ix patients. Boomerang™ use, in conjunction with MC, was associated with low rates of complications and demonstrated that Boomerang™ as an adjunct to MC can significantly decrease TTH and TTA after both Dx and Ix procedures. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4.

PubMed

Xiao, Junjie; Lv, Dongchao; Zhou, Jinzhe; Bei, Yihua; Chen, Ting; Hu, Muren; Zhou, Qiulian; Fu, Siyi; Huang, Qi

2017-01-01

Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.

Emerging Targets in Pituitary Adenomas: Role of the CXCL12/CXCR4-R7 System.

PubMed

Barbieri, Federica; Thellung, Stefano; Würth, Roberto; Gatto, Federico; Corsaro, Alessandro; Villa, Valentina; Nizzari, Mario; Albertelli, Manuela; Ferone, Diego; Florio, Tullio

2014-01-01

Chemokines are chemotactic regulators of immune surveillance in physiological and pathological conditions such as inflammation, infection, and cancer. Several chemokines and cognate receptors are constitutively expressed in the central nervous system, not only in glial and endothelial cells but also in neurons, controlling neurogenesis, neurite outgrowth, and axonal guidance during development. In particular, the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, form a functional network that controls plasticity in different brain areas, influencing neurotransmission, neuromodulation, and cell migration, and the dysregulation of this chemokinergic axis is involved in several neurodegenerative, neuroinflammatory, and malignant diseases. CXCR4 primarily mediates the transduction of proliferative signals, while CXCR7 seems to be mainly responsible for scavenging CXCL12. Importantly, the multiple intracellular signalling generated by CXCL12 interaction with its receptors influences hypothalamic modulation of neuroendocrine functions, although a direct modulation of pituitary functioning via autocrine/paracrine mechanisms was also reported. Both CXCL12 and CXCR4 are constitutively overexpressed in pituitary adenomas and their signalling induces cell survival and proliferation, as well as hormonal hypersecretion. In this review we focus on the physiological and pathological functions of immune-related cyto- and chemokines, mainly focusing on the CXCL12/CXCR4-7 axis, and their role in pituitary tumorigenesis. Accordingly, we discuss the potential targeting of CXCR4 as novel pharmacological approach for pituitary adenomas.

Stereotactically Standard Areas: Applied Mathematics in the Service of Brain Targeting in Deep Brain Stimulation.

PubMed

Mavridis, Ioannis N

2017-12-11

The concept of stereotactically standard areas (SSAs) within human brain nuclei belongs to the knowledge of the modern field of stereotactic brain microanatomy. These are areas resisting the individual variability of the nuclear location in stereotactic space. This paper summarizes the current knowledge regarding SSAs. A mathematical formula of SSAs was recently invented, allowing for their robust, reproducible, and accurate application to laboratory studies and clinical practice. Thus, SSAs open new doors for the application of stereotactic microanatomy to highly accurate brain targeting, which is mainly useful for minimally invasive neurosurgical procedures, such as deep brain stimulation.

Bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles as novel tumor targeting carriers

NASA Astrophysics Data System (ADS)

Ding, Hong; Yong, Ken-Tye; Roy, Indrajit; Hu, Rui; Wu, Fang; Zhao, Lingling; Law, Wing-Cheung; Zhao, Weiwei; Ji, Wei; Liu, Liwei; Bergey, Earl J.; Prasad, Paras N.

2011-04-01

In this study, we have developed a novel carrier, micelle-type bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles (NPs), for the detection and treatment of pancreatic cancer. These NPs contained 4-arm-PEG as corona, and PLGA as core, the particle surface was conjugated with cyclo(arginine-glycine-aspartate) (cRGD) as ligand for in vivo tumor targeting. The hydrodynamic size of the NPs was determined to be 150-180 nm and the critical micellar concentration (CMC) was estimated to be 10.5 mg l - 1. Our in vitro study shows that these NPs by themselves had negligible cytotoxicity to human pancreatic cancer (Panc-1) and human glioblastoma (U87) cell lines. Near infrared (NIR) microscopy and flow cytometry demonstrated that the cRGD conjugated PLGA-4-arm-PEG polymeric NPs were taken up more efficiently by U87MG glioma cells, over-expressing the αvβ3 integrin, when compared with the non-targeted NPs. Whole body imaging showed that the cRGD conjugated PLGA-4-arm-PEG branched polymeric NPs had the highest accumulation in the pancreatic tumor site of mice at 48 h post-injection. Physical, hematological, and pathological assays indicated low in vivo toxicity of this NP formulation. These studies on the ability of these bioconjugated PLGA-4-arm-PEG polymeric NPs suggest that the prepared polymeric NPs may serve as a promising platform for detection and targeted drug delivery for pancreatic cancer.

MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.

PubMed

Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

2015-03-27

Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Toll-like Receptor-4: A New Target for Preterm Labour Pharmacotherapies?

PubMed

Robertson, Sarah A; Wahid, Hanan H; Chin, Peck Yin; Hutchinson, Mark R; Moldenhauer, Lachlan M; Keelan, Jeffrey A

2018-01-01

Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks' gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Guide for geometric design and operational factors that impact truck use of toll roads.

DOT National Transportation Integrated Search

2010-09-01

Texas has approximately 300 miles of toll roads, predominantly in the three largest and : most congested urban areas of Austin, Dallas, and Houston. The Texas Turnpike Authority : (TTA) Division of the Texas Department of Transportation (TxDOT) and t...

Inhibition Mechanism of an Anti-CRISPR Suppressor AcrIIA4 Targeting SpyCas9.

PubMed

Yang, Hui; Patel, Dinshaw J

2017-07-06

Prokaryotic CRISPR-Cas adaptive immune systems utilize sequence-specific RNA-guided endonucleases to defend against infection by viruses, bacteriophages, and mobile elements, while these foreign genetic elements evolve diverse anti-CRISPR proteins to overcome the CRISPR-Cas-mediated defense of the host. Recently, AcrIIA2 and AcrIIA4, encoded by Listeria monocytogene prophages, were shown to block the endonuclease activity of type II-A Streptococcus pyogene Cas9 (SpyCas9). We now report the crystal structure of AcrIIA4 in complex with single-guide RNA-bound SpyCas9, thereby establishing that AcrIIA4 preferentially targets critical residues essential for PAM duplex recognition, as well as blocks target DNA access to key catalytic residues lining the RuvC pocket. These structural insights, validated by biochemical assays on key mutants, demonstrate that AcrIIA4 competitively occupies both PAM-interacting and non-target DNA strand cleavage catalytic pockets. Our studies provide insights into anti-CRISPR-mediated suppression mechanisms for inactivating SpyCas9, thereby broadening the applicability of CRISPR-Cas regulatory tools for genome editing. Published by Elsevier Inc.

The EML4-ALK oncogene: targeting an essential growth driver in human cancer.

PubMed

Mano, Hiroyuki

2015-01-01

Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK-positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment.

The EML4-ALK oncogene: targeting an essential growth driver in human cancer

PubMed Central

MANO, Hiroyuki

2015-01-01

Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK–positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment. PMID:25971657

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.

PubMed

Di Pisa, Flavio; Landi, Giacomo; Dello Iacono, Lucia; Pozzi, Cecilia; Borsari, Chiara; Ferrari, Stefania; Santucci, Matteo; Santarem, Nuno; Cordeiro-da-Silva, Anabela; Moraes, Carolina B; Alcantara, Laura M; Fontana, Vanessa; Freitas-Junior, Lucio H; Gul, Sheraz; Kuzikov, Maria; Behrens, Birte; Pöhner, Ina; Wade, Rebecca C; Costi, Maria Paola; Mangani, Stefano

2017-03-08

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues ( 1 - 3 ) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes ( Trypanosoma brucei PTR1- Tb PTR1 and Leishmania major-Lm PTR1) and parasites ( Trypanosoma brucei and Leishmania infantum ). A crystal structure of Tb PTR1 in complex with compound 1 and the first crystal structures of Lm PTR1-flavanone complexes (compounds 1 and 3 ) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.

PubMed

Beaino, Wissam; Nedrow, Jessie R; Anderson, Carolyn J

2015-06-01

Malignant melanoma is a highly aggressive cancer, and the incidence of this disease is increasing worldwide at an alarming rate. Despite advances in the treatment of melanoma, patients with metastatic disease still have a poor prognosis and low survival rate. New strategies, including targeted radiotherapy, would provide options for patients who become resistant to therapies such as BRAF inhibitors. Very late antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels in more aggressive and metastatic disease and may provide an ideal target for drug delivery and targeted radiotherapy. In this study, we evaluated (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A as a VLA-4-targeted radiotherapeutic with a companion PET agent for diagnosis and monitoring metastatic melanoma treatment. DOTA-PEG4-LLP2A was synthesized by solid-phase synthesis. The affinity of (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A to VLA-4 was determined in B16F10 melanoma cells by saturation binding and competitive binding assays, respectively. Biodistribution of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10 subcutaneous tumors, while PET/CT imaging was performed in subcutaneous and metastatic models. (177)Lu-DOTA-PEG4-LLP2A showed high affinity to VLA-4 with a Kd of 4.1 ± 1.5 nM and demonstrated significant accumulation in the B16F10 melanoma tumor after 4 h (31.5 ± 7.8%ID/g). The tumor/blood ratio of (177)Lu-DOTA-PEG4-LLP2A was highest at 24 h (185 ± 26). PET imaging of metastatic melanoma with (68)Ga-DOTA-PEG4-LLP2A showed high uptake in sites of metastases and correlated with bioluminescence imaging of the tumors. These data demonstrate that (177)Lu-DOTA-PEG4-LLP2A has potential as a targeted therapeutic for treating melanoma as well as other VLA-4-expressing tumors. In addition, (68)Ga-DOTA-PEG4-LLP2A is a readily translatable companion PET tracer for imaging of metastatic melanoma.

Modeling of a cyclotron target for the production of 11C with Geant4.

PubMed

Chiappiniello, Andrea; Zagni, Federico; Infantino, Angelo; Vichi, Sara; Cicoria, Gianfranco; Morigi, Maria Pia; Marengo, Mario

2018-04-12

In medical cyclotron facilities, 11C is produced according to the 14N(p,α)11C reaction and widely employed in studies of prostate and brain cancers by Positron Emission Tomography. It is known from literature [1] that the 11C-target assembly shows a reduction in efficiency during time, meaning a decrease of activity produced at the end of bombardment. This effect might depend on aspects still not completely known. Possible causes of the loss of performance of the 11C-target assembly were addressed by Monte Carlo simulations. Geant4 was used to model the 11C-target assembly of a GE PETtrace cyclotron. The physical and transport parameters to be used in the energy range of medical applications were extracted from literature data and 11C routine productions. The Monte Carlo assessment of 11C saturation yield was performed varying several parameters such as the proton energy and the angle of the target assembly with respect to the proton beam. The estimated 11C saturation yield is in agreement with IAEA data at the energy of interest, while is about the 35% greater than experimental value. A more comprehensive modeling of the target system, including thermodynamic effect, is required. The energy absorbed in the inner layer of the target chamber was up to 46.5 J/mm2 under typical irradiation conditions. This study shows that Geant4 is potentially a useful tool to design and optimize targetry for PET radionuclide productions. Tests to choose the Geant4 physics libraries should be performed before using this tool with different energies and materials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Modeling spallation reactions in tungsten and uranium targets with the Geant4 toolkit

NASA Astrophysics Data System (ADS)

Malyshkin, Yury; Pshenichnov, Igor; Mishustin, Igor; Greiner, Walter

2012-02-01

We study primary and secondary reactions induced by 600 MeV proton beams in monolithic cylindrical targets made of natural tungsten and uranium by using Monte Carlo simulations with the Geant4 toolkit [1-3]. Bertini intranuclear cascade model, Binary cascade model and IntraNuclear Cascade Liège (INCL) with ABLA model [4] were used as calculational options to describe nuclear reactions. Fission cross sections, neutron multiplicity and mass distributions of fragments for 238U fission induced by 25.6 and 62.9 MeV protons are calculated and compared to recent experimental data [5]. Time distributions of neutron leakage from the targets and heat depositions are calculated. This project is supported by Siemens Corporate Technology.

The Poughkeepsie Survey. A Report on Employment and Unemployment in a "Target Area" under the Model Cities Program.

ERIC Educational Resources Information Center

Kuper, Irvin, Ed.

Located in the heart of the Mid-Hudson area, Poughkeepsie is in one of the fastest growing regions of New York State, but the city itself has grown very little in the last five decades. The local Model Cities agency has created a target area which includes most of the older part of the city. In July 1967, the population was 35,970. A total of…

A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

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

Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young

2013-01-25

Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies.more » This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.« less

Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers.

PubMed

Iacobazzi, Rosa Maria; Porcelli, Letizia; Lopedota, Angela Assunta; Laquintana, Valentino; Lopalco, Antonio; Cutrignelli, Annalisa; Altamura, Emiliano; Di Fonte, Roberta; Azzariti, Amalia; Franco, Massimo; Denora, Nunzio

2017-08-07

Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R. Copyright © 2017 Elsevier B.V. All rights reserved.

Regulator of G protein signaling 4 is a novel target of GATA-6 transcription factor

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

Zhang, Yonggang; Li, Fang; Xiao, Xiao

GATA transcription factors regulate an array of genes important in cell proliferation and differentiation. Here we report the identification of regulator of G protein signaling 4 (RGS4) as a novel target for GATA-6 transcription factor. Although three sites (a, b, c) within the proximal region of rabbit RGS4 promoter for GATA transcription factors were predicted by bioinformatics analysis, only GATA-a site (16 bp from the core TATA box) is essential for RGS4 transcriptional regulation. RT-PCR analysis demonstrated that only GATA-6 was highly expressed in rabbit colonic smooth muscle cells but GATA-4/6 were expressed in cardiac myocytes and GATA-1/2/3 expressed inmore » blood cells. Adenovirus-mediated expression of GATA-6 but not GATA-1 significantly increased the constitutive and IL-1β-induced mRNA expression of the endogenous RGS4 in colonic smooth muscle cells. IL-1β stimulation induced GATA-6 nuclear translocation and increased GATA-6 binding to RGS4 promoter. These data suggest that GATA factor could affect G protein signaling through regulating RGS4 expression, and GATA signaling may develop as a future therapeutic target for RGS4-related diseases. - Highlights: • GATA-6 is highly expressed in colonic smooth muscle cells. • RGS4 is a novel target for GATA-6 transcription factor. • GATA-a response element is essential to regulate the core promoter of RGS4. • GATA-6 regulates IL-1β-induced RGS4 upregulation.« less

Italian: Area Background Information.

ERIC Educational Resources Information Center

Defense Language Inst., Washington, DC.

This booklet has been assembled in order to provide students of Italian with a compact source of cultural information on their target area. Chapters include discussion of: (1) introduction to Italian; (2) origins of the Italian population; (3) geography; (4) history including the Roman Era, the Middle Ages, the Renaissance, the "Risorgimento," and…

The Roots of Alzheimer's Disease: Are High-Expanding Cortical Areas Preferentially Targeted?†.

PubMed

Fjell, Anders M; Amlien, Inge K; Sneve, Markus H; Grydeland, Håkon; Tamnes, Christian K; Chaplin, Tristan A; Rosa, Marcello G P; Walhovd, Kristine B

2015-09-01

Alzheimer's disease (AD) is regarded a human-specific condition, and it has been suggested that brain regions highly expanded in humans compared with other primates are selectively targeted. We calculated shared and unique variance in the distribution of AD atrophy accounted for by cortical expansion between macaque and human, affiliation to the default mode network (DMN), ontogenetic development and normal aging. Cortical expansion was moderately related to atrophy, but a critical discrepancy was seen in the medial temporo-parietal episodic memory network. Identification of "hotspots" and "coldspots" of expansion across several primate species did not yield compelling evidence for the hypothesis that highly expanded regions are specifically targeted. Controlling for distribution of atrophy in aging substantially attenuated the expansion-AD relationship. A path model showed that all variables explained unique variance in AD atrophy but were generally mediated through aging. This supports a systems-vulnerability model, where critical networks are subject to various negative impacts, aging in particular, rather than being selectively targeted in AD. An alternative approach is suggested, focused on the interplay of the phylogenetically old and preserved medial temporal lobe areas with more highly expanded association cortices governed by different principles of plasticity and stability. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

MiR-30e suppresses proliferation of hepatoma cells via targeting prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA

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

Feng, Guoxing; Shi, Hui; Li, Jiong

Aberrant microRNA expression has been shown to be characteristic of many cancers. It has been reported that the expression levels of miR-30e are decreased in liver cancer tissues. However, the role of miR-30e in hepatocellular carcinoma remains poorly understood. In the present study, we investigated the significance of miR-30e in hepatocarcinogenesis. Bioinformatics analysis reveals a putative target site of miR-30e in the 3′-untranslated region (3′UTR) of prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA. Moreover, luciferase reporter gene assays verified that miR-30e directly targeted 3′UTR of P4HA1 mRNA. Then, we demonstrated that miR-30e was able to reduce the expression of P4HA1 atmore » the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blot analysis. Enforced expression of miR-30e suppressed proliferation of HepG2 cells by 5-ethynyl-2-deoxyuridine (EdU) assay and reduced colony formation of these cells by colony formation analysis. Conversely, anti-miR-30e enhanced the proliferation of hepatoma cells in vitro. Interestingly, the ectopic expression of P4HA1 could efficiently rescue the inhibition of cell proliferation mediated by miR-30e in HepG2 cells. Meanwhile, silencing of P4HA1 abolished the anti-miR-30e-induced proliferation of cells. Clinically, quantitative real-time PCR showed that miR-30e was down-regulated in liver tumor tissues relative to their peritumor tissues. The expression levels of miR-30e were negatively correlated to those of P4HA1 mRNA in clinical liver tumor tissues. Thus, we conclude that miR-30e suppresses proliferation of hepatoma cells through targeting P4HA1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. - Highlights: • P4HA1 is a novel target gene of miR-30e. • P4HA1 is increased in clinical HCC tissues. • MiR-30e is negatively correlated with P4HA1 in clinical HCC tissues. • MiR-30e suppresses the proliferation of HCC cells

HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer

PubMed Central

Chang, Hae Ryung; Nam, Seungyoon; Kook, Myeong-Cherl; Kim, Kyung-Tae; Liu, Xiuping; Yao, Hui; Jung, Hae Rim; Lemos, Robert; Seo, Hye Hyun; Park, Hee Seo; Gim, Youme; Hong, Dongwan; Huh, Iksoo; Kim, Young-Woo; Tan, Dongfeng; Liu, Chang-Gong; Powis, Garth; Park, Taesung; Liang, Han; Kim, Yon Hui

2016-01-01

Background Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. Methods We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. Results Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development. PMID:25410163

Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions.

PubMed

Neesse, Albrecht; Hahnenkamp, Anke; Griesmann, Heidi; Buchholz, Malte; Hahn, Stefan A; Maghnouj, Abdelouahid; Fendrich, Volker; Ring, Janine; Sipos, Bence; Tuveson, David A; Bremer, Christoph; Gress, Thomas M; Michl, Patrick

2013-07-01

Novel imaging methods based on specific molecular targets to detect both established neoplasms and their precursor lesions are highly desirable in cancer medicine. Previously, we identified claudin-4, an integral constituent of tight junctions, as highly expressed in various gastrointestinal tumours including pancreatic cancer. Here, we investigate the potential of targeting claudin-4 with a naturally occurring ligand to visualise pancreatic cancer and its precursor lesions in vitro and in vivo by near-infrared imaging approaches. A non-toxic C-terminal fragment of the claudin-4 ligand Clostridium perfringens enterotoxin (C-CPE) was labelled with a cyanine dye (Cy5.5). Binding of the optical tracer was analysed on claudin-4 positive and negative cells in vitro, and tumour xenografts in vivo. In addition, two genetically engineered mouse models for pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer were used for in vivo validation. Optical imaging studies were conducted using 2D planar fluorescence reflectance imaging (FRI) technology and 3D fluorescence-mediated tomography (FMT). In vitro, the peptide-dye conjugate showed high binding affinity to claudin-4 positive CAPAN1 cells, while claudin-4 negative HT1080 cells revealed little or no fluorescence. In vivo, claudin-4 positive tumour xenografts, endogenous pancreatic tumours, hepatic metastases, as well as preinvasive PanIN lesions, were visualised by FRI and FMT up to 48 h after injection showing a significantly higher average of fluorochrome concentration as compared with claudin-4 negative xenografts and normal pancreatic tissue. C-CPE-Cy5.5 combined with novel optical imaging methods enables non-invasive visualisation of claudin-4 positive murine pancreatic tumours and their precursor lesions, representing a promising modality for early diagnostic imaging.

MDM4 is a key therapeutic target in cutaneous melanoma

PubMed Central

Gembarska, Agnieszka; Luciani, Flavie; Fedele, Clare; Russell, Elisabeth A; Dewaele, Michael; Villar, Stéphanie; Zwolinska, Aleksandra; Haupt, Sue; de Lange, Job; Yip, Dana; Goydos, James; Haigh, Jody J; Haupt, Ygal; Larue, Lionel; Jochemsen, Aart; Shi, Hubing; Moriceau, Gatien; Lo, Roger S; Ghanem, Ghanem; Shackleton, Mark; Bernal, Federico; Marine, Jean-Christophe

2013-01-01

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma—a highly chemotherapy-resistant disease—TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I–IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy. PMID:22820643

Optimal use of EEG recordings to target active brain areas with transcranial electrical stimulation.

PubMed

Dmochowski, Jacek P; Koessler, Laurent; Norcia, Anthony M; Bikson, Marom; Parra, Lucas C

2017-08-15

To demonstrate causal relationships between brain and behavior, investigators would like to guide brain stimulation using measurements of neural activity. Particularly promising in this context are electroencephalography (EEG) and transcranial electrical stimulation (TES), as they are linked by a reciprocity principle which, despite being known for decades, has not led to a formalism for relating EEG recordings to optimal stimulation parameters. Here we derive a closed-form expression for the TES configuration that optimally stimulates (i.e., targets) the sources of recorded EEG, without making assumptions about source location or distribution. We also derive a duality between TES targeting and EEG source localization, and demonstrate that in cases where source localization fails, so does the proposed targeting. Numerical simulations with multiple head models confirm these theoretical predictions and quantify the achieved stimulation in terms of focality and intensity. We show that constraining the stimulation currents automatically selects optimal montages that involve only a few (4-7) electrodes, with only incremental loss in performance when targeting focal activations. The proposed technique allows brain scientists and clinicians to rationally target the sources of observed EEG and thus overcomes a major obstacle to the realization of individualized or closed-loop brain stimulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Optimal use of EEG recordings to target active brain areas with transcranial electrical stimulation

PubMed Central

Dmochowski, Jacek P.; Koessler, Laurent; Norcia, Anthony M.; Bikson, Marom; Parra, Lucas C.

2018-01-01

To demonstrate causal relationships between brain and behavior, investigators would like to guide brain stimulation using measurements of neural activity. Particularly promising in this context are electroencephalography (EEG) and transcranial electrical stimulation (TES), as they are linked by a reciprocity principle which, despite being known for decades, has not led to a formalism for relating EEG recordings to optimal stimulation parameters. Here we derive a closed-form expression for the TES configuration that optimally stimulates (i.e., targets) the sources of recorded EEG, without making assumptions about source location or distribution. We also derive a duality between TES targeting and EEG source localization, and demonstrate that in cases where source localization fails, so does the proposed targeting. Numerical simulations with multiple head models confirm these theoretical predictions and quantify the achieved stimulation in terms of focality and intensity. We show that constraining the stimulation currents automatically selects optimal montages that involve only a few (4–7) electrodes, with only incremental loss in performance when targeting focal activations. The proposed technique allows brain scientists and clinicians to rationally target the sources of observed EEG and thus overcomes a major obstacle to the realization of individualized or closed-loop brain stimulation. PMID:28578130

Targeting MDM4 as a Novel Therapeutic Approach for Hematologic Malignancies.

PubMed

Cao, Lei; Fan, Lei; Xu, Wei; Li, Jian-Yong

2015-01-01

Mouse double minute 4 (MDM4) as a member of MDM family, is an oncogene emerging as an imperative negative regulator of p53. Tumor suppressor protein p53 plays a crucial role in cell cycle arrest, apoptosis and homeostasis. It has been reported that frequent inactivation of p53 was observed in numerous human cancers including hematologic malignancies. MDM4, the newly discovered modulator of p53 protein, is frequently amplified in various solid tumors such as cutaneous melanoma, retinoblastoma and hematological malignances such as chronic lymphocytic leukemia, acute myeloid leukemia and mantle cell lymphoma. Multiple evidences implicate that over-expression of MDM4 is associated with tumor progression and poor prognosis which can be reversed by knockdown of MDM4 expression or restoration of p53 function, and support the rationale for the design of future MDM4-specific therapeutics. This article discusses and focuses on using MDM4 as a novel biomarker as well as a therapeutic target for hematologic malignancies.

Strategies to target non-T-cell HIV reservoirs.

PubMed

Sacha, Jonah B; Ndhlovu, Lishomwa C

2016-07-01

A central question for the HIV cure field is to determine new ways to target clinically relevant, latently and actively replicating HIV-infected cells beyond resting memory CD4 T cells, particularly in anatomical areas of low drug penetrability. HIV eradication strategies being positioned for targeting HIV for extinction in the CD4 T-cell compartment may also show promise in non-CD4 T-cells reservoirs. Furthermore, several exciting novel therapeutic approaches specifically focused on HIV clearance from non-CD4 T-cell populations are being developed. Although reservoir validity in these non-CD4 T cells continues to remain debated, this review will highlight recent advances and make an argument as to their clinical relevancy as we progress towards an HIV cure.

Biological Evaluation of 99mTc-HYNIC-EDDA/tricine-(Ser)-D4 Peptide for Tumor Targeting.

PubMed

Kazemi, Ziba; Zahmatkesh, Mona Haddad; Abedi, Seyed Mohammad; Hosseinimehr, Seyed Jalal

2017-08-24

D4 small peptide (Leu-Ala-Arg-Leu-Leu-Thr) was selected as an appropriate agent for specific targeting of epidermal growth factor receptor (EGFR). The aim of study was to investigate the 99mTc-labeled D4 peptide for non-small cell lung tumor targeting. HYNIC-(Ser)3-D4 peptide was labeled with 99mTc using mixture of tricine and ethylenediamine diacetic acid (EDDA) as co-ligands. The in vitro cellular uptake of radiolabeled peptide was evaluated by blocking test on human non-small cell lung cancer (A-549) cell line and its biodistribution was evaluated in A-549 xenografted nude mice. This conjugated peptide was labeled with 99mTc in high radiochemical purity and it was highly stable in buffer and serum. The un-blocked to blocked cellular radioactivity ratio was 4- fold that showed a specific binding of this radiolabeled peptide on A-549 cell. Animal biodistribution in A-549 xenografted nude mice showed rapid clearance from blood and other non-target organs. Tumor uptake values as %ID/g (percentage of injection dose per gram of tissue) were 2.47% and 1.30% at 1 and 4 h after injection. This study showed the 99mTc-EDDA/tricine-HYNIC-(Ser)3-D4 peptide had tumor targeting on the non-small cell lung tumor. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs.

PubMed

Bayliss, Richard; Choi, Jene; Fennell, Dean A; Fry, Andrew M; Richards, Mark W

2016-03-01

A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90.

Analysis of the phosphorescent dye concentration dependence of triplet-triplet annihilation in organic host-guest systems

NASA Astrophysics Data System (ADS)

Zhang, L.; van Eersel, H.; Bobbert, P. A.; Coehoorn, R.

2016-10-01

Using a novel method for analyzing transient photoluminescence (PL) experiments, a microscopic description is obtained for the dye concentration dependence of triplet-triplet annihilation (TTA) in phosphorescent host-guest systems. It is demonstrated that the TTA-mechanism, which could be a single-step dominated process or a diffusion-mediated multi-step process, can be deduced for any given dye concentration from a recently proposed PL intensity analysis. A comparison with the results of kinetic Monte Carlo simulations provides the TTA-Förster radius and shows that the TTA enhancement due to triplet diffusion can be well described in a microscopic manner assuming Förster- or Dexter-type energy transfer.

Triplet diffusion leads to triplet-triplet annihilation in organic phosphorescent emitters

NASA Astrophysics Data System (ADS)

Zhang, Yifan; Forrest, Stephen R.

2013-12-01

In organic materials, triplet-triplet annihilation (TTA) can be dominated by triplet diffusion or triplet-to-triplet energy transfer. Here, we discuss the diffusion and transfer dominated mechanisms in the context of photoluminescence (PL) transient measurements from thin films of archetype phosphorescent organic light emitters based on Ir and Pt complexes. We find that TTA in these emitters is controlled by diffusion due to a Dexter-type exchange interaction, suggesting triplet radiative decay and TTA are independent processes. Minimizing the PL and absorption spectral overlap in phosphorescent emitters can lead to a significantly decreased TTA rate, and thus suppressed efficiency roll-off in phosphorescent organic light emitting diodes at high brightness.

Modelling PET radionuclide production in tissue and external targets using Geant4

NASA Astrophysics Data System (ADS)

Amin, T.; Infantino, A.; Lindsay, C.; Barlow, R.; Hoehr, C.

2017-07-01

The Proton Therapy Facility in TRIUMF provides 74 MeV protons extracted from a 500 MeV H- cyclotron for ocular melanoma treatments. During treatment, positron emitting radionuclides such as 1C, 15O and 13N are produced in patient tissue. Using PET scanners, the isotopic activity distribution can be measured for in-vivo range verification. A second cyclotron, the TR13, provides 13 MeV protons onto liquid targets for the production of PET radionuclides such as 18F, 13N or 68Ga, for medical applications. The aim of this work was to validate Geant4 against FLUKA and experimental measurements for production of the above-mentioned isotopes using the two cyclotrons. The results show variable degrees of agreement. For proton therapy, the proton-range agreement was within 2 mm for 11C activity, whereas 13N disagreed. For liquid targets at the TR13 the average absolute deviation ratio between FLUKA and experiment was 1.9±2.7, whereas the average absolute deviation ratio between Geant4 and experiment was 0. 6±0.4. This is due to the uncertainties present in experimentally determined reaction cross sections.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells.

PubMed

Lu, Qianling; Dai, Xinyu; Zhang, Peng; Tan, Xiao; Zhong, Yuejiao; Yao, Cheng; Song, Mei; Song, Guili; Zhang, Zhenghai; Peng, Gang; Guo, Zhirui; Ge, Yaoqi; Zhang, Kangzhen; Li, Yuntao

2018-01-01

Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe 3 O 4 @Au magnetic nanoparticles (Fe 3 O 4 @Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. The core-shell Fe 3 O 4 @Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe 3 O 4 @Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe 3 O 4 @Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. The inhibitory and apoptotic rates of Fe 3 O 4 @Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe 3 O 4 @Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. Our studies illustrated that Fe 3 O 4 @Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells

PubMed Central

Tan, Xiao; Zhong, Yuejiao; Yao, Cheng; Song, Mei; Song, Guili; Zhang, Zhenghai; Peng, Gang; Guo, Zhirui; Ge, Yaoqi; Zhang, Kangzhen; Li, Yuntao

2018-01-01

Background Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. Methods The core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. Results The inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. Conclusion Our studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future. PMID:29719396

Voltage color tunable OLED with (Sm,Eu)-β-diketonate complex blend

NASA Astrophysics Data System (ADS)

Reyes, R.; Cremona, M.; Teotonio, E. E. S.; Brito, H. F.; Malta, O. L.

2004-09-01

Light emission from organic electroluminescent diodes (OLEDs) in which mixed samarium and europium β-diketonate complexes, [Sm 0.7Eu 0.3(TTA) 3(TPPO) 2], was used as the emitting layer is described. The electroluminescence spectra exhibit narrow peaks arising from 4f-intraconfigurational transitions of the Sm 3+ and Eu 3+ ions and a broad emission band attributed to the electrophosphorescence of the TTA ligand. The intensity ratio of the peaks determined by the bias voltage applied to the OLED, together with the ligand electrophosphorescence, allows to obtain a voltage-tunable color light source.

Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.

PubMed

Upadhyay, Anup K; Judge, Russell A; Li, Leiming; Pithawalla, Ron; Simanis, Justin; Bodelle, Pierre M; Marin, Violeta L; Henry, Rodger F; Petros, Andrew M; Sun, Chaohong

2018-06-01

The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain. Copyright © 2018 Elsevier Ltd. All rights reserved.

Study area evaluations. Volume 6-H. North plants study area exposure assessment version 4. 1. Final report

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

Not Available

The objectives of the Human Health Exposure Assessment include: (1) estimate the type and magnitude of exposures to contaminants; (2) Identify contaminants of concern; (3) Identify sites for remedial action; (4) Recommend sites for the no action remedial alternative; and (5) Provide a basis for detailed characterization of the risk associated with all sites. This document consists of the following: An executive summary. Vol I - Land use and exposed population evaluations. Vol. II III - Toxicity assessment (includes army and shell toxicity profiles). Vol. IV - PPLV Methodology. Vol. V - PPLV Calculations. Vol. VI - Study area exposuremore » analysis A introduction, B Western study ares, C Southern study area, D northern Central study area, E Central study area, F Eastern study area, G South plants study area, and H North plants study area. Vol. VII - Summary exposure assessment.« less

CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer.

PubMed

Gao, Dong-Yu; Lin, Ts-Ting; Sung, Yun-Chieh; Liu, Ya Chi; Chiang, Wen-Hsuan; Chang, Chih-Chun; Liu, Jia-Yu; Chen, Yunching

2015-10-01

Sorafenib, a multikinase inhibitor, has been used as an anti-angiogenic agent against highly vascular hepatocellular carcinoma (HCC) - yet associated with only moderate therapeutic effect and the high incidence of HCC recurrence. We have shown intratumoral hypoxia induced by sorafenib activated C-X-C receptor type 4 (CXCR4)/stromal-derived factor 1α (SDF1α) axis, resulting in polarization toward a tumor-promoting microenvironment and resistance to anti-angiogenic therapy in HCC. Herein, we formulated sorafenib in CXCR4-targeted lipid-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with a CXCR4 antagonist, AMD3100 to systemically deliver sorafenib into HCC and sensitize HCC to sorafenib treatment. We demonstrated that CXCR4-targeted NPs efficiently delivered sorafenib into HCCs and human umbilical vein endothelial cells (HUVECs) to achieve cytotoxicity and anti-angiogenic effect in vitro and in vivo. Despite the increased expression of SDF1α upon the persistent hypoxia induced by sorafenib-loaded CXCR4-targeted NPs, AMD3100 attached to the NPs can block CXCR4/SDF1α, leading to the reduced infiltration of tumor-associated macrophages, enhanced anti-angiogenic effect, a delay in tumor progression and increased overall survival in the orthotopic HCC model compared with other control groups. In conclusion, our results highlight the clinical potential of CXCR4-targeted NPs for delivering sorafenib and overcoming acquired drug resistance in liver cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin beta4 cytoplasmic domain.

PubMed Central

Murgia, C; Blaikie, P; Kim, N; Dans, M; Petrie, H T; Giancotti, F G

1998-01-01

The cytoplasmic domain of the integrin beta4 subunit mediates both association with the hemidesmosomal cytoskeleton and recruitment of the signaling adaptor protein Shc. To examine the significance of these interactions during development, we have generated mice carrying a targeted deletion of the beta4 cytoplasmic domain. Analysis of homozygous mutant mice indicates that the tail-less alpha6beta4 binds efficiently to laminin 5, but is unable to integrate with the cytoskeleton. Accordingly, these mice display extensive epidermal detachment at birth and die immmediately thereafter from a syndrome resembling the human disease junctional epidermolysis bullosa with pyloric atresia (PA-JEB). In addition, we find a significant proliferative defect. Specifically, the number of precursor cells in the intestinal epithelium, which remains adherent to the basement membrane, and in intact areas of the skin is reduced, and post-mitotic enterocytes display increased levels of the cyclin-dependent kinase inhibitor p27(Kip). These findings indicate that the interactions mediated by the beta4 tail are crucial for stable adhesion of stratified epithelia to the basement membrane and for proper cell-cycle control in the proliferative compartments of both stratified and simple epithelia. PMID:9670011

miR-124 radiosensitizes human esophageal cancer cell TE-1 by targeting CDK4.

PubMed

Zhang, Y H; Wang, Q Q; Li, H; Ye, T; Gao, F; Liu, Y C

2016-06-03

Radiotherapy is one of the most important treatments for esophageal cancer, but radioresistance remains a major challenge. Previous studies have shown that microRNAs (miRNAs or miRs) are involved in human cancers. miR-124 has been widely reported in various cancers and it is intimately involved in proliferation, cell cycle regulation, apoptosis, migration, and invasion of cancer cells. The aim of this study was to explore the relationship between the miR-124/cyclin-dependent kinase 4 (CDK4) axis and the radiosensitivity of esophageal cancer cells. In this study, we identified the reduced expression of miR-124 in 18 paired esophageal cancer tissues compared to their matched normal tissues. In order to investigate the physiological role of miR-124 in esophageal cancer, the cell counting kit-8 (CCK-8) assay and wound healing assay were performed, and the results suggest that miR-124 overexpression decreases tumor growth and aggression. Next, we detected the effects of ectopic miR-124 expression on the apoptosis of an esophageal cancer cell line (TE-1) following radiotherapy. Using the CCK-8 assay and Hoechst 332528 stain, we found that ectopic expression of miR-124 led to a higher percentage of apoptotic cells. Finally, we identified that CDK4 is a direct target of miR-124 in TE-1 cells using target prediction algorithms and a luciferase reporter assay. Moreover, western blot assay confirmed that CDK4 was downregulated during miR-124 transfection. Taken together, we illustrate that the miR-124/CDK4 axis plays an important role in radiation sensitivity of human esophageal cancer cells by targeting CDK4.

Rapid shape detection signals in area V4

PubMed Central

Weiner, Katherine F.; Ghose, Geoffrey M.

2014-01-01

Vision in foveate animals is an active process that requires rapid and constant decision-making. For example, when a new object appears in the visual field, we can quickly decide to inspect it by directing our eyes to the object's location. We studied the contribution of primate area V4 to these types of rapid foveation decisions. Animals performed a reaction time task that required them to report when any shape appeared within a peripherally-located noisy stimulus by making a saccade to the stimulus location. We found that about half of the randomly sampled V4 neurons not only rapidly and precisely represented the appearance of this shape, but they were also predictive of the animal's saccades. A neuron's ability to predict the animal's saccades was not related to the specificity with which the cell represented a single type of shape but rather to its ability to signal whether any shape was present. This relationship between sensory sensitivity and behavioral predictiveness was not due to global effects such as alertness, as it was equally likely to be observed for cells with increases and decreases in firing rate. Careful analysis of the timescales of reliability in these neurons implies that they reflect both feedforward and feedback shape detecting processes. In approximately 7% of our recorded sample, individual neurons were able to predict both the delay and precision of the animal's shape detection performance. This suggests that a subset of V4 neurons may have been directly and causally contributing to task performance and that area V4 likely plays a critical role in guiding rapid, form-based foveation decisions. PMID:25278828

Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression.

PubMed

Dou, Lin; Wang, Shuyue; Sun, Libo; Huang, Xiuqing; Zhang, Yang; Shen, Tao; Guo, Jun; Man, Yong; Tang, Weiqing; Li, Jian

2017-01-01

Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression. © 2017 The Author(s). Published by S. Karger AG, Basel.

Risk factor modifications and depression incidence: a 4-year longitudinal Canadian cohort of the Montreal Catchment Area Study

PubMed Central

Meng, Xiangfei; Brunet, Alain; Turecki, Gustavo; Liu, Aihua; D'Arcy, Carl; Caron, Jean

2017-01-01

Objective Few studies have examined the effect of risk factor modifications on depression incidence. This study was to explore psychosocial risk factors for depression and quantify the effect of risk factor modifications on depression incidence in a large-scale, longitudinal population-based study. Methods Data were from the Montreal Longitudinal Catchment Area study (N=2433). Multivariate modified Poisson regression was used to estimate relative risk (RR). Population attributable fractions were also used to estimate the potential impact of risk factor modifications on depression incidence. Results The cumulative incidence rate of major depressive disorder at the 2-year follow-up was 4.8%, and 6.6% at the 4-year follow-up. Being a younger adult, female, widowed, separated or divorced, Caucasian, poor, occasional drinker, having a family history of mental health problems, having less education and living in areas with higher unemployment rates and higher proportions of visible minorities, more cultural community centres and community organisations, were consistently associated with the increased risk of incident major depressive disorder. Although only 5.1% of the disease incidence was potentially attributable to occasional drinking (vs abstainers) at the 2-year follow-up, the attribution of occasional drinking doubled at the 4-year follow-up. A 10% reduction in the prevalence of occasional drinking in this population could potentially prevent half of incident cases. Conclusions Modifiable risk factors, both individual and societal, could be the targets for public depression prevention programmes. These programmes should also be gender-specific, as different risk factors have been identified for men and women. Public health preventions at individual levels could focus on the better management of occasional drinking, as it explained around 5%~10% of incident major depressive disorders. Neighbourhood characteristics could also be the target for public prevention

Risk factor modifications and depression incidence: a 4-year longitudinal Canadian cohort of the Montreal Catchment Area Study.

PubMed

Meng, Xiangfei; Brunet, Alain; Turecki, Gustavo; Liu, Aihua; D'Arcy, Carl; Caron, Jean

2017-06-10

Few studies have examined the effect of risk factor modifications on depression incidence. This study was to explore psychosocial risk factors for depression and quantify the effect of risk factor modifications on depression incidence in a large-scale, longitudinal population-based study. Data were from the Montreal Longitudinal Catchment Area study (N=2433). Multivariate modified Poisson regression was used to estimate relative risk (RR). Population attributable fractions were also used to estimate the potential impact of risk factor modifications on depression incidence. The cumulative incidence rate of major depressive disorder at the 2-year follow-up was 4.8%, and 6.6% at the 4-year follow-up. Being a younger adult, female, widowed, separated or divorced, Caucasian, poor, occasional drinker, having a family history of mental health problems, having less education and living in areas with higher unemployment rates and higher proportions of visible minorities, more cultural community centres and community organisations, were consistently associated with the increased risk of incident major depressive disorder. Although only 5.1% of the disease incidence was potentially attributable to occasional drinking (vs abstainers) at the 2-year follow-up, the attribution of occasional drinking doubled at the 4-year follow-up. A 10% reduction in the prevalence of occasional drinking in this population could potentially prevent half of incident cases. Modifiable risk factors, both individual and societal, could be the targets for public depression prevention programmes. These programmes should also be gender-specific, as different risk factors have been identified for men and women. Public health preventions at individual levels could focus on the better management of occasional drinking, as it explained around 5%~10% of incident major depressive disorders. Neighbourhood characteristics could also be the target for public prevention programmes. However, this could be very

LnPO 4 Nanoparticles Doped with Ac-225 and Sequestered Daughters for Targeted Alpha Therapy

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

McLaughlin, Mark F.; Robertson, David; Pevsner, Paul H.

2014-02-01

For targeted alpha therapy (TAT) with 225Ac, daughter radioisotopes from the parent emissions should be controlled. We report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate TAT of lung tumor colonies. NPs of La 3+, Gd 3+, and 225Ac 3+ ions were coated with additional layers of GdPO 4 and then coated with gold via citrate reduction of NaAuCl 4. MAb 201b, targeting thrombomodulin in lung endothelium, was added to a polyethylene glycol (dPEG)-COOH linker. Furthermore, we quantified the NPs:mAb ratio by labeling the mAb with 125I. NPs showed 30% injected dose/organ antibody-mediated uptake inmore » the lung, which increased to 47% in mice pretreated with clodronate liposomes to reduce phagocytosis. Retention of daughter 213Bi in lung tissue was more than 70% at one hour and about 90% at 24 hours postinjection. Treatment of mice with lung-targeted 225Ac NP reduced EMT-6 lung colonies relative to cold antibody competition for targeting or phosphate-buffered saline injected controls. Finally, we show that LnPO 4 NPs represent a viable solution to deliver the 225Ac as an in vivo α generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the α-radiation.« less

Target-distractor similarity has a larger impact on visual search in school-age children than spacing.

PubMed

Huurneman, Bianca; Boonstra, F Nienke

2015-01-22

In typically developing children, crowding decreases with increasing age. The influence of target-distractor similarity with respect to orientation and element spacing on visual search performance was investigated in 29 school-age children with normal vision (4- to 6-year-olds [N = 16], 7- to 8-year-olds [N = 13]). Children were instructed to search for a target E among distractor Es (feature search: all flanking Es pointing right; conjunction search: flankers in three orientations). Orientation of the target was manipulated in four directions: right (target absent), left (inversed), up, and down (vertical). Spacing was varied in four steps: 0.04°, 0.5°, 1°, and 2°. During feature search, high target-distractor similarity had a stronger impact on performance than spacing: Orientation affected accuracy until spacing was 1°, and spacing only influenced accuracy for identifying inversed targets. Spatial analyses showed that orientation affected oculomotor strategy: Children made more fixations in the "inversed" target area (4.6) than the vertical target areas (1.8 and 1.9). Furthermore, age groups differed in fixation duration: 4- to 6-year-old children showed longer fixation durations than 7- to 8-year-olds at the two largest element spacings (p = 0.039 and p = 0.027). Conjunction search performance was unaffected by spacing. Four conclusions can be drawn from this study: (a) Target-distractor similarity governs visual search performance in school-age children, (b) children make more fixations in target areas when target-distractor similarity is high, (c) 4- to 6-year-olds show longer fixation durations than 7- to 8-year-olds at 1° and 2° element spacing, and (d) spacing affects feature but not conjunction search-a finding that might indicate top-down control ameliorates crowding in children. © 2015 ARVO.

Structural basis for MTR4-ZCCHC8 interactions that stimulate the MTR4 helicase in the nuclear exosome-targeting complex.

PubMed

Puno, M Rhyan; Lima, Christopher D

2018-06-12

The nuclear exosome-targeting (NEXT) complex functions as an RNA exosome cofactor and is involved in surveillance and turnover of aberrant transcripts and noncoding RNAs. NEXT is a ternary complex composed of the RNA-binding protein RBM7, the scaffold zinc-knuckle protein ZCCHC8, and the helicase MTR4. While RNA interactions with RBM7 are known, it remains unclear how NEXT subunits collaborate to recognize and prepare substrates for degradation. Here, we show that MTR4 helicase activity is enhanced when associated with RBM7 and ZCCHC8. While uridine-rich substrates interact with RBM7 and are preferred, optimal activity is observed when substrates include a polyadenylated 3' end. We identify a bipartite interaction of ZCCHC8 with MTR4 and uncover a role for the conserved C-terminal domain of ZCCHC8 in stimulating MTR4 helicase and ATPase activities. A crystal structure reveals that the ZCCHC8 C-terminal domain binds the helicase core in a manner that is distinct from that observed for Saccharomyces cerevisiae exosome cofactors Trf4p and Air2p. Our results are consistent with a model whereby effective targeting of substrates by NEXT entails recognition of elements within the substrate and activation of MTR4 helicase activity. Copyright © 2018 the Author(s). Published by PNAS.

Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice.

PubMed

Bjørndal, Bodil; Alterås, Eva Katrine; Lindquist, Carine; Svardal, Asbjørn; Skorve, Jon; Berge, Rolf K

2018-01-01

The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% ( w /w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks ( n  = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver

Catastrophic Declines in Wilderness Areas Undermine Global Environment Targets.

PubMed

Watson, James E M; Shanahan, Danielle F; Di Marco, Moreno; Allan, James; Laurance, William F; Sanderson, Eric W; Mackey, Brendan; Venter, Oscar

2016-11-07

Humans have altered terrestrial ecosystems for millennia [1], yet wilderness areas still remain as vital refugia where natural ecological and evolutionary processes operate with minimal human disturbance [2-4], underpinning key regional- and planetary-scale functions [5, 6]. Despite the myriad values of wilderness areas-as critical strongholds for endangered biodiversity [7], for carbon storage and sequestration [8], for buffering and regulating local climates [9], and for supporting many of the world's most politically and economically marginalized communities [10]-they are almost entirely ignored in multilateral environmental agreements. This is because they are assumed to be relatively free from threatening processes and therefore are not a priority for conservation efforts [11, 12]. Here we challenge this assertion using new comparable maps of global wilderness following methods established in the original "last of the wild" analysis [13] to examine the change in extent since the early 1990s. We demonstrate alarming losses comprising one-tenth (3.3 million km 2 ) of global wilderness areas over the last two decades, particularly in the Amazon (30%) and central Africa (14%). We assess increases in the protection of wilderness over the same time frame and show that these efforts are failing to keep pace with the rate of wilderness loss, which is nearly double the rate of protection. Our findings underscore an immediate need for international policies to recognize the vital values of wilderness and the unprecedented threats they face and to underscore urgent large-scale, multifaceted actions needed to maintain them. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines*

PubMed Central

Hanes, Melinda S.; Salanga, Catherina L.; Chowdry, Arnab B.; Comerford, Iain; McColl, Shaun R.; Kufareva, Irina; Handel, Tracy M.

2015-01-01

The chemokine CXCL12 and its G protein-coupled receptors CXCR4 and ACKR3 are implicated in cancer and inflammatory and autoimmune disorders and are targets of numerous antagonist discovery efforts. Here, we describe a series of novel, high affinity CXCL12-based modulators of CXCR4 and ACKR3 generated by selection of N-terminal CXCL12 phage libraries on live cells expressing the receptors. Twelve of 13 characterized CXCL12 variants are full CXCR4 antagonists, and four have Kd values <5 nm. The new variants also showed high affinity for ACKR3. The variant with the highest affinity for CXCR4, LGGG-CXCL12, showed efficacy in a murine model for multiple sclerosis, demonstrating translational potential. Molecular modeling was used to elucidate the structural basis of binding and antagonism of selected variants and to guide future designs. Together, this work represents an important step toward the development of therapeutics targeting CXCR4 and ACKR3. PMID:26216880

Hydrology of area 4, Eastern Coal Province, Pennsylvania, Ohio, and West Virginia

USGS Publications Warehouse

Roth, Donald K.; Engelke, Morris J.; ,

1981-01-01

Area 4 (one of the 24 hydrologic areas defining the Eastern Coal Province) is located at the northern end of the Eastern Coal Province in eastern Ohio, northern West Virginia, and western Pennsylvania. It is part of the upper Ohio River basin, which includes the Beaver, Mahoning, and Shenango Rivers. The area is underlain by rocks of the Pottsville, Allegheny, Conemaugh, Monongahela Groups (or Formations) and Dunkard Group. Area 4 has a temperate climate with an annual average rainfall of 38 to 42 inches, most of its area is covered by forest. The soils have a high erosion potential where the vegetation cover is removed. In response to Public Law 95-87, 132 sites were added to the existing surface-water data-collection network in area 4. At these added sites, collected data includes discharge, water quality, sediment, and biology. The data are available from computer storage through the National Water Data Exchange (NAWDEX) or the published annual Water Resources Data reports for Ohio, Pennsylvania, and West Virginia. Hydrologic problems related to mining are: (1) Erosion and increased sedimentation, and (2) degradation of water quality. Erosion and sedimentation are associated chiefly with surface mining. Sediment yields increase drastically when vegetation is removed from the highly erosive soils. Degradation of water quality can be caused by acid-mine drainage from underground and surface mining. More than half the acid-mine drainage effluent in area 4 comes from underground mines. The rest seeps from abandoned surface mines. Usually in reclaimed surface mines the overburden is replaced in such a short time after the coal is taken out that oxidation of acid-forming minerals, commonly pyrite or marcasite, is not complete or is neutralized by the buffering action of calcareous minerals in the soils. (USGS)

Lubiprostone targets prostanoid EP4 receptors in ovine airways

PubMed Central

Cuthbert, AW

2011-01-01

BACKGROUND AND PURPOSE Lubiprostone, a prostaglandin E1 derivative, is reported to activate ClC-2 chloride channels located in the apical membranes of a number of transporting epithelia. Lack of functioning CFTR chloride channels in epithelia is responsible for the genetic disease cystic fibrosis, therefore, surrogate channels that can operate independently of CFTR are of interest. This study explores the target receptor(s) for lubiprostone in airway epithelium. EXPERIMENTAL APPROACH All experiments were performed on the ventral tracheal epithelium of sheep. Epithelia were used to measure anion secretion from the apical surface as short circuit current or as fluid secretion from individual airway submucosal glands, using an optical method. KEY RESULTS The EP4 antagonists L-161982 and GW627368 inhibited short circuit current responses to lubiprostone, while EP1,2&3 receptor antagonists were without effect. Similarly, lubiprostone induced secretion in airway submucosal glands was inhibited by L-161982. L-161982 effectively competed with lubiprostone with a Kd value of 0.058 µM, close to its value for binding to human EP4 receptors (0.024 µM). The selective EP4 agonist L-902688 and lubiprostone behaved similarly with respect to EP4 receptor antagonists. Results of experiments with H89, a protein kinase A inhibitor, were consistent with lubiprostone acting through a Gs-protein coupled EP4 receptor/cAMP cascade. CONCLUSIONS AND IMPLICATIONS Lubiprostone-induced short-circuit currents and submucosal gland secretions were inhibited by selective EP4 receptor antagonists. The results suggest EP4 receptor activation by lubiprostone triggers cAMP production necessary for CFTR activation and the secretory responses, a possibility precluded in CF tissues. PMID:20883477

Evaluation of target acquisition difficulty using recognition distance to measure required retinal area

NASA Astrophysics Data System (ADS)

Nilsson, Thomy H.

2001-09-01

The psychophysical method of limits was used to measure the distance at which observers could distinguish military vehicles photographed in natural landscapes. Obtained from the TNO-TM Search_2 dataset, these pictures either were rear-projected 35-mm slides or were presented on a computer monitor. Based on the rationale that more difficult vehicle targets would require more visual pathways for recognition, difficult of acquisition was defined in terms of the relative retinal area required for recognition. Relative retinal area was derived from the inverse square of the recognition distance of a particular vehicle relative to the distance of the vehicle that could be seen furthest away. Results are compared with data on the time required to find the vehicles in these pictures. These comparison indicate recognition distance thresholds can be a suitable means of defining standards for the effectiveness of vital graphic information; and the two methods are complementary with respect to distinguishing different degrees of acquisition difficulty, and together may provide a means to measure the total information processing required for recognition.

Gamma Knife irradiation method based on dosimetric controls to target small areas in rat brains

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

Constanzo, Julie; Paquette, Benoit; Charest, Gabriel

2015-05-15

Purpose: Targeted and whole-brain irradiation in humans can result in significant side effects causing decreased patient quality of life. To adequately investigate structural and functional alterations after stereotactic radiosurgery, preclinical studies are needed. The purpose of this work is to establish a robust standardized method of targeted irradiation on small regions of the rat brain. Methods: Euthanized male Fischer rats were imaged in a stereotactic bed, by computed tomography (CT), to estimate positioning variations relative to the bregma skull reference point. Using a rat brain atlas and the stereotactic bregma coordinates obtained from CT images, different regions of the brainmore » were delimited and a treatment plan was generated. A single isocenter treatment plan delivering ≥100 Gy in 100% of the target volume was produced by Leksell GammaPlan using the 4 mm diameter collimator of sectors 4, 5, 7, and 8 of the Gamma Knife unit. Impact of positioning deviations of the rat brain on dose deposition was simulated by GammaPlan and validated with dosimetric measurements. Results: The authors’ results showed that 90% of the target volume received 100 ± 8 Gy and the maximum of deposited dose was 125 ± 0.7 Gy, which corresponds to an excellent relative standard deviation of 0.6%. This dose deposition calculated with GammaPlan was validated with dosimetric films resulting in a dose-profile agreement within 5%, both in X- and Z-axes. Conclusions: The authors’ results demonstrate the feasibility of standardizing the irradiation procedure of a small volume in the rat brain using a Gamma Knife.« less

Monitoring Ground Deformation of Subway Area during the Construction Based on the Method of Multi-Temporal Coherent Targets Analysis

NASA Astrophysics Data System (ADS)

Zhang, L.; Wu, J.; Zhao, J.; Yuan, M.

2018-04-01

Multi-temporal coherent targets analysis is a high-precision and high-spatial-resolution monitoring method for urban surface deformation based on Differential Synthetic Aperture Radar (DInSAR), and has been successfully applied to measure land subsidence, landslide and strain accumulation caused by fault movement and so on. In this paper, the multi-temporal coherent targets analysis is used to study the settlement of subway area during the period of subway construction. The eastern extension of Shanghai Metro Line. 2 is taking as an example to study the subway settlement during the construction period. The eastern extension of Shanghai Metro Line. 2 starts from Longyang Road and ends at Pudong airport. Its length is 29.9 kilometers from east to west and it is a key transportation line to the Pudong Airport. 17 PalSAR images during 2007 and 2010 are applied to analyze and invert the settlement of the buildings nearby the subway based on the multi-temporal coherent targets analysis. But there are three significant deformation areas nearby the Line 2 between 2007 and 2010, with maximum subsidence rate up to 30 mm/y in LOS. The settlement near the Longyang Road station and Chuansha Town are both caused by newly construction and city expansion. The deformation of the coastal dikes suffer from heavy settlement and the rate is up to -30 mm/y. In general, the area close to the subway line is relatively stable during the construction period.

MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine cAMP binding sites as a tool for drug design.

PubMed

Yaneff, Agustín; Sahores, Ana; Gomez, Natalia; Carozzo, Alejandro; Shayo, Carina; Davio, Carlos

2017-12-29

MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology. The first step in the long process of drug rational design is to identify the therapeutic target and characterize the mechanism by which it affects the given pathology. In order to develop a pharmacological agent with high specific activity, the second step is to systematically study the structure of the target and identify all the possible binding sites. Using available homology models and mutagenesis assays, in this review we recapitulate the up-to-date knowledge about MRP structure and aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides bind. We have also listed the most relevant MRP inhibitors studied to date, considering drug safety and specificity for MRP4 in particular. This metaanalysis platform may serve as a basis for the future development of inhibitors of MRP4 cAMP specific transport. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

4. VIEW OF AREA EXCAVATED FOR ACCESS TO MERCURY RETORT. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. VIEW OF AREA EXCAVATED FOR ACCESS TO MERCURY RETORT. VIEW SOUTH FROM RETORT. (OCTOBER, 1995) - McCormick Group Mine, Mercury Retort, East slope of Buckskin Mountain, Paradise Valley, Humboldt County, NV

Role of Beam Spot Size in Heating Targets at Depth.

PubMed

Ross, E Victor; Childs, James

2015-12-01

Wavelength, fluence and pulse width are primary device parameters for the treatment of skin and hair conditions. Wavelength selection is based on tissue scatter and target chromophores. Pulse width is chosen to optimize target heating. Energy absorbed by a target is determined by fluence and spot size of the light source as well as the depth of the target. We conducted an in vitro skin study and simulations to compare heating of a target at a particular depth versus spot size. Porcine skin and fat tissue were prepared and separated to form a 2mm skin layer above a 1 cm thick fat layer. A 50 μm thermocouple was placed between the layers and centered beneath a 23 x 38 mm treatment window of an 805 nm diode laser device (Vectus, Cynosure, Westford, MA). Apertures provided various incident beam spot sizes and the temperature rise of the thermocouple was measured for a fixed fluence. The 2mm deep target's temperature rise versus treatment area showed two regimes with different positive slopes. The first regime up to approximately 1 cm(2) area has a greater temperature rise versus area than that for the regime greater than 1 cm(2). The slope in the second regime is nonetheless appreciable and provides a fluence reduction factor for skin safety. The same temperature rise in a target at 2 mm depth (typical hair bulb depth in some areas) is realized by increasing the area from 1 to 4 cm(2) while reducing the fluence by half. The role of spot size and in situ beam divergence is an important consideration to determine optimum fluence settings that increase skin safety when treating deeper targets.

Microstimulation of area V4 has little effect on spatial attention and on perception of phosphenes evoked in area V1

PubMed Central

Dagnino, Bruno; Gariel-Mathis, Marie-Alice

2014-01-01

Previous transcranial magnetic stimulation (TMS) studies suggested that feedback from higher to lower areas of the visual cortex is important for the access of visual information to awareness. However, the influence of cortico-cortical feedback on awareness and the nature of the feedback effects are not yet completely understood. In the present study, we used electrical microstimulation in the visual cortex of monkeys to test the hypothesis that cortico-cortical feedback plays a role in visual awareness. We investigated the interactions between the primary visual cortex (V1) and area V4 by applying microstimulation in both cortical areas at various delays. We report that the monkeys detected the phosphenes produced by V1 microstimulation but subthreshold V4 microstimulation did not influence V1 phosphene detection thresholds. A second experiment examined the influence of V4 microstimulation on the monkeys' ability to detect the dimming of one of three peripheral visual stimuli. Again, microstimulation of a group of V4 neurons failed to modulate the monkeys' perception of a stimulus in their receptive field. We conclude that conditions exist where microstimulation of area V4 has only a limited influence on visual perception. PMID:25392172

Statistical Algorithms for Designing Geophysical Surveys to Detect UXO Target Areas

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

O'Brien, Robert F.; Carlson, Deborah K.; Gilbert, Richard O.

2005-07-29

The U.S. Department of Defense is in the process of assessing and remediating closed, transferred, and transferring military training ranges across the United States. Many of these sites have areas that are known to contain unexploded ordnance (UXO). Other sites or portions of sites are not expected to contain UXO, but some verification of this expectation using geophysical surveys is needed. Many sites are so large that it is often impractical and/or cost prohibitive to perform surveys over 100% of the site. In that case, it is particularly important to be explicit about the performance required of the survey. Thismore » article presents the statistical algorithms developed to support the design of geophysical surveys along transects (swaths) to find target areas (TAs) of anomalous geophysical readings that may indicate the presence of UXO. The algorithms described here determine 1) the spacing between transects that should be used for the surveys to achieve a specified probability of traversing the TA, 2) the probability of both traversing and detecting a TA of anomalous geophysical readings when the spatial density of anomalies within the TA is either uniform (unchanging over space) or has a bivariate normal distribution, and 3) the probability that a TA exists when it was not found by surveying along transects. These algorithms have been implemented in the Visual Sample Plan (VSP) software to develop cost-effective transect survey designs that meet performance objectives.« less

Statistical Algorithms for Designing Geophysical Surveys to Detect UXO Target Areas

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

O'Brien, Robert F.; Carlson, Deborah K.; Gilbert, Richard O.

2005-07-28

The U.S. Department of Defense is in the process of assessing and remediating closed, transferred, and transferring military training ranges across the United States. Many of these sites have areas that are known to contain unexploded ordnance (UXO). Other sites or portions of sites are not expected to contain UXO, but some verification of this expectation using geophysical surveys is needed. Many sites are so large that it is often impractical and/or cost prohibitive to perform surveys over 100% of the site. In such cases, it is particularly important to be explicit about the performance required of the surveys. Thismore » article presents the statistical algorithms developed to support the design of geophysical surveys along transects (swaths) to find target areas (TAs) of anomalous geophysical readings that may indicate the presence of UXO. The algorithms described here determine (1) the spacing between transects that should be used for the surveys to achieve a specified probability of traversing the TA, (2) the probability of both traversing and detecting a TA of anomalous geophysical readings when the spatial density of anomalies within the TA is either uniform (unchanging over space) or has a bivariate normal distribution, and (3) the probability that a TA exists when it was not found by surveying along transects. These algorithms have been implemented in the Visual Sample Plan (VSP) software to develop cost-effective transect survey designs that meet performance objectives.« less

MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4

PubMed Central

LIANG, XUE; XU, ZHAO; YUAN, MENG; ZHANG, YUE; ZHAO, BO; WANG, JUNQIAN; ZHANG, AIXUE; LI, GUANGPING

2016-01-01

Programmed cell death 4 (PDCD4) is involved in a number of bioprocesses, such as apoptosis and inflammation. However, its regulatory mechanisms in atherosclerosis remain unclear. In this study, we investigated the role and mechanisms of action of PDCD4 in high-fat diet-induced atherosclerosis in mice and in foam cells (characteristic pathological cells in atherosclerotic lesions) derived from ox-LDL-stimulated macrophages. MicroRNA (miR)-16 was predicted to bind PDCD4 by bioinformatics analysis. In the mice with atherosclerosis and in the foam cells, PDCD4 protein expression (but not the mRNA expression) was enhanced, while that of miR-16 was reduced. Transfection with miR-16 mimic decreased the activity of a luciferase reporter containing the 3′ untranslated region (3′UTR) of PDCD4 in the macrophage-derived foam cells. Conversely, treatment with miR-16 inhibitor enhanced the luciferase activity. However, by introducing mutations in the predicted binding site located in the 3′UTR of PDCD4, the miR-16 mimic and inhibitor were unable to alter the level of PDCD4, suggesting that miR-16 is a direct negative regulator of PDCD4 in atherosclerosis. Furthermore, transfection wtih miR-16 mimic and siRNA targeting PDCD4 suppressed the secretion and mRNA expression of pro-inflammatory factors, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), whereas it enhanced the secretion and mRNA expression of the anti-inflammatory factor, IL-10. Treatment with miR-16 inhibitor exerted the opposite effects. In addition, the phosphorylation of p38 and extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB) expression were altered by miR-16. In conclusion, our data demonstrate that the targeting of PDCD4 by miR-16 may suppress the activation of inflammatory macrophages though mitogen-activated protein kinase (MAPK) and NF-κB signaling in atherosclerosis; thus, PDCD4 may prove to be a potential therapeutic target in the treatment of

MicroRNA-124 inhibits the proliferation of C6 glioma cells by targeting Smad4.

PubMed

Zhang, Zechuan; Gong, Qiaoyun; Li, Meiying; Xu, Jinying; Zheng, Yangyang; Ge, Pengfei; Chi, Guangfan

2017-10-01

MicroRNA-124 (miR-124) has been shown to be downregulated in glioma; however, its biological functions in glioma are not yet fully understood. The aim of this study was to examine the Smad4‑dependent effects of miR‑124 on C6 glioma cell proliferation. In this study, the level of miR‑124 was found to be enhanced in C6 cells upon transfection with miR‑124 mimics, and the mechanisms of action of miR‑124 in C6 cells were investigated by reverse transcriptase-quantitative polymerase chain reaction, MTT assay, western blot analysis and luciferase reporter assays in vitro. The results revealed that miR‑124 expression was significantly lower in the C6 cells than in either normal rat brain tissue or astrocytes. Upon the overexpression of miR‑124, the proliferation of the C6 cells decreased and Smad4 expression was significantly suppressed. Smad4 was identified as a direct target of miR‑124 through luciferase reporter assays. Furthermore, miR‑124 was found to modulate signal transducer and activator of transcription 3 (Stat3) by downregulating Smad4 expression. Using small interfering RNA targeting Smad4 mRNA, we also confirmed that miR‑124 downregulated c‑Myc by modulating Smad4 expression. In addition, caspase‑3 expression was induced by miR‑124 overexpression, but not via Smad4 downregulation. On the whole, our results demonstrate that miR‑124 upregulation inhibits the growth of C6 glioma cells by targeting Smad4 directly. These findings may be clinically useful for the development of therapeutic strategies directed toward miR‑124 function in patients with glioma.

13 CFR 123.4 - What is a disaster area and why is it important?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What is a disaster area and why is it important? 123.4 Section 123.4 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Overview § 123.4 What is a disaster area and why is it important? Each disaster...

4. WASHBURN POINT VISTA AREA. HALF DOME AT CENTER REAR. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. WASHBURN POINT VISTA AREA. HALF DOME AT CENTER REAR. LOOKING NE. GIS: N-37 43 13.7 / W-119 34 23.0 - Glacier Point Road, Between Chinquapin Flat & Glacier Point, Yosemite Village, Mariposa County, CA

Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area.

PubMed

Cui, Huxing; Sohn, Jong-Woo; Gautron, Laurent; Funahashi, Hisayuki; Williams, Kevin W; Elmquist, Joel K; Lutter, Michael

2012-12-15

The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of the hypothalamus and regulates multiple processes including food intake, reward behaviors, and autonomic function. By using a mouse line in which green fluorescent protein (GFP) is expressed under control of the MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology, and retrograde tracing techniques. We found that LHA MC4R-GFP neurons coexpress neurotensin as well as the leptin receptor but do not coexpress other peptide neurotransmitters found in the LHA including orexin, melanin-concentrating hormone, and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP- sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens, and spinal cord, and only limited number of neurons project to the nucleus of the solitary tract and parabrachial nucleus. Our findings provide new insights into MC4R signaling in the LHA and its potential implications in homeostatic regulation of body energy balance. Copyright © 2012 Wiley Periodicals, Inc.

Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area

PubMed Central

Cui, Huxing; Sohn, Jong-Woo; Gautron, Laurent; Funahashi, Hisayuki; Williams, Kevin W.; Elmquist, Joel K.; Lutter, Michael

2013-01-01

The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of hypothalamus and regulates multiple processes including food intake, reward behaviors and autonomic function. Using a mouse line in which green fluorescent protein (GFP) is expressed under control of MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology and retrograde tracing techniques. We found that LHA MC4R-GFP neurons co-express neurotensin as well as the leptin receptor but not with other peptide neurotransmitters found in the LHA including orexin, melanin concentrating hormone and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP-sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens and spinal cord, and only limited number of neurons project to the nucleus of solitary tract and parabrachial nucleus. Our findings provide new insight into MC4R signaling in the LHA and its potential implication in homeostatic regulation of body energy balance. PMID:22605619

50 CFR 32.4 - Opening of wildlife refuge areas to fishing.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 50 Wildlife and Fisheries 9 2014-10-01 2014-10-01 false Opening of wildlife refuge areas to fishing. 32.4 Section 32.4 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM HUNTING AND FISHING General Provisions...

50 CFR 32.4 - Opening of wildlife refuge areas to fishing.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 8 2011-10-01 2011-10-01 false Opening of wildlife refuge areas to fishing. 32.4 Section 32.4 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM HUNTING AND FISHING General Provisions...

50 CFR 32.4 - Opening of wildlife refuge areas to fishing.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 50 Wildlife and Fisheries 9 2013-10-01 2013-10-01 false Opening of wildlife refuge areas to fishing. 32.4 Section 32.4 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM HUNTING AND FISHING General Provisions...

50 CFR 32.4 - Opening of wildlife refuge areas to fishing.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 50 Wildlife and Fisheries 9 2012-10-01 2012-10-01 false Opening of wildlife refuge areas to fishing. 32.4 Section 32.4 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM HUNTING AND FISHING General Provisions...

50 CFR 32.4 - Opening of wildlife refuge areas to fishing.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Opening of wildlife refuge areas to fishing. 32.4 Section 32.4 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM HUNTING AND FISHING General Provisions...

Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells

PubMed Central

Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

2015-01-01

The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC. PMID:26517679

Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

PubMed

Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

2015-11-24

The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.

Microstimulation of area V4 has little effect on spatial attention and on perception of phosphenes evoked in area V1.

PubMed

Dagnino, Bruno; Gariel-Mathis, Marie-Alice; Roelfsema, Pieter R

2015-02-01

Previous transcranial magnetic stimulation (TMS) studies suggested that feedback from higher to lower areas of the visual cortex is important for the access of visual information to awareness. However, the influence of cortico-cortical feedback on awareness and the nature of the feedback effects are not yet completely understood. In the present study, we used electrical microstimulation in the visual cortex of monkeys to test the hypothesis that cortico-cortical feedback plays a role in visual awareness. We investigated the interactions between the primary visual cortex (V1) and area V4 by applying microstimulation in both cortical areas at various delays. We report that the monkeys detected the phosphenes produced by V1 microstimulation but subthreshold V4 microstimulation did not influence V1 phosphene detection thresholds. A second experiment examined the influence of V4 microstimulation on the monkeys' ability to detect the dimming of one of three peripheral visual stimuli. Again, microstimulation of a group of V4 neurons failed to modulate the monkeys' perception of a stimulus in their receptive field. We conclude that conditions exist where microstimulation of area V4 has only a limited influence on visual perception. Copyright © 2015 the American Physiological Society.

MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1

PubMed Central

Vishnubalaji, Radhakrishnan; Hamam, Rimi; Shijun, Yue; Al-Obeed, Omar; Kassem, Moustapha; Liu, Fei-Fei; Aldahmash, Abdullah; Alajez, Nehad M.

2016-01-01

Colorectal cancer (CRC) is the third most common cancer causing high mortality rates world-wide. Delineating the molecular mechanisms leading to CRC development and progression, including the role of microRNAs (miRNAs), are currently being unravelled at a rapid rate. Here, we report frequent downregulation of the microRNA miR-320 family in primary CRC tissues and cell lines. Lentiviral-mediated re-expression of miR-320c (representative member of the miR-320 family) inhibited HCT116 CRC growth and migration in vitro, sensitized CRC cells to 5-Fluorouracil (5-FU), and inhibited tumor formation in SCID mice. Global gene expression analysis in CRC cells over-expressing miR-320c, combined with in silico prediction identified 84 clinically-relevant potential gene targets for miR-320 in CRC. Using a series of biochemical assays and functional validation, SOX4, FOXM1, and FOXQ1 were validated as novel gene targets for the miR-320 family. Inverse correlation between the expression of miR-320 members with SOX4, FOXM1, and FOXQ1 was observed in primary CRC patients' specimens, suggesting that these genes are likely bona fide targets for the miR-320 family. Interestingly, interrogation of the expression levels of this gene panel (SOX4, FOXM1, and FOXQ1) in The Cancer Genome Atlas (TCGA) colorectal cancer data set (319 patients) revealed significantly poor disease-free survival in patients with elevated expression of this gene panel (P-Value: 0.0058). Collectively, our data revealed a novel role for the miR-320/SOX4/FOXM1/FOXQ1 axes in promoting CRC development and progression and suggest targeting those networks as potential therapeutic strategy for CRC. PMID:27119506

Reducing the photo-bleaching effect of a new europium complex embedded in styrene butadiene copolymer

NASA Astrophysics Data System (ADS)

Jiménez, G. Lesly; Reyes-Rodríguez, J. L.; Padilla, Isela; Alarcón-Flores, G.; Falcony, C.

2018-02-01

A highly luminescent europium complex obtained with two different ligands, succinimide (SI) and 2-thenoyltrifluoroacetone (TTA) , was synthetized with different TTA concentrations. The photoluminescence (PL) emission from these materials corresponds to the characteristic inter-electronic energy level transitions of the Eu3+ ions. However, the excitation spectrum is strongly dependent on the presence of TTA, having an optimum response when 0.75 mmol of this compound is added to the EuL3(H2O)3 complex. The quantum yield obtained by these powders were around 72 % ± 1.7 % indicating an optimum sensitization of these complex. The EuL3 TTA complex with the best PL properties was embedded in a styrene butadiene copolymer (SBC) film, produced by the drop casting method, obtaining similar PL behavior at different concentrations, the highest intensity was observed at 1.2% (w/v) of EuL3 TTA complex and the quantum yield of these composite films was 60.5 % ± 2 % . These films were exposed to continuous UV irradiation and after 141 h no photo-bleaching effect was observed in contrast with the EuL3 TTA complex that exhibited a noticeable photoluminescence intensity degradation at much shorter exposure times. Both the Eu-complexes and the composite films were characterized by FT-IR, XRD, SEM and fluorescence spectroscopy.

Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model.

PubMed

Sakkaki, Sophie; Gangarossa, Giuseppe; Lerat, Benoit; Françon, Dominique; Forichon, Luc; Chemin, Jean; Valjent, Emmanuel; Lerner-Natoli, Mireille; Lory, Philippe

2016-02-01

T-type (Cav3) calcium channels play important roles in neuronal excitability, both in normal and pathological activities of the brain. In particular, they contribute to hyper-excitability disorders such as epilepsy. Here we have characterized the anticonvulsant properties of TTA-A2, a selective T-type channel blocker, in mouse. Using the maximal electroshock seizure (MES) as a model of tonic-clonic generalized seizures, we report that mice treated with TTA-A2 (0.3 mg/kg and higher doses) were significantly protected against tonic seizures. Although no major change in Local Field Potential (LFP) pattern was observed during the MES seizure, analysis of the late post-ictal period revealed a significant increase in the delta frequency power in animals treated with TTA-A2. Similar results were obtained for Cav3.1-/- mice, which were less prone to develop tonic seizures in the MES test, but not for Cav3.2-/- mice. Analysis of extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and c-Fos expression revealed a rapid and elevated neuronal activation in the hippocampus following MES clonic seizures, which was unchanged in TTA-A2 treated animals. Overall, our data indicate that TTA-A2 is a potent anticonvulsant and that the Cav3.1 isoform plays a prominent role in mediating TTA-A2 tonic seizure protection. Copyright © 2015. Published by Elsevier Ltd.

MiR-214 regulates the function of osteoblast under simulated microgravity by targeting ATF4

NASA Astrophysics Data System (ADS)

Li, Yingxian; Wang, Xiaogang; Li, Qi; Lv, Ke; Wan, Yumin; Li, Yinghui; Bai, Yanqiang

Background: MicroRNAs (miRNAs) are small fragments of single-stranded RNA containing 18-24 nucleotides, and are generated from endogenous transcripts. MicroRNAs function in post-transcriptional gene silencing by targeting the 3'-untranslated region (UTR) of mRNAs, resulting in translational repression. Growing evidence shows that microRNAs (miRNAs) regu-late various developmental and homeostatic events in vertebrates and invertebrates. Osteoblast differentiation is a key step in proper skeletal development and acquisition of bone mass; How-ever, the physiological role of non-coding small RNAs, especially miRNAs, in osteoblast dif-ferentiation remains elusive. Methods: To study the potential involvement of miRNAs in osteoblast differentiation under stimulated microgravity, we analyzed the expression of 20 bone relative miRNAs using real time PCR platform to find particularly miRNAs whose expression is altered during osteoblast differentiation. TargetScan, miRBase and Miranda were used to predict the target gene of candidate miRNA. To investigate whether ATF4 can be directly targeted by miR-214, we engineered luciferase reporters that have either the wild-type 3'UTRs of these genes, or the mutant UTRs with a 6 base pair (bp) deletion in the target sites. Lastly, to address the in vivo role of miR-214 in bone formation, tail suspension mice model was used to simulate the change of osteoblast function and bone loss. Results: Recent studies have sug-gested that miRNAs might play a role in osteoblast differentiation and bone formation. Here, we identify miR-214 in MC3T3-E1 cells, which is a primary mouse osteoblasts cell line, to promote osteoblast differentiation by repressing Activating Transcription Factor4 (ATF4) ex-pression at the posttranscriptional level. What is more, miR-214 was found to be transcribed in C2C12 cells during bone morphogenetic protein 2-induced (BMP2-induced) osteogenesis, and overexpression of miR-214 attenuated BMP2-induced osteoblastogenesis

Target volume and artifact evaluation of a new data-driven 4D CT.

PubMed

Martin, Rachael; Pan, Tinsu

Four-dimensional computed tomography (4D CT) is often used to define the internal gross target volume (IGTV) for radiation therapy of lung cancer. Traditionally, this technique requires the use of an external motion surrogate; however, a new image, data-driven 4D CT, has become available. This study aims to describe this data-driven 4D CT and compare target contours created with it to those created using standard 4D CT. Cine CT data of 35 patients undergoing stereotactic body radiation therapy were collected and sorted into phases using standard and data-driven 4D CT. IGTV contours were drawn using a semiautomated method on maximum intensity projection images of both 4D CT methods. Errors resulting from reproducibility of the method were characterized. A comparison of phase image artifacts was made using a normalized cross-correlation method that assigned a score from +1 (data-driven "better") to -1 (standard "better"). The volume difference between the data-driven and standard IGTVs was not significant (data driven was 2.1 ± 1.0% smaller, P = .08). The Dice similarity coefficient showed good similarity between the contours (0.949 ± 0.006). The mean surface separation was 0.4 ± 0.1 mm and the Hausdorff distance was 3.1 ± 0.4 mm. An average artifact score of +0.37 indicated that the data-driven method had significantly fewer and/or less severe artifacts than the standard method (P = 1.5 × 10 -5 for difference from 0). On average, the difference between IGTVs derived from data-driven and standard 4D CT was not clinically relevant or statistically significant, suggesting data-driven 4D CT can be used in place of standard 4D CT without adjustments to IGTVs. The relatively large differences in some patients were usually attributed to limitations in automatic contouring or differences in artifacts. Artifact reduction and setup simplicity suggest a clinical advantage to data-driven 4D CT. Published by Elsevier Inc.

7 CFR 966.4 - Production area and regulated area.

Code of Federal Regulations, 2012 CFR

2012-01-01

...) Production area means the counties of Pinellas, Hillsborough, Polk, Osceola, and Brevard in the State of Florida, and all the counties of that State situated south of such counties. (b) Regulated area means that portion of the State of Florida which is bounded by the Suwannee River, the Georgia border, the Atlantic...

7 CFR 966.4 - Production area and regulated area.

Code of Federal Regulations, 2013 CFR

2013-01-01

...) Production area means the counties of Pinellas, Hillsborough, Polk, Osceola, and Brevard in the State of Florida, and all the counties of that State situated south of such counties. (b) Regulated area means that portion of the State of Florida which is bounded by the Suwannee River, the Georgia border, the Atlantic...

7 CFR 966.4 - Production area and regulated area.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) Production area means the counties of Pinellas, Hillsborough, Polk, Osceola, and Brevard in the State of Florida, and all the counties of that State situated south of such counties. (b) Regulated area means that portion of the State of Florida which is bounded by the Suwannee River, the Georgia border, the Atlantic...

7 CFR 966.4 - Production area and regulated area.

Code of Federal Regulations, 2014 CFR

2014-01-01

...) Production area means the counties of Pinellas, Hillsborough, Polk, Osceola, and Brevard in the State of Florida, and all the counties of that State situated south of such counties. (b) Regulated area means that portion of the State of Florida which is bounded by the Suwannee River, the Georgia border, the Atlantic...

Identification of the Transformational Properties and Transcriptional Targets of the Oncogenic SRY Transcription Factor SOX4

DTIC Science & Technology

2010-01-01

using linker -mediated PCR as described previously (25). Amplified DNA was labeled and hybridized in triplicate by NimbleGen Systems, Inc., to their human...leading edge analysis (37) of these gene sets identified TGFb–induced SMAD3 direct target genes (Supplementary Table S5) as enriched in SOX4 target...3.06E11 PAX5 Paired box 2.07E10 WHN Forkhead 2.94E10 SMAD3 SMAD 1.82E09 SMAD4 SMAD 3.33E09 MYC MYC 6.25E09 NFKAPPAB NF-nB 2.95E08 LEF1/TCF1 LEF

Where to Go Next? Identifying Target Areas in the North Atlantic for Future Seafloor Mapping Initiatives

NASA Astrophysics Data System (ADS)

Woelfl, A. C.; Jencks, J.; Johnston, G.; Varner, J. D.; Devey, C. W.

2017-12-01

Human activities are rapidly expanding into the oceans, yet detailed bathymetric maps do not exist for most of the seafloor that would permit governments to formulate sensible usage rules. Changing this situation will require an enormous international mapping effort. To ensure that this effort is directed towards the regions most in need of mapping, we need to know which areas have already been mapped and which areas are potentially most interesting. Despite various mapping efforts in recent years, large parts of the Atlantic still lack detailed bathymetric information. To successfully plan for future mapping efforts to fill these gaps, knowledge of current data coverage is imperative to avoid duplication of effort. While certain datasets are publically available online (e.g. NOAA's NCEI, EMODnet, IHO-DCDB, LDEO's GMRT), many are not. However, with the limited information we do have at hand, the question remains, where should we map next? And what criteria should we take into account? In 2016, a study was taken on as part of the efforts of the International Atlantic Seabed Mapping Working Group (ASMIWG). The ASMIWG, established by the Tri-Partite Galway Statement Implementation Committee, was tasked to develop a cohesive seabed mapping strategy for the Atlantic Ocean. The aim of our study was to develop a reproducible process for identifying and evaluating potential target areas within the North Atlantic that represent suitable sites for future bathymetric surveys. The sites were selected by applying a GIS-based suitability analysis that included specific user group-based parameters of the marine environment. Furthermore, information regarding current data coverage were gathered to take into account in the selection process. The results reveal the suitability of sites within the North Atlantic based on the selected criteria. Three potential target sites should be seen as flexible suggestions for future mapping initiatives rather than a rigid, defined set of areas

50 CFR Table 4 to Part 679 - Steller Sea Lion Protection Areas Pollock Fisheries Restrictions

Code of Federal Regulations, 2012 CFR

2012-10-01

... 50 Wildlife and Fisheries 13 2012-10-01 2012-10-01 false Steller Sea Lion Protection Areas Pollock... EXCLUSIVE ECONOMIC ZONE OFF ALASKA Pt. 679, Table 4 Table 4 to Part 679—Steller Sea Lion Protection Areas Pollock Fisheries Restrictions Steller Sea Lion Protection Areas Pollock Fisheries Restrictions Column...

50 CFR Table 4 to Part 679 - Steller Sea Lion Protection Areas Pollock Fisheries Restrictions

Code of Federal Regulations, 2013 CFR

2013-10-01

... 50 Wildlife and Fisheries 13 2013-10-01 2013-10-01 false Steller Sea Lion Protection Areas Pollock... EXCLUSIVE ECONOMIC ZONE OFF ALASKA Pt. 679, Table 4 Table 4 to Part 679—Steller Sea Lion Protection Areas Pollock Fisheries Restrictions Steller Sea Lion Protection Areas Pollock Fisheries Restrictions Column...

50 CFR Table 4 to Part 679 - Steller Sea Lion Protection Areas Pollock Fisheries Restrictions

Code of Federal Regulations, 2014 CFR

2014-10-01

... 50 Wildlife and Fisheries 13 2014-10-01 2014-10-01 false Steller Sea Lion Protection Areas Pollock... EXCLUSIVE ECONOMIC ZONE OFF ALASKA Pt. 679, Table 4 Table 4 to Part 679—Steller Sea Lion Protection Areas Pollock Fisheries Restrictions Steller Sea Lion Protection Areas Pollock Fisheries Restrictions Column...

Preliminary spectral and geologic analysis of Landsat-4 Thematic Mapper data, Wind River Basin area, Wyoming

NASA Technical Reports Server (NTRS)

Conel, J. E.; Lang, H. R.; Paylor, E. D.; Alley, R. E.

1985-01-01

A Landsat-4 Thematic Mapper (TM) image of the Wind River Basin area in Wyoming is currently under analysis for stratigraphic and structural mapping and for assessment of spectral and spatial characteristics using visible, near infrared, and short wavelength infrared bands. To estimate the equivalent Lambertian surface reflectance, TM radiance data were calibrated to remove atmospheric and instrumental effects. Reflectance measurements for homogeneous natural and cultural targets were acquired about one year after data acquisition. Calibration data obtained during the analysis were used to calculate new gains and offsets to improve scanner response for earth science applications. It is shown that the principal component images calculated from the TM data were the result of linear transformations of ground reflectance. In images prepared from this transform, the separation of spectral classes was independent of systematic atmospheric and instrumental factors. Several examples of the processed images are provided.

Automated Threshold Selection for Template-Based Sonar Target Detection

DTIC Science & Technology

2017-08-01

test based on the distribution of the matched filter correlations. From the matched filter output we evaluate target sized areas and surrounding...synthetic aperture sonar data that were part of the evaluation . Figure 3 shows a nearly uniform seafloor. Figure 4 is more complex, with

Setting conservation targets for sandy beach ecosystems

NASA Astrophysics Data System (ADS)

Harris, Linda; Nel, Ronel; Holness, Stephen; Sink, Kerry; Schoeman, David

2014-10-01

Representative and adequate reserve networks are key to conserving biodiversity. This begs the question, how much of which features need to be placed in protected areas? Setting specifically-derived conservation targets for most ecosystems is common practice; however, this has never been done for sandy beaches. The aims of this paper, therefore, are to propose a methodology for setting conservation targets for sandy beach ecosystems; and to pilot the proposed method using data describing biodiversity patterns and processes from microtidal beaches in South Africa. First, a classification scheme of valued features of beaches is constructed, including: biodiversity features; unique features; and important processes. Second, methodologies for setting targets for each feature under different data-availability scenarios are described. From this framework, targets are set for features characteristic of microtidal beaches in South Africa, as follows. 1) Targets for dune vegetation types were adopted from a previous assessment, and ranged 19-100%. 2) Targets for beach morphodynamic types (habitats) were set using species-area relationships (SARs). These SARs were derived from species richness data from 142 sampling events around the South African coast (extrapolated to total theoretical species richness estimates using previously-established species-accumulation curve relationships), plotted against the area of the beach (calculated from Google Earth imagery). The species-accumulation factor (z) was 0.22, suggesting a baseline habitat target of 27% is required to protect 75% of the species. This baseline target was modified by heuristic principles, based on habitat rarity and threat status, with final values ranging 27-40%. 3) Species targets were fixed at 20%, modified using heuristic principles based on endemism, threat status, and whether or not beaches play an important role in the species' life history, with targets ranging 20-100%. 4) Targets for processes and 5

Geometric Model for Tracker-Target Look Angles and Line of Slight Distance

DTIC Science & Technology

2015-10-20

412TW-PA-15239 Geometric Model for Tracker -Target Look Angles and Line of Slight Distance DANIEL T. LAIRD AIR FORCE TEST CENTER EDWARDS...15 – 23 OCT 15 4. TITLE AND SUBTITLE Geometric Model for Tracker -Target Look Angles and Line of Slight Distance 5a. CONTRACT...include area code) 661-277-8615 Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 GEOMETRIC MODEL FOR TRACKER -TARGET LOOK ANGLES

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity.

PubMed

Wang, Dongrui; Aguilar, Brenda; Starr, Renate; Alizadeh, Darya; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R; Forman, Stephen J; Brown, Christine E

2018-05-17

Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity

PubMed Central

Wang, Dongrui; Starr, Renate; Alizadeh, Darya; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R.; Forman, Stephen J.; Brown, Christine E.

2018-01-01

Chimeric antigen receptor–modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy. PMID:29769444

Novel fluorescence adjustable photonic crystal materials

NASA Astrophysics Data System (ADS)

Zhu, Cheng; Liu, Xiaoxia; Ni, Yaru; Fang, Jiaojiao; Fang, Liang; Lu, Chunhua; Xu, Zhongzi

2017-11-01

Novel photonic crystal materials (PCMs) with adjustable fluorescence were fabricated by distributing organic fluorescent powders of Yb0.2Er0.4Tm0.4(TTA)3Phen into the opal structures of self-assembled silica photonic crystals (PCs). Via removing the silica solution in a constant speed, PCs with controllable thicknesses and different periodic sizes were obtained on glass slides. Yb0.2Er0.4Tm0.4(TTA)3Phen powders were subsequently distributed into the opal structures. The structures and optical properties of the prepared PCMs were investigated. Finite-difference-time-domain (FDTD) calculation was used to further analyze the electric field distributions in PCs with different periodic sizes while the relation between periodic sizes and fluorescent spectra of PCMs was discussed. The results showed that the emission color of the PCMs under irradiation of 980 nm laser can be easily adjusted from green to blue by increasing the periodic size from 250 to 450 nm.

Countering resistance to protected-area extension.

PubMed

Lindenmayer, David; Thorn, Simon; Noss, Reed

2018-04-01

The establishment of protected areas is a critical strategy for conserving biodiversity. Key policy directives like the Aichi targets seek to expand protected areas to 17% of Earth's land surface, with calls by some conservation biologists for much more. However, in places such as the United States, Germany, and Australia, attempts to increase protected areas are meeting strong resistance from communities, industry groups, and governments. We examined case studies of such resistance in Victoria, Australia, Bavaria, Germany, and Florida, United States. We considered 4 ways to tackle this problem. First, broaden the case for protected areas beyond nature conservation to include economic, human health, and other benefits, and translate these into a persuasive business case for protected areas. Second, better communicate the conservation values of protected areas. This should include highlighting how many species, communities, and ecosystems have been conserved by protected areas and the counterfactual (i.e., what would have been lost without protected area establishment). Third, consider zoning of activities to ensure the maintenance of effective management. Finally, remind citizens to think about conservation when they vote, including holding politicians accountable for their environmental promises. Without tackling resistance to expanding the protected estate, it will be impossible to reach conservation targets, and this will undermine attempts to stem the global extinction crisis. © 2017 Society for Conservation Biology.

Preclinical Assessment of CAR T-Cell Therapy Targeting the Tumor Antigen 5T4 in Ovarian Cancer

PubMed Central

Owens, Gemma L.; Sheard, Victoria E.; Kalaitsidou, Milena; Blount, Daniel; Lad, Yatish; Cheadle, Eleanor J.; Edmondson, Richard J.; Kooner, Gurdeep; Gilham, David E.

2018-01-01

Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome both quantitative and qualitative shortfalls of the host immune system relating to the detection and subsequent destruction of tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step in the ability to utilize CAR T cells for the treatment of cancer. The 5T4 is a tumor-associated antigen which is expressed on the cell surface of most solid tumors including ovarian cancer. Matched blood and tumor samples were collected from 12 patients with ovarian cancer; all tumors were positive for 5T4 expression by immunohistochemistry. Patient T cells were effectively transduced with 2 different anti-5T4 CAR constructs which differed in their affinity for the target antigen. Co-culture of CAR T cells with matched autologous tumor disaggregates resulted in antigen-specific secretion of IFN-gamma. Furthermore, assessment of the efficacy of anti-5T4 CAR T cells in a mouse model resulted in therapeutic benefit against established ovarian tumors. These results demonstrate proof of principle that 5T4 is an attractive target for immune intervention in ovarian cancer and that patient T cells engineered to express a 5T4-specific CAR can recognize and respond physiologically to autologous tumor cells. PMID:29239915

Preliminary Quantification of Image Color Gradient on Genesis Concentrator Silicon Carbine Target 60001

NASA Technical Reports Server (NTRS)

Allton, J. H.; Calaway, M. J.; Rodriquez, M. C.

2008-01-01

The Genesis spacecraft concentrator was a device to focus solar wind ions onto a 6-cm diameter target area, thus concentrating the solar wind by 20X [1]. The target area was comprised of 4 quadrants held in place by a gold-coated stainless steel "cross" (Fig. 1). To date, two SiC and one chemical vapor deposited (CVD) quadrants have been imaged at 5X using a Leica DM-6000M in autoscan mode. Complete imaging of SiC sample 60001 required 1036 images. The mosaic of images is shown in Fig. 2 and position of analyzed areas in Fig. 3. This mosaic imaging is part of the curatorial documentation of surface condition and mapping of contamination. Higher magnification (50X) images of selected areas of the target and individual contaminant particles are compiled into reports which may be requested from the Genesis Curator [2].

LWIR hyperspectral change detection for target acquisition and situation awareness in urban areas

NASA Astrophysics Data System (ADS)

Dekker, Rob J.; Schwering, Piet B. W.; Benoist, Koen W.; Pignatti, Stefano; Santini, Federico; Friman, Ola

2013-05-01

This paper studies change detection of LWIR (Long Wave Infrared) hyperspectral imagery. Goal is to improve target acquisition and situation awareness in urban areas with respect to conventional techniques. Hyperspectral and conventional broadband high-spatial-resolution data were collected during the DUCAS trials in Zeebrugge, Belgium, in June 2011. LWIR data were acquired using the ITRES Thermal Airborne Spectrographic Imager TASI-600 that operates in the spectral range of 8.0-11.5 μm (32 band configuration). Broadband data were acquired using two aeroplanemounted FLIR SC7000 MWIR cameras. Acquisition of the images was around noon. To limit the number of false alarms due to atmospheric changes, the time interval between the images is less than 2 hours. Local co-registration adjustment was applied to compensate for misregistration errors in the order of a few pixels. The targets in the data that will be analysed in this paper are different kinds of vehicles. Change detection algorithms that were applied and evaluated are Euclidean distance, Mahalanobis distance, Chronochrome (CC), Covariance Equalisation (CE), and Hyperbolic Anomalous Change Detection (HACD). Based on Receiver Operating Characteristics (ROC) we conclude that LWIR hyperspectral has an advantage over MWIR broadband change detection. The best hyperspectral detector is HACD because it is most robust to noise. MWIR high spatial-resolution broadband results show that it helps to apply a false alarm reduction strategy based on spatial processing.

Causal evidence for frontal involvement in memory target maintenance by posterior brain areas during distracter interference of visual working memory

PubMed Central

Feredoes, Eva; Heinen, Klaartje; Weiskopf, Nikolaus; Ruff, Christian; Driver, Jon

2011-01-01

Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior cortical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFC-TMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction. PMID:21987824

Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies

NASA Astrophysics Data System (ADS)

Zarling, Joyce M.; Moran, Patricia A.; Haffar, Omar; Sias, Joan; Richman, Douglas D.; Spina, Celsa A.; Myers, Dorothea E.; Kuebelbeck, Virginia; Ledbetter, Jeffrey A.; Uckun, Fatih M.

1990-09-01

FUNCTIONAL impairment and selective depletion of CD4+ T cells, the hallmark of AIDS, are at least partly caused by human immunodeficiency virus (HIV-1) type 1 binding to the CD4 molecule and infecting CD4+ cells1,2. It may, therefore, be of therapeutic value to target an antiviral agent to CD4+ cells to prevent infection and to inhibit HIV-1 production in patients' CD4+ cells which contain proviral DNA3,4. We report here that HIV-1 replication in normal primary CD4+ T cells can be inhibited by pokeweed antiviral protein, a plant protein of relative molecular mass 30,000 (ref. 5), which inhibits replication of certain plant RNA viruses6-8, and of herpes simplex virus, poliovirus and influenza virus9-11. Targeting pokeweed antiviral protein to CD4+ T cells by conjugating it to monoclonal antibodies reactive with CDS, CD7 or CD4 expressed on CD4+ cells, increased its anti-HIV potency up to 1,000-fold. HIV-1 replication is inhibited at picomolar concentrations of conjugates of pokeweed antiviral protein and monoclonal antibodies, which do not inhibit proliferation of normal CD4+ T cells or CD4-dependent responses. These conjugates inhibit HIV-1 protein synthesis and also strongly inhibit HIV-1 production in activated CD4+ T cells from infected patients.

Folate conjugated Mn{sub 3}O{sub 4}@SiO{sub 2} nanoparticles for targeted magnetic resonance imaging in vivo

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

Yang, Xinyi; Zhou, Zhiguo, E-mail: zgzhou@shnu.edu.cn; Wang, Li

2014-09-15

Graphical abstract: The Mn{sub 3}O{sub 4}@SiO{sub 2}(PEG)–FA has been used as a T{sub 1}-MRI probe for in vivo. - Highlights: • The PEG and FA modified Mn{sub 3}O{sub 4}@SiO{sub 2} nanoparticles (Mn{sub 3}O{sub 4}@SiO{sub 2}–FA) were prepared. • Mn{sub 3}O{sub 4}@SiO{sub 2}–FA exhibited the good colloidal stability in the simulated biological medium. • Mn{sub 3}O{sub 4}@SiO{sub 2}–FA showed the targeting ability to HeLa cells overexpressed the FA receptor. • The T{sub 1}-weighted magnetic resonance (MR) imaging demonstrated the targeting ability of Mn{sub 3}O{sub 4}@SiO{sub 2}–FA in vivo tumor. - Abstract: The monodisperse silica-coated manganese oxide nanoparticles (Mn{sub 3}O{sub 4}@SiO{sub 2}more » NPs) were synthesized via the high temperature pyrolysis approach and were aminated through silanization. The amine-functionalized Mn{sub 3}O{sub 4} NPs enabled the covalent conjugation of hydrophilic methoxypoly(ethylene glycol) (PEG) and the targeting ligand of folate (FA) onto their surface. The formed PEG and FA modified Mn{sub 3}O{sub 4} NPs (Mn{sub 3}O{sub 4}@SiO{sub 2}(PEG)–FA) exhibited the good colloidal stability in the simulated biological medium and the targeting ability to HeLa cells overexpressed the FA receptor. The T{sub 1}-weighted magnetic resonance (MR) imaging and inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis of Mn{sub 3}O{sub 4}@SiO{sub 2}(PEG)–FA NPs further demonstrated their targeting ability in tumor.« less

Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting chemotypes.

PubMed

Musumeci, Domenica; Amato, Jussara; Zizza, Pasquale; Platella, Chiara; Cosconati, Sandro; Cingolani, Chiara; Biroccio, Annamaria; Novellino, Ettore; Randazzo, Antonio; Giancola, Concetta; Pagano, Bruno; Montesarchio, Daniela

2017-05-01

G-quadruplex (G4) structures are key elements in the regulation of cancer cell proliferation and their targeting is deemed to be a promising strategy in anticancer therapy. A tandem application of ligand-based virtual screening (VS) calculations together with the experimental G-quadruplex on Oligo Affinity Support (G4-OAS) assay was employed to discover novel G4-targeting compounds. The interaction of the selected compounds with the investigated G4 in solution was analysed through a series of biophysical techniques and their biological activity investigated by immunofluorescence and MTT assays. A focused library of 60 small molecules, designed as putative G4 groove binders, was identified through the VS. The G4-OAS experimental screening led to the selection of 7 ligands effectively interacting with the G4-forming human telomeric DNA. Evaluation of the biological activity of the selected compounds showed that 3 ligands of this sub-library induced a marked telomere-localized DNA damage response in human tumour cells. The combined application of virtual and experimental screening tools proved to be a successful strategy to identify new bioactive chemotypes able to target the telomeric G4 DNA. These compounds may represent useful leads for the development of more potent and selective G4 ligands. Expanding the repertoire of the available G4-targeting chemotypes with improved physico-chemical features, in particular aiming at the discovery of novel, selective G4 telomeric ligands, can help in developing effective anti-cancer drugs with fewer side effects. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2017 Elsevier B.V. All rights reserved.

microRNA-150 Regulates Mobilization and Migration of Bone Marrow-Derived Mononuclear Cells by Targeting Cxcr4

PubMed Central

Tano, Nobuko; Kim, Ha Won; Ashraf, Muhammad

2011-01-01

The interaction between chemokine receptor type 4 (CXCR4) and its ligand, stromal cell-derived factor (SDF)-1, plays an important role in stem cell mobilization and migration in ischemic tissues. MicroRNAs (miRs) are key regulators of stem cell function and are involved in regulation of stem cell survival and differentiation to adopt different cell lineages. In this study, we show that ischemia inhibits the expression of miR-150 in BM-derived mononuclear cells (MNC) and activates its target Cxcr4 gene. Our results show that miR-150/CXCR4 cascade enhances MNC mobilization and migration. By using mouse acute myocardial infarction (MI) model, we found that MNCs in peripheral blood (PB) were increased significantly at day 5 after AMI as compared to control group and the number of CXCR4 positive MNCs both in bone marrow (BM) and PB was also markedly increased after MI. Analysis by microarray-based miRNA profiling and real-time PCR revealed that the expression of miR-150 which targets Cxcr4 gene as predicted was significantly downregulated in BM-MNCs after MI. Abrogation of miR-150 markedly increased CXCR4 protein expression suggesting its target gene. To show that miR-150 regulates MNC mobilization, knockdown of miR-150 in BM-MNCs by specific antisense inhibitor resulted in their higher migration ability in vitro as compared to scramble-transfected MNCs. Furthermore, in vivo BM transplantation of MNCs lacking miR-150 expression by lentiviral vector into the irradiated wild type mice resulted in the increased number of MNCs in PB after AMI as compared to control. In conclusion, this study demonstrates that ischemia mobilizes BM stem cells via miR-150/CXCR4 dependent mechanism and miR-150 may be a novel therapeutic target for stem cell migration to the ischemic tissue for neovascularization and repair. PMID:22039399

Synthesis, characterization, and luminescent properties of Eu3+ dipyridophenazine functionalized complexes for potential bioimaging applications

NASA Astrophysics Data System (ADS)

Beasley, Jeremy

Luminescent properties of lanthanide complexes possess unique characteristics that make them good candidates for possible bioimaging agents and have inspired research initiatives to further explore these materials. However, the toxicity of these metals limits their applications as in-vivo bioimaging agents. One solution that eliminates the toxic effects is to encase these lanthanide complexes in silica. This project was designed to probe the variation in the fluorescence properties of a highly luminescent europium (III) complex, utilizing a fluorinated â-diketonate ligand (thenoyltrifluoroacetone (tta)), upon the substitution of the solvent molecules by various functionalized dipyrido[3,2-a:2',3'-c]phenazine (DPPZ) ligands. A method for covalently attaching, or occluding complexes in silica nanoparticles were also included in the project design. The structure and properties of the functionalized DPPZ ligands and their respective complexes were determined by FT-IR, 1H-NMR, UV-Vis, and fluorescence spectroscopy techniques. UV excitation of the complexes resulted in red luminescence (~ 614 nm) characteristic of trivalent europium ions. The differences in luminescence properties of the complexes are rationalized in terms of the electronic features of the different functionalized DPPZ ligands. The higher overall quantum yield of the un-functionalized DPPZ complex, Eu(tta)3DPPZ (Q.Y.= 7.68 +/- 0.06 %), and the low overall quantum yield observed for Eu(tta)3DPPZ-COOEt (Q.Y.= 1.08 +/- 0.05%), Eu(tta) 3DPPZ-Si (Q.Y.= 0.65+/- 0.04%), Eu(tta)3DPPZ-COOH (Q.Y.= 0.61+/- 0.07 %), Eu(tta)3DPPZ-CH3 (Q.Y.= 0.59+/-0.02 %) are rationalized in terms of how electron donating or withdrawing groups affect their respective ligand-to-metal energy transfer efficiencies. Eu(tta) 3DPPZ was the only complex to show enhanced luminescent properties capable of potential applications in biomedical imaging.

Beyond cysteine: recent developments in the area of targeted covalent inhibition.

PubMed

Mukherjee, Herschel; Grimster, Neil P

2018-05-29

Over the past decade targeted covalent inhibitors have undergone a renaissance due to the clinical validation and regulatory approval of several small molecule therapeutics that are designed to irreversibly modify their target protein. Invariably, these compounds rely on the serendipitous placement of a cysteine residue proximal to the small molecule binding site; while this strategy has afforded numerous successes, it necessarily limits the number of proteins that can be targeted by this approach. This drawback has led several research groups to develop novel methodologies that target non-cysteine residues for covalent modification. Herein, we survey the current literature of warheads that covalently modify non-cysteine amino acids in proteins. Copyright © 2018 Elsevier Ltd. All rights reserved.

Aquaporin 4 in Astrocytes is a Target for Therapy in Alzheimer's Disease.

PubMed

Lan, Yu-Long; Chen, Jian-Jiao; Hu, Gang; Xu, Jun; Xiao, Ming; Li, Shao

2017-01-01

Current experimental evidence points to the conclusion that aquaporin 4 (AQP4), which is an important water-channel membrane protein found in the brain, could play major roles in various brain conditions pathologically including pathogenesis of Alzheimer's disease (AD). In this paper, we review how AQP4 and altered astrocyte functions interact in AD, and provide experimental evidence highlighting the importance of this topic for the future investigations. The interactions of AQP4 are as follows: (i) AQP4 could influence astrocytic calcium signaling and potassium homeostasis. (ii) AQP4 is linked with the removal of interstitial β-amyloid and glutamate transmission. (iii) Furthermore, AQP4 modulates the reactive astrogliosis and neuroinflammation mechanisms. (iv) To add to this, AQP4 could participate in the AD pathogenesis through affecting neurotrophic factor production. It is therefore possible to identify certain functional molecules that regulate astrocyte make-up and functions. However, making crucial efforts to develop specific agents or drugs that target AQP4 function and test their therapeutic efficiency will be a breakthrough for addressing AD in that AQP4 controls the various physiological as well as pathophysiological features of astrocytes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

3D Long-Range Triplet Migration in a Water-Stable Metal-Organic Framework for Upconversion-Based Ultralow-Power in Vivo Imaging.

PubMed

Park, Jihye; Xu, Ming; Li, Fuyou; Zhou, Hong-Cai

2018-04-25

Triplet-triplet annihilation upconversion (TTA-UC) has gained increasing attention because it allows for harvesting of low-energy photons in the solar spectrum with high efficiency in relevant applications including solar cells and bioimaging. However, the utilization of conventional TTA-UC systems for low-power bioapplications is significantly hampered by their general incompatibility and low efficiency in aqueous media. Herein we report a metal-organic framework (MOF) as a biocompatible nanoplatform for TTA-UC to realize low-power in vivo imaging. Our MOF consists of a porphyrinic sensitizer in an anthracene-based Zr-MOF as a TTA-UC platform. In particular, closely aligned chromophores in the MOF facilitate a long-range 3D triplet diffusion of 1.6 μm allowing efficient energy migration in water. The tunable ratio between sensitizer and annihilator by our synthetic method also allows an optimization of the system for maximized TTA-UC efficiency in water at a very low excitation power density. Consequently, the low-power imaging of lymph node in a live mouse was successfully demonstrated with an excellent signal-to-noise ratio (SNR > 30 at 5 mW cm -2 ).

EphB4-targeted imaging with antibody h131, h131-F(ab′)2 and h131-Fab

PubMed Central

Li, Dan; Liu, Shuanglong; Liu, Ren; Zhou, Yue; Park, Ryan; Naga, Kranthi; Krasnoperov, Valery; Gill, Parkash S.; Li, Zibo; Shan, Hong; Conti, Peter S.

2013-01-01

Accumulating evidence suggests that overexpression of the tyrosine kinase receptor EphB4, a mediator of vascular development, is a novel target for tumor diagnosis, prognosis and therapy. Noninvasive imaging of EphB4 expression could therefore be valuable for evaluating disease course and therapeutic efficacy at the earliest stages of anti-EphB4 treatment. In this study, we systematically investigated the use of anti-EphB4 antibody h131 (150 kD) and its fragments (h131-F(ab′)2, 110 kD; h131-Fab, 50 kD) for near-infrared fluorescence (NIRF) imaging of EphB4 expression in vivo. h131-F(ab′)2 and h131-Fab were produced through pepsin and papain digestion of h131 respectively, whose purity was confirmed by FPLC and SDS-PAGE. After conjugation with Cy5.5, in vivo characteristics of h131, h131-F(ab′)2 and h131-Fab were evaluated in EphB4-positive HT29 tumor model. Although h131-Cy5.5 demonstrated highest tumor uptake among these probes, its optimal tumor uptake level was obtained at 2 d post injection (p.i.). For h131-Fab-Cy5.5, maximum tumor uptake was achieved at 4 h p.i.. However, no significant difference was observed between h131-Fab-Cy5.5 and hIgG-Fab-Cy5.5, indicating the tumor accumulation was mainly caused by passive targeting. In contrast, h131-F(ab′)2-Cy5.5 demonstrated prominent tumor uptake at 6 h p.i. The target specificity was confirmed by hIgG-F(ab′)2-Cy5.5 control and immunofluorescent staining. Collectively, h131-F(ab′)2 exhibited prominent and specific tumor uptake at early time points, which suggests it is a promising agent for EphB4-targeted imaging. PMID:24147882

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

PubMed Central

Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

2012-01-01

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

Predictive Coding in Area V4: Dynamic Shape Discrimination under Partial Occlusion

PubMed Central

Choi, Hannah; Pasupathy, Anitha; Shea-Brown, Eric

2018-01-01

The primate visual system has an exquisite ability to discriminate partially occluded shapes. Recent electrophysiological recordings suggest that response dynamics in intermediate visual cortical area V4, shaped by feedback from prefrontal cortex (PFC), may play a key role. To probe the algorithms that may underlie these findings, we build and test a model of V4 and PFC interactions based on a hierarchical predictive coding framework. We propose that probabilistic inference occurs in two steps. Initially, V4 responses are driven solely by bottom-up sensory input and are thus strongly influenced by the level of occlusion. After a delay, V4 responses combine both feedforward input and feedback signals from the PFC; the latter reflect predictions made by PFC about the visual stimulus underlying V4 activity. We find that this model captures key features of V4 and PFC dynamics observed in experiments. Specifically, PFC responses are strongest for occluded stimuli and delayed responses in V4 are less sensitive to occlusion, supporting our hypothesis that the feedback signals from PFC underlie robust discrimination of occluded shapes. Thus, our study proposes that area V4 and PFC participate in hierarchical inference, with feedback signals encoding top-down predictions about occluded shapes. PMID:29566355

Multifunctional NaYF4:Yb, Er@mSiO2@Fe3O4-PEG nanoparticles for UCL/MR bioimaging and magnetically targeted drug delivery.

PubMed

Liu, Bei; Li, Chunxia; Ma, Ping'an; Chen, Yinyin; Zhang, Yuanxin; Hou, Zhiyao; Huang, Shanshan; Lin, Jun

2015-02-07

A low toxic multifunctional nanoplatform, integrating both mutimodal diagnosis methods and antitumor therapy, is highly desirable to assure its antitumor efficiency. In this work, we show a convenient and adjustable synthesis of multifunctional nanoparticles NaYF4:Yb, Er@mSiO2@Fe3O4-PEG (MFNPs) based on different sizes of up-conversion nanoparticles (UCNPs). With strong up-conversion fluorescence offered by UCNPs, superparamagnetism properties attributed to Fe3O4 nanoparticles and porous structure coming from the mesoporous SiO2 shell, the as-obtained MFNPs can be utilized not only as a contrast agent for dual modal up-conversion luminescence (UCL)/magnetic resonance (MR) bio-imaging, but can also achieve an effective magnetically targeted antitumor chemotherapy both in vitro and in vivo. Furthermore, the UCL intensity of UCNPs and the magnetic properties of Fe3O4 in the MFNPs were carefully balanced. Silica coating and further PEG modifying can improve the hydrophilicity and biocompatibility of the as-synthesized MFNPs, which was confirmed by the in vitro/in vivo biocompatibility and in vivo long-time bio-distributions tests. Those results revealed that the UCNPs based magnetically targeted drug carrier system we synthesized has great promise in the future for multimodal bio-imaging and targeted cancer therapy.

Effects of the 'Consumer Game' on Learning and Attitudes of Selected Seventh Grade Students in A Target-Area School.

ERIC Educational Resources Information Center

Cohen, Karen C.

The following report describes one teacher's use of the Consumer Game in a class of seventh grade students in a target area school. These students were not highly motivated and displayed poor attitudes toward school, and it was hoped that a game experience might interest them. Despite unusual administrative conditions, the game appears to have…

7 CFR 301.86-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2010 CFR

2010-01-01

... experimental or scientific purposes; or (ii) The regulated article originates outside the quarantined area and... regulated articles from quarantined areas. 301.86-4 Section 301.86-4 Agriculture Regulations of the... regulated articles from quarantined areas. (a) Any regulated article may be moved interstate from a...

HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements

PubMed Central

Mielcarek, Michal; Zielonka, Daniel; Carnemolla, Alisia; Marcinkowski, Jerzy T.; Guidez, Fabien

2015-01-01

For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes. PMID:25759639

Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos.

PubMed

Goolam, Mubeen; Scialdone, Antonio; Graham, Sarah J L; Macaulay, Iain C; Jedrusik, Agnieszka; Hupalowska, Anna; Voet, Thierry; Marioni, John C; Zernicka-Goetz, Magdalena

2016-03-24

The major and essential objective of pre-implantation development is to establish embryonic and extra-embryonic cell fates. To address when and how this fundamental process is initiated in mammals, we characterize transcriptomes of all individual cells throughout mouse pre-implantation development. This identifies targets of master pluripotency regulators Oct4 and Sox2 as being highly heterogeneously expressed between blastomeres of the 4-cell embryo, with Sox21 showing one of the most heterogeneous expression profiles. Live-cell tracking demonstrates that cells with decreased Sox21 yield more extra-embryonic than pluripotent progeny. Consistently, decreasing Sox21 results in premature upregulation of the differentiation regulator Cdx2, suggesting that Sox21 helps safeguard pluripotency. Furthermore, Sox21 is elevated following increased expression of the histone H3R26-methylase CARM1 and is lowered following CARM1 inhibition, indicating the importance of epigenetic regulation. Therefore, our results indicate that heterogeneous gene expression, as early as the 4-cell stage, initiates cell-fate decisions by modulating the balance of pluripotency and differentiation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting.

PubMed

Hashimoto, Ayako; Ohkura, Katsuma; Takahashi, Masakazu; Kizu, Kumiko; Narita, Hiroshi; Enomoto, Shuichi; Miyamae, Yusaku; Masuda, Seiji; Nagao, Masaya; Irie, Kazuhiro; Ohigashi, Hajime; Andrews, Glen K; Kambe, Taiho

2015-12-01

Dietary zinc deficiency puts human health at risk, so we explored strategies for enhancing zinc absorption. In the small intestine, the zinc transporter ZIP4 functions as an essential component of zinc absorption. Overexpression of ZIP4 protein increases zinc uptake and thereby cellular zinc levels, suggesting that food components with the ability to increase ZIP4 could potentially enhance zinc absorption via the intestine. In the present study, we used mouse Hepa cells, which regulate mouse Zip4 (mZip4) in a manner indistinguishable from that in intestinal enterocytes, to screen for suitable food components that can increase the abundance of ZIP4. Using this ZIP4-targeting strategy, two such soybean extracts were identified that were specifically able to decrease mZip4 endocytosis in response to zinc. These soybean extracts also effectively increased the abundance of apically localized mZip4 in transfected polarized Caco2 and Madin-Darby canine kidney cells and, moreover, two apically localized mZip4 acrodermatitis enteropathica mutants. Soybean components were purified from one extract and soyasaponin Bb was identified as an active component that increased both mZip4 protein abundance and zinc levels in Hepa cells. Finally, we confirmed that soyasaponin Bb is capable of enhancing cell surface endogenous human ZIP4 in human cells. Our results suggest that ZIP4 targeting may represent a new strategy to improve zinc absorption in humans. © 2015 Authors; published by Portland Press Limited.

7 CFR 301.74-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2011 CFR

2011-01-01

... regulated articles from quarantined areas. 301.74-4 Section 301.74-4 Agriculture Regulations of the... articles from quarantined areas. The interstate movement of any regulated article from a quarantined area 2... quarantines and regulations must also be met. (a) The regulated article is moved by the United States...

7 CFR 301.32-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2011 CFR

2011-01-01

... regulated articles from quarantined areas. 301.32-4 Section 301.32-4 Agriculture Regulations of the... regulated articles from quarantined areas. Any regulated article may be moved interstate from a quarantined... permit if: (1) The regulated article originated outside the quarantined area and is either moved in an...

7 CFR 301.32-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2010 CFR

2010-01-01

... regulated articles from quarantined areas. 301.32-4 Section 301.32-4 Agriculture Regulations of the... regulated articles from quarantined areas. Any regulated article may be moved interstate from a quarantined... permit if: (1) The regulated article originated outside the quarantined area and is either moved in an...

7 CFR 301.50-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2010 CFR

2010-01-01

... regulated articles from quarantined areas. 301.50-4 Section 301.50-4 Agriculture Regulations of the... regulated articles from quarantined areas. Any regulated article may be moved interstate from a quarantined... certificate or limited permit, if: (1)(i) The regulated article originates outside any quarantined area and is...

7 CFR 301.74-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2010 CFR

2010-01-01

... regulated articles from quarantined areas. 301.74-4 Section 301.74-4 Agriculture Regulations of the... articles from quarantined areas. The interstate movement of any regulated article from a quarantined area 2... quarantines and regulations must also be met. (a) The regulated article is moved by the United States...

Development and evaluation of camptothecin loaded polymer stabilized nanoemulsion: Targeting potential in 4T1-breast tumour xenograft model.

PubMed

Sugumaran, Abimanyu; Ponnusamy, Chandrasekar; Kandasamy, Palanivel; Krishnaswami, Venkateshwaran; Palanichamy, Rajaguru; Kandasamy, Ruckmani; Lakshmanan, Manikandan; Natesan, Subramanian

2018-04-30

Targeted delivery of anticancer agents is poised to improve cancer therapy, for which polymers can serve as targeting ligands or nanocarriers for chemotherapeutic agents. In this study, we have developed and evaluated the efficacy of a camptothecin (CPT)-loaded polymer stabilized nanoemulsion (PSNE) for the passive targeted delivery to breast cancer. Based on the pseudo-ternary phase diagrams, PSNEs were developed using capmul MCM:poloxamer 407 (4:1), solutol HS 15:simulsol P23 (1:2) and water. CPT polymer mixture was developed by solvent evaporation technique. The PSNEs were characterized for droplet size distribution, plasma protein adsorption, drug release, in-vivo targeting potential, hemolytic potential, cytotoxicity, genotoxicity, in-vivo biodistribution and CPT lactone ring stability. The developed PSNEs showed uniform droplet distribution, extended drug release (76.59±6.12% at 24h), acceptable hemolytic potential, significant cytotoxicity (IC 50 =176±4.3ng/mL) and genotoxicity against MCF-7 cancer cells but low DNA damage potential in human peripheral blood lymphocytes. The efficiency of PSNEs for the targeted delivery of CPT into the tumour regions was documented in 4T1-breast tumour xenografted BALB/c mice. In-vivo biodistribution study shows that 7105.84±568.46ng/g of CPT was passively targeted from PSNE to breast cancer tissue. About 80% of the lactone form was stable for 24h. Taken together, our study provides a promising strategy for developing PSNE-targeted drug delivery system for the breast cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

[Clinical evaluation of anaerobic infections in patients with bronchopulmonary infections diagnosed by transtracheal aspiration].

PubMed

Konishi, M; Mori, K; Yoshimoto, E; Takahashi, K; Majima, T; Ueda, K; Murakawa, K; Sakamoto, M; Maeda, K; Mikasa, K; Narita, N; Sano, R; Masutani, T

1999-07-01

We evaluated the clinical and bacteriologic features in the patients with bronchopulmonary infections isolated anaerobes from transtracheal aspirates between April 1990 and March 1998. Some anaerobe was isolated in 42 (10.9%) in 387 patients whom we performed transtracheal aspiration (TTA), in 42 (15.7%) of 268 in whom some organism was isolated from TTA, or in 42 (16.3%) of 257 patients in whom some bacterium excluding acid-fast bacteria, fungi or mycoplasma from TTA. The isolation rate of anaerobic bacteria was 93.3% in the patients with lung abscess, 22.7% in the patients with nosocomial pneumonia, 19.4% in the patients with community-acquired pneumonia, 26.7% in the patients with acute exacerbation of chronic lower respiratory tract infection (CLRTI), 1.6% in the patients with persistent infection of CLRTI, and 3.0% in the patients with acute bronchitis, respectively. The major anaerobes, isolated from TTA, were Peptostreptococcus micros and Prevotella melaninogenica. The aerobic bacteria were isolated with anaerobic bacteria in 32 of 42 patients at the same time. The quantitive grade of colonial growth of anaerobes was equal to or more than aerobes in the patients with lung abscess and pneumonia. We mostly administrated 3rd generation cephems or carbapenems with or without clindamycin for the treatment of anaerobic infections. Forty-one of 42 patients were cured only by the therapy of antimicrobial agents, but pneumonia patient with lung cancer died in spite of adequate antimicrobial therapy. These results suggest that the anaerobic infections are important in the bronchopulmonary infections.

Developing a Novel Therapeutic Strategy Targeting Kallikrein-4 to Inhibit Prostate Cancer Growth and Metastasis

DTIC Science & Technology

2015-08-01

mesenchymal transition (EMT), animal models, cancer imaging, cancer stem cells , circulating tumor cells (CTCs), metabolomics, targeted therapeutics and...metastatic tissue, and has been reported to increase PCa cell proliferation, induce epithelial-to- mesenchymal (EMT)-like changes, and could have a role...KLK4 has been reported to increase PCa cell proliferation, induce an epithelial to mesenchymal transition (EMT)-like response in PC3 PCa cells [4

Savannah River Plant engineering and design history. Volume 4: 300/700 Areas & general services and facilities

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

Not Available

1957-01-01

The primary function of the 300 Area is the production and preparation of the fuel and target elements required for the 100 Area production reactors. Uranium slugs and lithium-aluminium alloy control and blanket rods are prepared in separate structures. Other facilities include a test pile, a physics assembly laboratory, an office and change house, an electrical substation, and various service facilities such as rail lines, roads, sewers, steam and water distribution lines, etc. The 700 Area contains housing and facilities for plant management, general plant services, and certain technical activities. The technical buildings include the Main Technical Laboratory, the Wastemore » Concentration Building, the Health Physics Headquarters, and the Health Physics Calibration building. Sections of this report describe the following: development of the 300-M Area; selection and description of process; design of main facilities of the 300 Area; development of the 700-A Area; design of the main facilities of the 700 Area; and general services and facilities, including transportation, plant protection, waste disposal and drainage, site work, pilot plants, storage, and furniture and fixtures.« less

MIR-27a regulates the TGF-β signaling pathway by targeting SMAD2 and SMAD4 in lung cancer.

PubMed

Chae, Dong-Kyu; Ban, Eunmi; Yoo, Young Sook; Kim, Eunice EunKyeong; Baik, Ja-Hyun; Song, Eun Joo

2017-08-01

The transforming growth factor-β (TGF-β) signaling pathway is associated with carcinogenesis and various biological processes. SMAD2 and SMAD4, which are putative tumor suppressors, have an important role in TGF-β signaling. The aberrant expression of these genes is implicated in some cancers. However, the mechanisms of SMAD2 and SMAD4 dysregulation are poorly understood. In this study, we observed that miR-27a was upregulated in lung cancer cell lines and patients. In addition, SMAD2 and SMAD4 genes were identified as targets of miR-27a by several target prediction databases and experimental validation. Functional studies revealed that miR-27a overexpression decreased SMAD2 and SMAD4 mRNA and protein levels. Furthermore, miR-27a contributed to cell proliferation and invasion by inhibiting TGF-β-induced cell cycle arrest. These results suggest that miR-27a may function as an oncogene by regulating SMAD2 and SMAD4 in lung cancer. Thus, miR-27a may be a potential target for cancer therapy. © 2017 Wiley Periodicals, Inc.

Transient receptor potential canonical 4 and 5 proteins as targets in cancer therapeutics.

PubMed

Gaunt, Hannah J; Vasudev, Naveen S; Beech, David J

2016-10-01

Novel approaches towards cancer therapy are urgently needed. One approach might be to target ion channels mediating Ca 2+ entry because of the critical roles played by Ca 2+ in many cell types, including cancer cells. There are several types of these ion channels, but here we address those formed by assembly of transient receptor potential canonical (TRPC) proteins, particularly those which involve two closely related members of the family: TRPC4 and TRPC5. We focus on these proteins because recent studies point to roles in important aspects of cancer: drug resistance, transmission of drug resistance through extracellular vesicles, tumour vascularisation, and evoked cancer cell death by the TRPC4/5 channel activator (-)-englerin A. We conclude that further research is both justified and necessary before these proteins can be considered as strong targets for anti-cancer cell drug discovery programmes. It is nevertheless already apparent that inhibitors of the channels would be unlikely to cause significant adverse effects, but, rather, have other effects which may be beneficial in the context of cancer and chemotherapy, potentially including suppression of innate fear, visceral pain and pathological cardiac remodelling.

RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4 Induced Mouse Model

DTIC Science & Technology

2017-10-01

mouse genetic breeding, provided genotyping, immunostaining, histological analysis, and molecular expertise. Funding Support NIH/NHLBI Name: Bert...AWARD NUMBER: W81XWH-16-1-0665 TITLE: RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4-Induced Mouse...2016 - 29 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in

A Tracking Analyst for large 3D spatiotemporal data from multiple sources (case study: Tracking volcanic eruptions in the atmosphere)

NASA Astrophysics Data System (ADS)

Gad, Mohamed A.; Elshehaly, Mai H.; Gračanin, Denis; Elmongui, Hicham G.

2018-02-01

This research presents a novel Trajectory-based Tracking Analyst (TTA) that can track and link spatiotemporally variable data from multiple sources. The proposed technique uses trajectory information to determine the positions of time-enabled and spatially variable scatter data at any given time through a combination of along trajectory adjustment and spatial interpolation. The TTA is applied in this research to track large spatiotemporal data of volcanic eruptions (acquired using multi-sensors) in the unsteady flow field of the atmosphere. The TTA enables tracking injections into the atmospheric flow field, the reconstruction of the spatiotemporally variable data at any desired time, and the spatiotemporal join of attribute data from multiple sources. In addition, we were able to create a smooth animation of the volcanic ash plume at interactive rates. The initial results indicate that the TTA can be applied to a wide range of multiple-source data.

ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice

PubMed Central

2013-01-01

Background Recent findings suggest that the pathological effects of apoE4, the most prevalent genetic risk factor for Alzheimer’s disease (AD), start many years before the onset of the disease and are already detectable at a young age. In the present study we investigated the extent to which such pathological and cognitive impairments also occur in young apoE4 mice. Results This study revealed that the levels of the presynaptic glutamatergic vesicular transporter, VGlut, in the CA3, CA1, and DG hippocampal subfields were lower in hippocampal neurons of young (4-month-old) apoE4-targeted replacement mice than in those of the apoE3 mice. In contrast, the corresponding inhibitory GABAergic nerve terminals and perikarya were not affected by apoE4. This synaptic effect was associated with hyperphosphorylation of tau in these neurons. In addition, apoE4 increased the accumulation of neuronal Aβ42 and induced mitochondrial changes, both of which were specifically pronounced in CA3 neurons. Spatial navigation behavioral studies revealed that these hippocampal pathological effects of apoE4 are associated with corresponding behavioral impairments. Time-course studies revealed that the effects of apoE4 on tau hyperphosphorylation and the mitochondria were already apparent at the age of 1 month and that the apoE4-driven accumulation of neuronal Aβ and reduced VGlut levels evolve later and are apparent at the age of 2–4 months. Furthermore, the levels of tau phosphorylation decrease in apoE3 mice and increase in apoE4 mice between 1 and 4 months, whereas the levels of Aβ42 decrease in apoE3 mice and are not affected in apoE4 mice over the same time period. Conclusions These findings show that apoE4 stimulates the accumulation of Aβ42 and hyperphosphorylated tau and reduces the levels of VGlut in hippocampal neurons of young apoE4-targeted replacement mice and that these neurochemical effects are associated with cognitive impairments. This model is not associated with

ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice.

PubMed

Liraz, Ori; Boehm-Cagan, Anat; Michaelson, Daniel M

2013-05-17

Recent findings suggest that the pathological effects of apoE4, the most prevalent genetic risk factor for Alzheimer's disease (AD), start many years before the onset of the disease and are already detectable at a young age. In the present study we investigated the extent to which such pathological and cognitive impairments also occur in young apoE4 mice. This study revealed that the levels of the presynaptic glutamatergic vesicular transporter, VGlut, in the CA3, CA1, and DG hippocampal subfields were lower in hippocampal neurons of young (4-month-old) apoE4-targeted replacement mice than in those of the apoE3 mice. In contrast, the corresponding inhibitory GABAergic nerve terminals and perikarya were not affected by apoE4.This synaptic effect was associated with hyperphosphorylation of tau in these neurons. In addition, apoE4 increased the accumulation of neuronal Aβ42 and induced mitochondrial changes, both of which were specifically pronounced in CA3 neurons. Spatial navigation behavioral studies revealed that these hippocampal pathological effects of apoE4 are associated with corresponding behavioral impairments. Time-course studies revealed that the effects of apoE4 on tau hyperphosphorylation and the mitochondria were already apparent at the age of 1 month and that the apoE4-driven accumulation of neuronal Aβ and reduced VGlut levels evolve later and are apparent at the age of 2-4 months. Furthermore, the levels of tau phosphorylation decrease in apoE3 mice and increase in apoE4 mice between 1 and 4 months, whereas the levels of Aβ42 decrease in apoE3 mice and are not affected in apoE4 mice over the same time period. These findings show that apoE4 stimulates the accumulation of Aβ42 and hyperphosphorylated tau and reduces the levels of VGlut in hippocampal neurons of young apoE4-targeted replacement mice and that these neurochemical effects are associated with cognitive impairments. This model is not associated with hypothesis-driven mechanistic

miR-27a induced by colon cancer cells in HLECs promotes lymphangiogenesis by targeting SMAD4

PubMed Central

Zhang, Chen-Peng; Xiao, Qian; Lin, Xiao-Lin

2017-01-01

Aim Metastasis of tumor cells occurs through lymphatic vessels, blood vessels and transcoelomic spreading. Growing evidence from in vivo and in vitro studies has indicated that tumor lymphangiogenesis facilitates metastasis. However, the regulation of lymphangiogenesis in colon cancer remains unclear. The aims of this study were to identify key miRNAs in colon cancer lymphangiogenesis and to investigate its target and mechanism. Methods miRNA microarray analysis was conducted to identify miRNAs in human lymphatic endothelial cells (HLECs) that were regulated by co-cultured human colon cancer cells. Gain- and loss-of-function studies were performed to determine the function of miR-27a, a top hint, on lymphangiogenesis and migration in HLECs. Furthermore, bioinformatics prediction and experimental validation were performed to identify miR-27a target genes in lymphangiogenesis. Results We found that expression of miR-27a in HLECs was induced by co-culturing with colon cancer cells. Over-expression of miR-27a in HLECs enhanced lymphatic tube formation and migration, whereas inhibition of miR-27a reduced lymphatic tube formation and migration. Luciferase reporter assays showed that miR-27a directly targeted SMAD4, a pivotal component of the TGF-β pathway. In addition, gain-of-function and loss-of-function experiments showed that SMAD4 negatively regulated the length of lymphatic vessels formed by HLECs and migration. Conclusions Our data indicated that colon cancer cell induced the expression of miR-27a in HLECs, which promoted lymphangiogenesis by targeting SMAD4. Our finding implicated miR-27a as a potential target for new anticancer therapies in colon cancer. PMID:29065177

Validation of a 4D-PET Maximum Intensity Projection for Delineation of an Internal Target Volume

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

Callahan, Jason, E-mail: jason.callahan@petermac.org; Kron, Tomas; Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne

2013-07-15

Purpose: The delineation of internal target volumes (ITVs) in radiation therapy of lung tumors is currently performed by use of either free-breathing (FB) {sup 18}F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT) or 4-dimensional (4D)-CT maximum intensity projection (MIP). In this report we validate the use of 4D-PET-MIP for the delineation of target volumes in both a phantom and in patients. Methods and Materials: A phantom with 3 hollow spheres was prepared surrounded by air then water. The spheres and water background were filled with a mixture of {sup 18}F and radiographic contrast medium. A 4D-PET/CT scan was performed of the phantom whilemore » moving in 4 different breathing patterns using a programmable motion device. Nine patients with an FDG-avid lung tumor who underwent FB and 4D-PET/CT and >5 mm of tumor motion were included for analysis. The 3 spheres and patient lesions were contoured by 2 contouring methods (40% of maximum and PET edge) on the FB-PET, FB-CT, 4D-PET, 4D-PET-MIP, and 4D-CT-MIP. The concordance between the different contoured volumes was calculated using a Dice coefficient (DC). The difference in lung tumor volumes between FB-PET and 4D-PET volumes was also measured. Results: The average DC in the phantom using 40% and PET edge, respectively, was lowest for FB-PET/CT (DCAir = 0.72/0.67, DCBackground 0.63/0.62) and highest for 4D-PET/CT-MIP (DCAir = 0.84/0.83, DCBackground = 0.78/0.73). The average DC in the 9 patients using 40% and PET edge, respectively, was also lowest for FB-PET/CT (DC = 0.45/0.44) and highest for 4D-PET/CT-MIP (DC = 0.72/0.73). In the 9 lesions, the target volumes of the FB-PET using 40% and PET edge, respectively, were on average 40% and 45% smaller than the 4D-PET-MIP. Conclusion: A 4D-PET-MIP produces volumes with the highest concordance with 4D-CT-MIP across multiple breathing patterns and lesion sizes in both a phantom and among patients. Freebreathing PET/CT consistently

7 CFR 301.51-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2014 CFR

2014-01-01

... regulated articles from quarantined areas. 301.51-4 Section 301.51-4 Agriculture Regulations of the... DOMESTIC QUARANTINE NOTICES Asian Longhorned Beetle § 301.51-4 Conditions governing the interstate movement of regulated articles from quarantined areas. (a) Any regulated article may be moved interstate from...

7 CFR 301.51-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2012 CFR

2012-01-01

... regulated articles from quarantined areas. 301.51-4 Section 301.51-4 Agriculture Regulations of the... DOMESTIC QUARANTINE NOTICES Asian Longhorned Beetle § 301.51-4 Conditions governing the interstate movement of regulated articles from quarantined areas. (a) Any regulated article may be moved interstate from...

7 CFR 301.51-4 - Conditions governing the interstate movement of regulated articles from quarantined areas.

Code of Federal Regulations, 2011 CFR

2011-01-01

... regulated articles from quarantined areas. 301.51-4 Section 301.51-4 Agriculture Regulations of the... DOMESTIC QUARANTINE NOTICES Asian Longhorned Beetle § 301.51-4 Conditions governing the interstate movement of regulated articles from quarantined areas. (a) Any regulated article may be moved interstate from...

MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes.

PubMed

Horie, Takahiro; Ono, Koh; Nishi, Hitoo; Iwanaga, Yoshitaka; Nagao, Kazuya; Kinoshita, Minako; Kuwabara, Yasuhide; Takanabe, Rieko; Hasegawa, Koji; Kita, Toru; Kimura, Takeshi

2009-11-13

GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3'UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.

Effect of Förster-mediated triplet-polaron quenching and triplet-triplet annihilation on the efficiency roll-off of organic light-emitting diodes

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

Eersel, H. van; Bobbert, P. A.; Janssen, R. A. J.

2016-04-28

We report the results of a systematic study of the interplay of triplet-polaron quenching (TPQ) and triplet-triplet annihilation (TTA) on the efficiency roll-off of organic light-emitting diodes (OLEDs) with increasing current density. First, we focus on OLEDs based on the green phosphorescent emitter tris[2-phenylpyridine]iridium(III) (Ir(ppy){sub 3}) and the red phosphorescent dye platinum octaethylporphyrin. It is found that the experimental data can be reproduced using kinetic Monte Carlo (kMC) simulations within which TPQ and TTA are due to a nearest-neighbor (NN) interaction, or due to a more long-range Förster-type process. Furthermore, we find a subtle interplay between TPQ and TTA: decreasingmore » the contribution of one process can increase the contribution of the other process, so that the roll-off is not significantly reduced. Furthermore, we find that just analyzing the shape of the roll-off is insufficient for determining the relative role of TPQ and TTA. Subsequently, we investigate the wider validity of this picture using kMC simulations for idealized but realistic symmetric OLEDs, with an emissive layer containing a small concentration of phosphorescent dye molecules in a matrix material. Whereas for NN-interactions the roll-off can be reduced when the dye molecules act as shallow hole and electron traps, we find that such an approach becomes counterproductive for long-range TTA and TPQ. Developing well-founded OLED design rules will thus require that more quantitative information is available on the rate and detailed mechanism of the TPQ and TTA processes.« less

Effect of Förster-mediated triplet-polaron quenching and triplet-triplet annihilation on the efficiency roll-off of organic light-emitting diodes

NASA Astrophysics Data System (ADS)

van Eersel, H.; Bobbert, P. A.; Janssen, R. A. J.; Coehoorn, R.

2016-04-01

We report the results of a systematic study of the interplay of triplet-polaron quenching (TPQ) and triplet-triplet annihilation (TTA) on the efficiency roll-off of organic light-emitting diodes (OLEDs) with increasing current density. First, we focus on OLEDs based on the green phosphorescent emitter tris[2-phenylpyridine]iridium(III) (Ir(ppy)3) and the red phosphorescent dye platinum octaethylporphyrin. It is found that the experimental data can be reproduced using kinetic Monte Carlo (kMC) simulations within which TPQ and TTA are due to a nearest-neighbor (NN) interaction, or due to a more long-range Förster-type process. Furthermore, we find a subtle interplay between TPQ and TTA: decreasing the contribution of one process can increase the contribution of the other process, so that the roll-off is not significantly reduced. Furthermore, we find that just analyzing the shape of the roll-off is insufficient for determining the relative role of TPQ and TTA. Subsequently, we investigate the wider validity of this picture using kMC simulations for idealized but realistic symmetric OLEDs, with an emissive layer containing a small concentration of phosphorescent dye molecules in a matrix material. Whereas for NN-interactions the roll-off can be reduced when the dye molecules act as shallow hole and electron traps, we find that such an approach becomes counterproductive for long-range TTA and TPQ. Developing well-founded OLED design rules will thus require that more quantitative information is available on the rate and detailed mechanism of the TPQ and TTA processes.

Long Term Functional Outcome of Tibial Tuberosity Advancement vs. Tibial Plateau Leveling Osteotomy and Extracapsular Repair in a Heterogeneous Population of Dogs.

PubMed

Krotscheck, Ursula; Nelson, Samantha A; Todhunter, Rory J; Stone, Marisa; Zhang, Zhiwu

2016-02-01

To determine a long term function of tibial tuberosity advancement (TTA) for treatment of ruptured cranial cruciate ligament (CCL) in dogs, and to compare this to the long term function of previously reported tibial plateau leveling osteotomy (TPLO), extracapsular reconstruction (ECR), and a population of normal dogs. Prospective clinical trial. Dogs with unilateral ruptured CCL treated with TTA (n = 14), TPLO (n = 15), and ECR (n = 23), and normal adult dogs (control, n = 80). Force plate gait analysis was performed at 1 time point for the normal control group and preoperatively, and at 2 and 8 weeks and 6 and 12 months postoperatively for the treatment groups. Using serial force plates, symmetry indices (SI) were calculated between the operated and unoperated pelvic limbs for peak vertical force (PVF), contact time (CT), and vertical impulse (VI). Ground reaction forces (GRF) of the treatment and control group were compared using a general linear model. Walk SI for dogs with TTA were not significantly different from the control group at 12 months postoperatively. At the trot, neither TTA nor ECR achieved normal GRF. SI of the TPLO group were not different from the normal control group by 6-12 months postoperatively. At the walk, TTA achieves normal function by 12 months; however, at the trot TTA is indistinguishable from ECR. TPLO resulted in operated limb function that was similar to the control population by 6-12 months postoperatively at the walk and the trot. © Copyright 2016 by The American College of Veterinary Surgeons.

Red-light-controllable liquid-crystal soft actuators via low-power excited upconversion based on triplet-triplet annihilation.

PubMed

Jiang, Zhen; Xu, Ming; Li, Fuyou; Yu, Yanlei

2013-11-06

A red-light-controllable soft actuator has been achieved, driven by low-power excited triplet-triplet annihilation-based upconversion luminescence (TTA-UCL). First, a red-to-blue TTA-based upconversion system with a high absolute quantum yield of 9.3 ± 0.5% was prepared by utilizing platinum(II) tetraphenyltetrabenzoporphyrin (PtTPBP) as the sensitizer and 9,10-bis(diphenylphosphoryl)anthracene (BDPPA) as the annihilator. In order to be employed as a highly effective phototrigger of photodeformable cross-linked liquid-crystal polymers (CLCPs), the PtTPBP&BDPPA system was incorporated into a rubbery polyurethane film and then assembled with an azotolane-containing CLCP film. The generating assembly film bent toward the light source when irradiated with a 635 nm laser at low power density of 200 mW cm(-2) because the TTA-UCL was effectively utilized by the azotolane moieties in the CLCP film, inducing their trans-cis photoisomerization and an alignment change of the mesogens via an emission-reabsorption process. It is the first example of a soft actuator in which the TTA-UCL is trapped and utilized to create photomechanical effect. Such advantages of using this novel red-light-controllable soft actuator in potential biological applications have also been demonstrated as negligible thermal effect and its excellent penetration ability into tissues. This work not only provides a novel photomanipulated soft actuation material system based on the TTA-UCL technology but also introduces a new technological application of the TTA-based upconversion system in photonic devices.

Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD)

PubMed Central

Ansseau, Eugénie; Vanderplanck, Céline; Wauters, Armelle; Harper, Scott Q.; Coppée, Frédérique; Belayew, Alexandra

2017-01-01

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of DUX4 mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD. PMID:28273791

Bolder science needed now for protected areas.

PubMed

Watson, James E M; Darling, Emily S; Venter, Oscar; Maron, Martine; Walston, Joe; Possingham, Hugh P; Dudley, Nigel; Hockings, Marc; Barnes, Megan; Brooks, Thomas M

2016-04-01

Recognizing that protected areas (PAs) are essential for effective biodiversity conservation action, the Convention on Biological Diversity established ambitious PA targets as part of the 2020 Strategic Plan for Biodiversity. Under the strategic goal to "improve the status of biodiversity by safeguarding ecosystems, species, and genetic diversity," Target 11 aims to put 17% of terrestrial and 10% of marine regions under PA status by 2020. Additionally and crucially, these areas are required to be of particular importance for biodiversity and ecosystem services, effectively and equitably managed, ecologically representative, and well-connected and to include "other effective area-based conservation measures" (OECMs). Whereas the area-based targets are explicit and measurable, the lack of guidance for what constitutes important and representative; effective; and OECMs is affecting how nations are implementing the target. There is a real risk that Target 11 may be achieved in terms of area while failing the overall strategic goal for which it is established because the areas are poorly located, inadequately managed, or based on unjustifiable inclusion of OECMs. We argue that the conservation science community can help establish ecologically sensible PA targets to help prioritize important biodiversity areas and achieve ecological representation; identify clear, comparable performance metrics of ecological effectiveness so progress toward these targets can be assessed; and identify metrics and report on the contribution OECMs make toward the target. By providing ecologically sensible targets and new performance metrics for measuring the effectiveness of both PAs and OECMs, the science community can actively ensure that the achievement of the required area in Target 11 is not simply an end in itself but generates genuine benefits for biodiversity. © 2016 Society for Conservation Biology.

Design of ligand-targeted nanoparticles for enhanced cancer targeting

NASA Astrophysics Data System (ADS)

Stefanick, Jared F.

Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted

Tibial Tuberosity Anteromedialization for Patellofemoral Chondral Disease: Prognostic Factors.

PubMed

Rosso, Federica; Rossi, Roberto; Governale, Giorgio; Marmotti, Antongiulio; Cherubini, Valeria; Cottino, Umberto; Bonasia, Davide Edoardo

2017-06-01

Tibial tuberosity anteromedialization (TTA) is a well-established treatment option for patellofemoral chondral disease that is resistant to nonoperative treatment. However, the prognostic factors of this procedure are unknown. To analyze the prognostic factors correlated with the midterm outcomes of TTA for patellofemoral chondral disease and determine the survivorship. Case series; Level of evidence, 4. Indications of TTA for chondral disease included skeletal maturity, age <65 years, TTA with or without lateral release, and (3) minimum 2-year follow-up. Exclusion criteria were (1) previous knee surgeries, (2) previous patellar dislocations, (3) inflammatory/rheumatic conditions, (4) major combined procedures other than lateral release, (5) focal chondral lesions amenable to cartilage repair, and (6) severe trochlear dysplasia. The patients were prospectively evaluated radiographically and clinically using the Western Ontario and McMaster Universities Osteoarthritis Index-Short-Form (WOMAC-SF) and Kujala scores. Different clinical and radiological data were collected (preoperative, intraoperative, and postoperative) and correlated with the outcomes using multiple logistic regression. The Kaplan-Meier survivorship was also evaluated. From January 2003 to December 2013, among 76 eligible patients, 69 patients (78 knees, 74.4% female) were included, with a mean follow-up of 67.9 ± 34.5 months (range, 24-163 months) and a mean age at the time of surgery of 43.5 ± 16.1 years. The mean preoperative WOMAC-SF (17.8 ± 5.3) and Kujala (49.3 ± 15.6) scores significantly ( P < .001) improved after surgery (WOMAC-SF: 6.6 ± 6.9; Kujala: 74.2 ± 20.5). The patients graded their operated knee as 7.2 ± 2.1 of 10 points, on average, and stated that they would undergo the surgery again in 58

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

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2.

PubMed

Gao, Ming; Liu, Yun; Chen, Yue; Yin, Chunyang; Chen, Jane-Jane; Liu, Sijin

2016-03-01

Nuclear factor (erythroid-derived 2) like 2 (Nrf2) is a key regulator in protecting cells against stress by targeting many anti-stress response genes. Recent evidence also reveals that Nrf2 functions partially by targeting mircroRNAs (miRNAs). However, the understanding of Nrf2-mediated cytoprotection through miRNA-dependent mechanisms is largely unknown. In the current study, we identified a direct Nrf2 targeting miRNA, miR-214, and demonstrated a protective role of miR-214 in erythroid cells against oxidative stresses generated by radiation, excess iron and arsenic (As) exposure. miR-214 expression was transcriptionally repressed by Nrf2 through a canonical antioxidant response element (ARE) within its promoter region, and this repression is ROS-dependence. The suppression of miR-214 by Nrf2 could antagonize oxidative stress-induced cell death in erythroid cells by two ways. First, miR-214 directly targeted ATF4, a crucial transcriptional factor involved in anti-stress responses, down regulation of miR-214 releases the repression of ATF4 translation and leads to increased ATF4 protein content. Second, miR-214 was able to prevent cell death by targeting EZH2, the catalytic core component of PRC2 complex that is responsible for tri-methylation reaction at lysine 27 (K27) of histone 3 (H3) (H3K27me3), by which As-induced miR-214 reduction resulted in an increased global H3K27me3 level and a compromised overexpression of a pro-apoptotic gene Bim. These two pathways downstream of miR-214 synergistically cooperated to antagonize erythroid cell death upon oxidative stress. Our combined data revealed a protective role of miR-214 signaling in erythroid cells against oxidative stress, and also shed new light on Nrf2-mediated cytoprotective machinery. Copyright © 2016 Elsevier Inc. All rights reserved.

2,4-Diaminopyrimidines as potent inhibitors of Trypanosoma brucei and identification of molecular targets by a chemical proteomics approach.

PubMed

Mercer, Luke; Bowling, Tana; Perales, Joe; Freeman, Jennifer; Nguyen, Tien; Bacchi, Cyrus; Yarlett, Nigel; Don, Robert; Jacobs, Robert; Nare, Bakela

2011-02-08

There is an urgent need to develop new, safe and effective treatments for human African trypanosomiasis (HAT) because current drugs have extremely poor safety profiles and are difficult to administer. Here we report the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide (SCYX-5070), as potent inhibitors of Trypanosoma brucei and the related trypanosomatid protozoans Leishmania spp. In this work we show that loss of T. brucei viability following SCYX-5070 exposure was dependent on compound concentration and incubation time. Pulse incubation of T. brucei with SCYX-5070 demonstrates that a short period of exposure (10-12 hrs) is required to produce irreversible effects on survival or commit the parasites to death. SCYX-5070 cured an acute trypanosomiasis infection in mice without exhibiting signs of compound related acute or chronic toxicity. To identify the molecular target(s) responsible for the mechanism of action of 2,4-diaminopyrimidines against trypanosomatid protozoa, a representative analogue was immobilized on a solid matrix (sepharose) and used to isolate target proteins from parasite extracts. Mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) were identified as the major proteins specifically bound to the immobilized compound, suggesting their participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. Results show that 2,4-diaminopyrimidines have a good in vitro and in vivo pharmacological profile against trypanosomatid protozoans and that MAPKs and CRKs are potential molecular targets of these compounds. The 2,4-diminipyrimidines may serve as suitable leads for the development of novel treatments for HAT.

West wall, display area (room 101), view 1 of 4: ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

West wall, display area (room 101), view 1 of 4: southwest corner, showing stairs to commander's quarters and viewing bridge, windows to controller's room (room 102), south end of control consoles, and holes in pedestal floor for computer equipment cables (tape drive I/O?) - March Air Force Base, Strategic Air Command, Combat Operations Center, 5220 Riverside Drive, Moreno Valley, Riverside County, CA

The Effect of a Microprocessor Prosthetic Foot on Function and Quality of Life in Transtibial Amputees Who Are Limited Community Ambulators

DTIC Science & Technology

with greater range of motion and active power, will translate into improved functional performance, ambulatory safety (risk of falls) and quality of... life in trans-tibial amputees (TTA) who function as limited community ambulators. We will assess these outcomes in 54 veterans with TTA by randomizing

Plasmon-Enhanced Sub-Bandgap Photocatalysis via Triplet-Triplet Annihilation Upconversion for Volatile Organic Compound Degradation.

PubMed

Kim, Hyoung-Il; Weon, Seunghyun; Kang, Homan; Hagstrom, Anna L; Kwon, Oh Seok; Lee, Yoon-Sik; Choi, Wonyong; Kim, Jae-Hong

2016-10-18

This study demonstrates the first reported photocatalytic decomposition of an indoor air pollutant, acetaldehyde, using low-energy, sub-bandgap photons harnessed through sensitized triplet-triplet annihilation (TTA) upconversion (UC). To utilize low-intensity noncoherent indoor light and maximize photocatalytic activity, we designed a plasmon-enhanced sub-bandgap photocatalyst device consisting of two main components: (1) TTA-UC rubbery polymer films containing broad-band plasmonic particles (Ag-SiO 2 ) to upconvert sub-bandgap photons, and (2) nanodiamond (ND)-loaded WO 3 as a visible-light photocatalyst composite. Effective decomposition of acetaldehyde was achieved using ND/WO 3 (E g = 2.8 eV) coupled with TTA-UC polymer films that emit blue photons (λ Em = 425 nm, 2.92 eV) upconverted from green photons (λ Ex = 532 nm, 2.33 eV), which are wasted in most environmental photocatalysis. The overall photocatalytic efficiency was amplified by the broad-band surface plasmon resonance of AgNP-SiO 2 particles incorporated into the TTA-UC films.

An Improved Compressive Sensing and Received Signal Strength-Based Target Localization Algorithm with Unknown Target Population for Wireless Local Area Networks.

PubMed

Yan, Jun; Yu, Kegen; Chen, Ruizhi; Chen, Liang

2017-05-30

In this paper a two-phase compressive sensing (CS) and received signal strength (RSS)-based target localization approach is proposed to improve position accuracy by dealing with the unknown target population and the effect of grid dimensions on position error. In the coarse localization phase, by formulating target localization as a sparse signal recovery problem, grids with recovery vector components greater than a threshold are chosen as the candidate target grids. In the fine localization phase, by partitioning each candidate grid, the target position in a grid is iteratively refined by using the minimum residual error rule and the least-squares technique. When all the candidate target grids are iteratively partitioned and the measurement matrix is updated, the recovery vector is re-estimated. Threshold-based detection is employed again to determine the target grids and hence the target population. As a consequence, both the target population and the position estimation accuracy can be significantly improved. Simulation results demonstrate that the proposed approach achieves the best accuracy among all the algorithms compared.

The National Emergency Access Target (NEAT) and the 4-hour rule: time to review the target.

PubMed

Sullivan, Clair; Staib, Andrew; Khanna, Sankalp; Good, Norm M; Boyle, Justin; Cattell, Rohan; Heiniger, Liam; Griffin, Bronwyn R; Bell, Anthony Jr; Lind, James; Scott, Ian A

2016-05-16

We explored the relationship between the National Emergency Access Target (NEAT) compliance rate, defined as the proportion of patients admitted or discharged from emergency departments (EDs) within 4 hours of presentation, and the risk-adjusted in-hospital mortality of patients admitted to hospital acutely from EDs. Retrospective observational study of all de-identified episodes of care involving patients who presented acutely to the EDs of 59 Australian hospitals between 1 July 2010 and 30 June 2014. The relationship between the risk-adjusted mortality of inpatients admitted acutely from EDs (the emergency hospital standardised mortality ratio [eHSMR]: the ratio of the numbers of observed to expected deaths) and NEAT compliance rates for all presenting patients (total NEAT) and admitted patients (admitted NEAT). ED and inpatient data were aggregated for 12.5 million ED episodes of care and 11.6 million inpatient episodes of care. A highly significant (P < 0.001) linear, inverse relationship between eHSMR and each of total and admitted NEAT compliance rates was found; eHSMR declined to a nadir of 73 as total and admitted NEAT compliance rates rose to about 83% and 65% respectively. Sensitivity analyses found no confounding by the inclusion of palliative care and/or short-stay patients. As NEAT compliance rates increased, in-hospital mortality of emergency admissions declined, although this direct inverse relationship is lost once total and admitted NEAT compliance rates exceed certain levels. This inverse association between NEAT compliance rates and in-hospital mortality should be considered when formulating targets for access to emergency care.

Triplet-triplet annihilation photon-upconversion: towards solar energy applications.

PubMed

Gray, Victor; Dzebo, Damir; Abrahamsson, Maria; Albinsson, Bo; Moth-Poulsen, Kasper

2014-06-14

Solar power production and solar energy storage are important research areas for development of technologies that can facilitate a transition to a future society independent of fossil fuel based energy sources. Devices for direct conversion of solar photons suffer from poor efficiencies due to spectrum losses, which are caused by energy mismatch between the optical absorption of the devices and the broadband irradiation provided by the sun. In this context, photon-upconversion technologies are becoming increasingly interesting since they might offer an efficient way of converting low energy solar energy photons into higher energy photons, ideal for solar power production and solar energy storage. This perspective discusses recent progress in triplet-triplet annihilation (TTA) photon-upconversion systems and devices for solar energy applications. Furthermore, challenges with evaluation of the efficiency of TTA-photon-upconversion systems are discussed and a general approach for evaluation and comparison of existing systems is suggested.

Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area

PubMed Central

García-Avilés, Álvaro; Albert-Gascó, Héctor; Arnal-Vicente, Isabel; Elhajj, Ebtisam; Sanjuan-Arias, Julio; Sanchez-Perez, Ana María; Olucha-Bordonau, Francisco

2015-01-01

Methylphenidate (MPD) is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD). Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if MPD administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered MPD doses (1.3, 2.7 and 5 mg/Kg) to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3 mg/Kg MPD; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum (MS), an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5 mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the MS the sparse tyrosine hydroxylase fibers did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons. PMID:25852493

Thematic mapping of likely target areas for the occurence of cassiterite in the Serra do Mocambo (GO) granitic massifs using LANDSAT 2 digital imaging

NASA Technical Reports Server (NTRS)

Almeidofilho, R. (Principal Investigator)

1984-01-01

The applicability of LANDSAT/MSS images, enhanced by computer derived techniques, as essential tools in mineral research was investigated and the Serra do Mocambo granitic massif was used as illustration. Given the peculiar factors founded in this area, orbital imagery permitted the delineation of potential target areas of mineralization occurrences, associated to albitized/greisenized types. Follow up prospection for primary tin deposits in this granitic massif should be restricted to the delineated areas which are less than 5% of the total superficial area of the massif.

Improving Photovoltaic Performance of a Fused-Ring Azepinedione Copolymer via a D-A-A Design.

PubMed

Zhang, Honghong; Li, Ting; Xiao, Zuo; Lei, Zhongli; Ding, Liming

2018-04-01

Two conjugated copolymer donors, PTTABDT and PBTTABDT, based on a fused-ring azepinedione acceptor unit, 5-(2-octyldodecyl)-4H-thieno[2',3':4,5]thieno[3,2-c]thieno[2',3':4,5]thieno[2,3-e]azepine-4,6(5H)-dione (TTA), are prepared. PTTABDT possesses a conventional donor-acceptor (D-A) structure with one TTA in the repeat unit, while PBTTABDT has a D-A-A structure with two TTAs in the repeat unit. Compared with PTTABDT, PBTTABDT shows a deeper highest occupied molecular orbital (HOMO) level, a narrower bandgap, and a higher hole mobility, and exhibits better performance in bulk heterojunction solar cells. Power conversion efficiencies of 6.18% and 7.81% are achieved from PTTABDT:PC 71 BM and PBTTABDT:PC 71 BM solar cells, respectively. The higher performance of PBTTABDT:PC 71 BM solar cells results from the enhanced open-circuit voltage (V oc ) and short-circuit current density (  J sc ). © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia.

PubMed

Boudreaux, Seth P; Duren, Ryan P; Call, Steven G; Nguyen, Loc; Freire, Pablo R; Narayanan, Padmini; Redell, Michele S; Conneely, Orla M

2018-06-08

NR4As are AML tumor suppressors that are frequently silenced in human acute myeloid leukemia (AML). Despite their potential as novel targets for therapeutic intervention, mechanisms of NR4A silencing and strategies for their reactivation remain poorly defined. Here we show that NR4A silencing in AML occurs through blockade of transcriptional elongation rather than epigenetic promoter silencing. By intersection of NR4A-regulated gene signatures captured upon acute, exogenous expression of NR4As in human AML cells with in silico chemical genomics screening, we identify several FDA-approved drugs including dihydroergotamine (DHE) that reactivate NR4A expression and regulate NR4A-dependent gene signatures. We show that DHE induces NR4A expression via recruitment of the super elongation complex to enable elongation of NR4A promoter paused RNA polymerase II. Finally, DHE exhibits AML selective NR4A-dependent anti-leukemic activity in cytogenetically distinct human AML cells in vitro and delays AML progression in mice revealing its potential as a novel therapeutic agent in AML.

MiR-130a inhibition protects rat cardiac myocytes from hypoxia-triggered apoptosis by targeting Smad4.

PubMed

Li, Yuanshi; Du, Yingrong; Cao, Junxian; Gao, Qianping; Li, Hongjuan; Chen, Yangjun; Lu, Nihong

2018-02-05

Cardiomyocyte death facilitates the pathological process underlying ischemic heart diseases, such as myocardial infarction. Emerging evidence suggests that microRNAs play a critical role in the pathological process underlying myocardial infarction by regulating cardiomyocyte apoptosis. However, the relevance of miR-130a in regulating cardiomyocyte apoptosis and the mechanism of regulation is still uncertain. This study aimed to explore the regulatory effect of miR-130a on hypoxic cardiomyocyte apoptosis. The expression of miR-130a was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell survival was determined by the MTT assay. The lactate dehydrogenase (LDH) assay was performed to determine the severity of hypoxia-induced cell injury. Apoptosis was assessed via caspase-3 analysis. Protein expression level was determined by Western blotting. The genes targeted by miR-130a were predicted using bioinformatics and were validated via the dual-luciferase reporter assay. We found that miR-130a expression was greatly increased in hypoxic cardiac myocytes, and that the downregulation of miR-130a effectively shielded cardiac myocytes from hypoxia-triggered apoptosis. The results of our bioinformatic analysis predicted the Smad4 gene to be the target of miR-130a. This finding was validated through the Western blot assay, dual-luciferase reporter gene assay, and qRT-PCR. MiR-130a inhibition significantly promoted the activation of Smad4 in hypoxic cardiomyocytes. Interestingly, knockdown of Smad4 markedly reversed the protective effects induced by miR-130a inhibition. Moreover, we found that the inhibition of miR-130a promoted the activation of TGF-β signaling. Blocking Smad4 signaling significantly abrogated the protective effects of miR-130a inhibition. Overall, these findings indicate that inhibition of miR-130a, which targets the Smad4 gene, shields cardiac myocytes from hypoxic apoptosis. This study offers a novel perspective of the

4D imaging for target definition in stereotactic radiotherapy for lung cancer.

PubMed

Slotman, Ben J; Lagerwaard, Frank J; Senan, Suresh

2006-01-01

Stereotactic radiotherapy of Stage I lung tumors has been reported to result in high local control rates that are far superior to those obtained with conventional radiotherapy techniques, and which approach those achieved with primary surgery. Breathing-induced motion of tumor and target tissues is an important issue in this technique and careful attention should be paid to the contouring and the generation of individualized margins. We describe our experience with the use of 4DCT scanning for this group of patients, the use of post-processing tools and the potential benefits of respiratory gating.

Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense.

PubMed

Ebiloma, Godwin U; Ayuga, Teresa Díaz; Balogun, Emmanuel O; Gil, Lucía Abad; Donachie, Anne; Kaiser, Marcel; Herraiz, Tomás; Inaoka, Daniel K; Shiba, Tomoo; Harada, Shigeharu; Kita, Kiyoshi; de Koning, Harry P; Dardonville, Christophe

2018-04-25

African trypanosomiasis is a neglected parasitic disease that is still of great public health relevance, and a severe impediment to agriculture in endemic areas. The pathogens possess certain unique metabolic features that can be exploited for the development of new drugs. Notably, they rely on an essential, mitochondrially-localized enzyme, Trypanosome Alternative Oxidase (TAO) for their energy metabolism, which is absent in the mammalian hosts and therefore an attractive target for the design of safe drugs. In this study, we cloned, expressed and purified the physiologically relevant form of TAO, which lacks the N-terminal 25 amino acid mitochondrial targeting sequence (ΔMTS-TAO). A new class of 32 cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde inhibitors was designed and synthesized, enabling the first structure-activity relationship studies on ΔMTS-TAO. Remarkably, we obtained compounds with enzyme inhibition values (IC 50 ) as low as 2 nM, which were efficacious against wild type and multidrug-resistant strains of T. brucei and T. congolense. The inhibitors 13, 15, 16, 19, and 30, designed with a mitochondrion-targeting lipophilic cation tail, displayed trypanocidal potencies comparable to the reference drugs pentamidine and diminazene, and showed no cross-resistance with the critical diamidine and melaminophenyl arsenical classes of trypanocides. The cationic inhibitors 15, 16, 19, 20, and 30 were also much more selective (900 - 344,000) over human cells than the non-targeted neutral derivatives (selectivity >8-fold). A preliminary in vivo study showed that modest doses of 15 and 16 reduced parasitaemia of mice infected with T. b. rhodesiense (STIB900). These compounds represent a promising new class of potent and selective hits against African trypanosomes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Thiazolidine-2,4-dione derivatives: programmed chemical weapons for key protein targets of various pathological conditions.

PubMed

Chadha, Navriti; Bahia, Malkeet Singh; Kaur, Maninder; Silakari, Om

2015-07-01

Thiazolidine-2,4-dione is an extensively explored heterocyclic nucleus for designing of novel agents implicated for a wide variety of pathophysiological conditions, that is, diabetes, diabetic complications, cancer, arthritis, inflammation, microbial infection, and melanoma, etc. The current paradigm of drug development has shifted to the structure-based drug design, since high-throughput screenings have continued to generate disappointing results. The gap between hit generation and drug establishment can be narrowed down by investigation of ligand interactions with its receptor protein. Therefore, it would always be highly beneficial to gain knowledge of molecular level interactions between specific protein target and developed ligands; since this information can be maneuvered to design new molecules with improved protein fitting. Thus, considering this aspect, we have corroborated the information about molecular (target) level implementations of thiazolidine-2,4-diones (TZD) derivatives having therapeutic implementations such as, but not limited to, anti-diabetic (glitazones), anti-cancer, anti-arthritic, anti-inflammatory, anti-oxidant and anti-microbial, etc. The structure based SAR of TZD derivatives for various protein targets would serve as a benchmark for the alteration of existing ligands to design new ones with better binding interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

NHSA Position Paper: The Design of a Head Start Training and Technical Assistance System.

ERIC Educational Resources Information Center

NHSA Journal, 1994

1994-01-01

This position paper examines the current Head Start training and technical assistance (TTA) system and proposes specific improvements. These include the creation of regional TTA offices, the use of satellite and interactive communications technology, and a reevaluation of the role of teaching centers, national training contracts, and Head Start…

Geological structure and ore mineralization of the South Sopchinsky and Gabbro-10 massifs and the Moroshkovoe Lake target, Monchegorsk area, Kola Peninsula, Russia

NASA Astrophysics Data System (ADS)

Pripachkin, Pavel V.; Rundkvist, Tatyana V.; Miroshnikova, Yana A.; Chernyavsky, Alexey V.; Borisenko, Elena S.

2016-12-01

The South Sopchinsky massif (SSM), Gabbro-10 (G-10) massif, and Moroshkovoe Lake (ML) target Monchegorsk area, Kola Peninsula, are located at the junction of the Monchepluton and Monchetundra layered intrusions. The intrusions were studied in detail as they are targets for platinum-group element (PGE) mineralization. The rocks in these targets comprise medium- to coarse-grained mesocratic to leucocratic gabbronorites, medium-grained mesocratic to melanocratic norites and pyroxenites, and various veins mainly comprising norite, plagioclase-amphibole-magnetite rocks, and quartz-magnetite rocks. The veins contain Ni-Cu-PGE mineralization associated with magnetite and chromite. In all targets, the contacts between gabbronorite and norite-pyroxenite are undulating, and the presence of magmatic (intrusive) breccias suggests that these rocks formed through mingling of two distinct magmatic pulses. In places, the gabbronorites clearly crosscut the modal layering of the norites and pyroxenites. Trace element data indicate that the gabbronorites have similar compositions to rocks of the upper part of the Monchetundra intrusion, whereas the norites and pyroxenites resemble rocks from the lower to intermediate stratigraphic levels of the Monchepluton, such as in the Nude-Poaz and Sopcha massifs. Sulfide mineralization in the studied targets principally consists of secondary bornite, millerite, and chalcopyrite. In contrast, the primary sulfide assemblage within the layered sequence of the adjacent Monchepluton is characterized by pentlandite, chalcopyrite, and pyrrhotite. Therefore, the mineralization in the studied targets is interpreted to be of a contact style. We argue that the studied area represents the contact zone between gabbronorites of the Monchetundra intrusion and norites and pyroxenites of the Monchepluton. In addition, the rocks were overprinted by postmagmatic veining and remobilization of contact style sulfide and PGE mineralization.

1,4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 2): action in other targets and antitargets.

PubMed

Carosati, E; Ioan, P; Micucci, M; Broccatelli, F; Cruciani, G; Zhorov, B S; Chiarini, A; Budriesi, R

2012-01-01

1,4-Dihydropyridines were introduced in the last century for the treatment of coronary diseases. Then medicinal chemists decorated the 1,4-DHP nucleus, the most studied scaffold among L-type calcium channel blockers, achieving diverse activities at several receptors, channels and enzymes. We already described (Ioan et al. Curr. Med. Chem. 2011, 18, 4901-4922) the effects of 1,4-DHPs at ion channels and G-protein coupled receptors. In this paper we continue the analysis of the wide range of biological effects exerted by compounds belonging to this chemical class. In particular, focus is given to the ability of 1,4-DHPs to revert multi drug resistance that, after over 20 years of research, continues to be of great interest. We also describe activities on other targets and the action of 1,4-DHPs against several diseases. Finally, we report and review the interaction of 1,4-DHPs with the hERG channel, transporters and phase I metabolizing enzymes. This work is a starting point for further exploration of the 1,4-DHP core activities on targets, off-targets and antitargets.