Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis

PubMed Central

Borin, Thaiz F.; Angara, Kartik; Rashid, Mohammad H.; Achyut, Bhagelu R.; Arbab, Ali S.

2017-01-01

Metastatic breast cancer (BC) (also referred to as stage IV) spreads beyond the breast to the bones, lungs, liver, or brain and is a major contributor to the deaths of cancer patients. Interestingly, metastasis is a result of stroma-coordinated hallmarks such as invasion and migration of the tumor cells from the primary niche, regrowth of the invading tumor cells in the distant organs, proliferation, vascularization, and immune suppression. Targeted therapies, when used as monotherapies or combination therapies, have shown limited success in decreasing the established metastatic growth and improving survival. Thus, novel therapeutic targets are warranted to improve the metastasis outcomes. We have been actively investigating the cytochrome P450 4 (CYP4) family of enzymes that can biosynthesize 20-hydroxyeicosatetraenoic acid (20-HETE), an important signaling eicosanoid involved in the regulation of vascular tone and angiogenesis. We have shown that 20-HETE can activate several intracellular protein kinases, pro-inflammatory mediators, and chemokines in cancer. This review article is focused on understanding the role of the arachidonic acid metabolic pathway in BC metastasis with an emphasis on 20-HETE as a novel therapeutic target to decrease BC metastasis. We have discussed all the significant investigational mechanisms and put forward studies showing how 20-HETE can promote angiogenesis and metastasis, and how its inhibition could affect the metastatic niches. Potential adjuvant therapies targeting the tumor microenvironment showing anti-tumor properties against BC and its lung metastasis are discussed at the end. This review will highlight the importance of exploring tumor-inherent and stromal-inherent metabolic pathways in the development of novel therapeutics for treating BC metastasis. PMID:29292756

Targeting NADPH oxidase decreases oxidative stress in the transgenic sickle cell mouse penis.

PubMed

Musicki, Biljana; Liu, Tongyun; Sezen, Sena F; Burnett, Arthur L

2012-08-01

Sickle cell disease (SCD) is a state of chronic vasculopathy characterized by endothelial dysfunction and increased oxidative stress, but the sources and mechanisms responsible for reactive oxygen species (ROS) production in the penis are unknown. We evaluated whether SCD activates NADPH oxidase, induces endothelial nitric oxide synthase (eNOS) uncoupling, and decreases antioxidants in the SCD mouse penis. We further tested the hypothesis that targeting NADPH oxidase decreases oxidative stress in the SCD mouse penis. SCD transgenic (sickle) mice were used as an animal model of SCD. Hemizygous (hemi) mice served as controls. Mice received an NADPH oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Penes were excised at baseline for molecular studies. Markers of oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NADPH oxidase subunits p67(phox) , p47(phox) , and gp91(phox) ), and enzymatic antioxidants (superoxide dismutase [SOD]1, SOD2, catalase, and glutathione peroxidase-1 [GPx1]) were measured by Western blot in penes. Sources of ROS, oxidative stress, and enzymatic antioxidants in the SCD penis. Relative to hemi mice, SCD increased (P<0.05) protein expression of NADPH oxidase subunits p67(phox) , p47(phox) , and gp91(phox) , 4-HNE-modified proteins, induced eNOS uncoupling, and reduced Gpx1 expression in the penis. Apocynin treatment of sickle mice reversed (P<0.05) the abnormalities in protein expressions of p47(phox) , gp91(phox) (but not p67(phox) ) and 4-HNE, but only slightly (P>0.05) prevented eNOS uncoupling in the penis. Apocynin treatment of hemi mice did not affect any of these parameters. NADPH oxidase and eNOS uncoupling are sources of oxidative stress in the SCD penis; decreased GPx1 further contributes to oxidative stress. Inhibition of NADPH oxidase upregulation decreases oxidative stress, implying a major role for NADPH oxidase as a ROS source and a potential target for improving vascular function in

Targeting NADPH Oxidase Decreases Oxidative Stress in the Transgenic Sickle Cell Mouse Penis

PubMed Central

Musicki, Biljana; Liu, Tongyun; Sezen, Sena F.; Burnett, Arthur L.

2012-01-01

Introduction Sickle cell disease (SCD) is a state of chronic vasculopathy characterized by endothelial dysfunction and increased oxidative stress, but the sources and mechanisms responsible for reactive oxygen species (ROS) production in the penis are unknown. Aims We evaluated whether SCD activates NADPH oxidase, induces endothelial nitric oxide synthase (eNOS) uncoupling, and decreases antioxidants in the SCD mouse penis. We further tested the hypothesis that targeting NADPH oxidase decreases oxidative stress in the SCD mouse penis. Methods SCD transgenic (sickle) mice were used as an animal model of SCD. Hemizygous (hemi) mice served as controls. Mice received an NADPH oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Penes were excised at baseline for molecular studies. Markers of oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NADPH oxidase subunits p67phox, p47phox, and gp91phox), and enzymatic antioxidants (superoxide dismutase [SOD]1, SOD2, catalase, and glutathione peroxidase-1 [GPx1]) were measured by Western blot in penes. Main Outcome Measures Sources of ROS, oxidative stress, and enzymatic antioxidants in the SCD penis. Results Relative to hemi mice, SCD increased (P < 0.05) protein expression of NADPH oxidase subunits p67phox, p47phox, and gp91phox, 4-HNE-modified proteins, induced eNOS uncoupling, and reduced Gpx1 expression in the penis. Apocynin treatment of sickle mice reversed (P < 0.05) the abnormalities in protein expressions of p47phox, gp91phox (but not p67phox) and 4-HNE, but only slightly (P > 0.05) prevented eNOS uncoupling in the penis. Apocynin treatment of hemi mice did not affect any of these parameters. Conclusion NADPH oxidase and eNOS uncoupling are sources of oxidative stress in the SCD penis; decreased GPx1 further contributes to oxidative stress. Inhibition of NADPH oxidase upregulation decreases oxidative stress, implying a major role for NADPH oxidase as a ROS source and a

Theoretical analysis of the formation driving force and decreased sensitivity for CL-20 cocrystals

NASA Astrophysics Data System (ADS)

Zhou, Jun-Hong; Shi, Liang-Wei; Zhang, Chao-Yang; Li, Hong-Zhen; Chen, Min-Bo; Chen, Wei-Ming

2016-07-01

Methods that analyze the driving force in the formation of the new energetic cocrystal are proposed in this paper. Various intermolecular interactions in the 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazatetracyclo [5.5.0.05,9.03,11]dodecane (CL-20) cocrystals are compared with those in pure CL-20 and coformer crystals by atom in molecule (AIM) and Hirshfeld surface methods under the supramolecular cluster model. The driving force in the formation of the CL-20 cocrystals is analyzed. The main driving force in the formation of the cocrystal CL-20/HMX comes from the O···H interactions, that in the formation of the cocrystal CL-20/TNT from the O···H and C···O interactions, and that in the formation of the cocrystal CL-20/BTF from the N···H and N···O interactions. Other interactions in the CL-20 cocrystals only contribute to their stabilization. At the same time, the reasons for the decreased impact sensitivity of the CL-20 cocrystals are also analyzed. They are the strengthening of the intermolecular interactions, the reducing of the free space, and the changing of the surrounding of CL-20 molecule in the CL-20 cocrystals in comparison with those in the pure CL-20 crystal.

A single alteration 20 nt 5′ to an editing target inhibits chloroplast RNA editing in vivo

PubMed Central

Reed, Martha L.; Peeters, Nemo M.; Hanson, Maureen R.

2001-01-01

Transcripts of typical dicot plant plastid genes undergo C→U RNA editing at approximately 30 locations, but there is no consensus sequence surrounding the C targets of editing. The cis-acting elements required for editing of the C located at tobacco rpoB editing site II were investigated by introducing translatable chimeric minigenes containing sequence –20 to +6 surrounding the C target of editing. When the –20 to +6 sequence specified by the homologous region present in the black pine chloroplast genome was incorporated, virtually no editing of the transcripts occurred in transgenic tobacco plastids. Nucleotides that differ between the black pine and tobacco sequence were tested for their role in C→U editing by designing chimeric genes containing one or more of these divergent nucleotides. Surprisingly, the divergent nucleotide that had the strongest negative effect on editing of the minigene transcript was located –20 nt 5′ to the C target of editing. Expression of transgene transcripts carrying the 27 nt sequence did not affect the editing extent of the endogenous rpoB transcripts, even though the chimeric transcripts were much more abundant than those of the endogenous gene. In plants carrying a 93 nt rpoB editing site sequence, transgene transcripts accumulated to a level three times greater than transgene transcripts in the plants carrying the 27 nt rpoB editing sites and resulted in editing of the endogenous transcripts from 100 to 50%. Both a lower affinity of the 27 nt site for a trans-acting factor and lower abundance of the transcript could explain why expression of minigene transcripts containing the 27 nt sequence did not affect endogenous editing. PMID:11266552

Antagonistic targeting of the histamine H3 receptor decreases caloric intake in higher mammalian species.

PubMed

Malmlöf, Kjell; Hastrup, Sven; Wulff, Birgitte Schellerup; Hansen, Barbara C; Peschke, Bernd; Jeppesen, Claus Bekker; Hohlweg, Rolf; Rimvall, Karin

2007-04-15

The main purpose of this study was to examine the effects of a selective histamine H(3) receptor antagonist, NNC 38-1202, on caloric intake in pigs and in rhesus monkeys. The compound was given intragastrically (5 or 15 mg/kg), to normal pigs (n=7) and subcutaneously (1 or 0.1mg/kg) to obese rhesus monkeys (n=9). The energy intake recorded following administration of vehicle to the same animals served as control for the effect of the compound. In addition, rhesus monkey and pig histamine H(3) receptors were cloned from hypothalamic tissues and expressed in mammalian cell lines. The in vitro antagonist potencies of NNC 38-1202 at the H(3) receptors were determined using a functional GTPgammaS binding assay. Porcine and human H(3) receptors were found to have 93.3% identity at the amino acid level and the close homology between the monkey and human H(3) receptors (98.4% identity) was confirmed. The antagonist potencies of NNC 38-1202 at the porcine, monkey and human histamine H(3) receptors were high as evidenced by K(i)-values being clearly below 20 nM, whereas the K(i)-value on the rat H(3) receptor was significantly higher (56+/-6.0 nM). NNC 38-1202, given to pigs in a dose of 15 mg/kg, produced a significant (p<0.05) reduction (55%) of calorie intake compared with vehicle alone, (132.6+/-10.0 kcal/kgday versus 59.7+/-10.2 kcal/kgday). In rhesus monkeys administration of 0.1 and 1mg/kg decreased (p<0.05) average calorie intakes by 40 and 75%, respectively. In conclusion, the present study demonstrates that antagonistic targeting of the histamine H(3) receptor decreases caloric intake in higher mammalian species.

Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis.

PubMed

Chacko, Balu K; Srivastava, Anup; Johnson, Michelle S; Benavides, Gloria A; Chang, Mi Jung; Ye, Yaozu; Jhala, Nirag; Murphy, Michael P; Kalyanaraman, Balaraman; Darley-Usmar, Victor M

2011-07-01

Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization. Copyright © 2011 American Association for the Study of Liver Diseases.

Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection.

PubMed

Ruiz, Joaquim

2003-05-01

Quinolones are broad-spectrum antibacterial agents, commonly used in both clinical and veterinary medicine. Their extensive use has resulted in bacteria rapidly developing resistance to these agents. Two mechanisms of quinolone resistance have been established to date: alterations in the targets of quinolones, and decreased accumulation due to impermeability of the membrane and/or an overexpression of efflux pump systems. Recently, mobile elements have also been described, carrying the qnr gene, which confers resistance to quinolones.

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes

PubMed Central

Yuan, Zhi-xiang; Jia, Lu; Lim, Lee Yong; Lin, Ju-chun; Shu, Gang; Zhao, Ling; Ye, Gang; Liang, Xiao-xia; Ji, Hongming; Fu, Hua-lin

2017-01-01

Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios – 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) – of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG5000 (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN. PMID:28848346

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes.

PubMed

Yuan, Zhi-Xiang; Jia, Lu; Lim, Lee Yong; Lin, Ju-Chun; Shu, Gang; Zhao, Ling; Ye, Gang; Liang, Xiao-Xia; Ji, Hongming; Fu, Hua-Lin

2017-01-01

Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios - 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) - of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC 50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG 5000 (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN.

The Mitochondria-targeted ubiquinone MitoQ decreases ethanol-dependent micro and macro hepatosteatosis

PubMed Central

Chacko, Balu K; Srivastava, Anup; Johnson, Michelle; Benavides, Gloria A.; Chang, Mi Jung; Ye, Yaozu; Jhala, Nirag; Murphy, Michael P; Kalyanaraman, Balaraman; Darley-Usmar, Victor M.

2011-01-01

Chronic alcohol-induced liver disease results in inflammation, steatosis and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone, MitoQ, (5 & 25 mg/kg/d for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α) and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis and induction of CYP2E1. MitoQ had a minor on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities, it did however decrease hepatic steatosis in ethanol consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocks the increase in HIF1α in all ethanol-fed groups which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol associated mitochondrial ROS and several downstream effects of ROS/RNS production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependant HIF1α stabilization. PMID:21520201

Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons.

PubMed

Pleticha, Josef; Jeng-Singh, Christian; Rezek, Rahaf; Zaibak, Manal; Beutler, Andreas S

2014-05-01

Gene therapy using adeno-associated virus (AAV) is an attractive strategy to treat disorders of the peripheral nervous system (PNS), such as chronic pain or peripheral neuropathies. Although intrathecal (IT) administration of AAV has been the standard in the field for targeting the PNS, it lacks anatomical specificity and results in wide rostro-caudal distribution of the vector. An alternative approach is to deliver AAV directly to the peripheral nerve axon. The present study employed convection-enhanced delivery (CED) of a novel AAV serotype, AAVrh20, expressing enhanced green fluorescent protein (EGFP) into rat sciatic nerve investigating its efficacy, anatomical selectivity, and safety, compared to the IT route. Intraneural CED resulted in transduction confined to the ipsilateral L4 and L5 DRG while IT administration led to promiscuous DRG transduction encompassing the entire lumbar region bilaterally. The transduction rate for intraneural AAV administration was similar to IT delivery (24% for L4 and 31.5% for L5 DRG versus 50% for L4 and 19.5% for L5 DRG). The use of hyperosmotic diluent did not further improve the transduction efficiency. AAVrh20 was superior to reference serotypes previously described to be most active for each route. Intraneural CED of AAV was associated with transient allodynia that resolved spontaneously. These findings establish intraneural CED as an alternative to IT administration for AAV mediated gene transfer to the PNS and, based on a reference rodent model, suggest AAVrh20 as a superior serotype for targeting the PNS. Copyright © 2014 Elsevier Inc. All rights reserved.

Decrease of motor cortex excitability following exposure to a 20 Hz magnetic field as generated by a rotating permanent magnet.

PubMed

Gallasch, Eugen; Rafolt, Dietmar; Postruznik, Magdalena; Fresnoza, Shane; Christova, Monica

2018-04-19

Rotation of a static magnet over the motor cortex (MC) generates a transcranial alternating magnetic field (tAMF), and a linked alternating electrical field. The aim of this transcranial magnetic stimulation (TMS) study is to investigate whether such fields are able to influence MC excitability, and whether there are parallels to tACS induced effects. Fourteen healthy volunteers received 20 Hz tAMF stimulation over the MC, over the vertex, and 20 Hz tACS over the MC, each with a duration of 15 min. TMS assessments were performed before and after the interventions. Changes in motor evoked potentials (MEP), short interval intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) were evaluated. The tACS and the tAMF stimulation over the MC affected cortical excitability in a different way. After tAMF stimulation MEP amplitudes and ICF decreased and the effect of SICI increased. After tACS MEP amplitudes increased and there were no effects on SICI and ICF. The recorded single and paired pulse MEPs indicate a general decrease of MC excitability following 15 min of tAMF stimulation. The effects demonstrate that devices based on rotating magnets are potentially suited to become a novel brain stimulation tool in clinical neurophysiology. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

PubMed

Dai, Dong-Wei; Lu, Qiong; Wang, Lai-Xing; Zhao, Wen-Yuan; Cao, Yi-Qun; Li, Ya-Nan; Han, Guo-Sheng; Liu, Jian-Min; Yue, Zhi-Jian

2013-10-14

MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs.

PubMed

Disney, Matthew D; Winkelsas, Audrey M; Velagapudi, Sai Pradeep; Southern, Mark; Fallahi, Mohammad; Childs-Disney, Jessica L

2016-06-17

The development of small molecules that target RNA is challenging yet, if successful, could advance the development of chemical probes to study RNA function or precision therapeutics to treat RNA-mediated disease. Previously, we described Inforna, an approach that can mine motifs (secondary structures) within target RNAs, which is deduced from the RNA sequence, and compare them to a database of known RNA motif-small molecule binding partners. Output generated by Inforna includes the motif found in both the database and the desired RNA target, lead small molecules for that target, and other related meta-data. Lead small molecules can then be tested for binding and affecting cellular (dys)function. Herein, we describe Inforna 2.0, which incorporates all known RNA motif-small molecule binding partners reported in the scientific literature, a chemical similarity searching feature, and an improved user interface and is freely available via an online web server. By incorporation of interactions identified by other laboratories, the database has been doubled, containing 1936 RNA motif-small molecule interactions, including 244 unique small molecules and 1331 motifs. Interestingly, chemotype analysis of the compounds that bind RNA in the database reveals features in small molecule chemotypes that are privileged for binding. Further, this updated database expanded the number of cellular RNAs to which lead compounds can be identified.

Decrease of miR-195 Promotes Chondrocytes Proliferation and Maintenance of Chondrogenic Phenotype via Targeting FGF-18 Pathway

PubMed Central

Wang, Yong; Yang, Tao; Liu, Yadong; Zhao, Wei; Zhang, Zhen; Lu, Ming; Zhang, Weiguo

2017-01-01

Slow growth and rapid loss of chondrogenic phenotypes are the major problems affecting chronic cartilage lesions. The role of microRNA-195 (miR-195) and its detailed working mechanism in the fore-mentioned process remains unknown. Fibroblastic growth factor 18 (FGF-18) plays a key role in cartilage homeostasis; whether miR-195 could regulate FGF-18 and its downstream signal pathway in chondrocyte proliferation and maintenance of chondrogenic phenotypes still remains unclear. The present research shows elevated miR-195 but depressed FGF-18 expressed in joint fluid specimens of 20 patients with chronic cartilage lesions and in CH1M and CH3M chondrocytes when compared with that in joint fluid specimens without cartilage lesions and in CH1W and CH2W chondrocytes, respectively. The following loss of function test revealed that downregulation of miR-195 by transfection of miR-195 inhibitors promoted chondrocyte proliferation and expression of a type II collagen α I chain (Col2a1)/aggrecan. Through the online informatics analysis we theoretically predicted that miR-195 could bind to a FGF-18 3′ untranslated region (3′UTR), also, we verified that a miR-195 could regulate the FGF-18 and its downstream pathway. The constructed dual luciferase assay further confirmed that FGF-18 was a direct target of miR-195. The executed anti-sense experiment displayed that miR-195 could regulate chondrocyte proliferation and Col2a1/aggrecan expression via the FGF-18 pathway. Finally, through an in vivo anterior cruciate ligament transection (ACLT) model, downregulation of miR-195 presented a significantly protective effect on chronic cartilage lesions. Evaluating all of the outcomes of the current research revealed that a decrease of miR-195 protected chronic cartilage lesions by promoting chondrocyte proliferation and maintenance of chondrogenic phenotypes via the targeting of the FGF-18 pathway and that the miR-195/FGF-18 axis could be a potential target in the treatment of

Decrease of miR-195 Promotes Chondrocytes Proliferation and Maintenance of Chondrogenic Phenotype via Targeting FGF-18 Pathway.

PubMed

Wang, Yong; Yang, Tao; Liu, Yadong; Zhao, Wei; Zhang, Zhen; Lu, Ming; Zhang, Weiguo

2017-05-04

Slow growth and rapid loss of chondrogenic phenotypes are the major problems affecting chronic cartilage lesions. The role of microRNA-195 (miR-195) and its detailed working mechanism in the fore-mentioned process remains unknown. Fibroblastic growth factor 18 (FGF-18) plays a key role in cartilage homeostasis; whether miR-195 could regulate FGF-18 and its downstream signal pathway in chondrocyte proliferation and maintenance of chondrogenic phenotypes still remains unclear. The present research shows elevated miR-195 but depressed FGF-18 expressed in joint fluid specimens of 20 patients with chronic cartilage lesions and in CH1M and CH3M chondrocytes when compared with that in joint fluid specimens without cartilage lesions and in CH1W and CH2W chondrocytes, respectively. The following loss of function test revealed that downregulation of miR-195 by transfection of miR-195 inhibitors promoted chondrocyte proliferation and expression of a type II collagen α I chain (Col2a1)/aggrecan. Through the online informatics analysis we theoretically predicted that miR-195 could bind to a FGF-18 3' untranslated region (3'UTR), also, we verified that a miR-195 could regulate the FGF-18 and its downstream pathway. The constructed dual luciferase assay further confirmed that FGF-18 was a direct target of miR-195. The executed anti-sense experiment displayed that miR-195 could regulate chondrocyte proliferation and Col2a1/aggrecan expression via the FGF-18 pathway. Finally, through an in vivo anterior cruciate ligament transection (ACLT) model, downregulation of miR-195 presented a significantly protective effect on chronic cartilage lesions. Evaluating all of the outcomes of the current research revealed that a decrease of miR-195 protected chronic cartilage lesions by promoting chondrocyte proliferation and maintenance of chondrogenic phenotypes via the targeting of the FGF-18 pathway and that the miR-195/FGF-18 axis could be a potential target in the treatment of cartilage

Intercepting moving targets: does memory from practice in a specific condition of target displacement affect movement timing?

PubMed

de Azevedo Neto, Raymundo Machado; Teixeira, Luis Augusto

2011-05-01

This investigation aimed at assessing the extent to which memory from practice in a specific condition of target displacement modulates temporal errors and movement timing of interceptive movements. We compared two groups practicing with certainty of future target velocity either in unchanged target velocity or in target velocity decrease. Following practice, both experimental groups were probed in the situations of unchanged target velocity and target velocity decrease either under the context of certainty or uncertainty about target velocity. Results from practice showed similar improvement of temporal accuracy between groups, revealing that target velocity decrease did not disturb temporal movement organization when fully predictable. Analysis of temporal errors in the probing trials indicated that both groups had higher timing accuracy in velocity decrease in comparison with unchanged velocity. Effect of practice was detected by increased temporal accuracy of the velocity decrease group in situations of decreased velocity; a trend consistent with the expected effect of practice was observed for temporal errors in the unchanged velocity group and in movement initiation at a descriptive level. An additional point of theoretical interest was the fast adaptation in both groups to a target velocity pattern different from that practiced. These points are discussed under the perspective of integration of vision and motor control by means of an internal forward model of external motion.

microRNA-497 overexpression decreases proliferation, migration and invasion of human retinoblastoma cells via targeting vascular endothelial growth factor A

PubMed Central

Li, Jianjun; Zhang, Yinghui; Wang, Xiuchao; Zhao, Ruibo

2017-01-01

The expression level and roles of microRNA-497 (miR-497) have been frequently reported in previous studies on cancer. However, its expression, function and associated molecular mechanisms in retinoblastoma remain unknown. In the present study, miR-497 expression levels in human retinoblastoma tissues, normal retinal tissues and retinoblastoma cell lines were determined using reverse transcription-quantitative polymerase chain reaction. In addition, a Cell Counting Kit-8 assay, cell migration assay, cell invasion assay, western blot analysis and Dual-Luciferase reporter assay were used to explore the expression, functions and molecular mechanisms of miR-497 in human retinoblastoma. It was demonstrated that miR-497 was significantly downregulated in retinoblastoma tissues and cell lines compared with normal retinal tissues. Ectopic expression of miR-497 decreased the proliferation, migration and invasion of retinoblastoma cells. Furthermore, VEGFA was verified as a potential direct target of miR-497 in vitro. Taken together, the results indicate that miR-497 functions as a tumor suppressor in the carcinogenesis and progression of retinoblastoma via targeting VEGFA. miR-497 should be investigated as a potential therapeutic target for the treatment of retinoblastoma. PMID:28588740

Hazards of decreasing marine oxygen: the near-term and millennial-scale benefits of meeting the Paris climate targets

NASA Astrophysics Data System (ADS)

Battaglia, Gianna; Joos, Fortunat

2018-06-01

Ocean deoxygenation is recognized as key ecosystem stressor of the future ocean and associated climate-related ocean risks are relevant for current policy decisions. In particular, benefits of reaching the ambitious 1.5 °C warming target mentioned by the Paris Agreement compared to higher temperature targets are of high interest. Here, we model oceanic oxygen, warming and their compound hazard in terms of metabolic conditions on multi-millennial timescales for a range of equilibrium temperature targets. Scenarios where radiative forcing is stabilized by 2300 are used in ensemble simulations with the Bern3D Earth System Model of Intermediate Complexity. Transiently, the global mean ocean oxygen concentration decreases by a few percent under low forcing and by 40 % under high forcing. Deoxygenation peaks about a thousand years after stabilization of radiative forcing and new steady-state conditions are established after AD 8000 in our model. Hypoxic waters expand over the next millennium and recovery is slow and remains incomplete under high forcing. Largest transient decreases in oxygen are projected for the deep sea. Distinct and near-linear relationships between the equilibrium temperature response and marine O2 loss emerge. These point to the effectiveness of the Paris climate target in reducing marine hazards and risks. Mitigation measures are projected to reduce peak decreases in oceanic oxygen inventory by 4.4 % °C-1 of avoided equilibrium warming. In the upper ocean, the decline of a metabolic index, quantified by the ratio of O2 supply to an organism's O2 demand, is reduced by 6.2 % °C-1 of avoided equilibrium warming. Definitions of peak hypoxia demonstrate strong sensitivity to additional warming. Volumes of water with less than 50 mmol O2 m-3, for instance, increase between 36 % and 76 % °C-1 of equilibrium temperature response. Our results show that millennial-scale responses should be considered in assessments of ocean deoxygenation and associated

Variations in the GCR Flux Associated with Heliospheric Transient Structures Near the August 20, 2006 Forbush Decrease

NASA Astrophysics Data System (ADS)

Mulligan, T.; Blake, J.; Spence, H. E.; Jordan, A. P.; Shaul, D.; Quenby, J.

2007-12-01

On August 20, 2006 a Forbush decrease observed at Polar in the Earth's magnetosphere was also seen at the INTEGRAL spacecraft outside the magnetosphere during a very active time in the solar wind. Data from Polar HIST and from INTEGRAL's Ge detector saturation rate (GEDSAT), which measures the GCR background with a threshold of ~200 MeV, show similar, short-period GCR variations in and around the Forbush decrease. The solar wind magnetic field and plasma conditions during this time reveals three interplanetary shocks present in the days leading up to and including the Forbush decrease. The first two shocks are driven by interplanetary coronal mass ejections (ICMEs) and the last one by a high-speed stream. However, the solar wind following these shocks and during the Forbush decrease is not particularly geoeffective. The Forbush decrease, which begins at ~1200 UT on August 20, 2006 is the largest intensity change during this active time, but there are many others on a variety of timescales. Looking at more than 14 consecutive hours of INTEGRAL and Polar data on August 21, 2006 shows great similarities in the time history of the measurements made aboard the two satellites coupled with differences that must be due to GCR variability on a scale size of the order or less than their separation distance. Despite the spacecraft separation of over 25 Re, many of the larger intensity fluctuations remain identical at both satellites. Autocorrelation and power spectral analyses have shown these are not ar-n processes and that these fluctuations are statistically significant. Such analyses can be done with high confidence because both detectors aboard Polar and INTEGRAL have large geometric factors that generate high count rates on the order of 1000 particles per spin, ensuring rigorous, statistically significant samples.

A thin gold coated hydrogen heat pipe-cryogenic target for external experiments at COSY

NASA Astrophysics Data System (ADS)

Abdel-Bary, M.; Abdel-Samad, S.; Elawadi, G. A.; Kilian, K.; Ritman, J.

2009-05-01

A gravity assisted Gold coated heat pipe (GCHP) with 5-mm diameter has been developed and tested to cool a liquid hydrogen target for external beam experiments at COSY. The need for a narrow target diameter leads us to study the effect of reducing the heat pipe diameter to 5 mm instead of 7 mm, to study the effect of coating the external surface of the heat pipe by a shiny gold layer (to decrease the radiation heat load), and to study the effect of using the heat pipe without using 20 layers of' super-insulation around it (aluminized Mylar foil) to keep the target diameter as small as possible. The developed gold coated heat pipe was tested with 20 layers of super-insulation (WI) and without super-insulation (WOI). The operating characteristics for both conditions were compared to show the advantages and disadvantages.

Targeting host calpain proteases decreases influenza A virus infection.

PubMed

Blanc, Fany; Furio, Laetitia; Moisy, Dorothée; Yen, Hui-Ling; Chignard, Michel; Letavernier, Emmanuel; Naffakh, Nadia; Mok, Chris Ka Pun; Si-Tahar, Mustapha

2016-04-01

Influenza A viruses (IAV) trigger contagious acute respiratory diseases. A better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient treatments of severe influenza. Calpains are intracellular proteases that participate in diverse cellular responses, including inflammation. Here, we used in vitro and in vivo approaches to investigate the role of calpain signaling in IAV pathogenesis. Calpain expression and activity were found altered in IAV-infected bronchial epithelial cells. With the use of small-interfering RNA (siRNA) gene silencing, specific synthetic inhibitors of calpains, and mice overexpressing calpastatin, we found that calpain inhibition dampens IAV replication and IAV-triggered secretion of proinflammatory mediators and leukocyte infiltration. Remarkably, calpain inhibition has a protective impact in IAV infection, since it significantly reduced mortality of mice challenged not only by seasonal H3N2- but also by hypervirulent H5N1 IAV strains. Hence, our study suggests that calpains are promising therapeutic targets for treating IAV acute pneumonia. Copyright © 2016 the American Physiological Society.

MicroRNA-20a/b regulates cholesterol efflux through post-transcriptional repression of ATP-binding cassette transporter A1.

PubMed

Liang, Bin; Wang, Xin; Song, Xiaosu; Bai, Rui; Yang, Huiyu; Yang, Zhiming; Xiao, Chuanshi; Bian, Yunfei

2017-09-01

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in reverse cholesterol transport and exhibits anti-atherosclerosis effects. Some microRNAs (miRs) regulate ABCA1 expression, and recent studies have shown that miR-20a/b might play a critical role in atherosclerotic diseases. Here, we attempted to clarify the potential contribution of miR-20a/b in post-transcriptional regulation of ABCA1, cholesterol efflux, and atherosclerosis. We performed bioinformatics analysis and found that miR-20a/b was highly conserved and directly bound to ABCA1 mRNA with low binding free energy. Luciferase-reporter assay also confirmed that miR-20a/b significantly reduced luciferase activity associated with the ABCA1 3' untranslated region reporter construct. Additionally, miR-20a/b decreased ABCA1 expression, which, in turn, decreased cholesterol efflux and increased cholesterol content in THP-1 and RAW 264.7 macrophage-derived foam cells. In contrast, miR-20a/b inhibitors increased ABCA1 expression and cholesterol efflux, decreased cholesterol content, and inhibited foam-cell formation. Consistent with our in vitro results, miR-20a/b-treated ApoE -/- mice showed decreased ABCA1expression in the liver and reductions of reverse cholesterol transport in vivo. Furthermore, miR-20a/b regulated the formation of nascent high-density lipoprotein and promoted atherosclerotic development, whereas miR-20a/b knockdown attenuated atherosclerotic formation. miR-20 is a new miRNA capable of targeting ABCA1 and regulating ABCA1 expression. Therefore, miR-20 inhibition constitutes a new strategy for ABCA1-based treatment of atherosclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

MicroRNA-20a is essential for normal embryogenesis by targeting vsx1 mRNA in fish

PubMed Central

Sun, Lei; Li, Heng; Xu, Xiaofeng; Xiao, Guanxiu; Luo, Chen

2015-01-01

MicroRNAs are major post-transcriptional regulators of gene expression and have essential roles in diverse developmental processes. In vertebrates, some regulatory genes play different roles at different developmental stages. These genes are initially transcribed in a wide embryonic region but restricted within distinct cell types at subsequent stages during development. Therefore, post-transcriptional regulation is required for the transition from one developmental stage to the next and the establishment of different cell identities. However, the regulation of many multiple functional genes at post-transcription level during development remains unknown. Here we show that miR-20a can target the mRNA of vsx1, a multiple functional gene, at the 3′-UTR and inhibit protein expression in both goldfish and zebrafish. The expression of miR-20a is initiated ubiquitously at late gastrula stage and exhibits a tissue-specific pattern in the developing retina. Inhibition of vsx1 3′-UTR mediated protein expression occurs when and where miR-20a is expressed. Decoying miR-20a resulted in severely impaired head, eye and trunk formation in association with excessive generation of vsx1 marked neurons in the spinal cord and defects of somites in the mesoderm region. These results demonstrate that miR-20a is essential for normal embryogenesis by restricting Vsx1 expression in goldfish and zebrafish, and that post-transcriptional regulation is an essential mechanism for Vsx1 playing different roles in diverse developmental processes. PMID:25833418

From Bioengineering to CRISPR/Cas9 – A Personal Retrospective of 20 Years of Research in Programmable Genome Targeting

PubMed Central

Jeltsch, Albert

2018-01-01

Genome targeting of restriction enzymes and DNA methyltransferases has many important applications including genome and epigenome editing. 15–20 years ago, my group was involved in the development of approaches for programmable genome targeting, aiming to connect enzymes with an oligodeoxynucleotide (ODN), which could form a sequence-specific triple helix at the genomic target site. Importantly, the target site of such enzyme-ODN conjugate could be varied simply by altering the ODN sequence promising great applicative values. However, this approach was facing many problems including the preparation and purification of the enzyme-ODN conjugates, their efficient delivery into cells, slow kinetics of triple helix formation and the requirement of a poly-purine target site sequence. Hence, for several years genome and epigenome editing approaches mainly were based on Zinc fingers and TAL proteins as targeting devices. More recently, CRISPR/Cas systems were discovered, which use a bound RNA for genome targeting that forms an RNA/DNA duplex with one DNA strand of the target site. These systems combine all potential advantages of the once imagined enzyme-ODN conjugates and avoid all main disadvantageous. Consequently, the application of CRISPR/Cas in genome and epigenome editing has exploded in recent years. We can draw two important conclusions from this example of research history. First, evolution still is the better bioengineer than humans and, whenever tested in parallel, natural solutions outcompete engineered ones. Second, CRISPR/Cas system were discovered in pure, curiosity driven, basic research, highlighting that it is basic, bottom-up research paving the way for fundamental innovation. PMID:29434619

MicroRNA-20b-5p inhibits platelet-derived growth factor-induced proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3.

PubMed

Tang, Jin; Luo, Lingying

2018-06-01

Pediatric asthma is still a health threat to the pediatric population in recent years. The airway remodeling induced by abnormal airway smooth muscle (ASM) cell proliferation is an important cause of asthma. MicroRNAs (miRNAs) are important regulators of ASM cell proliferation. Numerous studies have reported that miR-20b-5p is a critical regulator for cell proliferation. However, whether miR-20b-5p is involved in regulating ASM cell proliferation remains unknown. In this study, we aimed to investigate the potential role of miR-20b-5p in regulating the proliferation of fetal ASM cell induced by platelet-derived growth factor (PDGF). Here, we showed that miR-20b-5p was significantly decreased in fetal ASM cells treated with PDGF. Biological experiments showed that the overexpression of miR-20b-5p inhibited the proliferation while miR-20b-5p inhibition markedly promoted the proliferation of fetal ASM cells. Bioinformatics analysis and luciferase reporter assay showed that miR-20b-5p directly targeted the 3'-UTR of signal transducer and activator of transcription 3 (STAT3). Further data showed that miR-20b-5p negatively regulated the expression of STAT3 in fetal ASM cells. Moreover, miR-20b-5p regulates the transcriptional activity of STAT3 in fetal ASM cells. Overexpression of STAT3 reversed the inhibitory effect of miR-20b-5p overexpression on fetal ASM cell proliferation while the knockdown of STAT3 abrogated the promoted effect of miR-20b-5p inhibition on fetal ASM cell proliferation. Overall, our results show that miR-20b-5p impedes PDGF-induced proliferation of fetal ASM cells through targeting STAT3. Our study suggests that miR-20b-5p may play an important role in airway remodeling during asthma and suggests that miR-20b-5p may serve as a potential therapeutic target for pediatric asthma. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Gene Expression Analysis of CL-20-induced Reversible Neurotoxicity Reveals GABAA Receptors as Potential Target in the Earthworm Eisenia fetida

PubMed Central

Gong, Ping; Guan, Xin; Pirooznia, Mehdi; Liang, Chun; Perkins, Edward J.

2012-01-01

The earthworm Eisenia fetida is one of the most used species in standardized soil ecotoxicity tests. Endpoints such as survival, growth and reproduction are eco-toxicologically relevant but provide little mechanistic insight into toxicity pathways, especially at the molecular level. Here we applied a toxicogenomic approach to investigate the mode of action underlying the reversible neurotoxicity of hexanitrohexaazaisowurtzitane (CL-20), a cyclic nitroamine explosives compound. We developed an E. fetida-specific shotgun microarray targeting 15119 unique E. fetida transcripts. Using this array we profiled gene expression in E. fetida in response to exposure to CL-20. Eighteen earthworms were exposed for 6 days to 0.2 μg/cm2 of CL-20 on filter paper, half of which were allowed to recover in a clean environment for 7 days. Nine vehicle control earthworms were sacrificed at day 6 and 13, separately. Electrophysiological measurements indicated that the conduction velocity of earthworm medial giant nerve fiber decreased significantly after 6-day exposure to CL-20, but was restored after 7 days of recovery. Total RNA was isolated from the four treatment groups including 6-day control, 6-day exposed, 13-day control and 13-day exposed (i.e. 6-day exposure followed by 7-day recovery), and was hybridized to the 15K shot-gun oligo array. Statistical and bioinformatic analyses suggest that CL-20 initiated neurotoxicity by non-competitively blocking the ligand-gated GABAA receptor ion channel, leading to altered expression of genes involved in GABAergic, cholinergic, and Agrin-MuSK pathways. In the recovery phase, expression of affected genes returned to normality, possibly as a result of autophagy and CL-20 dissociation/metabolism. This study provides significant insights into potential mechanisms of CL-20-induced neurotoxicity and the recovery of earthworms from transient neurotoxicity stress. PMID:22191394

Partial Support Ventilation and Mitochondrial-Targeted Antioxidants Protect against Ventilator-Induced Decreases in Diaphragm Muscle Protein Synthesis.

PubMed

Hudson, Matthew B; Smuder, Ashley J; Nelson, W Bradley; Wiggs, Michael P; Shimkus, Kevin L; Fluckey, James D; Szeto, Hazel H; Powers, Scott K

2015-01-01

Mechanical ventilation (MV) is a life-saving intervention in patients in respiratory failure. Unfortunately, prolonged MV results in the rapid development of diaphragm atrophy and weakness. MV-induced diaphragmatic weakness is significant because inspiratory muscle dysfunction is a risk factor for problematic weaning from MV. Therefore, developing a clinical intervention to prevent MV-induced diaphragm atrophy is important. In this regard, MV-induced diaphragmatic atrophy occurs due to both increased proteolysis and decreased protein synthesis. While efforts to impede MV-induced increased proteolysis in the diaphragm are well-documented, only one study has investigated methods of preserving diaphragmatic protein synthesis during prolonged MV. Therefore, we evaluated the efficacy of two therapeutic interventions that, conceptually, have the potential to sustain protein synthesis in the rat diaphragm during prolonged MV. Specifically, these experiments were designed to: 1) determine if partial-support MV will protect against the decrease in diaphragmatic protein synthesis that occurs during prolonged full-support MV; and 2) establish if treatment with a mitochondrial-targeted antioxidant will maintain diaphragm protein synthesis during full-support MV. Compared to spontaneously breathing animals, full support MV resulted in a significant decline in diaphragmatic protein synthesis during 12 hours of MV. In contrast, diaphragm protein synthesis rates were maintained during partial support MV at levels comparable to spontaneous breathing animals. Further, treatment of animals with a mitochondrial-targeted antioxidant prevented oxidative stress during full support MV and maintained diaphragm protein synthesis at the level of spontaneous breathing animals. We conclude that treatment with mitochondrial-targeted antioxidants or the use of partial-support MV are potential strategies to preserve diaphragm protein synthesis during prolonged MV.

Top-Down Targeted Proteomics Reveals Decrease in Myosin Regulatory Light-Chain Phosphorylation That Contributes to Sarcopenic Muscle Dysfunction.

PubMed

Gregorich, Zachery R; Peng, Ying; Cai, Wenxuan; Jin, Yutong; Wei, Liming; Chen, Albert J; McKiernan, Susan H; Aiken, Judd M; Moss, Richard L; Diffee, Gary M; Ge, Ying

2016-08-05

Sarcopenia, the loss of skeletal muscle mass and function with advancing age, is a significant cause of disability and loss of independence in the elderly and thus, represents a formidable challenge for the aging population. Nevertheless, the molecular mechanism(s) underlying sarcopenia-associated muscle dysfunction remain poorly understood. In this study, we employed an integrated approach combining top-down targeted proteomics with mechanical measurements to dissect the molecular mechanism(s) in age-related muscle dysfunction. Top-down targeted proteomic analysis uncovered a progressive age-related decline in the phosphorylation of myosin regulatory light chain (RLC), a critical protein involved in the modulation of muscle contractility, in the skeletal muscle of aging rats. Top-down tandem mass spectrometry analysis identified a previously unreported bis-phosphorylated proteoform of fast skeletal RLC and localized the sites of decreasing phosphorylation to Ser14/15. Of these sites, Ser14 phosphorylation represents a previously unidentified site of phosphorylation in RLC from fast-twitch skeletal muscle. Subsequent mechanical analysis of single fast-twitch fibers isolated from the muscles of rats of different ages revealed that the observed decline in RLC phosphorylation can account for age-related decreases in the contractile properties of sarcopenic fast-twitch muscles. These results strongly support a role for decreasing RLC phosphorylation in sarcopenia-associated muscle dysfunction and suggest that therapeutic modulation of RLC phosphorylation may represent a new avenue for the treatment of sarcopenia.

A High-Protein Diet Reduces Weight Gain, Decreases Food Intake, Decreases Liver Fat Deposition, and Improves Markers of Muscle Metabolism in Obese Zucker Rats

PubMed Central

French, William W.; Dridi, Sami; Shouse, Stephanie A.; Wu, Hexirui; Hawley, Aubree; Lee, Sun-Ok; Gu, Xuan; Baum, Jamie I.

2017-01-01

A primary factor in controlling and preventing obesity is through dietary manipulation. Diets higher in protein have been shown to improve body composition and metabolic health during weight loss. The objective of this study was to examine the effects of a high-protein diet versus a moderate-protein diet on muscle, liver and fat metabolism and glucose regulation using the obese Zucker rat. Twelve-week old, male, Zucker (fa/fa) and lean control (Fa/fa) rats were randomly assigned to either a high-protein (40% energy) or moderate-protein (20% energy) diet for 12 weeks, with a total of four groups: lean 20% protein (L20; n = 8), lean 40% protein (L40; n = 10), obese 20% protein (O20; n = 8), and obese 40% protein (O40; n = 10). At the end of 12 weeks, animals were fasted and euthanized. There was no difference in food intake between L20 and L40. O40 rats gained less weight and had lower food intake (p < 0.05) compared to O20. O40 rats had lower liver weight (p < 0.05) compared to O20. However, O40 rats had higher orexin (p < 0.05) levels compared to L20, L40 and O20. Rats in the L40 and O40 groups had less liver and muscle lipid deposition compared to L20 and L40 diet rats, respectively. O40 had decreased skeletal muscle mechanistic target of rapamycin complex 1 (mTORC1) phosphorylation and peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to O20 (p < 0.05), with no difference in 5′ AMP-activated protein kinase (AMPK), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), protein kinase B (Akt) or p70 ribosomal S6 kinase (p70S6K) phosphorylation. The data suggest that high-protein diets have the potential to reduce weight gain and alter metabolism, possibly through regulation of an mTORC1-dependent pathway in skeletal muscle. PMID:28594375

A High-Protein Diet Reduces Weight Gain, Decreases Food Intake, Decreases Liver Fat Deposition, and Improves Markers of Muscle Metabolism in Obese Zucker Rats.

PubMed

French, William W; Dridi, Sami; Shouse, Stephanie A; Wu, Hexirui; Hawley, Aubree; Lee, Sun-Ok; Gu, Xuan; Baum, Jamie I

2017-06-08

A primary factor in controlling and preventing obesity is through dietary manipulation. Diets higher in protein have been shown to improve body composition and metabolic health during weight loss. The objective of this study was to examine the effects of a high-protein diet versus a moderate-protein diet on muscle, liver and fat metabolism and glucose regulation using the obese Zucker rat. Twelve-week old, male, Zucker (fa/fa) and lean control (Fa/fa) rats were randomly assigned to either a high-protein (40% energy) or moderate-protein (20% energy) diet for 12 weeks, with a total of four groups: lean 20% protein (L20; n = 8), lean 40% protein (L40; n = 10), obese 20% protein (O20; n = 8), and obese 40% protein (O40; n = 10). At the end of 12 weeks, animals were fasted and euthanized. There was no difference in food intake between L20 and L40. O40 rats gained less weight and had lower food intake ( p < 0.05) compared to O20. O40 rats had lower liver weight ( p < 0.05) compared to O20. However, O40 rats had higher orexin ( p < 0.05) levels compared to L20, L40 and O20. Rats in the L40 and O40 groups had less liver and muscle lipid deposition compared to L20 and L40 diet rats, respectively. O40 had decreased skeletal muscle mechanistic target of rapamycin complex 1 (mTORC1) phosphorylation and peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to O20 ( p < 0.05), with no difference in 5' AMP-activated protein kinase (AMPK), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), protein kinase B (Akt) or p70 ribosomal S6 kinase (p70S6K) phosphorylation. The data suggest that high-protein diets have the potential to reduce weight gain and alter metabolism, possibly through regulation of an mTORC1-dependent pathway in skeletal muscle.

miR-20a Regulates FAS Expression in Osteosarcoma Cells by Modulating FAS Promoter Activity and Can be Therapeutically Targeted to Inhibit Lung Metastases.

PubMed

Yang, Yuanzheng; Huang, Gangxiong; Zhou, Zhichao; Fewell, Jason G; Kleinerman, Eugenie S

2018-01-01

The metastatic potential of osteosarcoma cells is inversely correlated to cell surface FAS expression. Downregulation of FAS allows osteosarcoma cells to escape FAS ligand-mediated apoptosis when they enter a FAS ligand-positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates FAS expression in osteosarcoma. We further demonstrated an inverse correlation between FAS expression and miR-20a expression. However, the mechanism of FAS regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of FAS regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo We investigated whether miR-20a's downregulation of FAS was mediated by binding to the 3'-untranslated region (3'-UTR) of FAS mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the FAS mRNA 3'-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated FAS 3'-UTR. In contrast, overexpression of miR-20a resulted in downregulation of FAS promoter activity. Similarly, the inhibition of miR-20a increased FAS promoter activity. The critical region identified on the FAS promoter was between -240 bp and -150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of FAS and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates FAS expression through the modulation of the FAS promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential. Mol Cancer Ther; 17(1); 130-9. ©2017 AACR . ©2017 American Association for Cancer Research.

The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice.

PubMed

Mercer, John R; Yu, Emma; Figg, Nichola; Cheng, Kian-Kai; Prime, Tracy A; Griffin, Julian L; Masoodi, Mojgan; Vidal-Puig, Antonio; Murphy, Michael P; Bennett, Martin R

2012-03-01

A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants. Copyright © 2011 Elsevier Inc. All rights reserved.

New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0

PubMed Central

2014-01-01

Background We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible. Results We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a näive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets. Conclusions TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool. PMID:25302078

New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0.

PubMed

Clark, Alex M; Sarker, Malabika; Ekins, Sean

2014-01-01

We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible. We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a näive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets. TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool.

A comparison of bilateral versus unilateral target and distractor presentation in the remote distractor paradigm.

PubMed

Benson, Valerie

2008-01-01

The remote distractor effect (RDE) is a robust finding of an increase in saccade onset latencies (20-40 ms) when a distractor is presented simultaneously with a target, compared to when a target is presented on its own (Walker, Deubel, Schneider, & Findlay, 1997). Distractors presented at fixation produce the largest RDE and the effect decreases as distractors are moved into the periphery. Data from two experiments that contrast with these standard findings are reported. Under bilateral target presentation, larger RDE magnitudes occurred for peripheral than for central distractors, whereas under unilateral presentation, the pattern reversed. The findings are discussed with reference to discrimination processes, attentional factors and current models of oculomotor control. It is suggested that in bilateral target presentation the competition between the distractor and the target results in the programming of a saccade to the distractor, as well as a saccade to the target. Time taken to cancel the saccade to the distractor produces the increased saccade latency for peripheral distractors in that condition.

Repeat prostate-specific antigen (PSA) test before prostate biopsy: a 20% decrease in PSA values is associated with a reduced risk of cancer and particularly of high-grade cancer.

PubMed

De Nunzio, Cosimo; Lombardo, Riccardo; Nacchia, Antonio; Tema, Giorgia; Tubaro, Andrea

2018-07-01

To analyse the impact of repeating a prostate-specific antigen (PSA) level assessment on prostate biopsy decision in a cohort of men undergoing prostate biopsy. From 2015 onwards, we consecutively enrolled, at a single institution in Italy, men undergoing 12-core transrectal ultrasonography-guided prostate needle biopsy. Indication for prostate biopsy was a PSA level of ≥4 ng/mL. Demographic, clinical, and histopathological data were collected. The PSA level was tested at enrolment (PSA 1 ) and 4 weeks later on the day before biopsy (PSA 2 ). Variations in PSA level were defined as: stable PSA 2 within a 10% variation, stable PSA 2 within a 20% variation, PSA 2 decreased by ≥10%, PSA 2 decreased by ≥20%, PSA 2 increased by ≥10%, PSA 2 increased by ≥20%, and PSA 2 <4 ng/mL. Percentages and multinomial logistic regression were used to analyse biopsy outcomes. High-grade cancer was defined as Grade group ≥3. Overall, 331 patients were enrolled. Prostate cancer was diagnosed in 153/331 (46%) patients and of them 80/153 (52%) had high-grade disease. When compared to the rest of the population, patients with a stable PSA within 20% variation had a higher risk of prostate cancer (odds ratio [OR] 1.80, P < 0.05) and high grade disease (OR 2.56, P < 0.05), patients with a PSA2 decreased by ≥20% had a lower risk of prostate cancer (OR 0.37, P < 0.05) and high grade disease (OR 0.13, P < 0.05), whilst patients with a PSA2 increased by ≥10% had an increased risk of high-grade prostate cancer (OR 1.93, P < 0.05). When PSA returned to normal values (<4 ng/mL) both risks of prostate cancer and high-grade disease were reduced (OR 0.33 and 0.01, respectively, P = 0.001). In a cohort of Italian men undergoing prostate biopsy, a reduction of ≥20% in PSA levels significantly reduced the risk of high-grade prostate cancer. Further multicentre studies should validate our present results. © 2018 The Authors BJU International © 2018 BJU International Published by John

Using a Peer-Mediated Extinction Procedure to Decrease Obscene Language.

ERIC Educational Resources Information Center

Salend, Spencer J.; Meddaugh, Dona

1985-01-01

A peer extinction procedure in which students refrained from laughing at or attending to a targeted student's inappropriate behavior decreased the adolescent learning disabled student's obscene language. (CL)

NMR investigations of the dual targeting peptide of Thr-tRNA synthetase and its interaction with the mitochondrial Tom20 receptor in Arabidopsis thaliana.

PubMed

Ye, Weihua; Spånning, Erika; Unnerståle, Sofia; Gotthold, David; Glaser, Elzbieta; Mäler, Lena

2012-10-01

Most mitochondrial proteins are synthesized in the cytosol as precursor proteins containing an N-terminal targeting peptide and are imported into mitochondria through the import machineries, the translocase of the outer mitochondrial membrane (TOM) and the translocase of the inner mitochondrial membrane (TIM). The N-terminal targeting peptide of precursor proteins destined for the mitochondrial matrix is recognized by the Tom20 receptor and plays an important role in the import process. Protein import is usually organelle specific, but several plant proteins are dually targeted into mitochondria and chloroplasts using an ambiguous dual targeting peptide. We present NMR studies of the dual targeting peptide of Thr-tRNA synthetase and its interaction with Tom20 in Arabidopsis thaliana. Our findings show that the targeting peptide is mostly unstructured in buffer, with a propensity to form α-helical structure in one region, S6-F27, and a very weak β-strand propensity for Q34-Q38. The α-helical structured region has an amphiphilic character and a φχχφφ motif, both of which have previously been shown to be important for mitochondrial import. Using NMR we have mapped out two regions in the peptide that are important for Tom20 recognition: one of them, F9-V28, overlaps with the amphiphilic region, and the other comprises residues L30-Q39. Our results show that the targeting peptide may interact with Tom20 in several ways. Furthermore, our results indicate a weak, dynamic interaction. The results provide for the first time molecular details on the interaction of the Tom20 receptor with a dual targeting peptide. © 2012 The Authors Journal compilation © 2012 FEBS.

Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice.

PubMed

Yuan, Zhi-Xin; Rapoport, Stanley I

2015-10-01

Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.

Methyl-parathion decreases sperm function and fertilization capacity after targeting spermatocytes and maturing spermatozoa

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

Pina-Guzman, Belem; Sanchez-Gutierrez, M.; Marchetti, Francesco

Paternal germline exposure to organophosphorous pesticides (OP) has been associated with reproductive failures and adverse effects in the offspring. Methyl parathion (Me-Pa), a worldwide-used OP, has reproductive adverse effects and is genotoxic to sperm. Oxidative damage has been involved in the genotoxic and reproductive effects of OP. The purpose of this study was to determine the effects of Me-Pa on spermatozoa function and ability to fertilize. Male mice were exposed to Me-Pa (20 mg/kg bw, i.p.) and spermatozoa from epididymis-vas deferens were collected at 7 or 28 days post-treatment (dpt) to assess the effects on maturing spermatozoa and spermatocytes, respectively.more » DNA damage was evaluated by nick translation (NT-positive cells) and SCSA (percentDFI); lipoperoxidation (LPO) by malondialdehyde production; sperm function by spontaneous- and induced-acrosome reactions (AR); mitochondrial membrane potential (MMP) by using the JC-1 flurochrome; and, fertilization ability by an in vitro assay and in vivo mating. Results showed alterations in DNA integrity (percentDFI and NT-positive cells) at 7 and 28 dpt, in addition to decreased sperm quality and a decrease in induced-AR; reduced MMP and LPO was observed only at 7 dpt. We found negative correlations between LPO and all sperm alterations. Altered sperm functional parameters were associated with reduced fertilization rates at both times, evaluated either in vitro or in vivo. These results show that Me-Pa exposure of maturing spermatozoa and spermatocytes affects many sperm functional parameters that result in a decreased fertilizing capacity. Oxidative stress seems to be a likely mechanism ofthe detrimental effects of Me-Pa in male germ cells.« less

One target, different effects: a comparison of distinct therapeutic antibodies against the same targets.

PubMed

Shim, Hyunbo

2011-10-31

To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-α, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.

A curative regimen would decrease HIV prevalence but not HIV incidence unless targeted to an ART-naïve population.

PubMed

Dimitrov, Dobromir T; Kiem, Hans-Peter; Jerome, Keith R; Johnston, Christine; Schiffer, Joshua T

2016-02-24

HIV curative strategies currently under development aim to eradicate latent provirus, or prevent viral replication, progression to AIDS, and transmission. The impact of implementing curative programs on HIV epidemics has not been considered. We developed a mathematical model of heterosexual HIV transmission to evaluate the independent and synergistic impact of ART, HIV prevention interventions and cure on HIV prevalence and incidence. The basic reproduction number was calculated to study the potential for the epidemic to be eliminated. We explored scenarios with and without the assumption that patients enrolled into HIV cure programs need to be on antiretroviral treatment (ART). In our simulations, curative regimes had limited impact on HIV incidence if only ART patients were eligible for cure. Cure implementation had a significant impact on HIV incidence if ART-untreated patients were enrolled directly into cure programs. Concurrent HIV prevention programs moderately decreased the percent of ART treated or cured patients needed to achieve elimination. We project that widespread implementation of HIV cure would decrease HIV prevalence under all scenarios but would only lower rate of new infections if ART-untreated patients were targeted. Current efforts to identify untreated HIV patients will gain even further relevance upon availability of an HIV cure.

Effects of seed mixture sowing with transgenic Bt rice and its parental line on the population dynamics of target stemborers and leafrollers, and non-target planthoppers.

PubMed

Li, Zhuo; Li, Li-Kun; Liu, Bin; Wang, Long; Parajulee, Megha N; Chen, Fa-Jun

2018-01-24

The widespread planting of insect-resistant crops has caused a dramatic shift in agricultural landscapes, thus raising concerns about the potential impacts on both target and non-target pests. In this study, we examined the potential effects of intra-specific seed mixture sowing with transgenic Bt rice (Bt) and its parental non-transgenic line (Nt) (100% Bt rice [Bt 100 ], 5% Nt+95% Bt [Nt 05 Bt 95 ], 10% Nt+90% Bt [Nt 10 Bt 90 ], 20% Nt+80% Bt [Nt 20 Bt 80 ], 40% Nt+60% Bt [Nt 40 Bt 60 ] and 100% Nt rice [Nt 100 ]) on target and non-target pests in a 2-year field trial in southern China. The occurrence of target pests, Sesamia inferens, Chilo suppressalis and Cnaphalocrocis medinalis, decreased with the increased ratio of Bt rice, and the mixture ratios with more than 90% Bt rice (Bt 100 and Nt 05 Bt 95 ) significantly increased the pest suppression efficiency, with the lowest occurrences of non-target planthoppers, Nilaparvata lugens and Sogatella furcifera in Nt 100 and Nt 05 Bt 95 . Furthermore, there were no significant differences in 1000-grain dry weight and grain dry weight per 100 plants between Bt 100 and Nt 05 Bt 95 . Seed mixture sowing of Bt rice with ≤10% (especially 5%) of its parent line was sufficient to overcome potential compliance issues that exist with the use of block or structured refuge to provide most effective control of both target and non-target pests without compromising the grain yield. It is also expected that the strategy of seed mixture sowing with transgenic Bt rice and the non-transgenic parental line would provide rice yield stability while decreasing the insecticide use frequency in rice production. © 2018 Institute of Zoology, Chinese Academy of Sciences.

Targeting an efficient target-to-target interval for P300 speller brain–computer interfaces

PubMed Central

Sellers, Eric W.; Wang, Xingyu

2013-01-01

Longer target-to-target intervals (TTI) produce greater P300 event-related potential amplitude, which can increase brain–computer interface (BCI) classification accuracy and decrease the number of flashes needed for accurate character classification. However, longer TTIs requires more time for each trial, which will decrease the information transfer rate of BCI. In this paper, a P300 BCI using a 7 × 12 matrix explored new flash patterns (16-, 18- and 21-flash pattern) with different TTIs to assess the effects of TTI on P300 BCI performance. The new flash patterns were designed to minimize TTI, decrease repetition blindness, and examine the temporal relationship between each flash of a given stimulus by placing a minimum of one (16-flash pattern), two (18-flash pattern), or three (21-flash pattern) non-target flashes between each target flashes. Online results showed that the 16-flash pattern yielded the lowest classification accuracy among the three patterns. The results also showed that the 18-flash pattern provides a significantly higher information transfer rate (ITR) than the 21-flash pattern; both patterns provide high ITR and high accuracy for all subjects. PMID:22350331

Optimization of the photoneutron target geometry for e-accelerator based BNCT.

PubMed

Chegeni, Nahid; Pur, Saleh Boveiry; Razmjoo, Sasan; Hoseini, Seydeh Khadijed

2017-06-01

Today, electron accelerators are taken into consideration as photoneutron sources. Therefore, for maximum production of epithermal neutron flux, designing a photoneutron target is of significant importance. In this paper, the effect of thickness and geometric shape of a photoneutron target on neutron output were investigated. In this study, a pencil photon source with 13, 15, 18, 20 and 25 MeV energies and a diameter of 2 mm was investigated using Monte Carlo simulation method using MCNP code. To optimize the design of the photoneutron target, the tungsten target with various geometries and thicknesses was investigated. The maximum neutron flux produced for all target geometries and thicknesses occurred at neutron energy peak of around 0.46 MeV. As the thickness increased to 2 cm, neutron flux increased and then a decreasing trend was observed. For various geometrical shapes, the determining factor in photoneutron output was the effective target thickness in the photon interaction path that increased by the increase in the area of interaction. Another factor was the angle of the photon's incidence with the target surface that resulted in a significant decrease in photoneutron output in cone-shaped targets. Three factors including the total neutron flux, neutrons energy spectrum, and convergence of neutrons plays an important role in the selection of geometry and shape of the target that should be investigated considering beam shaping assembly (BSA) shape.

Evolution of Magnetized Liner Inertial Fusion (MagLIF) Targets

DOE PAGES

Fooks, J. A.; Carlson, L. C.; Fitzsimmons, P.; ...

2017-12-19

Here, the magnetized liner inertial fusion (MagLIF) experimental campaign conducted at the University of Rochester’s Laboratory for Laser Energetics (LLE) has evolved significantly since its start in 2014. Scientific requirements and OMEGA EP system technology both have progressed, resulting in necessary and available updates to the target design. These include, but are not limited to: optimizing target dimensions and aspect ratios to maximize survival at desired pressures; coating target components to enhance physics diagnosis; precision-machining diagnostic windows along the axis of the target; improving fiducial placement reproducibility and reducing subsequent assembly time by 50%; and implementing gas-pressure transducers on themore » targets. In addition, target fabrication techniques have changed and improved, allowing for simpler target reproducibility and decreased assembly time. To date, eleven variations of targets have been fabricated, with successful target fielding ranging from 1 to 20atm internal pressure and a maximum survivability of 33atm.« less

Evolution of Magnetized Liner Inertial Fusion (MagLIF) Targets

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

Fooks, J. A.; Carlson, L. C.; Fitzsimmons, P.

Here, the magnetized liner inertial fusion (MagLIF) experimental campaign conducted at the University of Rochester’s Laboratory for Laser Energetics (LLE) has evolved significantly since its start in 2014. Scientific requirements and OMEGA EP system technology both have progressed, resulting in necessary and available updates to the target design. These include, but are not limited to: optimizing target dimensions and aspect ratios to maximize survival at desired pressures; coating target components to enhance physics diagnosis; precision-machining diagnostic windows along the axis of the target; improving fiducial placement reproducibility and reducing subsequent assembly time by 50%; and implementing gas-pressure transducers on themore » targets. In addition, target fabrication techniques have changed and improved, allowing for simpler target reproducibility and decreased assembly time. To date, eleven variations of targets have been fabricated, with successful target fielding ranging from 1 to 20atm internal pressure and a maximum survivability of 33atm.« less

miR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn’s disease

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

Chen, Yu; Wang, Chengxiao; Liu, Ying

2013-08-16

Highlights: •NOD2 is a target gene of miR-122. •miR-122 inhibits LPS-induced apoptosis by suppressing NOD2 in HT-29 cells. •miR-122 reduces the expression of pro-inflammatory cytokines (TNF-α and IFN-γ). •miR-122 promotes the release of anti-inflammatory cytokines (IL-4 and IL-10). •NF-κB signaling pathway is involved in inflammatory response induced by LPS. -- Abstract: Crohn’s disease (CD) is one of the two major types of inflammatory bowel disease (IBD) thought to be caused by genetic and environmental factors. Recently, miR-122 was found to be deregulated in association with CD progression. However, the underlying molecular mechanisms remain unclear. In the present study, the genemore » nucleotide-binding oligomerization domain 2 (NOD2/CARD15), which is strongly associated with susceptibility to CD, was identified as a functional target of miR-122. MiR-122 inhibited LPS-induced apoptosis by suppressing NOD2 in HT-29 cells. NOD2 interaction with LPS initiates signal transduction mechanisms resulting in the activation of nuclear factor κB (NF-κB) and the stimulation of downstream pro-inflammatory events. The activation of NF-κB was inhibited in LPS-stimulated HT-29 cells pretreated with miR-122 precursor or NOD2 shRNA. The expression of the pro-inflammatory cytokines TNF-α and IFN-γ was significantly decreased, whereas therelease of the anti-inflammatory cytokines IL-4 and IL-10 was increased in LPS-stimulated HT-29 cells pretreated with miR-122 precursor, NOD2 shRNA or the NF-κB inhibitor QNZ. Taken together, these results indicate that miR-122 and its target gene NOD2 may play an important role in the injury of intestinal epithelial cells induced by LPS.« less

Development of a Muon Rotating Target for J-PARC/MUSE

NASA Astrophysics Data System (ADS)

Makimura, Shunsuke; Kobayashi, Yasuo; Miyake, Yasuhiro; Kawamura, Naritoshi; Strasser, Patrick; Koda, Akihiro; Shimomura, Koichiro; Fujimori, Hiroshi; Nishiyama, Kusuo; Kato, Mineo; Kojima, Kenji; Higemoto, Wataru; Ito, Takashi; Shimizu, Ryou; Kadono, Ryosuke

At the J-PARC muon science facility (J-PARC/MUSE), a graphite target with a thickness of 20 mm has been used in vacuum to obtain an intense pulsed muon beam from the RCS 3-GeV proton beam [1], [2]. In the current design, the target frame is constructed using copper with a stainless steel tube embedded for water cooling. The energy deposited by the proton beam at 1 MW is evaluated to be 3.3 kW on the graphite target and 600 W on the copper frame by a Monte-Carlo simulation code, PHITS [3]. Graphite materials are known to lose their crystal structure and can be shrunk under intense proton beam irradiation. Consequently, the lifetime of the muon target is essentially determined by the radiation damage in graphite, and is evaluated to be half a year [4]. Hence, we are planning to distribute the radiation damage by rotating a graphite wheel. Although the lifetime of graphite in this case will be more than 10 years, the design of the bearing must be carefully considered. Because the bearing in JPARC/MUSE is utilized in vacuum, under high radiation, and at high temperature, an inorganic and solid lubricant must be applied to the bearing. Simultaneously, the temperature of the bearing must also be decreased to extend the lifetime. In 2009, a mock-up of the Muon Rotating Target, which could heat up and rotate a graphite wheel, was fabricated. Then several tests were started to select the lubricant and to determine the structure of the Muon Rotating Target, the control system and so on. In this report, the present status of the Muon Rotating Target for J-PARC/MUSE, especially the development of a rotation system in vacuum, is described.

Impedance modulation and feedback corrections in tracking targets of variable size and frequency.

PubMed

Selen, Luc P J; van Dieën, Jaap H; Beek, Peter J

2006-11-01

Humans are able to adjust the accuracy of their movements to the demands posed by the task at hand. The variability in task execution caused by the inherent noisiness of the neuromuscular system can be tuned to task demands by both feedforward (e.g., impedance modulation) and feedback mechanisms. In this experiment, we studied both mechanisms, using mechanical perturbations to estimate stiffness and damping as indices of impedance modulation and submovement scaling as an index of feedback driven corrections. Eight subjects tracked three differently sized targets (0.0135, 0.0270, and 0.0405 rad) moving at three different frequencies (0.20, 0.25, and 0.33 Hz). Movement variability decreased with both decreasing target size and movement frequency, whereas stiffness and damping increased with decreasing target size, independent of movement frequency. These results are consistent with the theory that mechanical impedance acts as a filter of noisy neuromuscular signals but challenge stochastic theories of motor control that do not account for impedance modulation and only partially for feedback control. Submovements during unperturbed cycles were quantified in terms of their gain, i.e., the slope between their duration and amplitude in the speed profile. Submovement gain decreased with decreasing movement frequency and increasing target size. The results were interpreted to imply that submovement gain is related to observed tracking errors and that those tracking errors are expressed in units of target size. We conclude that impedance and submovement gain modulation contribute additively to tracking accuracy.

Oh! Web 2.0, Virtual Reference Service 2.0, Tools and Techniques (I): A Basic Approach

ERIC Educational Resources Information Center

Arya, Harsh Bardhan; Mishra, J. K.

2011-01-01

This study targets librarians and information professionals who use Web 2.0 tools and applications with a view to providing snapshots on how Web 2.0 technologies are used. It also aims to identify values and impact that such tools have exerted on libraries and their services, as well as to detect various issues associated with the implementation…

Optimization of the photoneutron target geometry for e-accelerator based BNCT

PubMed Central

Chegeni, Nahid; Pur, Saleh Boveiry; Razmjoo, Sasan; Hoseini, Seydeh Khadijed

2017-01-01

Background and aim Today, electron accelerators are taken into consideration as photoneutron sources. Therefore, for maximum production of epithermal neutron flux, designing a photoneutron target is of significant importance. In this paper, the effect of thickness and geometric shape of a photoneutron target on neutron output were investigated. Methods In this study, a pencil photon source with 13, 15, 18, 20 and 25 MeV energies and a diameter of 2 mm was investigated using Monte Carlo simulation method using MCNP code. To optimize the design of the photoneutron target, the tungsten target with various geometries and thicknesses was investigated. Results The maximum neutron flux produced for all target geometries and thicknesses occurred at neutron energy peak of around 0.46 MeV. As the thickness increased to 2 cm, neutron flux increased and then a decreasing trend was observed. For various geometrical shapes, the determining factor in photoneutron output was the effective target thickness in the photon interaction path that increased by the increase in the area of interaction. Another factor was the angle of the photon’s incidence with the target surface that resulted in a significant decrease in photoneutron output in cone-shaped targets Conclusion Three factors including the total neutron flux, neutrons energy spectrum, and convergence of neutrons plays an important role in the selection of geometry and shape of the target that should be investigated considering beam shaping assembly (BSA) shape. PMID:28848635

Moderate (20%) fructose-enriched diet stimulates salt-sensitive hypertension with increased salt retention and decreased renal nitric oxide.

PubMed

Gordish, Kevin L; Kassem, Kamal M; Ortiz, Pablo A; Beierwaltes, William H

2017-04-01

Previously, we reported that 20% fructose diet causes salt-sensitive hypertension. In this study, we hypothesized that a high salt diet supplemented with 20% fructose (in drinking water) stimulates salt-sensitive hypertension by increasing salt retention through decreasing renal nitric oxide. Rats in metabolic cages consumed normal rat chow for 5 days (baseline), then either: (1) normal salt for 2 weeks, (2) 20% fructose in drinking water for 2 weeks, (3) 20% fructose for 1 week, then fructose + high salt (4% NaCl) for 1 week, (4) normal chow for 1 week, then high salt for 1 week, (5) 20% glucose for 1 week, then glucose + high salt for 1 week. Blood pressure, sodium excretion, and cumulative sodium balance were measured. Systolic blood pressure was unchanged by 20% fructose or high salt diet. 20% fructose + high salt increased systolic blood pressure from 125 ± 1 to 140 ± 2 mmHg ( P  < 0.001). Cumulative sodium balance was greater in rats consuming fructose + high salt than either high salt, or glucose + high salt (114.2 ± 4.4 vs. 103.6 ± 2.2 and 98.6 ± 5.6 mEq/Day19; P  < 0.05). Sodium excretion was lower in fructose + high salt group compared to high salt only: 5.33 ± 0.21 versus 7.67 ± 0.31 mmol/24 h; P  < 0.001). Nitric oxide excretion was 2935 ± 256  μ mol/24 h in high salt-fed rats, but reduced by 40% in the 20% fructose + high salt group (2139 ± 178  μ mol /24 hrs P  < 0.01). Our results suggest that fructose predisposes rats to salt-sensitivity and, combined with a high salt diet, leads to sodium retention, increased blood pressure, and impaired renal nitric oxide availability. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Decreased 16:0/20:4-phosphatidylinositol level in the post-mortem prefrontal cortex of elderly patients with schizophrenia

PubMed Central

Matsumoto, Junya; Nakanishi, Hiroki; Kunii, Yasuto; Sugiura, Yuki; Yuki, Dai; Wada, Akira; Hino, Mizuki; Niwa, Shin-Ichi; Kondo, Takeshi; Waki, Michihiko; Hayasaka, Takahiro; Masaki, Noritaka; Akatsu, Hiroyasu; Hashizume, Yoshio; Yamamoto, Sakon; Sato, Shinji; Sasaki, Takehiko; Setou, Mitsutoshi; Yabe, Hirooki

2017-01-01

The etiology of schizophrenia includes phospholipid abnormalities. Phospholipids are bioactive substances essential for brain function. To analyze differences in the quantity and types of phospholipids present in the brain tissue of patients with schizophrenia, we performed a global analysis of phospholipids in multiple brain samples using liquid chromatography electrospray ionization mass/mass spectrometry (LC-ESI/MS/MS) and imaging mass spectrometry (IMS). We found significantly decreased 16:0/20:4-phosphatidylinositol (PI) levels in the prefrontal cortex (PFC) in the brains from patients with schizophrenia in the LC-ESI/MS/MS, and that the 16:0/20:4-PI in grey matter was most prominently diminished according to the IMS experiments. Previous reports investigating PI pathology of schizophrenia did not identify differences in the sn-1 and sn-2 fatty acyl chains. This study is the first to clear the fatty acid composition of PI in brains from patients with schizophrenia. Alteration in the characteristic fatty acid composition of PI may also affect neuronal function, and could play a role in the etiology of schizophrenia. Although further studies are necessary to understand the role of reduced 16:0/20:4-PI levels within the prefrontal cortex in the etiology of schizophrenia, our results provide insight into the development of a novel therapy for the clinical treatment of schizophrenia. PMID:28332626

Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity

PubMed Central

Pokrzywinski, Kaytee L.; Biel, Thomas G.; Kryndushkin, Dmitry; Rao, V. Ashutosh

2016-01-01

Mitochondrial dysregulation is closely associated with excessive reactive oxygen species (ROS) production. Altered redox homeostasis has been implicated in the onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and proteins are particularly sensitive to ROS as they are in close proximity to the respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, selectively damages breast cancer cells possibly through damage induced via enhanced ROS production. However, the effects of MitoQ and other triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis remain unknown. The primary objective of this study was to determine the impact of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy number, as well as by measuring mitochondrial proteins essential to mtDNA stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial status was evaluated by measuring superoxide production, mitochondrial membrane depolarization, oxygen consumption, extracellular acidification and mRNA or protein levels of the RC complexes along with TCA cycle activity. In this study, we demonstrated that all investigated MTAs impair mitochondrial health and decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the degree of mitochondrial damage and mtDNA degradation suggest unique properties among each MTA that may be cell line, dose and time dependent. Collectively, our study indicates the potential for TPP+ conjugated molecules to impair breast and lung cancer cells by targeting mitochondrial homeostasis. PMID:28030582

Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity.

PubMed

Pokrzywinski, Kaytee L; Biel, Thomas G; Kryndushkin, Dmitry; Rao, V Ashutosh

2016-01-01

Mitochondrial dysregulation is closely associated with excessive reactive oxygen species (ROS) production. Altered redox homeostasis has been implicated in the onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and proteins are particularly sensitive to ROS as they are in close proximity to the respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, selectively damages breast cancer cells possibly through damage induced via enhanced ROS production. However, the effects of MitoQ and other triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis remain unknown. The primary objective of this study was to determine the impact of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy number, as well as by measuring mitochondrial proteins essential to mtDNA stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial status was evaluated by measuring superoxide production, mitochondrial membrane depolarization, oxygen consumption, extracellular acidification and mRNA or protein levels of the RC complexes along with TCA cycle activity. In this study, we demonstrated that all investigated MTAs impair mitochondrial health and decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the degree of mitochondrial damage and mtDNA degradation suggest unique properties among each MTA that may be cell line, dose and time dependent. Collectively, our study indicates the potential for TPP+ conjugated molecules to impair breast and lung cancer cells by targeting mitochondrial homeostasis.

Effects of seed mixture sowing with resistant and susceptible rice on population dynamics of target planthoppers and non-target stemborers and leaffolders.

PubMed

Li, Zhuo; Wan, Guijun; Wang, Long; Parajulee, Megha N; Zhao, Zihua; Chen, Fajun

2018-07-01

The widespread planting of insect-resistant crops has caused a dramatic shift in agricultural landscapes, thus raising concerns about the potential impact on both target and non-target pests worldwide. In this study, we examined the potential effects of six seed mixture ratios of insect-resistance dominance [100% (R100), 95% (S05R95), 90% (S10R90), 80% (S20R80), 60% (S40R60), and 0% (S100)] on target and non-target pests in a 2-year field trial in southern China. The occurrence of the target pests Nilaparvata lugens and Sogatella furcifera decreased with an increase in the ratio of resistant rice, and mixture ratios with ≥90% resistant rice significantly increased the pest suppression efficiency, with the lowest occurrences of the non-target pests Sesamia inferens, Chilo suppressalis and Cnaphalocrocis medinalis for S100 and S10R90 seed mixture ratios. Furthermore, there were no significant differences in the 1000-grain dry weight and grain yield between R100 and other treatments with ≥80% resistant seeds in the mixture (S20R80, S10R90 and S05R95). S10R90 produced a good yield and provided the most effective control of both target and non-target pests, with the potential to significantly reduce the application of chemical pesticides for integrated pest management in paddy fields. It is further presumed that the strategy of seed mixture with resistant and susceptible rice would be advantageous for rice yield stability. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

P20A inhibits HIV-1 fusion through its electrostatic interaction with the distal region of the gp41 fusion core.

PubMed

Fu, Shushu; Tong, Pei; Tan, Yue; Zhu, Yun; Chen, Ying-Hua

2015-09-01

We previously identified an HIV-1 fusion inhibitor P20A targeting HIV-1 gp41 6-HB fusion core. Using alanine scanning mutagenesis, we investigated the effect of 6-HB surface residue mutations on the binding affinity between P20A and 6-HB. Substitution of positively or negatively charged residues in the distal region of 6-HB with alanines resulted in significant decrease or increase of its binding affinity to P20A, respectively. The 6-HB with E630K, D632K, or E634K mutation exhibited enhanced binding affinity with P20A, suggesting that P20A blocks HIV-1 fusion through electrostatic interaction with the positively charged residues in the distal region of the gp41 fusion core. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Target depth dependence of damage rate in metals by 150 MeV proton irradiation

NASA Astrophysics Data System (ADS)

Yoshiie, T.; Ishi, Y.; Kuriyama, Y.; Mori, Y.; Sato, K.; Uesugi, T.; Xu, Q.

2015-01-01

A series of irradiation experiments with 150 MeV protons was performed. The relationship between target depth (or shield thickness) and displacement damage during proton irradiation was obtained by in situ electrical resistance measurements at 20 K. Positron annihilation lifetime measurements were also performed at room temperature after irradiation, as a function of the target thickness. The displacement damage was found to be high close to the beam incident surface area, and decreased with increasing target depth. The experimental results were compared with damage production calculated with an advanced Monte Carlo particle transport code system (PHITS).

Mitochondrial-Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation.

PubMed

Lee, Hui-Young; Lee, Jae Sung; Alves, Tiago; Ladiges, Warren; Rabinovitch, Peter S; Jurczak, Michael J; Choi, Cheol Soo; Shulman, Gerald I; Samuel, Varman T

2017-08-01

We explored the role of reactive oxygen species (ROS) in the pathogenesis of muscle insulin resistance. We assessed insulin action in vivo with a hyperinsulinemic-euglycemic clamp in mice expressing a mitochondrial-targeted catalase (MCAT) that were fed regular chow (RC) or a high-fat diet (HFD) or underwent an acute infusion of a lipid emulsion. RC-fed MCAT mice were similar to littermate wild-type (WT) mice. However, HFD-fed MCAT mice were protected from diet-induced insulin resistance. In contrast, an acute lipid infusion caused muscle insulin resistance in both MCAT and WT mice. ROS production was decreased in both HFD-fed and lipid-infused MCAT mice and cannot explain the divergent response in insulin action. MCAT mice had subtly increased energy expenditure and muscle fat oxidation with decreased intramuscular diacylglycerol (DAG) accumulation, protein kinase C-θ (PKCθ) activation, and impaired insulin signaling with HFD. In contrast, the insulin resistance with the acute lipid infusion was associated with increased muscle DAG content in both WT and MCAT mice. These studies suggest that altering muscle mitochondrial ROS production does not directly alter the development of lipid-induced insulin resistance. However, the altered energy balance in HFD-fed MCAT mice protected them from DAG accumulation, PKCθ activation, and impaired muscle insulin signaling. © 2017 by the American Diabetes Association.

Effects of age and eccentricity on visual target detection.

PubMed

Gruber, Nicole; Müri, René M; Mosimann, Urs P; Bieri, Rahel; Aeschimann, Andrea; Zito, Giuseppe A; Urwyler, Prabitha; Nyffeler, Thomas; Nef, Tobias

2013-01-01

The aim of this study was to examine the effects of aging and target eccentricity on a visual search task comprising 30 images of everyday life projected into a hemisphere, realizing a ±90° visual field. The task performed binocularly allowed participants to freely move their eyes to scan images for an appearing target or distractor stimulus (presented at 10°; 30°, and 50° eccentricity). The distractor stimulus required no response, while the target stimulus required acknowledgment by pressing the response button. One hundred and seventeen healthy subjects (mean age = 49.63 years, SD = 17.40 years, age range 20-78 years) were studied. The results show that target detection performance decreases with age as well as with increasing eccentricity, especially for older subjects. Reaction time also increases with age and eccentricity, but in contrast to target detection, there is no interaction between age and eccentricity. Eye movement analysis showed that younger subjects exhibited a passive search strategy while older subjects exhibited an active search strategy probably as a compensation for their reduced peripheral detection performance.

IL-20 bone diseases involvement and therapeutic target potential.

PubMed

Wang, Hsiao-Hsuan; Hsu, Yu-Hsiang; Chang, Ming-Shi

2018-04-24

Millions of people around the world suffer from bone disorders, likes osteoporosis, rheumatoid arthritis (RA), and cancer-induced osteolysis. In general, the bone remodeling balance is determined by osteoclasts and osteoblasts, respectively responsible for bone resorption and bone formation. Excessive inflammation disturbs the activities of these two kinds of cells, typically resulting in the bone loss. IL-20 is emerging as a potent angiogenic, chemotactic, and proinflammatory cytokine related to several chronic inflammatory disorders likes psoriasis, atherosclerosis, cancer, liver fibrosis, and RA. IL-20 has an important role in the regulation of osteoclastogenesis and osteoblastogenesis and is upregulated in several bone-related diseases. The anti-IL-20 monoclonal antibody treatment has a therapeutic potential in several experimental disease models including ovariectomy-induced osteoporosis, cancer-induced osteolysis, and bone fracture. This review article provides an overview describing the IL-20's biological functions in the common bone disorders and thus providing a novel therapeutic strategy in the future.

Near monochromatic 20 Me V proton acceleration using fs laser irradiating Au foils in target normal sheath acceleration regime

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

Torrisi, L., E-mail: Lorenzo.Torrisi@unime.it; Ceccio, G.; Cannavò, A.

2016-04-15

A 200 mJ laser pulse energy, 39 fs-pulse duration, 10 μm focal spot, p-polarized radiation has been employed to irradiate thin Au foils to produce proton acceleration in the forward direction. Gold foils were employed to produce high density relativistic electrons emission in the forward direction to generate a high electric field driving the ion acceleration. Measurements were performed by changing the focal position in respect of the target surface. Proton acceleration was monitored using fast SiC detectors in time-of-flight configuration. A high proton energy, up to about 20 Me V, with a narrow energy distribution, was obtained in particular conditions dependingmore » on the laser parameters, the irradiation conditions, and a target optimization.« less

FGF1-gold nanoparticle conjugates targeting FGFR efficiently decrease cell viability upon NIR irradiation

PubMed Central

Szlachcic, Anna; Pala, Katarzyna; Zakrzewska, Malgorzata; Jakimowicz, Piotr; Wiedlocha, Antoni; Otlewski, Jacek

2012-01-01

Fibroblast growth factor receptors (FGFRs) are overexpressed in a wide variety of tumors, such as breast, bladder, and prostate cancer, and therefore they are attractive targets for different types of anticancer therapies. In this study, we designed, constructed, and characterized FGFR-targeted gold nanoconjugates suitable for infrared-induced thermal ablation (localized heating leading to cancer cell death) based on gold nanoparticles (AuNPs). We showed that a recombinant ligand of all FGFRs, human fibroblast growth factor 1 (FGF1), can be used as an agent targeting covalently bound AuNPs to cancer cells overexpressing FGFRs. To assure thermal stability, protease resistance, and prolonged half-life of the targeting protein, we employed highly stable FGF1 variant that retains the biological activities of the wild type FGF1. Novel FGF1 variant, AuNP conjugates are specifically internalized only by the cells expressing FGFRs, and they significantly reduce their viability after irradiation with near-infrared light (down to 40% of control cell viability), whereas the proliferation potential of cells lacking FGFRs is not affected. These results demonstrate the feasibility of FGF1-coated AuNPs for targeted cancer therapy. PMID:23226697

Dependency of human target detection performance on clutter and quality of supporting image analysis algorithms in a video surveillance task

NASA Astrophysics Data System (ADS)

Huber, Samuel; Dunau, Patrick; Wellig, Peter; Stein, Karin

2017-10-01

Background: In target detection, the success rates depend strongly on human observer performances. Two prior studies tested the contributions of target detection algorithms and prior training sessions. The aim of this Swiss-German cooperation study was to evaluate the dependency of human observer performance on the quality of supporting image analysis algorithms. Methods: The participants were presented 15 different video sequences. Their task was to detect all targets in the shortest possible time. Each video sequence showed a heavily cluttered simulated public area from a different viewing angle. In each video sequence, the number of avatars in the area was altered to 100, 150 and 200 subjects. The number of targets appearing was kept at 10%. The number of marked targets varied from 0, 5, 10, 20 up to 40 marked subjects while keeping the positive predictive value of the detection algorithm at 20%. During the task, workload level was assessed by applying an acoustic secondary task. Detection rates and detection times for the targets were analyzed using inferential statistics. Results: The study found Target Detection Time to increase and Target Detection Rates to decrease with increasing numbers of avatars. The same is true for the Secondary Task Reaction Time while there was no effect on Secondary Task Hit Rate. Furthermore, we found a trend for a u-shaped correlation between the numbers of markings and RTST indicating increased workload. Conclusion: The trial results may indicate useful criteria for the design of training and support of observers in observational tasks.

Forward-backward multiplicity correlations of target fragments in nucleus-emulsion collisions at a few hundred MeV/u

NASA Astrophysics Data System (ADS)

Zhang, Dong-Hai; Chen, Yan-Ling; Wang, Guo-Rong; Li, Wang-Dong; Wang, Qing; Yao, Ji-Jie; Zhou, Jian-Guo; Li, Rong; Li, Jun-Sheng; Li, Hui-Ling

2015-01-01

The forward-backward multiplicity and correlations of a target evaporated fragment (black track particle) and target recoiled proton (grey track particle) emitted from 150 A MeV 4He, 290 A MeV 12C, 400 A MeV 12C, 400 A MeV 20Ne and 500 A MeV 56Fe induced different types of nuclear emulsion target interactions are investigated. It is found that the forward and backward averaged multiplicity of a grey, black and heavily ionized track particle increases with the increase of the target size. The averaged multiplicity of a forward black track particle, backward black track particle, and backward grey track particle do not depend on the projectile size and energy, but the averaged multiplicity of a forward grey track particle increases with an increase of projectile size and energy. The backward grey track particle multiplicity distribution follows an exponential decay law and the decay constant decreases with an increase of target size. The backward-forward multiplicity correlations follow linear law which is independent of the projectile size and energy, and the saturation effect is observed in some heavy target data sets.

Single-Isocenter Multiple-Target Stereotactic Radiosurgery: Risk of Compromised Coverage

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

Roper, Justin, E-mail: justin.roper@emory.edu; Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, Georgia; Chanyavanich, Vorakarn

2015-11-01

Purpose: To determine the dosimetric effects of rotational errors on target coverage using volumetric modulated arc therapy (VMAT) for multitarget stereotactic radiosurgery (SRS). Methods and Materials: This retrospective study included 50 SRS cases, each with 2 intracranial planning target volumes (PTVs). Both PTVs were planned for simultaneous treatment to 21 Gy using a single-isocenter, noncoplanar VMAT SRS technique. Rotational errors of 0.5°, 1.0°, and 2.0° were simulated about all axes. The dose to 95% of the PTV (D95) and the volume covered by 95% of the prescribed dose (V95) were evaluated using multivariate analysis to determine how PTV coverage was relatedmore » to PTV volume, PTV separation, and rotational error. Results: At 0.5° rotational error, D95 values and V95 coverage rates were ≥95% in all cases. For rotational errors of 1.0°, 7% of targets had D95 and V95 values <95%. Coverage worsened substantially when the rotational error increased to 2.0°: D95 and V95 values were >95% for only 63% of the targets. Multivariate analysis showed that PTV volume and distance to isocenter were strong predictors of target coverage. Conclusions: The effects of rotational errors on target coverage were studied across a broad range of SRS cases. In general, the risk of compromised coverage increased with decreasing target volume, increasing rotational error and increasing distance between targets. Multivariate regression models from this study may be used to quantify the dosimetric effects of rotational errors on target coverage given patient-specific input parameters of PTV volume and distance to isocenter.« less

Minus-Lens–Stimulated Accommodative Amplitude Decreases Sigmoidally with Age: A Study of Objectively Measured Accommodative Amplitudes from Age 3

PubMed Central

Anderson, Heather A.; Hentz, Gloria; Glasser, Adrian; Stuebing, Karla K.; Manny, Ruth E.

2009-01-01

Purpose Guidelines for predicting accommodative amplitude by age are often based on subjective push-up test data that overestimate the accommodative response. Studies in which objective measurements were used have defined expected amplitudes for adults, but expected amplitudes for children remain unknown. In this study, objective methods were used to measure accommodative amplitude in a wide age range of individuals, to define the relationship of amplitude and age from age 3. Methods Accommodative responses were measured in 140 subjects aged 3 to 40 years. Measurements were taken with the Grand Seiko autorefractor (RyuSyo Industrial Co., Ltd., Kagawa, Japan) as the subjects viewed a high-contrast target at 33 cm through minus lenses of increasing power until the responses showed no further increase in accommodation. Results The maximum accommodative amplitude of each subject was plotted by age, and a curvilinear function fit to the data: y = 7.33 − 0.0035(age − 3)2 (P < 0.001). Tangent analysis of the fit indicated that the accommodative amplitude remained relatively stable until age 20. Data from this study were then pooled with objective amplitudes from previous studies of adults up to age 70. A sigmoidal function was fit to the data: y = 7.083/(1 + e[0.2031(age-36.2)−0.6109]) (P < 0.001). The sigmoidal function indicated relatively stable amplitudes below age 20 years, a rapid linear decline between 20 and 50 years, and a taper to 0 beyond 50 years. Conclusions These data indicate that accommodative amplitude decreases in a curvilinear manner from 3 to 40 years. When combined with data from previous studies, a sigmoidal function describes the overall trend throughout life with the biggest decrease occurring between 20 and 50 years. PMID:18326693

Decreasing Excessive Bids for Attention in a Simulated Early Education Classroom

ERIC Educational Resources Information Center

Becraft, Jessica L.; Borrero, John C.; Mendres-Smith, Amber E.; Castillo, Mariana I.

2017-01-01

Differential-reinforcement-of-low-rate (DRL) schedules can be used to decrease, but not eliminate, excessive bids for teacher attention in a classroom. There are two primary methods of implementing a DRL: full session and spaced responding. Some research suggests that the full-session DRL may eliminate target responding. The purpose of the current…

Calpain5 expression is decreased in endometriosis and regulated by HOXA10 in human endometrial cells

PubMed Central

Penna, Ivan; Du, Hongling; Ferriani, Rui; Taylor, Hugh S.

2008-01-01

Calpains have been implicated in the regulation of apoptosis. Here, we identified Calpain5 as a target of HOXA10 transcriptional regulation in endometrial cells as well as its aberrant regulation in endometriosis. Histologically confirmed biopsies of endometriosis were obtained from 20 women. Eutopic endometrium was collected by endometrial biopsy from 30 controls and from the 20 subjects with endometriosis. First trimester decidual samples were obtained from five subjects at the time of pregnancy termination. Immunohistochemistry was used to identify Calpain5 expression. Calpain5 was expressed in endometrial stromal and glandular cells throughout the menstrual cycle and in decidua. Calpain5 protein expression was decreased in both stromal and glandular cells from women with endometriosis compared with that of fertile controls. Human endometrial stromal and epithelial cell lines were transfected with pcDNA/HOXA10, HOXA10 siRNA or respective controls. Quantitative real-time RT–PCR was performed to determine expression of HOXA10 and Calpain5 in each group. Transfection of HESC cells with an HOXA10 expression construct led to increased Calpain5 expression, whereas transfection with siRNA resulted in decreased expression. In conclusion, Calpain5 expression is regulated by HOXA10. Calpain5 expression was decreased in endometriosis likely as a result of decreased HOXA10 expression. Decreased apoptosis in endometrial cells may promote the development of endometriosis through a pathway involving HOXA10, Calpain5 and caspase. PMID:18829447

A hypothesis of target cell formation in sickle cell disease.

PubMed

Wong, P

2016-08-01

A fraction of erythrocytes appear as target cells in stained blood smears in sickle cell disease, due to a inheritance of the hemoglobin variant Hb S, polymerizing upon deoxygenation. These cells appear in a three dimension as thin cups. A process of their formation in this disease is proposed based on a band 3-based mechanism of the erythrocyte shape control, able to explain the erythrocyte echinocytosis by glucose depletion. It indicates that their formation is due to a stomatocytogenic slow outward transport of the dibasic form of endogenous Pi with an H(+) by band 3, promoted by the decrease of the Donnan ratio, which decreases cell pH and volume, attributed by a decrease of cell KCl concentration by the higher efflux of K(+)Cl(-) cotransport and Ca(2+) activation of the Gardos channel. Its implications are briefly discussed with respect to target cells per se, target cell formation in other hemoglobinopathies, acquired and inherited disorders of the lipid metabolism and dehydrated hereditary stomatocytosis as well as a stomatocyte presence in a double heterozygote of Hb S and Hb C and of an involvement of the process of target cell formation in acanthocytosis in acquired and inherited disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Darkside-20k: A 20 ton Liquid Argon Dark Matter Experiment

NASA Astrophysics Data System (ADS)

Back, Henning; Darkside-20k Collaboration

2016-03-01

The Darkside-20k detector is the next step in the Darkside dark matter search program at the Laboratori Nazionali del Gran Sasso in Italy. The Darkside detectors have grown in fiducial mass starting with 10kg in Darkside10, to 50 kg in Darkside50, and finally a proposed 20,000 kg fiducial mass, Darkside20k. The Darkside detectors are dual-phase argon TPCs that combine the very powerful scintillation pulse-shape analysis and ionization information to discriminate against background events. Two unique aspects to the Darkside program is the use of an external neutron veto based on borated liquid scintillator, and the use of low radioactivity argon from underground sources as the target. Argon from the atmosphere has an 39Ar activity of 1Bq/kg, which would be the limiting background, but the underground argon is essentially free of 39Ar. Additionally, the detector is placed in a water Cherenkov muon veto. Combining all these techniques allows Darkside-20k to achieve a background-free 100 t-yr exposure accumulated in a 5 yr run. Darkside-20k is expected to start operations in 2020 with data taking starting in 2021, and will be sensitive to WIMP-nucleon interaction cross sections of 1×10-47 cm2 (1x10-46 cm2) for WIMPs of 1 TeV/c2 (10 TeV/c2) mass.

Cognitive processing load during listening is reduced more by decreasing voice similarity than by increasing spatial separation between target and masker speech.

PubMed

Zekveld, Adriana A; Rudner, Mary; Kramer, Sophia E; Lyzenga, Johannes; Rönnberg, Jerker

2014-01-01

We investigated changes in speech recognition and cognitive processing load due to the masking release attributable to decreasing similarity between target and masker speech. This was achieved by using masker voices with either the same (female) gender as the target speech or different gender (male) and/or by spatially separating the target and masker speech using HRTFs. We assessed the relation between the signal-to-noise ratio required for 50% sentence intelligibility, the pupil response and cognitive abilities. We hypothesized that the pupil response, a measure of cognitive processing load, would be larger for co-located maskers and for same-gender compared to different-gender maskers. We further expected that better cognitive abilities would be associated with better speech perception and larger pupil responses as the allocation of larger capacity may result in more intense mental processing. In line with previous studies, the performance benefit from different-gender compared to same-gender maskers was larger for co-located masker signals. The performance benefit of spatially-separated maskers was larger for same-gender maskers. The pupil response was larger for same-gender than for different-gender maskers, but was not reduced by spatial separation. We observed associations between better perception performance and better working memory, better information updating, and better executive abilities when applying no corrections for multiple comparisons. The pupil response was not associated with cognitive abilities. Thus, although both gender and location differences between target and masker facilitate speech perception, only gender differences lower cognitive processing load. Presenting a more dissimilar masker may facilitate target-masker separation at a later (cognitive) processing stage than increasing the spatial separation between the target and masker. The pupil response provides information about speech perception that complements intelligibility data.

Cognitive processing load during listening is reduced more by decreasing voice similarity than by increasing spatial separation between target and masker speech

PubMed Central

Zekveld, Adriana A.; Rudner, Mary; Kramer, Sophia E.; Lyzenga, Johannes; Rönnberg, Jerker

2014-01-01

We investigated changes in speech recognition and cognitive processing load due to the masking release attributable to decreasing similarity between target and masker speech. This was achieved by using masker voices with either the same (female) gender as the target speech or different gender (male) and/or by spatially separating the target and masker speech using HRTFs. We assessed the relation between the signal-to-noise ratio required for 50% sentence intelligibility, the pupil response and cognitive abilities. We hypothesized that the pupil response, a measure of cognitive processing load, would be larger for co-located maskers and for same-gender compared to different-gender maskers. We further expected that better cognitive abilities would be associated with better speech perception and larger pupil responses as the allocation of larger capacity may result in more intense mental processing. In line with previous studies, the performance benefit from different-gender compared to same-gender maskers was larger for co-located masker signals. The performance benefit of spatially-separated maskers was larger for same-gender maskers. The pupil response was larger for same-gender than for different-gender maskers, but was not reduced by spatial separation. We observed associations between better perception performance and better working memory, better information updating, and better executive abilities when applying no corrections for multiple comparisons. The pupil response was not associated with cognitive abilities. Thus, although both gender and location differences between target and masker facilitate speech perception, only gender differences lower cognitive processing load. Presenting a more dissimilar masker may facilitate target-masker separation at a later (cognitive) processing stage than increasing the spatial separation between the target and masker. The pupil response provides information about speech perception that complements intelligibility data

Target-present guessing as a function of target prevalence and accumulated information in visual search.

PubMed

Peltier, Chad; Becker, Mark W

2017-05-01

Target prevalence influences visual search behavior. At low target prevalence, miss rates are high and false alarms are low, while the opposite is true at high prevalence. Several models of search aim to describe search behavior, one of which has been specifically intended to model search at varying prevalence levels. The multiple decision model (Wolfe & Van Wert, Current Biology, 20(2), 121--124, 2010) posits that all searches that end before the observer detects a target result in a target-absent response. However, researchers have found very high false alarms in high-prevalence searches, suggesting that prevalence rates may be used as a source of information to make "educated guesses" after search termination. Here, we further examine the ability for prevalence level and knowledge gained during visual search to influence guessing rates. We manipulate target prevalence and the amount of information that an observer accumulates about a search display prior to making a response to test if these sources of evidence are used to inform target present guess rates. We find that observers use both information about target prevalence rates and information about the proportion of the array inspected prior to making a response allowing them to make an informed and statistically driven guess about the target's presence.

A new urease-inhibiting formulation decreases ammonia volatilization and improves maize nitrogen utilization in North China Plain

PubMed Central

Li, Qianqian; Cui, Xiaoqing; Liu, Xuejun; Roelcke, Marco; Pasda, Gregor; Zerulla, Wolfram; Wissemeier, Alexander H.; Chen, Xinping; Goulding, Keith; Zhang, Fusuo

2017-01-01

Overuse of urea, low nitrogen (N) utilization, and large N losses are common in maize production in North China Plain (NCP). To solve these problems, we conducted two field experiments at Shangzhuang and Quzhou in NCP to test the ability of a newly developed urease inhibitor product Limus® to decrease NH3 volatilization from urea applied to maize. Grain yield, apparent N recovery efficiency (REN) and N balance when using urea applied with or without Limus were also measured over two maize growing seasons. Cumulative NH3 loss in the two weeks following urea application without Limus ranged from 9–108 kg N ha−1, while Limus addition significantly decreased NH3 loss by a mean of 84%. Urea with Limus did not significantly increase maize yields (P < 0.05) compared with urea alone. However, a significant 11–17% improvement in REN with Limus was observed at QZ. The use of urea-N plus Limus would permit a reduction in N applications of 55–60% compared to farmers’ practice and/or further 20% N saving compared with optimized urea-N rate (150 kg N ha−1, based on N requirement by target yield of 7.5 t ha−1), and would achieve the same maize yields but with significantly decreased NH3 loss and increased N utilization. PMID:28272451

A new urease-inhibiting formulation decreases ammonia volatilization and improves maize nitrogen utilization in North China Plain

NASA Astrophysics Data System (ADS)

Li, Qianqian; Cui, Xiaoqing; Liu, Xuejun; Roelcke, Marco; Pasda, Gregor; Zerulla, Wolfram; Wissemeier, Alexander H.; Chen, Xinping; Goulding, Keith; Zhang, Fusuo

2017-03-01

Overuse of urea, low nitrogen (N) utilization, and large N losses are common in maize production in North China Plain (NCP). To solve these problems, we conducted two field experiments at Shangzhuang and Quzhou in NCP to test the ability of a newly developed urease inhibitor product Limus® to decrease NH3 volatilization from urea applied to maize. Grain yield, apparent N recovery efficiency (REN) and N balance when using urea applied with or without Limus were also measured over two maize growing seasons. Cumulative NH3 loss in the two weeks following urea application without Limus ranged from 9-108 kg N ha-1, while Limus addition significantly decreased NH3 loss by a mean of 84%. Urea with Limus did not significantly increase maize yields (P < 0.05) compared with urea alone. However, a significant 11-17% improvement in REN with Limus was observed at QZ. The use of urea-N plus Limus would permit a reduction in N applications of 55-60% compared to farmers’ practice and/or further 20% N saving compared with optimized urea-N rate (150 kg N ha-1, based on N requirement by target yield of 7.5 t ha-1), and would achieve the same maize yields but with significantly decreased NH3 loss and increased N utilization.

TargetLink, a new method for identifying the endogenous target set of a specific microRNA in intact living cells.

PubMed

Xu, Yan; Chen, Yan; Li, Daliang; Liu, Qing; Xuan, Zhenyu; Li, Wen-Hong

2017-02-01

MicroRNAs are small non-coding RNAs acting as posttranscriptional repressors of gene expression. Identifying mRNA targets of a given miRNA remains an outstanding challenge in the field. We have developed a new experimental approach, TargetLink, that applied locked nucleic acid (LNA) as the affinity probe to enrich target genes of a specific microRNA in intact cells. TargetLink also consists a rigorous and systematic data analysis pipeline to identify target genes by comparing LNA-enriched sequences between experimental and control samples. Using miR-21 as a test microRNA, we identified 12 target genes of miR-21 in a human colorectal cancer cell by this approach. The majority of the identified targets interacted with miR-21 via imperfect seed pairing. Target validation confirmed that miR-21 repressed the expression of the identified targets. The cellular abundance of the identified miR-21 target transcripts varied over a wide range, with some targets expressed at a rather low level, confirming that both abundant and rare transcripts are susceptible to regulation by microRNAs, and that TargetLink is an efficient approach for identifying the target set of a specific microRNA in intact cells. C20orf111, one of the novel targets identified by TargetLink, was found to reside in the nuclear speckle and to be reliably repressed by miR-21 through the interaction at its coding sequence.

Feeling powerless: Locus of control as a potential target for supportive care interventions to increase quality of life and decrease anxiety in ovarian cancer patients.

PubMed

Brown, Alaina J; Sun, Charlotte C; Urbauer, Diana L; Bodurka, Diane C; Thaker, Premal H; Ramondetta, Lois M

2015-08-01

To evaluate if an individual's locus of control (LOC) predicts various quality of life (QOL) and mental well-being measures. To identify targets that might enhance the overall spiritual well-being and QOL of ovarian cancer patients. Multi-site analysis of women with newly diagnosed stages II-IV ovarian, primary peritoneal or fallopian tube cancer. Patients completed the following surveys: Locus of Control Scale (LOC), Functional Assessment of Chronic Illness Therapy-Ovarian (FACT-O), Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp), Edmonton Symptom Assessment score (ESAS), Hospital Anxiety Depression Scale (HADS), Templer's Death Anxiety Scale (DAS), and Herth Hope Index (HHI). Regression models were created to examine the effect of LOC upon QOL, symptoms, and other measures of mental well-being. These models adjusted for the effect of site of care, race, and partnership status as potential confounders. This study enrolled 104 patients from three separate treatment facilities. After adjusting for site, race and partnership status, higher levels of external LOC predicted decreased QOL (FACT-O) (p<0.05). Higher levels of external LOC also correlated with increased death anxiety and general anxiety (p≤0.05). Additionally, higher levels of external LOC predicted decreased hope (HHI) (p≤0.01). Ovarian cancer patients with a high external LOC may be at risk for decreased QOL at the time of their cancer diagnosis. They may also experience higher levels of anxiety and decreased feelings of hope. Identification of these women and interventions designed to increase a woman's sense of control over her situation may improve QOL and overall mental well-being. Copyright © 2015. Published by Elsevier Inc.

Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

NASA Astrophysics Data System (ADS)

Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

1982-02-01

The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies.

PubMed

Dai, Chun-ling; Chen, Xia; Kazim, Syed Faraz; Liu, Fei; Gong, Cheng-Xin; Grundke-Iqbal, Inge; Iqbal, Khalid

2015-04-01

Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aβ accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aβ pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aβ pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

A cryogenic target for Compton scattering experiments at HIγS

DOE PAGES

Kendellen, D. P.; Ahmed, M. W.; Baird, E.; ...

2016-10-06

We have developed a cryogenic target for use at the High Intensity γ-ray Source (HIγS). The target system is able to liquefy 4He at 4 K, hydrogen at 20 K, and deuterium at 23 K to fill a 0.3 L Kapton cell. Liquid temperatures and condenser pressures are recorded throughout each run in order to ensure that the target's areal density is known to ~1%. The target is being utilized in a series of experiments which probe the electromagnetic polarizabilities of the nucleon.

The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals.

PubMed

Su, Y C; Maurel-Zaffran, C; Treisman, J E; Skolnik, E Y

2000-07-01

We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct

The Ste20 Kinase Misshapen Regulates Both Photoreceptor Axon Targeting and Dorsal Closure, Acting Downstream of Distinct Signals

PubMed Central

Su, Yi-Chi; Maurel-Zaffran, Corinne; Treisman, Jessica E.; Skolnik, Edward Y.

2000-01-01

We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct

Target-responsive aptamer release from manganese dioxide nanosheets for electrochemical sensing of cocaine with target recycling amplification.

PubMed

Chen, Zongbao; Lu, Minghua

2016-11-01

A novel electrochemical sensing platform based on manganese dioxide (MnO2) nanosheets was developed for sensitive screening of target cocaine with the signal amplification. Ferrocene-labeled cocaine aptamers were initially immobilized onto MnO2 nanosheets-modified screen-printed carbon electrode because of π-stacking interaction between nucleobases and nanosheets. The immobilized ferrocene-aptamer activated the electrical contact with the electrode, thereby resulting in the sensor circuit to switch on. Upon target cocaine introduction, the analyte reacted with the aptamer and caused the dissociation of ferrocene-aptamer from the electrode, thus giving rise to the detection circuit to switch off. The released aptamer was cleaved by DNase I with target recycling. Under optimal conditions, the decreasing percentage of the electronic signal relative to background current increased with the increasing cocaine concentration in the dynamic range of 0.1-20nM, and the detection limit was 32pM. The reproducibility, selectivity and method accuracy were acceptable. Importantly, this concept offers promise for rapid, simple, and cost-effective analysis of cocaine biological samples without the needs of sample separation and multiple washing steps. Copyright © 2016 Elsevier B.V. All rights reserved.

Attentional Control via Parallel Target-Templates in Dual-Target Search

PubMed Central

Barrett, Doug J. K.; Zobay, Oliver

2014-01-01

Simultaneous search for two targets has been shown to be slower and less accurate than independent searches for the same two targets. Recent research suggests this ‘dual-target cost’ may be attributable to a limit in the number of target-templates than can guide search at any one time. The current study investigated this possibility by comparing behavioural responses during single- and dual-target searches for targets defined by their orientation. The results revealed an increase in reaction times for dual- compared to single-target searches that was largely independent of the number of items in the display. Response accuracy also decreased on dual- compared to single-target searches: dual-target accuracy was higher than predicted by a model restricting search guidance to a single target-template and lower than predicted by a model simulating two independent single-target searches. These results are consistent with a parallel model of dual-target search in which attentional control is exerted by more than one target-template at a time. The requirement to maintain two target-templates simultaneously, however, appears to impose a reduction in the specificity of the memory representation that guides search for each target. PMID:24489793

Decreased natural killer cell activity in atopic eczema.

PubMed Central

Hall, T J; Rycroft, R; Brostoff, J

1985-01-01

We have studied NK cell activity in atopic and non-atopic subjects using a standard 51Cr-release assay and K562 target cells. In atopics (AT) with allergic rhinitis and/or asthma, NK cell activity was similar to that in non-atopic (N) subjects, whilst patients with severe atopic eczema (AE) had depressed NK cell activity compared to AT or N subjects. In addition, circulating T-cell numbers and Con A responsiveness was decreased in AE, although neither parameter was correlated with decreased NK cell activity. However, decreased NK cell activity in atopic eczema was positively correlated with decreased numbers of Fc gamma + lymphocytes (P = 0.01) and decreased effector: target cell binding (P = 0.05), and negatively correlated with increased monocytes in AE (P = 0.09). AE NK cell activity was equally or more sensitive to the inhibitory effects of drugs such as dibutyryl cyclic AMP, prostaglandins (PG) D2,E2 and histamine. The relative percentage increase in NK cell activity by the interferon inducer poly I:C was similar in AE patients and controls. The results suggest that reduced numbers of circulating NK cells and pre-NK cells account for the depressed level of NK cell activity in subjects with severe atopic eczema. PMID:3876984

MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad4.

PubMed

Cheng, Dantong; Zhao, Senlin; Tang, Huamei; Zhang, Dongyuan; Sun, Hongcheng; Yu, Fudong; Jiang, Weiliang; Yue, Ben; Wang, Jingtao; Zhang, Meng; Yu, Yang; Liu, Xisheng; Sun, Xiaofeng; Zhou, Zongguang; Qin, Xuebin; Zhang, Xin; Yan, Dongwang; Wen, Yugang; Peng, Zhihai

2016-07-19

Tumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. Loss of Smad4 contributes to aggression process in many human cancers. However, the underlying precise mechanism of aberrant Smad4 expression in CRC development is still little known. miR-20a-5p negatively regulated Smad4 by directly targeting its 3'UTR in human colorectal cancer cells. miR-20a-5p not only promoted CRC cells aggression capacity in vitro and liver metastasis in vivo, but also promoted the epithelial-to-mesenchymal transition process by downregulating Smad4 expression. In addition, tissue microarray analysis obtained from 544 CRC patients' clinical characters showed that miR-20a-5p was upregulated in human CRC tissues, especially in the tissues with metastasis. High level of miR-20a-5p predicted poor prognosis in CRC patients. Five miRNA target prediction programs were applied to identify potential miRNA(s) that target(s) Smad4 in CRC. Luciferase reporter assay and transfection technique were used to validate the correlation between miR-20a-5p and Smad4 in CRC. Wound healing, transwell and tumorigenesis assays were used to explore the function of miR-20a-5p and Smad4 in CRC progression in vitro and in vivo. The association between miR-20a-5p expression and the prognosis of CRC patients was evaluated by Kaplan-Meier analysis and multivariate cox proportional hazard analyses based on tissue microarray data. miR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in CRC cells, and high miR-20a-5p predicted poor prognosis for CRC patients, providing a novel and promising therapeutic target in human colorectal cancer.

Structure, mechanical and tribological properties of TiSiC films deposited by magnetron sputtering segment target

NASA Astrophysics Data System (ADS)

Jiang, Jinlong; He, Kaichen; He, XingXing; Huang, Hao; Pang, Xianjuan; Wei, Zhiqiang

2017-12-01

In this work, the TiSiC films were deposited by magnetron sputtering segment target with various areal ratio of Ti80Si20 to C. The effects of segment target component on the structure, mechanical and tribological properties of the films were investigated. The results revealed that the deposited films exhibited a structural transform from a cubic TiC structure to a nanocomposite structure with nanocrystalline TiC in a-C:Si matrix, and finally x-ray amorphous structures with decreasing areal ratio of Ti80Si20 to C. The TiSiC film deposited at the Ti80Si20:C areal ratio of 7:7 showed superior mechanical and tribological properties such as high hardness (18.6 Gpa), good scratch resistant (46 N), low friction coefficient (0.2) and low wear rate (8.6  ×  10-7 mm3 Nm-1), which suggests that it is a promising candidate for the protective films.

Interleukin-20 targets podocytes and is upregulated in experimental murine diabetic nephropathy.

PubMed

Hsu, Yu-Hsiang; Li, Hsing-Hui; Sung, Junne-Ming; Chen, Wei-Yu; Hou, Ya-Chin; Weng, Yun-Han; Lai, Wei-Ting; Wu, Chih-Hsing; Chang, Ming-Shi

2017-03-31

Interleukin (IL)-20, a proinflammatory cytokine of the IL-10 family, is involved in acute and chronic renal failure. The aim of this study was to elucidate the role of IL-20 during diabetic nephropathy development. We found that IL-20 and its receptor IL-20R1 were upregulated in the kidneys of mice and rats with STZ-induced diabetes. In vitro, IL-20 induced MMP-9, MCP-1, TGF-β1 and VEGF expression in podocytes. IL-20 was upregulated by hydrogen peroxide, high-dose glucose and TGF-β1. In addition, IL-20 induced apoptosis in podocytes by activating caspase-8. In STZ-induced early diabetic nephropathy, IL-20R1-deficient mice had lower blood glucose and serum BUN levels and a smaller glomerular area than did wild-type controls. Anti-IL-20 monoclonal antibody (7E) treatment reduced blood glucose and the glomerular area and improved renal functions in mice in the early stage of STZ-induced diabetic nephropathy. ELISA showed that the serum IL-20 level was higher in patients with diabetes mellitus than in healthy controls. The findings of this study suggest that IL-20 induces cell apoptosis of podocytes and plays a role in the pathogenesis of early diabetic nephropathy.

The transcription factor DREAM represses A20 and mediates inflammation

PubMed Central

Tiruppathi, Chinnaswamy; Soni, Dheeraj; Wang, Dong-Mei; Xue, Jiaping; Singh, Vandana; Thippegowda, Prabhakar B.; Cheppudira, Bopaiah P.; Mishra, Rakesh K.; DebRoy, Auditi; Qian, Zhijian; Bachmaier, Kurt; Zhao, Youyang; Christman, John W.; Vogel, Stephen M.; Ma, Averil; Malik, Asrar B.

2014-01-01

Here we show that the transcription-repressor DREAM binds to the A20 promoter to repress the expression of A20, the deubiquitinase suppressing inflammatory NF-κB signaling. DREAM-deficient (Dream−/−) mice displayed persistent and unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, USF1 binding to the DRE-associated E-box domain activated A20 expression in response to inflammatory stimuli. These studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-κB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy in diseases such as acute lung injury associated with unconstrained NF-κB activity. PMID:24487321

Electric Vehicle Technologies and Targets | Transportation Research | NREL

Science.gov Websites

. Table showing 2022 targets for decreases in battery cost ($125/kWh) and increases in battery capacity exchanger. Table showing 2022 targets for decreases in power electronics cost ($8/kW, $440 system cost) and , high performing, and long lasting. DOE has targeted a 75% reduction in battery cost and a 75% increase

Common pitfalls in preclinical cancer target validation.

PubMed

Kaelin, William G

2017-07-01

An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.

Measurement of thick target neutron yield from the reaction (p+181 Ta) with projectiles in the range of 6-20 MeV

NASA Astrophysics Data System (ADS)

Paul, Sabyasachi; Sahoo, G. S.; Tripathy, S. P.; Sharma, S. C.; Joshi, D. S.; Bandyopadhyay, T.

2018-02-01

181Ta is a commonly used backing material for many targets in nuclear reaction studies. When the target thickness is less than the range of bombarded projectiles, the interaction via Ta(p,n) reactions in the backing can be a significant source of background. In this study, the neutron spectral yields from the reaction of protons of different energies (between 6 to 20 MeV) with a thick Ta target were determined using CR-39 detectors. The results from this study can be used as a correction factor in such situations. The parameters of registered tracks in CR-39 were analysed using an in-house image analysing program autoTRAK_n and then to derive the associated dose values. The spectral yields obtained experimentally were compared with those obtained from the theoretical calculations. The neutron yield was found to increase with increase in projectile energy mainly due to the opening of reaction channels from (p, n) to (p, 3n).

CpG oligodeoxynucleotide induces apoptosis and cell cycle arrest in A20 lymphoma cells via TLR9-mediated pathways.

PubMed

Qi, Xu-Feng; Zheng, Li; Kim, Cheol-Su; Lee, Kyu-Jae; Kim, Dong-Heui; Cai, Dong-Qing; Qin, Jun-Wen; Yu, Yan-Hong; Wu, Zheng; Kim, Soo-Ki

2013-07-01

Recent studies have suggested that the anti-cancer activity of CpG-oligodeoxynucleotides (CpG-ODNs) is owing to their immunomodulatory effects in tumor-bearing host. The purpose of this study is to investigate the directly cytotoxic activity of KSK-CpG, a novel CpG-ODN with an alternative CpG motif, against A20 and EL4 lymphoma cells in comparison with previously used murine CpG motif (1826-CpG). To evaluate the potential cytotoxic effects of KSK-CpG on lymphoma cells, cell viability assay, confocal microscopy, flow cytometry, DNA fragmentation, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used. We found that KSK-CpG induced direct cytotoxicity in A20 lymphoma cells, but not in EL4 lymphoma cells, at least in part via TLR9-mediated pathways. Apoptotic cell death was demonstrated to play an important role in CpG-ODNs-induced cytotoxicity. In addition, both mitochondrial membrane potential decrease and G1-phase arrest were involved in KSK-CpG-induced apoptosis in A20 cells. The activities of apoptotic molecules such as caspase-3, PARP, and Bax were increased, but the activation of p27 Kip1 and ERK were decreased in KSK-CpG-treated A20 cells. Furthermore, autocrine IFN-γ partially contributed to apoptotic cell death in KSK-CpG-treated A20 cells. Collectively, our findings suggest that KSK-CpG induces apoptotic cell death in A20 lymphoma cells at least in part by inducing G1-phase arrest and autocrine IFN-γ via increasing TLR9 expression, without the need for immune system of tumor-bearing host. This new understanding supports the development of TLR9-targeted therapy with CpG-ODN as a direct therapeutic agent for treating B lymphoma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Observed decrease in atmospheric mercury explained by global decline in anthropogenic emissions.

PubMed

Zhang, Yanxu; Jacob, Daniel J; Horowitz, Hannah M; Chen, Long; Amos, Helen M; Krabbenhoft, David P; Slemr, Franz; St Louis, Vincent L; Sunderland, Elsie M

2016-01-19

Observations of elemental mercury (Hg(0)) at sites in North America and Europe show large decreases (∼ 1-2% y(-1)) from 1990 to present. Observations in background northern hemisphere air, including Mauna Loa Observatory (Hawaii) and CARIBIC (Civil Aircraft for the Regular Investigation of the atmosphere Based on an Instrument Container) aircraft flights, show weaker decreases (<1% y(-1)). These decreases are inconsistent with current global emission inventories indicating flat or increasing emissions over that period. However, the inventories have three major flaws: (i) they do not account for the decline in atmospheric release of Hg from commercial products; (ii) they are biased in their estimate of artisanal and small-scale gold mining emissions; and (iii) they do not properly account for the change in Hg(0)/Hg(II) speciation of emissions from coal-fired utilities after implementation of emission controls targeted at SO2 and NOx. We construct an improved global emission inventory for the period 1990 to 2010 accounting for the above factors and find a 20% decrease in total Hg emissions and a 30% decrease in anthropogenic Hg(0) emissions, with much larger decreases in North America and Europe offsetting the effect of increasing emissions in Asia. Implementation of our inventory in a global 3D atmospheric Hg simulation [GEOS-Chem (Goddard Earth Observing System-Chemistry)] coupled to land and ocean reservoirs reproduces the observed large-scale trends in atmospheric Hg(0) concentrations and in Hg(II) wet deposition. The large trends observed in North America and Europe reflect the phase-out of Hg from commercial products as well as the cobenefit from SO2 and NOx emission controls on coal-fired utilities.

MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad4

PubMed Central

Zhang, Dongyuan; Sun, Hongcheng; Yu, Fudong; Yue, Ben; Wang, Jingtao; Zhang, Meng; Yu, Yang; Liu, Xisheng; Sun, Xiaofeng; Zhou, Zongguang; Qin, Xuebin; Zhang, Xin; Yan, Dongwang; Wen, Yugang; Peng, Zhihai

2016-01-01

Background Tumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. Loss of Smad4 contributes to aggression process in many human cancers. However, the underlying precise mechanism of aberrant Smad4 expression in CRC development is still little known. Results miR-20a-5p negatively regulated Smad4 by directly targeting its 3′UTR in human colorectal cancer cells. miR-20a-5p not only promoted CRC cells aggression capacity in vitro and liver metastasis in vivo, but also promoted the epithelial-to-mesenchymal transition process by downregulating Smad4 expression. In addition, tissue microarray analysis obtained from 544 CRC patients’ clinical characters showed that miR-20a-5p was upregulated in human CRC tissues, especially in the tissues with metastasis. High level of miR-20a-5p predicted poor prognosis in CRC patients. Methods Five miRNA target prediction programs were applied to identify potential miRNA(s) that target(s) Smad4 in CRC. Luciferase reporter assay and transfection technique were used to validate the correlation between miR-20a-5p and Smad4 in CRC. Wound healing, transwell and tumorigenesis assays were used to explore the function of miR-20a-5p and Smad4 in CRC progression in vitro and in vivo. The association between miR-20a-5p expression and the prognosis of CRC patients was evaluated by Kaplan–Meier analysis and multivariate cox proportional hazard analyses based on tissue microarray data. Conclusions miR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in CRC cells, and high miR-20a-5p predicted poor prognosis for CRC patients, providing a novel and promising therapeutic target in human colorectal cancer. PMID:27286257

Does precision decrease with set size?

PubMed Central

Mazyar, Helga; van den Berg, Ronald; Ma, Wei Ji

2012-01-01

The brain encodes visual information with limited precision. Contradictory evidence exists as to whether the precision with which an item is encoded depends on the number of stimuli in a display (set size). Some studies have found evidence that precision decreases with set size, but others have reported constant precision. These groups of studies differed in two ways. The studies that reported a decrease used displays with heterogeneous stimuli and tasks with a short-term memory component, while the ones that reported constancy used homogeneous stimuli and tasks that did not require short-term memory. To disentangle the effects of heterogeneity and short-memory involvement, we conducted two main experiments. In Experiment 1, stimuli were heterogeneous, and we compared a condition in which target identity was revealed before the stimulus display with one in which it was revealed afterward. In Experiment 2, target identity was fixed, and we compared heterogeneous and homogeneous distractor conditions. In both experiments, we compared an optimal-observer model in which precision is constant with set size with one in which it depends on set size. We found that precision decreases with set size when the distractors are heterogeneous, regardless of whether short-term memory is involved, but not when it is homogeneous. This suggests that heterogeneity, not short-term memory, is the critical factor. In addition, we found that precision exhibits variability across items and trials, which may partly be caused by attentional fluctuations. PMID:22685337

Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy.

PubMed

Skarzynski, Martin; Niemann, Carsten U; Lee, Yuh Shan; Martyr, Sabrina; Maric, Irina; Salem, Dalia; Stetler-Stevenson, Maryalice; Marti, Gerald E; Calvo, Katherine R; Yuan, Constance; Valdez, Janet; Soto, Susan; Farooqui, Mohammed Z H; Herman, Sarah E M; Wiestner, Adrian

2016-01-01

Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAb) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in preclinical studies, in vitro ibrutinib was reported to decrease CD20 expression and inhibit cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox. Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs. We demonstrate that CD20 expression on ibrutinib was rapidly and persistently downregulated (median reduction 74%, day 28, P < 0.001) compared with baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and downregulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pretreatment cells (median reduction 75%, P < 0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay-accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. In addition, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal antitumor effects of such combinations requires further investigation. ©2015 American Association for Cancer Research.

Interactions between ibrutinib and anti-CD20 antibodies; competing effects on the outcome of combination therapy

PubMed Central

Skarzynski, Martin; Niemann, Carsten U; Lee, Yuh Shan; Martyr, Sabrina; Maric, Irina; Salem, Dalia; Stetler-Stevenson, Maryalice; Marti, Gerald E; Calvo, Katherine R; Yuan, Constance; Valdez, Janet; Soto, Susan; Farooqui, Mohammed Z.H.; Herman, Sarah E.M.; Wiestner, Adrian

2015-01-01

Purpose Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAbs) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in pre-clinical studies in vitro ibrutinib was reported to decrease CD20 expression and inhibits cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox. Experimental Design Patients received single agent ibrutinib (420mg daily) on an investigator-initiated phase 2 trial. Serial blood samples were collected pre-treatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs. Results We demonstrate that CD20 expression on ibrutinib was rapidly and persistently down-regulated (median reduction 74%, day 28, P<0.001) compared to baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and down-regulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pre-treatment cells (median reduction 75%, P<0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. Additionally, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. Conclusions Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal anti-tumor effects of such combinations requires further investigation. PMID:26283682

Dietary β-conglycinin prevents fatty liver induced by a high-fat diet by a decrease in peroxisome proliferator-activated receptor γ2 protein.

PubMed

Yamazaki, Tomomi; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

2012-02-01

Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). Mice fed a high-fat diet, especially that of saturated-fat-rich oil, develop fatty liver with an increase in peroxisome proliferator-activated receptor (PPAR) γ2 protein in liver. The fatty liver induced by a high-fat diet is improved by knockdown of liver PPARγ2. In this study, we investigated whether β-conglycinin (a major protein of soy protein) could reduce PPARγ2 protein and prevent high-fat-diet-induced fatty liver in ddY mice. Mice were fed a high-starch diet (70 energy% [en%] starch) plus 20% (wt/wt) sucrose in their drinking water or a high-safflower-oil diet (60 en%) or a high-butter diet (60 en%) for 11 weeks, by which fatty liver is developed. As a control, mice were fed a high-starch diet with drinking water. Either β-conglycinin or casein (control) was given as dietary protein. β-Conglycinin supplementation completely prevented fatty liver induced by each type of diet, along with a reduction in adipose tissue weight. β-Conglycinin decreased sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP) messenger RNAs (mRNAs) in sucrose-supplemented mice, whereas it decreased PPARγ2 mRNA (and its target genes CD36 and FSP27), but did not decrease SREBP-1c and ChREBP mRNAs, in mice fed a high-fat diet. β-Conglycinin decreased PPARγ2 protein and liver triglyceride (TG) concentration in a dose-dependent manner in mice fed a high-butter diet; a significant decrease in liver TG concentration was observed at a concentration of 15 en%. In conclusion, β-conglycinin effectively prevents fatty liver induced by a high-fat diet through a decrease in liver PPARγ2 protein. Copyright © 2012 Elsevier Inc. All rights reserved.

Exogenous spatial attention decreases audiovisual integration.

PubMed

Van der Stoep, N; Van der Stigchel, S; Nijboer, T C W

2015-02-01

Multisensory integration (MSI) and spatial attention are both mechanisms through which the processing of sensory information can be facilitated. Studies on the interaction between spatial attention and MSI have mainly focused on the interaction between endogenous spatial attention and MSI. Most of these studies have shown that endogenously attending a multisensory target enhances MSI. It is currently unclear, however, whether and how exogenous spatial attention and MSI interact. In the current study, we investigated the interaction between these two important bottom-up processes in two experiments. In Experiment 1 the target location was task-relevant, and in Experiment 2 the target location was task-irrelevant. Valid or invalid exogenous auditory cues were presented before the onset of unimodal auditory, unimodal visual, and audiovisual targets. We observed reliable cueing effects and multisensory response enhancement in both experiments. To examine whether audiovisual integration was influenced by exogenous spatial attention, the amount of race model violation was compared between exogenously attended and unattended targets. In both Experiment 1 and Experiment 2, a decrease in MSI was observed when audiovisual targets were exogenously attended, compared to when they were not. The interaction between exogenous attention and MSI was less pronounced in Experiment 2. Therefore, our results indicate that exogenous attention diminishes MSI when spatial orienting is relevant. The results are discussed in terms of models of multisensory integration and attention.

MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1–regulated pathways in mice

PubMed Central

Meenhuis, Annemarie; van Veelen, Peter A.; de Looper, Hans; van Boxtel, Nicole; van den Berge, Iris J.; Sun, Su M.; Taskesen, Erdogan; Stern, Patrick; de Ru, Arnoud H.; van Adrichem, Arjan J.; Demmers, Jeroen; Jongen-Lavrencic, Mojca; Löwenberg, Bob; Touw, Ivo P.; Sharp, Phillip A.

2011-01-01

MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expression in hematopoietic progenitors in vitro and in mice. Further, SQSTM1 binds to the ligand-activated colony-stimulating factor 3 receptor (CSF3R) mainly in the late endosomal compartment, but not in LC3 positive autophagosomes. SQSTM1 regulates CSF3R stability and ligand-induced mitogen-activated protein kinase signaling. We demonstrate that AAAGUGC seed-containing miRNAs promote cell expansion, replating capacity and signaling in hematopoietic cells by interference with SQSTM1-regulated pathways. PMID:21628417

Age Targeting of Voluntary Medical Male Circumcision Programs Using the Decision Makers' Program Planning Toolkit (DMPPT) 2.0.

PubMed

Kripke, Katharine; Opuni, Marjorie; Schnure, Melissa; Sgaier, Sema; Castor, Delivette; Reed, Jason; Njeuhmeli, Emmanuel; Stover, John

2016-01-01

Despite considerable efforts to scale up voluntary medical male circumcision (VMMC) for HIV prevention in priority countries over the last five years, implementation has faced important challenges. Seeking to enhance the effect of VMMC programs for greatest and most immediate impact, the U. S. President's Plan for AIDS Relief (PEPFAR) supported the development and application of a model to inform national planning in five countries from 2013-2014. The Decision Makers' Program Planning Toolkit (DMPPT) 2.0 is a simple compartmental model designed to analyze the effects of client age and geography on program impact and cost. The DMPPT 2.0 model was applied in Malawi, South Africa, Swaziland, Tanzania, and Uganda to assess the impact and cost of scaling up age-targeted VMMC coverage. The lowest number of VMMCs per HIV infection averted would be produced by circumcising males ages 20-34 in Malawi, South Africa, Tanzania, and Uganda and males ages 15-34 in Swaziland. The most immediate impact on HIV incidence would be generated by circumcising males ages 20-34 in Malawi, South Africa, Tanzania, and Uganda and males ages 20-29 in Swaziland. The greatest reductions in HIV incidence over a 15-year period would be achieved by strategies focused on males ages 10-19 in Uganda, 15-24 in Malawi and South Africa, 10-24 in Tanzania, and 15-29 in Swaziland. In all countries, the lowest cost per HIV infection averted would be achieved by circumcising males ages 15-34, although in Uganda this cost is the same as that attained by circumcising 15- to 49-year-olds. The efficiency, immediacy of impact, magnitude of impact, and cost-effectiveness of VMMC scale-up are not uniform; there is important variation by age group of the males circumcised and countries should plan accordingly.

Anomalies in target-controlled infusion: an analysis after 20 years of clinical use.

PubMed

Engbers, F H M; Dahan, A

2018-05-01

Although target-controlled infusion has been in use for more than two decades, its benefits are being obscured by anomalies in clinical practice caused by a number of important problems. These include: a variety of pharmacokinetic models available in open target-controlled infusion systems, which often confuse the user; the extrapolation of anthropomorphic data which provokes anomalous adjustments of dosing by such systems; and the uncertainty of regulatory requirements for the application of target-controlled infusion which causes uncontrolled exploitation of drugs and pharmacokinetic models in target-controlled infusion devices. Comparison of performance of pharmacokinetic models is complex and mostly inconclusive. However, a specific behaviour of a model in a target-controlled infusion system that is neither intended nor supported by scientific data can be considered an artefact or anomaly. Several of these anomalies can be identified in the current commercially available target-controlled infusion systems and are discussed in this review. © 2018 The Association of Anaesthetists of Great Britain and Ireland.

Strain-specific detection of orally administered canine jejunum-dominated Lactobacillus acidophilus LAB20 in dog faeces by real-time PCR targeted to the novel surface layer protein.

PubMed

Tang, Y; Saris, P E J

2013-10-01

Lactobacillus acidophilus LAB20 has potential to be a probiotic strain because it can be present at high numbers in the jejunum of dog. To specifically detect LAB20 from dog faecal samples, a real-time PCR protocol was developed targeting the novel surface (S) layer protein gene of LAB20. The presence of S-layer protein was verified by N-terminal sequencing of the approximately 50-kDa major band from SDS-PAGE gel. The corresponding S-layer gene was amplified by inverse PCR using homology to known S-layers and sequenced. This novel S-layer protein has low sequence similarity to other S-layer proteins in the N-terminal region (32-211 aa, 7-39%). This enabled designing strain-specific PCR primers. The primer set was utilized to study intestinal persistence of LAB20 in dog that was fed with LAB20 fermented milk for 5 days. The results showed that LAB20 can be detected from dog faecal sample after 6 weeks with 10(4·53)  DNA copies g(-1) postadministration. It suggested that LAB20 could be a good candidate to study the mechanism behind its persistence and dominance in dog intestine and maybe utilize it as a probiotic for canine. A real-time PCR method was developed to detect Lactobacillus acidophilus LAB20, a strain that was previously found dominant in canine gastrointestinal (GI) tract. The quantitative detection was based on targeting to variation region of a novel S-layer protein found in LAB20, allowing to specifically enumerate LAB20 from dog faeces. The results showed that the real-time PCR method was sensitive enough to be used in later intervention studies. Interestingly, LAB20 was found to persist in dog GI tract for 6 weeks. Therefore, LAB20 could be a good candidate to study its colonization and potentially utilize as a canine probiotic. © 2013 The Society for Applied Microbiology.

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2012-11-01

DATES COVERED 4 October 2011- 3 October 2012 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a...interventions aimed at modulation of the endocannabinoid (EC) system targeting degradation of 20arachidonoyl glycerlol (2- AG) and N-arachidonoyl...percussion, traumatic brain injury, blood brain barrier, neuroinflammination, neurological dysfunction, endocannabinoids . 16. SECURITY CLASSIFICATION

In vitro modulation of inflammatory target gene expression by a polyphenol-enriched fraction of rose oil distillation waste water.

PubMed

Wedler, Jonas; Weston, Anna; Rausenberger, Julia; Butterweck, Veronika

2016-10-01

Classical production of rose oil is based on water steam distillation from the flowers of Rosa damascena. During this process, large quantities of waste water accrue which are discharged to the environment, causing severe pollution of both, groundwater and surface water due to a high content of polyphenols. We recently developed a strategy to purify the waste water into a polyphenol-depleted and a polyphenol-enriched fraction RF20-(SP-207). RF20-(SP-207) and sub-fraction F(IV) significantly inhibited cell proliferation and migration of HaCaT cells. Since there is a close interplay between these actions and inflammatory processes, here we focused on the fractions' influence on pro-inflammatory biomarkers. HaCaT keratinocytes were treated with RF20-(SP-207), F(IV) (both at 50μg/mL) and ellagic acid (10μM) for 24h under TNF-α (20ng/mL) stimulated and non-stimulated conditions. Gene expression of IL-1β, IL-6, IL-8, RANTES and MCP-1 was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and cellular protein secretion of IL-8, RANTES and MCP-1 was determined by ELISA based assays. RF20-(SP-207) and F(IV) significantly decreased the expression and cellular protein secretion of IL-1β, IL-6, IL-8, RANTES and MCP-1. The diminishing effects on inflammatory target gene expression were slightly less pronounced under TNF-α stimulated conditions. In conclusion, the recovered polyphenol fraction RF20-(SP-207) from rose oil distillation waste water markedly modified inflammatory target gene expression in vitro, and, therefore, could be further developed as alternative treatment of acute and chronic inflammation. Copyright © 2016 Elsevier B.V. All rights reserved.

Extracorporeal adsorption therapy: A Method to improve targeted radiation delivered by radiometal-labeled monoclonal antibodies.

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

Nemecek, Eneida R.; Green, Damian J.; Fisher, Darrell R.

2008-04-01

Many investigators have demonstrated the ability to treat hematologic malignancies with radiolabeled monoclonal antibodies targeting hematopoietic antigens such as anti-CD20 and anti-CD45. [1-5] Although the remission rates achieved with radioimmunotherapy (RIT) are relatively high, many patients subsequently relapse presumably due to suboptimal delivery of enough radiation to eradicate the malignancy. The dose-response of leukemia and lymphoma to radiation has been proven. Substantial amounts of radiation can be delivered by RIT if followed by hematopoietic cell transplantation to rescue the bone marrow from myeloablation.[ref] However, the maximum dose of RIT that can be used is still limited by toxicity to normalmore » tissues affected by nonspecific delivery of radiation. Efforts to improve RIT focus on improving the therapeutic ratios of radiation in target versus non-target tissues by removing the fraction of radioisotope that fails to bind to target tissues and circulates freely in the bloodstream perfusing non-target tissues. Our group and others have explored several alternatives for removal of unbound circulating antibody. [refs] One such method, extracorporeal adsorption therapy (ECAT) consists of removing unbound antibody by a method similar to plasmapheresis after critical circulation time and distribution of antibody into target tissues have been achieved. Preclinical studies of ECAT in murine xenograft models demonstrated significant improvement in therapeutic ratios of radioactivity. Chen and colleagues demonstrated that a 2-hour ECAT procedure could remove 40 to 70% of the radioactivity from liver, lung and spleen. [ref] Although isotope concentration in the tumor was initially unaffected, a 50% decrease was noted approximately 36 hours after the procedure. This approach was also evaluated in a limited phase I pilot study of patients with refractory B-cell lymphoma. [ref] After radiographic confirmation of tumor localization of a test dose of

Studies of uranium carbide targets of a high density

NASA Astrophysics Data System (ADS)

Panteleev, V. N.; Alyakrinskiy, O.; Barbui, M.; Barzakh, A. E.; Dubois, M.; Eleon, C.; Essabaa, S.; Fedorov, D. V.; Gaubert, G.; Ionan, A. M.; Ivanov, V. S.; Jardin, P.; Lau, C.; Leroy, R.; Lhersonneau, G.; Mezilev, K. A.; Mhamed, C.; Molkanov, P. L.; Moroz, F. V.; Orlov, S. Yu.; Saint Laurent, M. G.; Stroe, L.; Tecchio, L. B.; Tonezzer, M.; Villari, A. C. C.; Volkov, Yu. M.

2008-10-01

Production of Cs and Fr isotopes from uranium carbide targets of a high density has been investigated at IRIS (Investigation Radioactive Isotopes at Synchrocyclotron), Gatchina. The UC target material with a density of 12 g/cm3 was prepared in a form of pellets. Two targets were tested on-line under the same temperature conditions: (a) a reference small target with a thickness of 4.5 g/cm2; (b) a heavier (so called intermediate) target with a thickness of 91 g/cm2. Yields and release efficiencies of nuclides with half-lives from some minutes to some milliseconds produced by 1 GeV protons in these targets are presented. It is remarkable that yields, even those of very short-lived isotopes such as 214Fr (T1/2 = 5 ms) and 219Fr (T1/2 = 20 ms), increase proportionally to the target thickness. A one month off-line heating test of the 91 g/cm2 target at a temperature of 2000 °C has been carried out successfully. The yields and release efficiencies of Cs and Fr measured on-line before and after the heating test coincided within the limits of measurement errors, thereby demonstrating the conservation of the target unit parameters. Based on these very promising results, a heavier target with a mass about 0.7 kg is prepared presently at IRIS.

Systemic hyperfibrinolysis after trauma: a pilot study of targeted proteomic analysis of superposed mechanisms in patient plasma.

PubMed

Banerjee, Anirban; Silliman, Christopher C; Moore, Ernest E; Dzieciatkowska, Monika; Kelher, Marguerite; Sauaia, Angela; Jones, Kenneth; Chapman, Michael P; Gonzalez, Eduardo; Moore, Hunter B; D'Alessandro, Angelo; Peltz, Erik; Huebner, Benjamin E; Einerson, Peter; Chandler, James; Ghasabayan, Arsen; Hansen, Kirk

2018-06-01

Viscoelastic measurements of hemostasis indicate that 20% of seriously injured patients exhibit systemic hyperfibrinolysis, with increased early mortality. These patients have normal clot formation with rapid clot lysis. Targeted proteomics was applied to quantify plasma proteins from hyperfibrinolytic (HF) patients to elucidate potential pathophysiology. Blood samples were collected in the field or at emergency department arrival and thrombelastography (TEG) was used to characterize in vitro clot formation under native and tissue plasminogen activator (tPA)-stimulated conditions. Ten samples were taken from injured patients exhibiting normal lysis time at 30 min (Ly30), "eufibrinolytic" (EF), 10 from HF patients, defined as tPA-stimulated TEG Ly30 >50%, and 10 from healthy controls. Trauma patient samples were analyzed by targeted proteomics and ELISA assays for specific coagulation proteins. HF patients exhibited increased plasminogen activation. Thirty-three proteins from the HF patients were significantly decreased compared with healthy controls and EF patients; 17 were coagulation proteins with anti-protease consumption (p < 0.005). The other 16 decreased proteins indicate activation of the alternate complement pathway, depletion of carrier proteins, and four glycoproteins. CXC7 was elevated in all injured patients versus healthy controls (p < 0.005), and 35 proteins were unchanged across all groups (p > 0.1 and fold change of concentrations of 0.75-1.3). HF patients had significant decreases in specific proteins and support mechanisms known in trauma-induced hyperfibrinolysis and also unexpected decreases in coagulation factors, factors II, X, and XIII, without changes in clot formation (SP, R times, or angle). Decreased clot stability in HF patients was corroborated with tPA-stimulated TEGs. Prognostic, level III.

Visuo-vestibular interaction: predicting the position of a visual target during passive body rotation.

PubMed

Mackrous, I; Simoneau, M

2011-11-10

Following body rotation, optimal updating of the position of a memorized target is attained when retinal error is perceived and corrective saccade is performed. Thus, it appears that these processes may enable the calibration of the vestibular system by facilitating the sharing of information between both reference frames. Here, it is assessed whether having sensory information regarding body rotation in the target reference frame could enhance an individual's learning rate to predict the position of an earth-fixed target. During rotation, participants had to respond when they felt their body midline had crossed the position of the target and received knowledge of result. During practice blocks, for two groups, visual cues were displayed in the same reference frame of the target, whereas a third group relied on vestibular information (vestibular-only group) to predict the location of the target. Participants, unaware of the role of the visual cues (visual cues group), learned to predict the location of the target and spatial error decreased from 16.2 to 2.0°, reflecting a learning rate of 34.08 trials (determined from fitting a falling exponential model). In contrast, the group aware of the role of the visual cues (explicit visual cues group) showed a faster learning rate (i.e. 2.66 trials) but similar final spatial error 2.9°. For the vestibular-only group, similar accuracy was achieved (final spatial error of 2.3°), but their learning rate was much slower (i.e. 43.29 trials). Transferring to the Post-test (no visual cues and no knowledge of result) increased the spatial error of the explicit visual cues group (9.5°), but it did not change the performance of the vestibular group (1.2°). Overall, these results imply that cognition assists the brain in processing the sensory information within the target reference frame. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Evaluation of a dietary targets monitor.

PubMed

Lean, M E J; Anderson, A S; Morrison, C; Currall, J

2003-05-01

To evaluate a two-page food frequency list for use as a Dietary Targets Monitor in large scale surveys to quantify consumptions of the key foods groups targeted in health promotion. Intakes of fruit and vegetables, starchy foods and fish estimated from a validated food frequency questionnaire (FFQ) were compared with a short food frequency list (the Dietary Targets Monitor) specifically designed to assess habitual frequency of consumption of foods in relation to dietary targets which form the basis of a National (Scottish) Food and Health Policy. A total of 1085 adults aged 25-64 y from the Glasgow MONICA Study. : The two questionnaires both collected data on frequencies of food consumption for fruit and vegetables, starchy foods and fish. Comparing the two questionnaires, there were consistent biases, best expressed as ratios (FFQ:Dietary Targets Monitor) between the methods for fruit and vegetables (1.33, 95% CI 1.29, 1.38) and 'starchy foods' (1.08, 95% CI 1.05, 1.12), the DTM showing systematic under-reporting by men. For fish consumption, there was essentially no bias between the methods (0.99, 95% CI 0.94, 1.03). Using calibration factors to adjust for biases, the Dietary Targets Monitor indicated that 16% of the subjects were achieving the Scottish Diet food target (400 g/day) for fruit and vegetable consumption. Nearly one-third (32%) of the subjects were eating the recommended intakes of fish (three portions per week). The Dietary Targets Monitor measure of starchy foods consumption was calibrated using FFQ data to be able to make quantitative estimates: 20% of subjects were eating six or more portions of starchy food daily. A similar estimation of total fat intake and saturated fat intake (g/day) allowed the categorization of subjects as low, moderate or high fat consumers, with broad agreement between the methods. The levels of agreement demonstrated by Bland-Altman analysis, were insufficient to permit use of the adjusted DTM to estimate quantitative

A Retrieval System for Radioactive Target Materials at the NIF

NASA Astrophysics Data System (ADS)

Krieger, M.; Shibata, K.; Fallica, J.; Henchen, R.; Pogozelski, E.; Padalino, S.; Sangster, T. C.; Suny Collaboration; Laboratory Collaboration

2011-10-01

Currently, solid radioactive material collection from the NIF target chamber is performed via the DIM. The retrieval process takes several hours to complete. To decrease this time for short lived radioisotopes, the Target Materials Retrieval System (TMRS) is being designed to move a radioactive sample from the target chamber to the counting station in less than 50 seconds, using a closed-loop helium filled RaPToRS system. The TMRS consists of three components: the retrieval apparatus, RaPToRS and the counting station. Starting at 0.5 meters from TCC, the sample will move from the vacuum chamber, travel through 60 meters of 10 centimeter diameter RaPToRS tubes, reaching speeds of 10 m/s. The sample will then arrive at the counting station, where it be robotically placed in front of a gamma ray detector. The use of helium will decrease background gamma radiation produced by activated N2 normally found in a pressurized air system. This work was supported in part by the US Department of Energy through the LLE.

Targeting both viral and host determinants of human immunodeficiency virus entry, using a new lentiviral vector coexpressing the T20 fusion inhibitor and a selective CCL5 intrakine.

PubMed

Petit, Nicolas; Dorgham, Karim; Levacher, Béatrice; Burlion, Aude; Gorochov, Guy; Marodon, Gilles

2014-08-01

Numerous strategies targeting early and late steps of the HIV life cycle have been proposed for gene therapy. However, targeting viral and host determinants of HIV entry is the only strategy that would prevent viral DNA-mediated CD4(+) cell death while diminishing the possibility for the virus to escape. To this end, we devised a bicistronic lentiviral vector expressing the membrane-bound form of the T20 fusion inhibitor, referred to as the C46 peptide, and a CCR5 superagonist, modified to sequester CCR5 away from the cell surface, referred to as the P2-CCL5 intrakine. We tested the effects of the vector on HIV infection and replication, using the human CEMR5 cell line expressing CD4 and CCR5, and primary human T cells. Transduced cells expressed the C46 peptide, detected with the 2F5 monoclonal antibody by flow cytometry. Expression of the P2-CCL5 intrakine correlates with lower levels of cell surface CCR5. Complete protection against HIV infection could be observed in cells expressing the protective transgenes. Importantly, we show that the combination of the transgenes was more potent than either transgene alone, showing the interest of expressing two entry inhibitors to inhibit HIV infection. Last, genetically modified cells possessed a selective advantage over nonmodified cells on HIV challenge in vitro, showing that modified cells were protected from HIV-induced cell death. Our results demonstrate that lentiviral vectors coexpressing the T20 fusion inhibitor and the P2-CCL5 intrakine represent promising tools for HIV gene therapy.

A targeted liposome delivery system for combretastatin A4: formulation optimization through drug loading and in vitro release studies.

PubMed

Nallamothu, Ramakrishna; Wood, George C; Kiani, Mohammad F; Moore, Bob M; Horton, Frank P; Thoma, Laura A

2006-01-01

Efficient liposomal therapeutics require high drug loading and low leakage. The objective of this study is to develop a targeted liposome delivery system for combretastatin A4 (CA4), a novel antivascular agent, with high loading and stable drug encapsulation. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, and distearoyl phosphoethanolamine-PEG-2000 conjugate (DSPE-PEG) were prepared by the lipid film hydration and extrusion process. Cyclic arginine-glycine-aspartic acid (RGD) peptides with affinity for alphav beta3-integrins overexpressed on tumor vascular endothelial cells were coupled to the distal end of polyethylene glycol (PEG) on the liposomes sterically stabilized with PEG (non-targeted liposomes; LCLs). Effect of lipid concentration, drug-to-lipid ratio, cholesterol, and DSPE-PEG content in the formulation on CA4 loading and its release from the liposomes was studied. Total liposomal CA4 levels obtained increased with increasing lipid concentration in the formulation. As the drug-to-lipid ratio increased from 10:100 to 20:100, total drug in the liposome formulation increased from 1.05+/-0.11 mg/mL to 1.55+/-0.13 mg/mL, respectively. When the drug-to-lipid ratio was further raised to 40:100, the total drug in liposome formulation did not increase, but the amount of free drug increased significantly, thereby decreasing the percent of entrapped drug. Increasing cholesterol content in the formulation decreased drug loading. In vitro drug leakage from the liposomes increased with increase in drug-to-lipid ratio or DSPE-PEG content in the formulation; whereas increasing cholesterol content of the formulation up to 30 mol-percent, decreased CA4 leakage from the liposomes. Ligand coupling to the liposome surface increased drug leakage as a function of ligand density. Optimized liposome formulation with 100 mM lipid concentration, 20:100 drug-to-lipid ratio, 30 mol-percent cholesterol, 4 mol-percent DSPE-PEG, and 1 mol

JM-20 Treatment After MCAO Reduced Astrocyte Reactivity and Neuronal Death on Peri-infarct Regions of the Rat Brain.

PubMed

Ramírez-Sánchez, Jeney; Pires, Elisa Nicoloso Simões; Meneghetti, André; Hansel, Gisele; Nuñez-Figueredo, Yanier; Pardo-Andreu, Gilberto L; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Delgado-Hernández, René; Salbego, Christianne; Souza, Diogo O

2018-05-03

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1β levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN + cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

PubMed Central

Flores, Orielyz; Santra, Santimukul; Kaittanis, Charalambos; Bassiouni, Rania; Khaled, Amr S; Khaled, Annette R.; Grimm, Jan; Perez, J Manuel

2017-01-01

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size. PMID:28744329

Impact of Target Distance, Target Size, and Visual Acuity on the Video Head Impulse Test.

PubMed

Judge, Paul D; Rodriguez, Amanda I; Barin, Kamran; Janky, Kristen L

2018-05-01

The video head impulse test (vHIT) assesses the vestibulo-ocular reflex. Few have evaluated whether environmental factors or visual acuity influence the vHIT. The purpose of this study was to evaluate the influence of target distance, target size, and visual acuity on vHIT outcomes. Thirty-eight normal controls and 8 subjects with vestibular loss (VL) participated. vHIT was completed at 3 distances and with 3 target sizes. Normal controls were subdivided on the basis of visual acuity. Corrective saccade frequency, corrective saccade amplitude, and gain were tabulated. In the normal control group, there were no significant effects of target size or visual acuity for any vHIT outcome parameters; however, gain increased as target distance decreased. The VL group demonstrated higher corrective saccade frequency and amplitude and lower gain as compared with controls. In conclusion, decreasing target distance increases gain for normal controls but not subjects with VL. Preliminarily, visual acuity does not affect vHIT outcomes.

Observed decrease in atmospheric mercury explained by global decline in anthropogenic emissions

PubMed Central

Zhang, Yanxu; Jacob, Daniel J.; Horowitz, Hannah M.; Chen, Long; Amos, Helen M.; Krabbenhoft, David P.; Slemr, Franz; St. Louis, Vincent L.; Sunderland, Elsie M.

2016-01-01

Observations of elemental mercury (Hg0) at sites in North America and Europe show large decreases (∼1–2% y−1) from 1990 to present. Observations in background northern hemisphere air, including Mauna Loa Observatory (Hawaii) and CARIBIC (Civil Aircraft for the Regular Investigation of the atmosphere Based on an Instrument Container) aircraft flights, show weaker decreases (<1% y−1). These decreases are inconsistent with current global emission inventories indicating flat or increasing emissions over that period. However, the inventories have three major flaws: (i) they do not account for the decline in atmospheric release of Hg from commercial products; (ii) they are biased in their estimate of artisanal and small-scale gold mining emissions; and (iii) they do not properly account for the change in Hg0/HgII speciation of emissions from coal-fired utilities after implementation of emission controls targeted at SO2 and NOx. We construct an improved global emission inventory for the period 1990 to 2010 accounting for the above factors and find a 20% decrease in total Hg emissions and a 30% decrease in anthropogenic Hg0 emissions, with much larger decreases in North America and Europe offsetting the effect of increasing emissions in Asia. Implementation of our inventory in a global 3D atmospheric Hg simulation [GEOS-Chem (Goddard Earth Observing System-Chemistry)] coupled to land and ocean reservoirs reproduces the observed large-scale trends in atmospheric Hg0 concentrations and in HgII wet deposition. The large trends observed in North America and Europe reflect the phase-out of Hg from commercial products as well as the cobenefit from SO2 and NOx emission controls on coal-fired utilities. PMID:26729866

Time reversal optical tomography locates fluorescent targets in a turbid medium

NASA Astrophysics Data System (ADS)

Wu, Binlin; Cai, W.; Gayen, S. K.

2013-03-01

A fluorescence optical tomography approach that extends time reversal optical tomography (TROT) to locate fluorescent targets embedded in a turbid medium is introduced. It uses a multi-source illumination and multi-detector signal acquisition scheme, along with TR matrix formalism, and multiple signal classification (MUSIC) to construct pseudo-image of the targets. The samples consisted of a single or two small tubes filled with water solution of Indocyanine Green (ICG) dye as targets embedded in a 250 mm × 250 mm × 60 mm rectangular cell filled with Intralipid-20% suspension as the scattering medium. The ICG concentration was 1μM, and the Intralipid-20% concentration was adjusted to provide ~ 1-mm transport length for both excitation wavelength of 790 nm and fluorescence wavelength around 825 nm. The data matrix was constructed using the diffusely transmitted fluorescence signals for all scan positions, and the TR matrix was constructed by multiplying data matrix with its transpose. A pseudo spectrum was calculated using the signal subspace of the TR matrix. Tomographic images were generated using the pseudo spectrum. The peaks in the pseudo images provided locations of the target(s) with sub-millimeter accuracy. Concurrent transmission TROT measurements corroborated fluorescence-TROT findings. The results demonstrate that TROT is a fast approach that can be used to obtain accurate three-dimensional position information of fluorescence targets embedded deep inside a highly scattering medium, such as, a contrast-enhanced tumor in a human breast.

In vivo magnetofection: a novel approach for targeted topical delivery of nucleic acids for rectoanal motility disorders.

PubMed

Singh, Jagmohan; Mohanty, Ipsita; Rattan, Satish

2018-01-01

In these studies, we developed a novel approach of in vivo magnetofection for localized delivery of nucleic acids such as micro-RNA-139-5p (miR-139-5p; which is known to target Rho kinase2) to the circular smooth muscle layer of the internal anal sphincter (IAS). The IAS tone is known to play a major role in the rectoanal continence via activation of RhoA-associated kinase (RhoA/ROCK2). These studies established an optimized protocol for efficient gene delivery using an assembly of equal volumes of in vivo PolyMag and miR139-5p or anti-miR-139-5p (100 nM each) injected in the circular smooth muscle layer in the pinpointed areas of the rat perianal region and then incubated for 20 min under magnetic field. Magnetofection efficiency was confirmed and analyzed by confocal microscopy of FITC-tagged siRNA. Using physiological and biochemical approaches, we investigated the effects of miR-139-5p and anti-miR-139-5p on basal intraluminal IAS pressure (IASP), fecal pellet count, IAS tone, agonist-induced contraction, contraction-relaxation kinetics, and RhoA/ROCK2 signaling. Present studies demonstrate that magnetofection-mediated miR-139-5p delivery significantly decreased RhoA/ROCK2, p-MYPT1, and p-MLC 20 signaling, leading to decreases in the basal IASP and IAS tone and in rates of contraction and relaxation associated with increase in fecal pellet output. Interestingly, anti-miR-139-5p transfection had opposite effects on these parameters. Collectively, these data demonstrate that magnetofection is a promising novel method of in vivo gene delivery and of nucleotides to the internal anal sphincter for the site-directed and targeted therapy for rectoanal motility disorders. NEW & NOTEWORTHY These studies for the first time demonstrate the success of topical in vivo magnetofection (MF) of nucleic acids using perianal injections. To demonstrate its effectiveness, we used FITC-tagged siRNA via immunofluorescence microcopy and functional and biochemical evidence using mi

Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach.

PubMed

Ferrario, Manuela; Cambiaghi, Alice; Brunelli, Laura; Giordano, Silvia; Caironi, Pietro; Guatteri, Luca; Raimondi, Ferdinando; Gattinoni, Luciano; Latini, Roberto; Masson, Serge; Ristagno, Giuseppe; Pastorelli, Roberta

2016-02-05

Septic shock remains a major problem in Intensive Care Unit, with high lethality and high-risk second lines treatments. In this preliminary retrospective investigation we examined plasma metabolome and clinical features in a subset of 20 patients with severe septic shock (SOFA score >8), enrolled in the multicenter Albumin Italian Outcome Sepsis study (ALBIOS, NCT00707122). Our purpose was to evaluate the changes of circulating metabolites in relation to mortality as a pilot study to be extended in a larger cohort. Patients were analyzed according to their 28-days and 90-days mortality. Metabolites were measured using a targeted mass spectrometry-based quantitative metabolomic approach that included acylcarnitines, aminoacids, biogenic amines, glycerophospholipids, sphingolipids, and sugars. Data-mining techniques were applied to evaluate the association of metabolites with mortality. Low unsaturated long-chain phosphatidylcholines and lysophosphatidylcholines species were associated with long-term survival (90-days) together with circulating kynurenine. Moreover, a decrease of these glycerophospholipids was associated to the event at 28-days and 90-days in combination with clinical variables such as cardiovascular SOFA score (28-day mortality model) or renal replacement therapy (90-day mortality model). Early changes in the plasma levels of both lipid species and kynurenine associated with mortality have potential implications for early intervention and discovering new target therapy.

Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach

PubMed Central

Ferrario, Manuela; Cambiaghi, Alice; Brunelli, Laura; Giordano, Silvia; Caironi, Pietro; Guatteri, Luca; Raimondi, Ferdinando; Gattinoni, Luciano; Latini, Roberto; Masson, Serge; Ristagno, Giuseppe; Pastorelli, Roberta

2016-01-01

Septic shock remains a major problem in Intensive Care Unit, with high lethality and high-risk second lines treatments. In this preliminary retrospective investigation we examined plasma metabolome and clinical features in a subset of 20 patients with severe septic shock (SOFA score >8), enrolled in the multicenter Albumin Italian Outcome Sepsis study (ALBIOS, NCT00707122). Our purpose was to evaluate the changes of circulating metabolites in relation to mortality as a pilot study to be extended in a larger cohort. Patients were analyzed according to their 28-days and 90-days mortality. Metabolites were measured using a targeted mass spectrometry-based quantitative metabolomic approach that included acylcarnitines, aminoacids, biogenic amines, glycerophospholipids, sphingolipids, and sugars. Data-mining techniques were applied to evaluate the association of metabolites with mortality. Low unsaturated long-chain phosphatidylcholines and lysophosphatidylcholines species were associated with long-term survival (90-days) together with circulating kynurenine. Moreover, a decrease of these glycerophospholipids was associated to the event at 28-days and 90-days in combination with clinical variables such as cardiovascular SOFA score (28-day mortality model) or renal replacement therapy (90-day mortality model). Early changes in the plasma levels of both lipid species and kynurenine associated with mortality have potential implications for early intervention and discovering new target therapy. PMID:26847922

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice.

PubMed

Hu, Wei; Lu, Tina; Chen, Alan; Huang, Ying; Hansen, Rolf; Chandler, L Judson; Zhang, Han-Ting

2011-11-01

Cyclic AMP (cAMP)-protein kinase A signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. The objective of this study is to examine whether PDE4 was involved in regulating ethanol intake. The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

Air Force, Cyberpower, Targeting: Airpower Lessons for an Air Force Cyberpower Targeting Theory

DTIC Science & Technology

2013-06-01

apply in future war. Following World War I, Airmen at the Air Corps Tactical School (ACTS) developed an “Industrial Web Theory” for targeting to...throughout its use. The targeting theory was employed with mixed results from World War II through the Vietnam War. In the late 20th century, Colonel...A review of the Inter-War period, World War II, Korean War, and Desert Storm intends to evaluate airpower targeting theories in order to develop

The response of soil solution chemistry in European forests to decreasing acid deposition.

PubMed

Johnson, James; Graf Pannatier, Elisabeth; Carnicelli, Stefano; Cecchini, Guia; Clarke, Nicholas; Cools, Nathalie; Hansen, Karin; Meesenburg, Henning; Nieminen, Tiina M; Pihl-Karlsson, Gunilla; Titeux, Hugues; Vanguelova, Elena; Verstraeten, Arne; Vesterdal, Lars; Waldner, Peter; Jonard, Mathieu

2018-03-31

Acid deposition arising from sulphur (S) and nitrogen (N) emissions from fossil fuel combustion and agriculture has contributed to the acidification of terrestrial ecosystems in many regions globally. However, in Europe and North America, S deposition has greatly decreased in recent decades due to emissions controls. In this study, we assessed the response of soil solution chemistry in mineral horizons of European forests to these changes. Trends in pH, acid neutralizing capacity (ANC), major ions, total aluminium (Al tot ) and dissolved organic carbon were determined for the period 1995-2012. Plots with at least 10 years of observations from the ICP Forests monitoring network were used. Trends were assessed for the upper mineral soil (10-20 cm, 104 plots) and subsoil (40-80 cm, 162 plots). There was a large decrease in the concentration of sulphate (SO42-) in soil solution; over a 10-year period (2000-2010), SO42- decreased by 52% at 10-20 cm and 40% at 40-80 cm. Nitrate was unchanged at 10-20 cm but decreased at 40-80 cm. The decrease in acid anions was accompanied by a large and significant decrease in the concentration of the nutrient base cations: calcium, magnesium and potassium (Bc = Ca 2+  + Mg 2+  + K + ) and Al tot over the entire dataset. The response of soil solution acidity was nonuniform. At 10-20 cm, ANC increased in acid-sensitive soils (base saturation ≤10%) indicating a recovery, but ANC decreased in soils with base saturation >10%. At 40-80 cm, ANC remained unchanged in acid-sensitive soils (base saturation ≤20%, pHCaCl2 ≤ 4.5) and decreased in better-buffered soils (base saturation >20%, pHCaCl2 > 4.5). In addition, the molar ratio of Bc to Al tot either did not change or decreased. The results suggest a long-time lag between emission abatement and changes in soil solution acidity and underline the importance of long-term monitoring in evaluating ecosystem response to decreases in deposition. © 2018 John Wiley & Sons

Decreased summer drought affects plant productivity and soil carbon dynamics in a Mediterranean woodland

NASA Astrophysics Data System (ADS)

Cotrufo, M. F.; Alberti, G.; Inglima, I.; Marjanović, H.; Lecain, D.; Zaldei, A.; Peressotti, A.; Miglietta, F.

2011-09-01

Precipitation patterns are expected to change in the Mediterranean region within the next decades, with projected decreases in total rainfall and increases in extreme events. We manipulated precipitation patterns in a Mediterranean woodland, dominated by Arbutus unedo L., to study the effects of changing precipitation regimes on above-ground net primary production (ANPP) and soil C dynamics, specifically plant-derived C input to soil and soil respiration (SR). Experimental plots were exposed to either a 20 % reduction of throughfall or to water addition targeted at maintaining soil water content above a minimum of 10 % v/v. Treatments were compared to control plots which received ambient precipitation. Enhanced soil moisture during summer months highly stimulated annual stem primary production, litter fall, SR and net annual plant-derived C input to soil which on average increased by 130 %, 26 %, 58 % and 220 %, respectively, as compared to the control. In contrast, the 20 % reduction in throughfall (equivalent to 10 % reduction in precipitation) did not significantly change soil moisture at the site, and therefore did not significantly affect ANPP or SR. We conclude that minor changes (around 10 % reduction) in precipitation amount are not likely to significantly affect ANPP or soil C dynamics in Mediterranean woodlands. However, if summer rain increases, C cycling will significantly accelerate but soil C stocks are not likely to be changed in the short-term. More studies involving modelling of long-term C dynamics are needed to predict if the estimated increases in soil C input under wet conditions is going to be sustained and if labile C is being substituted to stable C, with a negative effect on long-term soil C stocks.

Capture of shrinking targets with realistic shrink patterns.

PubMed

Hoffmann, Errol R; Chan, Alan H S; Dizmen, Coskun

2013-01-01

Previous research [Hoffmann, E. R. 2011. "Capture of Shrinking Targets." Ergonomics 54 (6): 519-530] reported experiments for capture of shrinking targets where the target decreased in size at a uniform rate. This work extended this research for targets having a shrink-size versus time pattern that of an aircraft receding from an observer. In Experiment 1, the time to capture the target in this case was well correlated in terms of Fitts' index of difficulty, measured at the time of capture of the target, a result that is in agreement with the 'balanced' model of Johnson and Hart [Johnson, W. W., and Hart, S. G. 1987. "Step Tracking Shrinking Targets." Proceedings of the human factors society 31st annual meeting, New York City, October 1987, 248-252]. Experiment 2 measured the probability of target capture for varying initial target sizes and target shrink rates constant, defined as the time for the target to shrink to half its initial size. Data of shrink time constant for 50% probability of capture were related to initial target size but did not greatly affect target capture as the rate of target shrinking decreased rapidly with time.

Neurotrophin Receptors TrkA, p75NTR, and Sortilin Are Increased and Targetable in Thyroid Cancer.

PubMed

Faulkner, Sam; Jobling, Philip; Rowe, Christopher W; Rodrigues Oliveira, S M; Roselli, Severine; Thorne, Rick F; Oldmeadow, Christopher; Attia, John; Jiang, Chen Chen; Zhang, Xu Dong; Walker, Marjorie M; Hondermarck, Hubert

2018-01-01

Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75 NTR , and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75 NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75 NTR , and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75 NTR , and sortilin as potential therapeutic targets in thyroid cancer. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The cost-effectiveness of targeted or universal screening for vasa praevia at 18-20 weeks of gestation in Ontario.

PubMed

Cipriano, L E; Barth, W H; Zaric, G S

2010-08-01

To estimate the cost-effectiveness of targeted and universal screening for vasa praevia at 18-20 weeks of gestation in singleton and twin pregnancies. Cost-utility analysis based on a decision-analytic model comparing relevant strategies and life-long outcomes for mother and infant(s). Ontario, Canada. A cohort of pregnant women in 1 year. We constructed a decision-analytic model to estimate the lifetime incremental costs and benefits of screening for vasa praevia. Inputs were estimated from the literature. Costs were collected from the London Health Sciences Centre, the Ontario Health Insurance Program, and other sources. We used one-way, scenario and probabilistic sensitivity analysis to determine the robustness of the results. Incremental costs, life expectancy, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER). Universal transvaginal ultrasound screening of twin pregnancies has an ICER of $5488 per QALY-gained. Screening all singleton pregnancies with the risk factors low-lying placentas, in vitro fertilisation (IVF) conception, accessory placental lobes, or velamentous cord insertion has an ICER of $15,764 per QALY-gained even though identifying some of these risk factors requires routine use of colour Doppler during transabdominal examinations. Screening women with a marginal cord insertion costs an additional $27,603 per QALY-gained. Universal transvaginal screening for vasa praevia in singleton pregnancies costs $579,164 per QALY compared with targeted screening. Compared with current practice, screening all twin pregnancies for vasa praevia with transvaginal ultrasound is cost-effective. Among the alternatives considered, the use of colour Doppler at all transabdominal ultrasound examinations of singleton pregnancies and targeted use of transvaginal ultrasound for IVF pregnancies or when the placenta has been found to be associated with one or more risk factors is cost-effective. Universal screening of singleton pregnancies

Addition of 20-kDa PEG to Insulin Lispro Alters Absorption and Decreases Clearance in Animals.

PubMed

Knadler, Mary Pat; Nguyen, Tri-Hung; Campanale, Kristina; De Veer, Michael J; Beals, John M; Li, Shun; Hansen, Ryan; Siesky, Angela; Michael, M Dodson; Porter, Christopher J H

2016-12-01

Determine the pharmacokinetics of insulin peglispro (BIL) in 5/6-nephrectomized rats and study the absorption in lymph duct cannulated (LDC) sheep. BIL is insulin lispro modified with 20-kDa linear PEG at lysine B28 increasing the hydrodynamic size to 4-fold larger than insulin lispro. Pharmacokinetics of BIL and insulin lispro after IV administration were compared in 5/6-nephrectomized and sham rats. BIL was administered IV or SC into the interdigital space of the hind leg, and peripheral lymph and/or serum samples were collected from both LDC and non-LDC sheep to determine pharmacokinetics and absorption route of BIL. The clearance of BIL was similar in 5/6-nephrectomized and sham rats, while the clearance of insulin lispro was 3.3-fold slower in 5/6-nephrectomized rats than in the sham rats. In non-LDC sheep, the terminal half-life after SC was about twice as long vs IV suggesting flip-flop pharmacokinetics. In LDC sheep, bioavailability decreased to <2%; most of the dose was absorbed via the lymphatic system, with 88% ± 19% of the dose collected in the lymph after SC administration. This work demonstrates that increasing the hydrodynamic size of insulin lispro through PEGylation can impact both absorption and clearance to prolong drug action.

[CT-guided intervention by means of a laser marking and targeting aid].

PubMed

Klöppel, R; Wilke, W; Weisse, T; Steinecke, R

1997-08-01

The present study evaluates the use of a laser guidance system for CT-guided intervention. 94 cases of diagnostic biopsies and lumbar sympathectomies (54 cases with laser guidance system and 40 without) were compared. Using the laser guidance system, the number of control scans decreased by 30 to 50%, and necessary corrections of needle location were reduced by a maximum of 30%. The average target deviation of the needle decreased to less than 5 mm in 50% of cases. The laser guidance system is strongly recommended in CT-guided interventions for quality assurance and higher efficiency. The advantage is especially marked if the target area is small.

CD20-based Immunotherapy of B-cell Derived Hematologic Malignancies.

PubMed

Shanehbandi, Dariush; Majidi, Jafar; Kazemi, Tohid; Baradaran, Behzad; Aghebati-Maleki, Leili

2017-01-01

CD20 is a surface antigen, which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/ relapsed disease. In this regard, new generations of MAbs with enhanced affinity or improved anti-tumor properties have been developed. CD20 directed therapeutics have heterogeneous features and mechanisms of action. Hence, having sufficient knowledge on the immunological and molecular aspects of CD20 based cancer therapy is necessary for predicting the clinical outcomes and taking the necessary measures. An extensive search was performed in PubMed and similar databases for peer-reviewed articles concerning the biology, function and characteristics of CD20 molecule as well as the mechanisms of action and evolutionary process of CD20 targeting agents. This review provides information about the current situation of CD20 targeting immunotherapeutics including MAbs, bispecific antibodies (which exert multiple functions or involve Tcells in tumor elimination) and CAR T-cells (engineered T-cells armed with chimeric antigen receptors). Moreover, limitations, challenges and available solutions regarding the application of CD20 targeting treatments are addressed. Utilization of CD20-targeted therapeutics, due to their diverse properties, requires special considerations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A 20-Amino Acid Module of Protein Kinase Cϵ Involved in Translocation and Selective Targeting at Cell-Cell Contacts*

PubMed Central

Diouf, Barthélémy; Collazos, Alejandra; Labesse, Gilles; Macari, Françoise; Choquet, Armelle; Clair, Philippe; Gauthier-Rouvière, Cécile; Guérineau, Nathalie C.; Jay, Philippe; Hollande, Frédéric; Joubert, Dominique

2009-01-01

In the pituitary gland, activated protein kinase C (PKC) isoforms accumulate either selectively at the cell-cell contact (α and ϵ) or at the entire plasma membrane (β1 and δ). The molecular mechanisms underlying these various subcellular locations are not known. Here, we demonstrate the existence within PKCϵ of a cell-cell contact targeting sequence (3CTS) that, upon stimulation, is capable of targeting PKCδ, chimerin-α1, and the PKCϵ C1 domain to the cell-cell contact. We show that this selective targeting of PKCϵ is lost upon overexpression of 3CTS fused to a (R-Ahx-R)4 (where Ahx is 6-aminohexanoic acid) vectorization peptide, reflecting a dominant-negative effect of the overexpressed 3CTS on targeting selectivity. 3CTS contains a putative amphipathic α-helix, a 14-3-3-binding site, and the Glu-374 amino acid, involved in targeting selectivity. We show that the integrity of the α-helix is important for translocation but that 14-3-3 is not involved in targeting selectivity. However, PKCϵ translocation is increased when PKCϵ/14-3-3 interaction is abolished, suggesting that phorbol 12-myristate 13-acetate activation may initiate two sets of PKCϵ functions, those depending on 14-3-3 and those depending on translocation to cell-cell contacts. Thus, 3CTS is involved in the modulation of translocation via its 14-3-3-binding site, in cytoplasmic desequestration via the α-helix, and in selective PKCϵ targeting at the cell-cell contact via Glu-374. PMID:19429675

Primary prevention of overweight in children and adolescents: a meta-analysis of the effectiveness of interventions aiming to decrease sedentary behaviour

PubMed Central

2012-01-01

The objectives of this meta-analysis were to provide an overview of the evidence regarding the effects of interventions, implemented in the school- and general population setting, aiming to prevent excessive sedentary behaviour in children and adolescents on (1) the amount of sedentary behaviour and (2) BMI. Differences in effects on sedentary behaviour and BMI between single health behaviour interventions (sedentary behaviour only) and multiple health behaviour interventions were explored. A literature search was conducted in PubMed, EMBASE, Web of Science, PsycINFO and Cochrane Database of Systematic Reviews. Thirty-four (R)CT studies evaluating 33 general population interventions, published between 1990 and April 2011, aiming to decrease sedentary behaviour in normal weight children or adolescents (0–18 years) were included. Intervention duration ranged from 7 days to 4 years. Mean change in sedentary behaviour and BMI from baseline to post-intervention was calculated using a random effects model. Results showed significant decreases for the amount of sedentary behaviour and BMI. For sedentary behaviour the post-intervention mean difference was −17.95 min/day (95%CI:-26.61;–9.28); the change-from-baseline mean difference was −20.44 min/day (95%CI:-30.69;–10.20). For BMI the post-intervention mean difference was −0.25 kg/m² (95%CI:-0.40;–0.09); the change-from-baseline mean difference was −0.14 kg/m² (95%CI:-0.23;–0.05). No differences were found between single and multiple health behaviour interventions. Interventions in the school- and general population setting aiming to reduce only sedentary behaviour and interventions targeting multiple health behaviours can result in significant decreases in sedentary behaviour. Studies need to increase follow-up time to estimate the sustainability of the intervention effects found. PMID:22640437

Decrease in hematopoietic stem cell domains as a delayed effect of x-irradiation

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

Maloney, M.A.; Lamela, R.A.; Patt, H.M.

Although the hematopoietic integrity of locally X-irradiated sites can be restored for a time even after fairly large doses, a secondary aplasia often occurs some months later. To gain further insight into this delayed effect within the framework of the stem cell regulatory domain hypothesis, we characterized the growth kinetics of spleen colony forming units (CFU-S) in WBB6FI-+/+ bone marrow transplanted into WBB6FI-W/WV mice in which one leg had been exposed to 10-30 Gy of X rays 4-5 months previously. Compared to unirradiated contralateral marrow, fewer CFU-S either reached the previously irradiated marrow or were seeded into sites that couldmore » support growth. The initial exponential growth of effectively seeded CFU-S was unchanged, but growth deceleration (inflection point) occurred at a lower level of CFU-S in marrow previously irradiated with 20-30 Gy. This change in the inflection point indicates a radiation dose-dependent decrease consistent with the decrease in bone marrow cellularity. The decrease in effective stem cell domains after 20 Gy was calculated to be about 35%. We interpret these results to reflect the highly localized nature of delayed radiation damage to the marrow microenvironment.« less

A Decrease in Temperature and Humidity Precedes Human Rhinovirus Infections in a Cold Climate.

PubMed

Ikäheimo, Tiina M; Jaakkola, Kari; Jokelainen, Jari; Saukkoriipi, Annika; Roivainen, Merja; Juvonen, Raija; Vainio, Olli; Jaakkola, Jouni J K

2016-09-02

Both temperature and humidity may independently or jointly contribute to the risk of human rhinovirus (HRV) infections, either through altered survival and spread of viruses in the environment or due to changes in host susceptibility. This study examined the relationship between short-term variations in temperature and humidity and the risk of HRV infections in a subarctic climate. We conducted a case-crossover study among conscripts (n = 892) seeking medical attention due to respiratory symptoms during their military training and identified 147 HRV cases by real-time PCR. An average temperature, a decline in daily ambient temperature and absolute humidity (AH) during the three preceding days of the onset (hazard period) and two reference periods (a week prior and after the onset) were obtained. The average daily temperature preceding HRV infections was -9.9 ± 4.9 °C and the average AH was 2.2 ± 0.9 g/m³. An average (odds ratios (OR) 1.07 (95% confidence interval (CI) 1.00-1.15)) and maximal (OR 1.08 (1.01-1.17)) change in temperature increased the risk of HRV infections by 8% per 1 °C decrease. An average (OR 1.20 (CI 1.03-1.40)) and maximal decrease (OR 1.13 (CI 0.96-1.34)) in AH increased the risk of HRV infection by 13% and 20% per 0.5 g/m³ decrease. A higher average temperature during the three preceding days was positively associated with HRV infections (OR 1.07 (CI 1.00-1.15)). A decrease rather than low temperature and humidity per se during the preceding few days increases the risk of HRV infections in a cold climate. The information is applicable to populations residing in cold climates for appropriate personal protection and prevention of adverse health effects.

A Decrease in Temperature and Humidity Precedes Human Rhinovirus Infections in a Cold Climate

PubMed Central

Ikäheimo, Tiina M.; Jaakkola, Kari; Jokelainen, Jari; Saukkoriipi, Annika; Roivainen, Merja; Juvonen, Raija; Vainio, Olli; Jaakkola, Jouni J.K.

2016-01-01

Both temperature and humidity may independently or jointly contribute to the risk of human rhinovirus (HRV) infections, either through altered survival and spread of viruses in the environment or due to changes in host susceptibility. This study examined the relationship between short-term variations in temperature and humidity and the risk of HRV infections in a subarctic climate. We conducted a case-crossover study among conscripts (n = 892) seeking medical attention due to respiratory symptoms during their military training and identified 147 HRV cases by real-time PCR. An average temperature, a decline in daily ambient temperature and absolute humidity (AH) during the three preceding days of the onset (hazard period) and two reference periods (a week prior and after the onset) were obtained. The average daily temperature preceding HRV infections was −9.9 ± 4.9 °C and the average AH was 2.2 ± 0.9 g/m3. An average (odds ratios (OR) 1.07 (95% confidence interval (CI) 1.00–1.15)) and maximal (OR 1.08 (1.01–1.17)) change in temperature increased the risk of HRV infections by 8% per 1 °C decrease. An average (OR 1.20 (CI 1.03–1.40)) and maximal decrease (OR 1.13 (CI 0.96–1.34)) in AH increased the risk of HRV infection by 13% and 20% per 0.5 g/m3 decrease. A higher average temperature during the three preceding days was positively associated with HRV infections (OR 1.07 (CI 1.00–1.15)). A decrease rather than low temperature and humidity per se during the preceding few days increases the risk of HRV infections in a cold climate. The information is applicable to populations residing in cold climates for appropriate personal protection and prevention of adverse health effects. PMID:27598190

MetaRanker 2.0: a web server for prioritization of genetic variation data.

PubMed

Pers, Tune H; Dworzyński, Piotr; Thomas, Cecilia Engel; Lage, Kasper; Brunak, Søren

2013-07-01

MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein-protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, MetaRanker 2.0 prioritizes the protein-coding part of the human genome to shortlist candidate genes for targeted follow-up studies. MetaRanker 2.0 is made freely available at www.cbs.dtu.dk/services/MetaRanker-2.0.

A half-mile walk decreases visual acuity in active older people.

PubMed

De Oliveira Filho, Ciro Winckler; Dias, Roges Ghidini; Tavares, Graziela Morgana Silva; Santos, Gilmar Moraes; Mazo, Giovana Zarpellon

2010-06-01

The influence of a half-mile walk on the visual acuity of older people who engaged in physical activity was examined. 91 elderly people of both sexes (20 men, 71 women; M age = 69 yr., SD = 6) participated. All were assessed before and after the half-mile walking test for visual acuity (Snellen Optotype Scale) and heart rate. The data indicated a significant decrease in visual acuity as a result of the half-mile test.

Dodecafluoropentane Emulsion Decreases Infarct Volume in a Rabbit Ischemic Stroke Model

PubMed Central

Culp, William C.; Woods, Sean D.; Skinner, Robert D.; Brown, Aliza T.; Lowery, John D.; Johnson, Jennifer L. H.; Unger, Evan C.; Hennings, Leah J.; Borrelli, Michael J.; Roberson, Paula K.

2011-01-01

Purpose To assess the efficacy of dodecafluoropentane emulsion (DDFPe), a nano droplet emulsion with significant oxygen transport potential, in decreasing infarct volume using an insoluble emboli rabbit stroke model. Methods New Zealand White rabbits (n=64; 5.1±0.50 kg) received angiography and embolic spheres in the internal carotid artery occluding branches. Rabbits were randomly assigned to groups in 4-hour and 7-hour studies. Four-hour groups included: control (n=7, embolized without treatment) or DDFPe treatment 30-min before stroke (n=7), or at stroke onset (n=8), 30-min after stroke (n=5), 1-hour after stroke (n=7), 2-hours after stroke (n=5), or 3-hours after stroke (n=6). Seven-hour groups included control (n=6), DDFPe at 1-hour after stroke (n=8), and DDFPe at 6-hours after stroke (n=5). DDFPe dose was 2% w/v (weight/volume) intravenous injection, 0.6 mL/kg, and repeated every 90 minutes as time allowed. Following euthanasia infarct volume was determined using vital stains on brain sections. Results At 4-hours, median percent infarct volume decreased for all DDFPe treatment times (pre-treatment=0.30%, p=0.004; onset=0.20%, p=0.004; 30-min=0.35%, p=0.009, 1-hour=0.30%, p=0.01, 2-hours=0.40%, p=0.009, 3-hours=0.25%, p=0.003) compared with controls (3.20%). At 7-hours, median percent infarct volume decreased with treatment at 1-hour (0.25%, p=0.007) but not for 6-hours (1.4%, p=0.49) compared with controls (2.2%). Conclusions Intravenous DDFPe in an animal model decreases infarct volumes and protects brain tissue from ischemia justifying further investigation. PMID:22079515

The METTL20 Homologue from Agrobacterium tumefaciens Is a Dual Specificity Protein-lysine Methyltransferase That Targets Ribosomal Protein L7/L12 and the β Subunit of Electron Transfer Flavoprotein (ETFβ)*

PubMed Central

Małecki, Jędrzej; Dahl, Helge-André; Moen, Anders; Davydova, Erna; Falnes, Pål Ø.

2016-01-01

Human METTL20 is a mitochondrial, lysine-specific methyltransferase that methylates the β-subunit of electron transfer flavoprotein (ETFβ). Interestingly, putative METTL20 orthologues are found in a subset of α-proteobacteria, including Agrobacterium tumefaciens. Using an activity-based approach, we identified in bacterial extracts two substrates of recombinant METTL20 from A. tumefaciens (AtMETTL20), namely ETFβ and the ribosomal protein RpL7/L12. We show that AtMETTL20, analogous to the human enzyme, methylates ETFβ on Lys-193 and Lys-196 both in vitro and in vivo. ETF plays a key role in mediating electron transfer from various dehydrogenases, and we found that its electron transferring ability was diminished by AtMETTL20-mediated methylation of ETFβ. Somewhat surprisingly, AtMETTL20 also catalyzed monomethylation of RpL7/L12 on Lys-86, a common modification also found in many bacteria that lack METTL20. Thus, we here identify AtMETTL20 as the first enzyme catalyzing RpL7/L12 methylation. In summary, here we have identified and characterized a novel bacterial lysine-specific methyltransferase with unprecedented dual substrate specificity within the seven β-strand class of lysine-specific methyltransferases, as it targets two apparently unrelated substrates, ETFβ and RpL7/L12. Moreover, the present work establishes METTL20-mediated methylation of ETFβ as the first lysine methylation event occurring in both bacteria and humans. PMID:26929405

Study on a two-dimensional scanning micro-mirror and its application in a MOEMS target detector.

PubMed

Zhang, Chi; You, Zheng; Huang, Hu; Li, Guanhua

2010-01-01

A two-dimensional (2D) scanning micro-mirror for target detection and measurement has been developed. This new micro-mirror is used in a MOEMS target detector to replace the conventional scanning detector. The micro-mirror is fabricated by MEMS process and actuated by a piezoelectric actuator. To achieve large deflection angles, the micro-mirror is excited in the resonance modes. It has two degrees of freedom and changes the direction of the emitted laser beam for a regional 2D scanning. For the deflection angles measurement, piezoresistors are integrated in the micro-mirror and the deflection angles of each direction can be detected independently and precisely. Based on the scanning micro-mirror and the phase-shift ranging technology, a MOEMS target detector has been developed in a size of 90 mm × 35 mm × 50 mm. The experiment shows that the target can be detected in the scanning field and the relative range and orientation can be measured by the MOEMS target detector. For the target distance up to 3 m with a field of view about 20° × 20°, the measurement resolution is about 10.2 cm in range, 0.15° in the horizontal direction and 0.22° in the vertical direction for orientation.

Study on a Two-Dimensional Scanning Micro-Mirror and Its Application in a MOEMS Target Detector

PubMed Central

Zhang, Chi; You, Zheng; Huang, Hu; Li, Guanhua

2010-01-01

A two-dimensional (2D) scanning micro-mirror for target detection and measurement has been developed. This new micro-mirror is used in a MOEMS target detector to replace the conventional scanning detector. The micro-mirror is fabricated by MEMS process and actuated by a piezoelectric actuator. To achieve large deflection angles, the micro-mirror is excited in the resonance modes. It has two degrees of freedom and changes the direction of the emitted laser beam for a regional 2D scanning. For the deflection angles measurement, piezoresistors are integrated in the micro-mirror and the deflection angles of each direction can be detected independently and precisely. Based on the scanning micro-mirror and the phase-shift ranging technology, a MOEMS target detector has been developed in a size of 90 mm × 35 mm × 50 mm. The experiment shows that the target can be detected in the scanning field and the relative range and orientation can be measured by the MOEMS target detector. For the target distance up to 3 m with a field of view about 20° × 20°, the measurement resolution is about 10.2 cm in range, 0.15° in the horizontal direction and 0.22° in the vertical direction for orientation. PMID:22163580

2'-Hydroxyflavanone: A novel strategy for targeting breast cancer.

PubMed

Singhal, Jyotsana; Nagaprashantha, Lokesh; Chikara, Shireen; Awasthi, Sanjay; Horne, David; Singhal, Sharad S

2017-09-26

Breast cancer is the most common cancer in women that is driven by cross-talk with hormonal and cellular signaling pathways. The natural phytochemicals, due to broad-spectrum anti-inflammatory and anti-cancerous properties, present with novel opportunities for targeting breast cancer. Intake of citrus fruits is known to reduce the risk for incidence of breast cancer. Hence, we tested the efficacy of citrus flavonoid 2'-hydroxyflavanone (2HF) in breast cancer. 2HF inhibited survival, clonogenic ability, cell cycle progression and induced apoptosis in breast cancer cells. 2HF also decreased VEGF levels and inhibited migratory capacity of breast cancer cells. Administration of 2HF led to regression of triple-negative MDA-MB-231 tumors in the mice xenograft model. 2HF decreased the levels of RLIP76 both in vitro studies and in vivo MDA-MB-231 xenograft model of breast cancer. Western blot and histopathological analyses of resected tumors showed a decline in the levels of survival and proliferation markers Ki67, pAkt, survivin, and cell cycle proteins CDK4 and cyclin B1. 2HF treatment led to inhibition of angiogenesis as determined by decreased VEGF levels in vitro and angiogenesis marker CD31 in vivo . 2HF reversed the pro-/anti-apoptotic ratio of BAX/BCL-2 by decreasing anti-apoptotic protein BCL-2 and increasing pro-apoptotic proteins BAX and BIM in vivo . 2HF also decreased the mesenchymal markers vimentin and fibronectin along with causing a parallel increase in pro-differentiation protein E-cadherin. Collectively, the ability of 2HF to decrease RLIP76, VEGF and regulate critical proliferative, apoptotic and differentiation proteins together provides strong rationale to further develop 2HF based interventions for targeting breast cancer.

SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation.

PubMed

Kidder, Benjamin L; Hu, Gangqing; Cui, Kairong; Zhao, Keji

2017-01-01

Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone 4 lysine 20 (H4K20me3) in pluripotency and development are largely unknown. Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5-bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and perturbed differentiation of SMYD5-depleted ES cells. Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin.

MiRNA-20 and mirna-106a regulate spermatogonial stem cell renewal at the post-transcriptional level via targeting STAT3 and Ccnd1.

PubMed

He, Zuping; Jiang, Jiji; Kokkinaki, Maria; Tang, Lin; Zeng, Wenxian; Gallicano, Ian; Dobrinski, Ina; Dym, Martin

2013-10-01

Studies on spermatogonial stem cells (SSCs) are of unusual significance because they are the unique stem cells that transmit genetic information to subsequent generations and they can acquire pluripotency to become embryonic stem-like cells that have therapeutic applications in human diseases. MicroRNAs (miRNAs) have recently emerged as critical endogenous regulators in mammalian cells. However, the function and mechanisms of individual miRNAs in regulating SSC fate remain unknown. Here, we report for the first time that miRNA-20 and miRNA-106a are preferentially expressed in mouse SSCs. Functional assays in vitro and in vivo using miRNA mimics and inhibitors reveal that miRNA-20 and miRNA-106a are essential for renewal of SSCs. We further demonstrate that these two miRNAs promote renewal at the post-transcriptional level via targeting STAT3 and Ccnd1 and that knockdown of STAT3, Fos, and Ccnd1 results in renewal of SSCs. This study thus provides novel insights into molecular mechanisms regulating renewal and differentiation of SSCs and may have important implications for regulating male reproduction. © AlphaMed Press.

[Accuracy of Modulation Transfer Function for Target Size and Field of View in a Circular Edge Strategy Using the CT Image Measurement Program].

PubMed

Fukunaga, Masaaki; Onishi, Hideo; Matsutomo, Norikazu; Yamamoto, Hiroyuki

2016-06-01

The purpose of this study was to evaluate the effects of target diameter and display-field of view (D-FOV) in modulation transfer function (MTF) by circular edge strategy using the computed tomography (CT) image measurement program "CTmeasure". We calculated the MTF (MTF(edge)) using the circular edge strategy applied to cylindrical phantom (200 mmφ) that inserted with cylinders have 10, 20, 30, and 40 mm diameters. The phantom images were reconstructed using filtered back projection method varied with D-FOV (240, 320, 400, and 500 mm). The study compared both MTF(edge) and MTF(wire) at MTF50% and MTF(10%) for target diameter and D-FOV, respectively. The MTF(edge) by the different of target diameter indicated in rough compatibility. However, MTF(edge) of D-FOV diameters (320, 400, and 500 mm) decreased in the high frequency range. The circular edge strategy for MTF depended on the D-FOV, however, it was little dependent on target diameter using the CT image measurement program "CTmeasure".

Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice.

PubMed

Gioscia-Ryan, Rachel A; Battson, Micah L; Cuevas, Lauren M; Eng, Jason S; Murphy, Michael P; Seals, Douglas R

2018-05-01

Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes-including collagen overabundance and elastin degradation-and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk. Both baseline and postintervention aPWV values were higher in OC vs. YC (post: 482 ± 21 vs. 420 ± 5 cm/s, P < 0.05). MitoQ had no effect in young mice but decreased aPWV in old mice (OMQ, 426 ± 20, P < 0.05 vs. OC). MitoQ did not affect age-associated increases in aortic collagen-region EM, collagen expression, or proinflammatory cytokine expression, but partially attenuated age-associated decreases in elastin region EM and elastin expression. Our results demonstrate that MitoQ reverses in vivo aortic stiffness in old mice and suggest that mitochondria-targeted antioxidants may represent a novel, promising therapeutic strategy for decreasing aortic stiffness with primary aging and, possibly, age-related clinical disorders in humans. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation/reversal of age-related aortic elastin degradation. NEW & NOTEWORTHY We show that 4 wk of treatment with the mitochondria-specific antioxidant MitoQ in mice completely reverses the age-associated elevation in aortic stiffness

Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice

PubMed Central

Gioscia-Ryan, Rachel A.; Battson, Micah L.; Cuevas, Lauren M.; Eng, Jason S.; Murphy, Michael P.

2018-01-01

Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes—including collagen overabundance and elastin degradation—and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk. Both baseline and postintervention aPWV values were higher in OC vs. YC (post: 482 ± 21 vs. 420 ± 5 cm/s, P < 0.05). MitoQ had no effect in young mice but decreased aPWV in old mice (OMQ, 426 ± 20, P < 0.05 vs. OC). MitoQ did not affect age-associated increases in aortic collagen-region EM, collagen expression, or proinflammatory cytokine expression, but partially attenuated age-associated decreases in elastin region EM and elastin expression. Our results demonstrate that MitoQ reverses in vivo aortic stiffness in old mice and suggest that mitochondria-targeted antioxidants may represent a novel, promising therapeutic strategy for decreasing aortic stiffness with primary aging and, possibly, age-related clinical disorders in humans. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation/reversal of age-related aortic elastin degradation. NEW & NOTEWORTHY We show that 4 wk of treatment with the mitochondria-specific antioxidant MitoQ in mice completely reverses the age-associated elevation in aortic stiffness

MetaRanker 2.0: a web server for prioritization of genetic variation data

PubMed Central

Pers, Tune H.; Dworzyński, Piotr; Thomas, Cecilia Engel; Lage, Kasper; Brunak, Søren

2013-01-01

MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein–protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, MetaRanker 2.0 prioritizes the protein-coding part of the human genome to shortlist candidate genes for targeted follow-up studies. MetaRanker 2.0 is made freely available at www.cbs.dtu.dk/services/MetaRanker-2.0. PMID:23703204

Commissioning a Rotating Target Wheel Assembly for Heavy Element Studies

NASA Astrophysics Data System (ADS)

Fields, L. D.; Bennett, M. E.; Mayorov, D. A.; Folden, C. M.

2013-10-01

The heaviest elements are produced artificially by fusing nuclei of light elements within an accelerator to form heavier nuclei. The most direct method to increase the production rate of nuclei is to increase the beam intensity, necessitating the use of a rotating target to minimize damage to the target by deposited heat. Such a target wheel was constructed for heavy element research at Texas A&M University, Cyclotron Institute, consisting of a wheel with three banana-shaped target cutouts. The target is designed to rotate at 1700 rpm, and a fiber optic cable provides a signal to trigger beam pulsing in order to avoid irradiating the spokes between target segments. Following minor mechanical modifications and construction of a dedicated electrical panel, the rotating target assembly was commissioned for a beam experiment. A 15 MeV/u beam of 20Ne was delivered from the K500 cyclotron and detected by a ruggedized silicon detector. The beam pulsing response time was characterized as a function of the rational frequency of the target wheel. Preliminary analysis suggests that the K500 is capable of pulsing at rates of up to 250 Hz, which is sufficient for planned future experiments. Funded by DOE and NSF-REU Program.

Biosonar signals impinging on the target during interception by big brown bats, Eptesicus fuscus.

PubMed

Saillant, Prestor A; Simmons, James A; Bouffard, Frederick H; Lee, David N; Dear, Steven P

2007-05-01

Big brown bats (Eptesicus fuscus) were videotaped in the dark with a night-vision lens and infrared illumination while flying repeatedly along the same straight course to seize a tethered mealworm or a small electret microphone used to record biosonar signals impinging on the target. Bats emitted frequency-modulated sounds with first to third harmonics covering frequencies from 23 to 105 kHz. As the bats neared the target, the first harmonic shifted lower in frequency while the third harmonic strengthened and the fourth harmonic, and sometimes the fifth harmonic, appeared. Incident-sound bandwidth remained broad throughout the maneuver, a feature not seen in field recordings of rapidly moving bats due to propagation losses and uncontrolled directional effects. Sound pressures at the microphone increased by about 20 dB during approach from 2.5 m down to 50 cm and then leveled off, indicating that emitted amplitudes were approximately constant until the terminal stage, when they progressively decreased for the remainder of the maneuver. Interpulse intervals decreased from 80-100 ms down to about 6-7 ms and then stabilized throughout the terminal stage, while durations decreased smoothly from 3-4 ms (limited by adjacent wall) down to 0.5 ms during the terminal stage, which ended with capture.

An increase or a decrease in myosin II phosphorylation inhibits macrophage motility

PubMed Central

1991-01-01

Myosin II purified from mammalian non-muscle cells is phosphorylated on the 20-kD light chain subunit (MLC20) by the Ca2+/calmodulin-dependent enzyme myosin light chain kinase (MLCK). The importance of MLC20 phosphorylation in regulating cell motility was investigated by introducing either antibodies to MLCK (MK-Ab) or a Ca2+/calmodulin- independent, constitutively active form of MLCK (MK-) into macrophages. The effects of these proteins on cell motility were then determined using a quantitative chemotaxis assay. Chemotaxis is significantly diminished in macrophages containing MK-Ab compared to macrophages containing control antibodies. Moreover, there is an inverse relationship between the number of cells that migrate and the amount of MK-Ab introduced into cells. Interestingly, there is also an inverse relationship between the number of cells that migrate and the amount of MK- introduced into cells. Other experiments demonstrated that MK-Ab decreased intracellular MLC20 phosphorylation while MK- increased MLC20 phosphorylation. MK- also increased the amount of myosin associated with the cytoskeleton. These data demonstrate that the regulation of MLCK is an important aspect of cell motility and suggest that MLC20 phosphorylation must be maintained within narrow limits during translational motility by mammalian cells. PMID:2071674

Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease.

PubMed

Park, Steven I; Shenoi, Jaideep; Pagel, John M; Hamlin, Don K; Wilbur, D Scott; Orgun, Nural; Kenoyer, Aimee L; Frayo, Shani; Axtman, Amanda; Bäck, Tom; Lin, Yukang; Fisher, Darrell R; Gopal, Ajay K; Green, Damian J; Press, Oliver W

2010-11-18

Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (²¹³Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [²¹³Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)₄SA was 16.5% ± 7.0% injected dose per gram compared with 2.3% ± .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 μ Ci [²¹³Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 ± .02 vs. 203.38 ± 83.03 mm³ after 19 days, respectively). The median survival for the 1F5(scFv)₄SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with ²¹³Bi-labeled anti-CD20 PRIT.

Glucocorticosteroids associated with a decreased risk of psychosis.

PubMed

Laan, Wijnand; Smeets, Hugo; de Wit, Niek J; Kahn, René S; Grobbee, Diederick E; Burger, Huibert

2009-06-01

The hypothesis that chronic inflammation may play a role in psychosis receives increasing attention. In this study, we aim to investigate whether the use of steroidal anti-inflammatory drugs is associated with a decreased risk of psychosis.A longitudinal nested case-control study was performed investigating the association of glucocorticosteroid (GCS) consumption with a new diagnosis of a psychotic disorder. Significantly reduced odds ratios of 0.52 (95% confidence interval, 0.36-0.75) were found for GCS in men only (odds ratio in women, 0.84 [95% confidence interval, 0.590-1.20]). Similar risk reductions were present for the inhaled and systemic GCSs. A dose-response relationship was present. Our finding of an inverse relation between GCS consumption and new psychotic episodes may promote further research into inflammation in schizophrenia.

A quick reality check for microRNA target prediction.

PubMed

Kast, Juergen

2011-04-01

The regulation of protein abundance by microRNA (miRNA)-mediated repression of mRNA translation is a rapidly growing area of interest in biochemical research. In animal cells, the miRNA seed sequence does not perfectly match that of the mRNA it targets, resulting in a large number of possible miRNA targets and varied extents of repression. Several software tools are available for the prediction of miRNA targets, yet the overlap between them is limited. Jovanovic et al. have developed and applied a targeted, quantitative approach to validate predicted miRNA target proteins. Using a proteome database, they have set up and tested selected reaction monitoring assays for approximately 20% of more than 800 predicted let-7 targets, as well as control genes in Caenorhabditis elegans. Their results demonstrate that such assays can be developed quickly and with relative ease, and applied in a high-throughput setup to verify known and identify novel miRNA targets. They also show, however, that the choice of the biological system and material has a noticeable influence on the frequency, extent and direction of the observed changes. Nonetheless, selected reaction monitoring assays, such as those developed by Jovanovic et al., represent an attractive new tool in the study of miRNA function at the organism level.

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

Eye-Head Coordination in 31 Space Shuttle Astronauts during Visual Target Acquisition.

PubMed

Reschke, Millard F; Kolev, Ognyan I; Clément, Gilles

2017-10-27

Between 1989 and 1995, NASA evaluated how increases in flight duration of up to 17 days affected the health and performance of Space Shuttle astronauts. Thirty-one Space Shuttle pilots participating in 17 space missions were tested at 3 different times before flight and 3 different times after flight, starting within a few hours of return to Earth. The astronauts moved their head and eyes as quickly as possible from the central fixation point to a specified target located 20°, 30°, or 60° off center. Eye movements were measured with electro-oculography (EOG). Head movements were measured with a triaxial rate sensor system mounted on a headband. The mean time to visually acquire the targets immediately after landing was 7-10% (30-34 ms) slower than mean preflight values, but results returned to baseline after 48 hours. This increase in gaze latency was due to a decrease in velocity and amplitude of both the eye saccade and head movement toward the target. Results were similar after all space missions, regardless of length.

A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma

PubMed Central

Faltermeier, Claire; Busuttil, Ronald W.; Zarrinpar, Ali

2015-01-01

Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%–30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC. PMID:28943622

SeedVicious: Analysis of microRNA target and near-target sites.

PubMed

Marco, Antonio

2018-01-01

Here I describe seedVicious, a versatile microRNA target site prediction software that can be easily fitted into annotation pipelines and run over custom datasets. SeedVicious finds microRNA canonical sites plus other, less efficient, target sites. Among other novel features, seedVicious can compute evolutionary gains/losses of target sites using maximum parsimony, and also detect near-target sites, which have one nucleotide different from a canonical site. Near-target sites are important to study population variation in microRNA regulation. Some analyses suggest that near-target sites may also be functional sites, although there is no conclusive evidence for that, and they may actually be target alleles segregating in a population. SeedVicious does not aim to outperform but to complement existing microRNA prediction tools. For instance, the precision of TargetScan is almost doubled (from 11% to ~20%) when we filter predictions by the distance between target sites using this program. Interestingly, two adjacent canonical target sites are more likely to be present in bona fide target transcripts than pairs of target sites at slightly longer distances. The software is written in Perl and runs on 64-bit Unix computers (Linux and MacOS X). Users with no computing experience can also run the program in a dedicated web-server by uploading custom data, or browse pre-computed predictions. SeedVicious and its associated web-server and database (SeedBank) are distributed under the GPL/GNU license.

Repurposing the CRISPR-Cas9 system for targeted DNA methylation.

PubMed

Vojta, Aleksandar; Dobrinić, Paula; Tadić, Vanja; Bočkor, Luka; Korać, Petra; Julg, Boris; Klasić, Marija; Zoldoš, Vlatka

2016-07-08

Epigenetic studies relied so far on correlations between epigenetic marks and gene expression pattern. Technologies developed for epigenome editing now enable direct study of functional relevance of precise epigenetic modifications and gene regulation. The reversible nature of epigenetic modifications, including DNA methylation, has been already exploited in cancer therapy for remodeling the aberrant epigenetic landscape. However, this was achieved non-selectively using epigenetic inhibitors. Epigenetic editing at specific loci represents a novel approach that might selectively and heritably alter gene expression. Here, we developed a CRISPR-Cas9-based tool for specific DNA methylation consisting of deactivated Cas9 (dCas9) nuclease and catalytic domain of the DNA methyltransferase DNMT3A targeted by co-expression of a guide RNA to any 20 bp DNA sequence followed by the NGG trinucleotide. We demonstrated targeted CpG methylation in a ∼35 bp wide region by the fusion protein. We also showed that multiple guide RNAs could target the dCas9-DNMT3A construct to multiple adjacent sites, which enabled methylation of a larger part of the promoter. DNA methylation activity was specific for the targeted region and heritable across mitotic divisions. Finally, we demonstrated that directed DNA methylation of a wider promoter region of the target loci IL6ST and BACH2 decreased their expression. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Rasch Analysis of the Adult Strabismus Quality of Life Questionnaire (AS-20) among Chinese Adult Patients with Strabismus.

PubMed

Wang, Zonghua; Zhou, Juan; Luo, Xingli; Xu, Yan; She, Xi; Chen, Ling; Yin, Honghua; Wang, Xianyuan

2015-01-01

The impact of strabismus on visual function, self-image, self-esteem, and social interactions decrease health-related quality of life (HRQoL).The purpose of this study was to evaluate and refine the adult strabismus quality of life questionnaire (AS-20) by using Rasch analysis among Chinese adult patients with strabismus. We evaluated the fitness of the AS-20 with Rasch model in Chinese population by assessing unidimensionality, infit and outfit, person and item separation index and reliability, response ordering, targeting and differential item functioning (DIF). The overall AS-20 did not demonstrate unidimensional; however, it was achieved separately in the two Rasch-revised subscales: the psychosocial subscale (11 items) and the function subscale (9 items). The features of good targeting, optimal item infit and outfit, and no notable local dependence were found for each of the subscales. The rating scale was appropriate for the psychosocial subscale but a reduction to four response categories was required for the function subscale. No significant DIF were revealed for any demographic and clinical factors (e.g., age, gender, and strabismus types). The AS-20 was demonstrated by Rasch analysis to be a rigorous instrument for measuring health-related quality of life in Chinese strabismus patents if some revisions were made regarding the subscale construct and response options.

psRNATarget: a plant small RNA target analysis server

PubMed Central

Dai, Xinbin; Zhao, Patrick Xuechun

2011-01-01

Plant endogenous non-coding short small RNAs (20–24 nt), including microRNAs (miRNAs) and a subset of small interfering RNAs (ta-siRNAs), play important role in gene expression regulatory networks (GRNs). For example, many transcription factors and development-related genes have been reported as targets of these regulatory small RNAs. Although a number of miRNA target prediction algorithms and programs have been developed, most of them were designed for animal miRNAs which are significantly different from plant miRNAs in the target recognition process. These differences demand the development of separate plant miRNA (and ta-siRNA) target analysis tool(s). We present psRNATarget, a plant small RNA target analysis server, which features two important analysis functions: (i) reverse complementary matching between small RNA and target transcript using a proven scoring schema, and (ii) target-site accessibility evaluation by calculating unpaired energy (UPE) required to ‘open’ secondary structure around small RNA’s target site on mRNA. The psRNATarget incorporates recent discoveries in plant miRNA target recognition, e.g. it distinguishes translational and post-transcriptional inhibition, and it reports the number of small RNA/target site pairs that may affect small RNA binding activity to target transcript. The psRNATarget server is designed for high-throughput analysis of next-generation data with an efficient distributed computing back-end pipeline that runs on a Linux cluster. The server front-end integrates three simplified user-friendly interfaces to accept user-submitted or preloaded small RNAs and transcript sequences; and outputs a comprehensive list of small RNA/target pairs along with the online tools for batch downloading, key word searching and results sorting. The psRNATarget server is freely available at http://plantgrn.noble.org/psRNATarget/. PMID:21622958

Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer

PubMed Central

Johnson, Jennifer M; Lai, Stephen Y.; Cotzia, Paolo; Cognetti, David; Luginbuhl, Adam; Pribitkin, Edmund A.; Zhan, Tingting; Mollaee, Mehri; Domingo-Vidal, Marina; Chen, Yunyun; Campling, Barbara; Bar-Ad, Voichita; Birbe, Ruth; Tuluc, Madalina; Outschoorn, Ubaldo Martinez; Curry, Joseph

2015-01-01

Aims Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically Monocarboxylate Transporter 1 (MCT1) and Translocase of the Outer Mitochondrial Membrane Member 20 (TOMM20). Methods Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer (PTC), and 8 non-cancerous thyroid) and 9 ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. Results MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (p<0.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (p<0.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (p<0.001). These xenograft tumors have high 13C- pyruvate uptake. Conclusions Anaplastic thyroid cancer has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target. PMID:26615136

Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer.

PubMed

Johnson, Jennifer M; Lai, Stephen Y; Cotzia, Paolo; Cognetti, David; Luginbuhl, Adam; Pribitkin, Edmund A; Zhan, Tingting; Mollaee, Mehri; Domingo-Vidal, Marina; Chen, Yunyun; Campling, Barbara; Bar-Ad, Voichita; Birbe, Ruth; Tuluc, Madalina; Martinez Outschoorn, Ubaldo; Curry, Joseph

2015-12-01

Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

ClinicalKey 2.0: Upgrades in a Point-of-Care Search Engine.

PubMed

Huslig, Mary Ann; Vardell, Emily

2015-01-01

ClinicalKey 2.0, launched September 23, 2014, offers a mobile-friendly design with a search history feature for targeting point-of-care resources for health care professionals. Browsing is improved with searchable, filterable listings of sources highlighting new resources. ClinicalKey 2.0 improvements include more than 1,400 new Topic Pages for quick access to point-of-care content. A sample search details some of the upgrades and content options.

WE-D-18A-04: How Iterative Reconstruction Algorithms Affect the MTFs of Variable-Contrast Targets in CT Images

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

Dodge, C.T.; Rong, J.; Dodge, C.W.

2014-06-15

Purpose: To determine how filtered back-projection (FBP), adaptive statistical (ASiR), and model based (MBIR) iterative reconstruction algorithms affect the measured modulation transfer functions (MTFs) of variable-contrast targets over a wide range of clinically applicable dose levels. Methods: The Catphan 600 CTP401 module, surrounded by an oval, fat-equivalent ring to mimic patient size/shape, was scanned on a GE HD750 CT scanner at 1, 2, 3, 6, 12 and 24 mGy CTDIvol levels with typical patient scan parameters: 120kVp, 0.8s, 40mm beam width, large SFOV, 2.5mm thickness, 0.984 pitch. The images were reconstructed using GE's Standard kernel with FBP; 20%, 40% andmore » 70% ASiR; and MBIR. A task-based MTF (MTFtask) was computed for six cylindrical targets: 2 low-contrast (Polystyrene, LDPE), 2 medium-contrast (Delrin, PMP), and 2 high-contrast (Teflon, air). MTFtask was used to compare the performance of reconstruction algorithms with decreasing CTDIvol from 24mGy, which is currently used in the clinic. Results: For the air target and 75% dose savings (6 mGy), MBIR MTFtask at 5 lp/cm measured 0.24, compared to 0.20 for 70% ASiR and 0.11 for FBP. Overall, for both high-contrast targets, MBIR MTFtask improved with increasing CTDIvol and consistently outperformed ASiR and FBP near the system's Nyquist frequency. Conversely, for Polystyrene at 6 mGy, MBIR (0.10) and 70% ASiR (0.07) MTFtask was lower than for FBP (0.18). For medium and low-contrast targets, FBP remains the best overall algorithm for improved resolution at low CTDIvol (1–6 mGy) levels, whereas MBIR is comparable at higher dose levels (12–24 mGy). Conclusion: MBIR improved the MTF of small, high-contrast targets compared to FBP and ASiR at doses of 50%–12.5% of those currently used in the clinic. However, for imaging low- and mediumcontrast targets, FBP performed the best across all dose levels. For assessing MTF from different reconstruction algorithms, task-based MTF measurements are necessary.« less

Tumor Specific Detection of an Optically Targeted Antibody Combined with a Quencher-conjugated Neutravidin “Quencher-Chaser”: A Dual “Quench and Chase” Strategy to Improve Target to Non-target Ratios for Molecular Imaging of Cancer

PubMed Central

Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L; Kobayashi, Hisataka

2009-01-01

In vivo molecular cancer imaging with monoclonal antibodies has great potential not only for cancer detection but also for cancer characterization. However, the prolonged retention of intravenously injected antibody in the blood causes low target tumor-to-background ratio (TBR). Avidin has been used as a “chase” to clear the unbound, circulating biotinylated antibody and decrease the background signal. Here, we utilize a combined approach of a Fluorescence Resonance Energy Transfer (FRET) quenched antibody with an “avidin chase” to increase TBR. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), was biotinylated and conjugated with the near-infrared (NIR) fluorophore Alexa680 to synthesize Tra-Alexa680-biotin. Next, the FRET quencher, QSY-21, was conjugated to avidin, neutravidin (nAv) or streptavidin (sAv), thus creating Av-QSY21, nAv-QSY21 or sAv-QSY21 as “chasers”. The fluorescence was quenched in vitro by binding Tra-Alexa680-biotin to Av-QSY21, nAv-QSY21 or sAv-QSY21. To evaluate if the injection of quencher-conjugated avidin-derivatives can improve target TBR by using a dual “quench and chase” strategy, both target (3T3/HER2+) and non-target (Balb3T3/ZsGreen) tumor bearing mice were employed. The “FRET quench” effect induced by all the QSY21 avidin-based conjugates reduced but did not totally eliminate background signal from the blood pool. The addition of nAv-QSY21 administration increased target TBR mainly due to the “chase” effect where unbound conjugated antibody was preferentially cleared to the liver. The relatively slow clearance of unbound nAv-QSY21 leads to further reductions in background signal by leaking out of the vascular space and binding to unbound antibodies in the extravascular space of tumors resulting in decreased non-target tumor-to-background ratios but increased target TBR due to the “FRET quench” effect because target-bound antibodies were internalized

Solar-geophysical activity reports for STIP (study of travelling interplanetary phenomena) Interval 15, 12-21 February 1984 ground-level event and STIP Interval 16, 20 April-4 May 1984 Forbush decrease

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

Coffey, H.E.; Allen, J.H.

1987-07-01

Contents include: solar-geophysical activity reports for STIP Interval XV 12-21 February 1984 ground-level event and STIP interval XVI 20 April-4 May 1984 Forbush decrease; overview of solar-terrestrial physics phenomena for STIP interval XV (12-21 February 1984) and STIP interval XVI (20 April-4 May 1984) (solar optical reports, solar radio events, spacecraft observations, cosmic ray observations, ionosphere, geomagnetism).

Home interventions are effective at decreasing indoor nitrogen dioxide concentrations.

PubMed

Paulin, L M; Diette, G B; Scott, M; McCormack, M C; Matsui, E C; Curtin-Brosnan, J; Williams, D L; Kidd-Taylor, A; Shea, M; Breysse, P N; Hansel, N N

2014-08-01

Nitrogen dioxide (NO2 ), a by-product of combustion produced by indoor gas appliances such as cooking stoves, is associated with respiratory symptoms in those with obstructive airways disease. We conducted a three-armed randomized trial to evaluate the efficacy of interventions aimed at reducing indoor NO2 concentrations in homes with unvented gas stoves: (i) replacement of existing gas stove with electric stove; (ii) installation of ventilation hood over existing gas stove; and (iii) placement of air purifiers with high-efficiency particulate air (HEPA) and carbon filters. Home inspection and NO2 monitoring were conducted at 1 week pre-intervention and at 1 week and 3 months post-intervention. Stove replacement resulted in a 51% and 42% decrease in median NO2 concentration at 3 months of follow-up in the kitchen and bedroom, respectively (P = 0.01, P = 0.01); air purifier placement resulted in an immediate decrease in median NO2 concentration in the kitchen (27%, P < 0.01) and bedroom (22%, P = 0.02), but at 3 months, a significant reduction was seen only in the kitchen (20%, P = 0.05). NO2 concentrations in the kitchen and bedroom did not significantly change following ventilation hood installation. Replacing unvented gas stoves with electric stoves or placement of air purifiers with HEPA and carbon filters can decrease indoor NO2 concentrations in urban homes. Several combustion sources unique to the residential indoor environment, including gas stoves, produce nitrogen dioxide (NO2), and higher NO2 concentrations, are associated with worse respiratory morbidity in people with obstructive lung disease. A handful of studies have modified the indoor environment by replacing unvented gas heaters; this study, to our knowledge, is the first randomized study to target unvented gas stoves. The results of this study show that simple home interventions, including replacement of an unvented gas stove with an electric stove or placement of HEPA air purifiers with carbon

Sex and Age Differences in Target Choice on an Aggressive Task.

ERIC Educational Resources Information Center

Campbell, James N.; Nadelman, Lorraine

The role of inhibition as related to sex differences in aggression was investigated using 20 nursery school and 20 second grade children. A dart gun was employed, with choices of four targets--drawings of a boy, a girl, a zebra, and an object. There were three sessions and eight target choices per session. Choice of the human target was assumed to…

A free-jet Hg target operating in a high magnetic field intersecting a high-power proton beam

NASA Astrophysics Data System (ADS)

Graves, Van; Spampinato, Philip; Gabriel, Tony; Kirk, Harold; Simos, Nicholas; Tsang, Thomas; McDonald, Kirk; Peter Titus; Fabich, Adrian; Haseroth, Helmut; Lettry, Jacques

2006-06-01

A proof-of-principal experiment to investigate the interaction of a proton beam, high magnetic field, and high-Z target is planned to take place at CERN in early 2007. This experiment is part of the Muon Collider Collaboration, with participants from Brookhaven National Laboratory, Princeton University, Massachusetts Institute Of Technology, European Organization for Nuclear Research-CERN, Rutherford Appleton Laboratory, and Oak Ridge National Laboratory. An unconstrained mercury jet target system that interacts with a high power (1 MW) proton beam in a high magnetic field (15 T) is being designed. The Hg jet diameter is 1-cm with a velocity up to 20 m/s. A laser optical diagnostic system will be incorporated into the target design to permit observation of the dispersal of the jet resulting from interaction with a 24 GeV proton beam with up to 20×1012 ppp. The target system includes instruments for sensing mercury vapor, temperature, flow rate, and sump tank level, and the means to position the jet relative to the magnetic axis of a solenoid and the proton beam. The design considerations for the system include all issues dealing with safely handling approximately 23 l of Hg, transporting the target system and the mercury to CERN, decommissioning the experiment, and returning the mildly activated equipment and Hg to the US.

A free-jet Hg target operating in a high magnetic field intersecting a high-power proton beam

NASA Astrophysics Data System (ADS)

Van Graves; Spampinato, Philip; Gabriel, Tony; Kirk, Harold; Simos, Nicholas; Tsang, Thomas; McDonald, Kirk; Peter Titus; Fabich, Adrian; Haseroth, Helmut; Lettry, Jacques

2006-06-01

A proof-of-principal experiment to investigate the interaction of a proton beam, high magnetic field, and high- Z target is planned to take place at CERN in early 2007. This experiment is part of the Muon Collider Collaboration, with participants from Brookhaven National Laboratory, Princeton University, Massachusetts Institute Of Technology, European Organization for Nuclear Research-CERN, Rutherford Appleton Laboratory, and Oak Ridge National Laboratory. An unconstrained mercury jet target system that interacts with a high power (1 MW) proton beam in a high magnetic field (15 T) is being designed. The Hg jet diameter is 1-cm with a velocity up to 20 m/s. A laser optical diagnostic system will be incorporated into the target design to permit observation of the dispersal of the jet resulting from interaction with a 24 GeV proton beam with up to 20×10 12 ppp. The target system includes instruments for sensing mercury vapor, temperature, flow rate, and sump tank level, and the means to position the jet relative to the magnetic axis of a solenoid and the proton beam. The design considerations for the system include all issues dealing with safely handling approximately 23 l of Hg, transporting the target system and the mercury to CERN, decommissioning the experiment, and returning the mildly activated equipment and Hg to the US.

Smooth Pursuit Eye Movement Deficits in Patients With Whiplash and Neck Pain are Modulated by Target Predictability.

PubMed

Janssen, Malou; Ischebeck, Britta K; de Vries, Jurryt; Kleinrensink, Gert-Jan; Frens, Maarten A; van der Geest, Jos N

2015-10-01

This is a cross-sectional study. The purpose of this study is to support and extend previous observations on oculomotor disturbances in patients with neck pain and whiplash-associated disorders (WADs) by systematically investigating the effect of static neck torsion on smooth pursuit in response to both predictably and unpredictably moving targets using video-oculography. Previous studies showed that in patients with neck complaints, for instance due to WAD, extreme static neck torsion deteriorates smooth pursuit eye movements in response to predictably moving targets compared with healthy controls. Eye movements in response to a smoothly moving target were recorded with video-oculography in a heterogeneous group of 55 patients with neck pain (including 11 patients with WAD) and 20 healthy controls. Smooth pursuit performance was determined while the trunk was fixed in 7 static rotations relative to the head (from 45° to the left to 45° to right), using both predictably and unpredictably moving stimuli. Patients had reduced smooth pursuit gains and smooth pursuit gain decreased due to neck torsion. Healthy controls showed higher gains for predictably moving targets compared with unpredictably moving targets, whereas patients with neck pain had similar gains in response to both types of target movements. In 11 patients with WAD, increased neck torsion decreased smooth pursuit performance, but only for predictably moving targets. Smooth pursuit of patients with neck pain is affected. The previously reported WAD-specific decline in smooth pursuit due to increased neck torsion seems to be modulated by the predictability of the movement of the target. The observed oculomotor disturbances in patients with WAD are therefore unlikely to be induced by impaired neck proprioception alone. 3.

Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

PubMed

Gao, Jian-Qing; Lv, Qing; Li, Li-Ming; Tang, Xin-Jiang; Li, Fan-Zhu; Hu, Yu-Lan; Han, Min

2013-07-01

Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting inflammation in diabetes: Newer therapeutic options

PubMed Central

Agrawal, Neeraj Kumar; Kant, Saket

2014-01-01

Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications. PMID:25317247

Association Between Hospital Penalty Status Under the Hospital Readmission Reduction Program and Readmission Rates for Target and Non-Target Conditions

PubMed Central

Desai, Nihar R.; Ross, Joseph S.; Kwon, Ji Young; Herrin, Jeph; Dharmarajan, Kumar; Bernheim, Susannah M.; Krumholz, Harlan M.; Horwitz, Leora I.

2017-01-01

Importance Readmission rates declined after announcement of the Hospital Readmission Reduction Program (HRRP), which penalizes hospitals for excess readmissions for acute myocardial infarction (AMI), heart failure (HF), and pneumonia. Objective To compare trends in readmission rates for target and non-target conditions, stratified by hospital penalty status. Design, Setting, Participants Retrospective cohort study of 48,137,102 hospitalizations of 20,351,161 Medicare fee-for-service beneficiaries over 64 years discharged between January 1, 2008 and June 30, 2015 from 3,497 hospitals. Difference interrupted time series models were used to compare trends in readmission rates by condition and penalty status. Exposure Hospital penalty status or target condition under the HRRP. Outcome 30-day risk adjusted, all-cause unplanned readmission rates for target and non-target conditions. Results In January 2008, the mean readmission rates for AMI, HF, pneumonia and non-target conditions were 21.9%, 27.5%, 20.1%, and 18.4% respectively at hospitals later subject to financial penalties (n=2,189) and 18.7%, 24.2%, 17.4%, and 15.7% at hospitals not subject to penalties (n=1,283). Between January 2008 and March 2010, prior to HRRP announcement, readmission rates were stable across hospitals (except AMI at non-penalty hospitals). Following announcement of HRRP (March 2010), readmission rates for both target and non-target conditions declined significantly faster for patients at hospitals later subject to financial penalties compared with those at non-penalized hospitals (AMI, additional decrease of −1.24 (95% CI, −1.84, −0.65) percentage points per year relative to non-penalty discharges; HF, −1.25 (−1.64, −0.65); pneumonia, −1.37 (−0.95, −1.80); non-target, −0.27 (−0.38, −0.17); p<0.001 for all). For penalty hospitals, readmission rates for target conditions declined significantly faster compared with non-target conditions (AMI: additional decline of −0

Impact of the national targeted Hepatitis A immunisation program in Australia: 2000-2014.

PubMed

Thompson, Craig; Dey, Aditi; Fearnley, Emily; Polkinghorne, Benjamin; Beard, Frank

2017-01-03

In November 2005, hepatitis A vaccine was funded under the Australian National Immunisation Program for Aboriginal and Torres Strait Islander (Indigenous) children aged 12-24months in the targeted jurisdictions of Queensland, South Australia, Western Australia and the Northern Territory. We reviewed the epidemiology of hepatitis A from 2000 to 2014 using data from the Australian National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database, and Australian Bureau of Statistics causes-of-death data. The impact of the national hepatitis A immunisation program was assessed by comparison of pre-vaccine (2000-2005) and post-vaccine time periods (2006-2014), by age group, Indigenous status and jurisdiction using incidence rate ratios (IRR) per 100,000 population and 95% confidence intervals (CI). The national pre-vaccine notification rate in Indigenous people was four times higher than the non-Indigenous rate, and declined from 8.41 per 100,000 (95% CI 5.03-11.79) pre-vaccine to 0.85 per 100,000 (95% CI 0.00-1.99) post-vaccine, becoming similar to the non-Indigenous rate. Notification and hospitalisation rates in Indigenous children aged <5years from targeted jurisdictions declined in the post-vaccine period when compared to the pre-vaccine period (notifications: IRR=0.07; 95% CI 0.04-0.13; hospitalisations: IRR=0.04; 95% CI 0.01-0.16). As did notification rates in Indigenous people aged 5-19 (IRR=0.08; 95% CI 0.05-0.13) and 20-49years (IRR=0.06; 95% CI 0.02-0.15) in targeted jurisdictions. For non-Indigenous people from targeted jurisdictions, notification rates decreased significantly in children aged <5years (IRR 0.47; 95% CI 0.31-0.71), and significantly more overall (IRR=0.43; 95% CI 0.39-0.47) compared to non-Indigenous people from non-targeted jurisdictions (IRR=0.60; 95% CI 0.56-0.64). The national hepatitis A immunisation program has had a significant impact in the targeted population with relatively modest vaccine coverage, with

Optimal Systolic Blood Pressure Target After SPRINT: Insights from a Network Meta-Analysis of Randomized Trials.

PubMed

Bangalore, Sripal; Toklu, Bora; Gianos, Eugenia; Schwartzbard, Arthur; Weintraub, Howard; Ogedegbe, Gbenga; Messerli, Franz H

2017-06-01

The optimal on-treatment blood pressure (BP) target has been a matter of debate. The recent SPRINT trial showed significant benefits of a BP target of <120 mm Hg, albeit with an increase in serious adverse effects related to low BP. PubMed, EMBASE, and CENTRAL were searched for randomized trials comparing treating with different BP targets. Trial arms were grouped into 5 systolic BP target categories: 1) <160 mm Hg, 2) <150 mm Hg, 3) <140 mm Hg, 4) <130 mm Hg, and 5) <120 mm Hg. Efficacy outcomes of stroke, myocardial infarction, death, cardiovascular death, heart failure, and safety outcomes of serious adverse effects were evaluated using a network meta-analysis. Seventeen trials that enrolled 55,163 patients with 204,103 patient-years of follow-up were included. There was a significant decrease in stroke (rate ratio [RR] 0.54; 95% confidence interval [CI], 0.29-1.00) and myocardial infarction (RR 0.68; 95% CI, 0.47-1.00) with systolic BP <120 mm Hg (vs <160 mm Hg). Sensitivity analysis using achieved systolic BP showed a 72%, 97%, and 227% increase in stroke with systolic BP of <140 mm Hg, <150 mm Hg, and <160 mm, respectively, when compared with systolic BP <120 mm Hg. There was no difference in death, cardiovascular death, or heart failure when comparing any of the BP targets. However, the point estimate favored lower BP targets (<120 mm Hg, <130 mm Hg) when compared with higher BP targets (<140 mm Hg or <150 mm Hg). BP targets of <120 mm Hg and <130 mm Hg ranked #1 and #2, respectively, as the most efficacious target. There was a significant increase in serious adverse effects with systolic BP <120 mm Hg vs <150 mm Hg (RR 1.83; 95% CI, 1.05-3.20) or vs <140 mm Hg (RR 2.12; 95% CI, 1.46-3.08). BP targets of <140 mm Hg and <150 mm Hg ranked #1 and #2, respectively, as the safest target for the outcome of serious adverse effects. Cluster plots for combined efficacy and safety showed that a systolic BP target of <130 mm Hg had optimal balance between efficacy

Decreasing child mortality, spatial clustering and decreasing disparity in North-Western Burkina Faso.

PubMed

Becher, Heiko; Müller, Olaf; Dambach, Peter; Gabrysch, Sabine; Niamba, Louis; Sankoh, Osman; Simboro, Seraphin; Schoeps, Anja; Stieglbauer, Gabriele; Yé, Yazoume; Sié, Ali

2016-04-01

Within relatively small areas, there exist high spatial variations of mortality between villages. In rural Burkina Faso, with data from 1993 to 1998, clusters of particularly high child mortality were identified in the population of the Nouna Health and Demographic Surveillance System (HDSS), a member of the INDEPTH Network. In this paper, we report child mortality with respect to temporal trends, spatial clustering and disparity in this HDSS from 1993 to 2012. Poisson regression was used to describe village-specific child mortality rates and time trends in mortality. The spatial scan statistic was used to identify villages or village clusters with higher child mortality. Clustering of mortality in the area is still present, but not as strong as before. The disparity of child mortality between villages has decreased. The decrease occurred in the context of an overall halving of child mortality in the rural area of Nouna HDSS between 1993 and 2012. Extrapolated to the Millennium Development Goals target period 1990-2015, this yields an estimated reduction of 54%, which is not too far off the aim of a two-thirds reduction. © 2016 John Wiley & Sons Ltd.

Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

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

Silva, Patricio; Soto, Nicolás; Díaz, Jorge

2015-08-21

The early endosomal protein Rab5 is highly expressed in tumor samples, although a causal relationship between Rab5 expression and cell transformation has not been established. Here, we report the functional effects of targeting endogenous Rab5 with specific shRNA sequences in different tumor cell lines. Rab5 down-regulation in B16-F10 cells decreased tumor formation by subcutaneous injection into C57/BL6 mice. Accordingly, Rab5 targeting in B16-F10 and A549, but not MDA-MB-231 cells was followed by decreased cell proliferation, increased apoptosis and decreased anchorage-independent growth. These findings suggest that Rab5 expression is required to maintain characteristics associated with cell transformation. - Highlights: • Rab5more » is important to the maintenance of cell transformation characteristics. • Down-regulation of Rab5 decreases cell proliferation and increases apoptosis in different cancer cells. • Rab5 is required for anchorage-independent growth and tumorigenicity in-vivo.« less

Synovial tissue volume: a treatment target in knee osteoarthritis (OA).

PubMed

O'Neill, Terence W; Parkes, Matthew J; Maricar, Nasimah; Marjanovic, Elizabeth J; Hodgson, Richard; Gait, Andrew D; Cootes, Timothy F; Hutchinson, Charles E; Felson, David T

2016-01-01

Synovitis occurring frequently in osteoarthritis (OA) may be a targeted outcome. There are no data examining whether synovitis changes following intra-articular intervention. Persons aged 40 years and older with painful knee OA participated in an open label trial of intra-articular steroid therapy. At all time points they completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. They had a contrast-enhanced (CE) MRI immediately prior to an intra-articular steroid injection with a repeat scan within 20 days. Response status was assessed using the Osteoarthritis Research Society International (OARSI) response criteria. OARSI responders were followed until their pain relapsed either within 20% of baseline or 6 months, shortly after which a third MRI was performed. Synovial tissue volume (STV) was measured on postcontrast knee images. We looked at changes in the STV and in pain, and their association. 120 subjects with preinjection and postinjection CE MRI were followed. Their mean age was 62.3 years (SD=10.3) and 62 (52%) were women. The median time between injection and follow-up scan was 8 days (IQR 7-14 days). 85/120 (71%) were OARSI responders. Pain decreased (mean change in KOOS=+23.9; 95% CI 20.1 to 27.8, p<0.001) following steroid injection, as did mean STV (mean change=-1071 mm(3); 95% CI -1839 mm(3) to -303 mm(3), p=0.01). Of the 80 who returned for a third MRI, pain relapsed in 57, and in the 48 of those with MRI data, STV increased between follow-up and final visit (+1220 mm(3); 95% CI 25 mm(3) to 2414 mm(3), p=0.05). 23 were persistent responders at 6 months and, in these, STV did not increase (mean change=-202 mm(3); 95% CI -2008 mm(3) to 1604 mm(3), p=0.83). Controlling for variation over time, there was a significant association between synovitis volume and KOOS pain (b coefficient-change in KOOS pain score per 1000 mm(3) change in STV=-1.13; 95% CI -1.87 to -0.39, p=0.003), although STV accounted for only a small proportion of

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43*

PubMed Central

Stribl, Carola; Samara, Aladin; Trümbach, Dietrich; Peis, Regina; Neumann, Manuela; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabě de Angelis, Martin; Rathkolb, Birgit; Wolf, Eckhard; Beckers, Johannes; Horsch, Marion; Neff, Frauke; Kremmer, Elisabeth; Koob, Sebastian; Reichert, Andreas S.; Hans, Wolfgang; Rozman, Jan; Klingenspor, Martin; Aichler, Michaela; Walch, Axel Karl; Becker, Lore; Klopstock, Thomas; Glasl, Lisa; Hölter, Sabine M.; Wurst, Wolfgang; Floss, Thomas

2014-01-01

The majority of amyotrophic lateral sclerosis (ALS) cases as well as many patients suffering from frontotemporal lobar dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR DNA-binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes, whereas the endogenous mouse Tdp-43 was decreased to 20% of wild type levels as a result of disturbed feedback regulation. Heterozygous TDP-43A315TKi mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals, we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol, and glucose in the blood. As seen in transmission electron microscopy, neuronal cells in motor cortices of TDP-43A315TKi animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90%, but only slight motoric impairment was detected. The observed phenotype was interpreted as a predisease model, which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration. PMID:24515116

Secreted Frizzled-related protein 2 as a target in antifibrotic therapeutic intervention.

PubMed

Mastri, Michalis; Shah, Zaeem; Hsieh, Karin; Wang, Xiaowen; Wooldridge, Bailey; Martin, Sean; Suzuki, Gen; Lee, Techung

2014-03-15

Progressive fibrosis is a pathological hallmark of many chronic diseases responsible for organ failure. Although there is currently no therapy on the market that specifically targets fibrosis, the dynamic fibrogenic process is known to be regulated by multiple soluble mediators that may be therapeutically intervened. The failing hamster heart exhibits marked fibrosis and increased expression of secreted Frizzled-related protein 2 (sFRP2) amenable to reversal by mesenchymal stem cell (MSC) therapy. Given the previous demonstration that sFRP2-null mice subjected to myocardial infarction exhibited reduced fibrosis and improved function, we tested whether antibody-based sFRP2 blockade might counteract the fibrogenic pathway and repair cardiac injury. Cardiomyopathic hamsters were injected intraperitoneally twice a week each with 20 μg of sFRP2 antibody. Echocardiography, histology, and biochemical analyses were performed after 1 mo. sFRP2 antibody increased left ventricular ejection fraction from 40 ± 1.2 to 49 ± 6.5%, whereas saline and IgG control exhibited a further decline to 37 ± 0.9 and 31 ± 3.2%, respectively. Functional improvement is associated with a ∼ 50% reduction in myocardial fibrosis, ∼ 65% decrease in apoptosis, and ∼ 75% increase in wall thickness. Consistent with attenuated fibrosis, both MSC therapy and sFRP2 antibody administration significantly increased the activity of myocardial matrix metalloproteinase-2. Gene expression analysis of the hamster heart and cultured fibroblasts identified Axin2 as a downstream target, the expression of which was activated by sFRP2 but inhibited by therapeutic intervention. sFRP2 blockade also increased myocardial levels of VEGF and hepatocyte growth factor (HGF) along with increased angiogenesis. These findings highlight the pathogenic effect of dysregulated sFRP2, which may be specifically targeted for antifibrotic therapy.

Development, Characterization and Validation of Trastuzumab-Modified Gold Nanoparticles for Molecularly Targeted Radiosensitization of Breast Cancer

NASA Astrophysics Data System (ADS)

Chattopadhyay, Niladri

The overexpression of the human epidermal growth factor receptor-2 (HER-2) in 20--25% of human breast cancers was investigated as a target for development of a gold nanoparticle (AuNP) based radiosensitizer for improving the efficacy of neoadjuvant X-radiation therapy of the disease. HER-2 targeted AuNPs were developed by covalently conjugating trastuzumab, a Health Canada approved monoclonal antibody for the treatment of HER-2-overexpressing breast cancer, to 30 nm AuNPs. Trastuzumab conjugated AuNPs were efficiently internalized by HER-2-overexpressing breast cancer cells (as assessed by darkfield microscopy and transmission electron microscopy) and increased DNA damage from X-radiation in these cells by more than 5-fold. To optimize delivery of AuNPs to HER-2-overexpressing tumors, high resolution microSPECT/CT imaging was used to track the in vivo fate of 111In-labelled non-targeted and HER-2 targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and non-specific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to non-targeted AuNPs. This phenomenon could be attributed to Fc-mediated recognition and subsequent sequestration of trastuzumab conjugated AuNP by the reticuloendothelial system (RES). Blocking of the RES did not increase tumor uptake of either HER-2 targeted or non-targeted AuNPs. Following i.t. injection, our results suggest that Au-NTs redistribute over time and traffick to the liver via the ipsilateral axillary lymph node leading to comparable exposure as seen with i.v. administration. In contrast, targeted AuNPs are bound and internalized by HER-2

Decreasing radiation exposure on pediatric portable chest radiographs.

PubMed

Hawking, Nancy G; Sharp, Ted D

2013-01-01

To determine whether additional shielding designed for pediatric patients during portable chest exams that ascertain endotracheal tube placement would significantly decrease the amount of scatter radiation. Children aged 24 months or younger were intubated and received daily morning chest radiographs to determine endotracheal tube placement. For each measurement, the amount of scatter radiation decreased by more than 20% from a nonshielded exposure to a shielded exposure. There was a significant decrease in scatter radiation when using the lead shielding device along with appropriate collimation vs appropriate collimation alone. These results suggest that applying additional shielding to appropriately collimated chest radiographs could significantly reduce scatter radiation and therefore the overall dose to young children.

Biosonar adjustments to target range of echolocating bottlenose dolphins (Tursiops sp.) in the wild.

PubMed

Jensen, F H; Bejder, L; Wahlberg, M; Madsen, P T

2009-04-01

Toothed whales use echolocation to locate and track prey. Most knowledge of toothed whale echolocation stems from studies on trained animals, and little is known about how toothed whales regulate and use their biosonar systems in the wild. Recent research suggests that an automatic gain control mechanism in delphinid biosonars adjusts the biosonar output to the one-way transmission loss to the target, possibly a consequence of pneumatic restrictions in how fast the sound generator can be actuated and still maintain high outputs. This study examines the relationships between target range (R), click intervals, and source levels of wild bottlenose dolphins (Tursiops sp.) by recording regular (non-buzz) echolocation clicks with a linear hydrophone array. Dolphins clicked faster with decreasing distance to the array, reflecting a decreasing delay between the outgoing echolocation click and the returning array echo. However, for interclick intervals longer than 30-40 ms, source levels were not limited by the repetition rate. Thus, pneumatic constraints in the sound-production apparatus cannot account for source level adjustments to range as a possible automatic gain control mechanism for target ranges longer than a few body lengths of the dolphin. Source level estimates drop with reducing range between the echolocating dolphins and the target as a function of 17 log(R). This may indicate either (1) an active form of time-varying gain in the biosonar independent of click intervals or (2) a bias in array recordings towards a 20 log(R) relationship for apparent source levels introduced by a threshold on received click levels included in the analysis.

Socioeconomic Implications of Achieving 2.0 °C and 1.5 °C Climate Targets under Scientific Uncertainties

NASA Astrophysics Data System (ADS)

Su, X.; Takahashi, K.; Fujimori, S.; Hasegawa, T.; Tanaka, K.; Shiogama, H.; Emori, S.; LIU, J.; Hanasaki, N.; Hijioka, Y.; Masui, T.

2017-12-01

Large uncertainty exists in the temperature projections, including contributions from carbon cycle, climate system and aerosols. For the integrated assessment models (IAMs), like DICE, FUND and PAGE, however, the scientific uncertainties mainly rely on the distribution of (equilibrium) climate sensitivity. This study aims at evaluating the emission pathways by limiting temperature increase below 2.0 ºC or 1.5 ºC after 2100 considering scientific uncertainties, and exploring how socioeconomic indicators are affected by such scientific uncertainties. We use a stochastic version of the SCM4OPT, with an uncertainty measurement by considering alternative ranges of key parameters. Three climate cases, namely, i) base case of SSP2, ii) limiting temperature increase below 2.0 ºC after 2100 and iii) limiting temperature increase below 1.5 ºC after 2100, and three types of probabilities - i) >66% probability or likely, ii) >50% probability or more likely than not and iii) the mean of the probability distribution, are considered in the study. The results show that, i) for the 2.0ºC case, the likely CO2 reduction rate in 2100 ranges from 75.5%-102.4%, with mean value of 88.1%, and 93.0%-113.1% (mean 102.5%) for the 1.5ºC case; ii) a likely range of forcing effect is found for the 2.0 ºC case (2.7-3.9 Wm-2) due to scientific uncertainty, and 1.9-3.1 Wm-2 for the 1.5 ºC case; iii) the carbon prices within 50% confidential interval may differ a factor of 3 for both the 2.0ºC case and the 1.5 ºC case; iv) the abatement costs within 50% confidential interval may differ a factor of 4 for both the 2.0ºC case and the 1.5 ºC case. Nine C4MIP carbon cycle models and nineteen CMIP3 AOGCMs are used to account for the scientific uncertainties, following MAGICC 6.0. These uncertainties will result in a likely radiative forcing range of 6.1-7.5 Wm-2 and a likely temperature increase of 3.1-4.5 ºC in 2100 for the base case of SSP2. If we evaluate the 2 ºC target by limiting the

Transmit/receive 3-20 GHz 1.2 mW packaged double-pole-16-throw switching matrix for radar-based target detection

NASA Astrophysics Data System (ADS)

Azhari, Afreen; Kuwano, Yuki; Xiao, Xia; Kikkawa, Takamaro

2018-01-01

A 3-20 GHz transmit/receive (T/R) double-pole-16-throw (DP16T) switching matrix has been developed on a printed circuit board (PCB) to control sixteen antennas in a radar-based portable breast-cancer detection system. The DP16T switch consists of four 65 nm CMOS 0.01-20 GHz double-pole-four-throw (DP4T) switches. The proposed switch increase the number of T/R combinations to 224 from the 196 of a conventional switching matrix in order to construct high-resolution images. Using this switch and a 4 × 4 slot antenna array, a 10 × 10 mm2 aluminum target was detected with an 8-GHz-center-frequency Gaussian monocycle pulse. The power consumption of the switch is only 1.2 mW. To the best of the authors’ knowledge, this is the first T/R radio frequency (RF) DP16T switching matrix, which was realized with four CMOS DP4T switches on a PCB and was measured with RF PCB connectors.

Efficacy of a Universal Parent Training Program (HOPE-20): Cluster Randomized Controlled Trial

ERIC Educational Resources Information Center

Leung, Cynthia; Tsang, Sandra; Kwan, H. W.

2017-01-01

Objective: This study examined the efficacy of Hands-On Parent Empowerment-20 (HOPE-20) program. Methods: Eligible participants were parents residing in Hong Kong with target children aged 2 years attending nursery schools. Cluster randomized control trial was adopted, with 10 schools (110 participants) assigned to intervention group and 8 schools…

Small target pre-detection with an attention mechanism

NASA Astrophysics Data System (ADS)

Wang, Yuehuan; Zhang, Tianxu; Wang, Guoyou

2002-04-01

We introduce the concept of predetection based on an attention mechanism to improve the efficiency of small-target detection by limiting the image region of detection. According to the characteristics of small-target detection, local contrast is taken as the only feature in predetection and a nonlinear sampling model is adopted to make the predetection adaptive to detect small targets with different area sizes. To simplify the predetection itself and decrease the false alarm probability, neighboring nodes in the sampling grid are used to generate a saliency map, and a short-term memory is adopted to accelerate the `pop-out' of targets. We discuss the fact that the proposed approach is simple enough in computational complexity. In addition, even in a cluttered background, attention can be led to targets in a satisfying few iterations, which ensures that the detection efficiency will not be decreased due to false alarms. Experimental results are presented to demonstrate the applicability of the approach.

Chewing gum decreases energy intake at lunch following a controlled breakfast.

PubMed

Melanson, Kathleen J; Kresge, Daniel L

2017-11-01

The impact of chewing gum on fasting appetite or meal intake has not been studied. We tested the hypothesis that chewing gum would decrease lunch intake after a controlled breakfast, and reduce hunger in fasting and fed states. Seventeen males and sixteen females (21.4 ± 6.3y, BMI 23.8 ± 2.7 kg/m 2 ) participated in a randomized crossover study in which subjects chewed sugar-free gum a total of 1 h on the test day (GC), and did not chew gum on a control day (NG). The 1 h of gum chewing included 20 min while fasting, and two 20-min sessions between breakfast and lunch. Subjects rated their appetite and mood on visual analog scales. After completing the fasting measures, subjects consumed a breakfast shake containing 30% of their measured resting energy expenditure. Three hours later they consumed an ad libitum lunch with water. Fasting ratings of hunger were lower in GC than NG (t = 2.66, p = 0.01). Subjects consumed significantly less pasta (41 g, 68 kcals, t = 2.32, p = 0.03) during GC than NG. In conclusion, gum chewing decreased fasting hunger ratings and lunch energy consumed. Chewing gum may be a useful tool impacting energy balance in this population. Longer studies, especially in other populations, will be required. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of prolonged unilateral cervical muscle contraction on head repositioning--decreased overshoot after a 5-min static muscle contraction task.

PubMed

Malmström, Eva-Maj; Karlberg, Mikael; Holmström, Eva; Fransson, Per-Anders; Hansson, Gert-Ake; Magnusson, Måns

2010-06-01

The ability to reproduce a specified head-on-trunk position can be an indirect test of cervical proprioception. This ability is affected in subjects with neck pain, but it is unclear whether and how much pain or continuous muscle contraction factors contribute to this effect. We studied the influence of a static unilateral neck muscle contraction task (5 min of lateral flexion at 30% of maximal voluntary contraction) on head repositioning ability in 20 subjects (10 women, 10 men; mean age 37 years) with healthy necks. Head repositioning ability was tested in the horizontal plane with 30 degrees target and neutral head position tests; head position was recorded by Zebris((R)), an ultrasound-based motion analyser. Head repositioning ability was analysed for accuracy (mean of signed differences between introduced and reproduced positions) and precision (standard deviation of the differences). Accuracy of head repositioning ability increased significantly after the muscle contraction task, as the normal overshoot was reduced. An average overshoot of 7.1 degrees decreased to 4.6 degrees after the muscle contraction task for the 30 degrees target and from 2.2 degrees to 1.4 degrees for neutral head position. The increased accuracy was most pronounced for movements directed towards the activated side. Hence, prolonged unilateral neck muscle contraction may increase the sensitivity of cervical proprioceptors.

Multiplicity fluctuation analysis of target residues in nucleus-emulsion collisions at a few hundred MeV/nucleon

NASA Astrophysics Data System (ADS)

Zhang, Dong-Hai; Chen, Yan-Ling; Wang, Guo-Rong; Li, Wang-Dong; Wang, Qing; Yao, Ji-Jie; Zhou, Jian-Guo; Zheng, Su-Hua; Xu, Li-Ling; Miao, Hui-Feng; Wang, Peng

2014-07-01

Multiplicity fluctuation of the target evaporated fragments emitted in 290 MeV/u 12C-AgBr, 400 MeV/u 12C-AgBr, 400 MeV/u 20Ne-AgBr and 500 MeV/u 56Fe-AgBr interactions is investigated using the scaled factorial moment method in two-dimensional normal phase space and cumulative variable space, respectively. It is found that in normal phase space the scaled factorial moment (ln) increases linearly with the increase of the divided number of phase space (lnM)for lower q-value and increases linearly with the increase of lnM, and then becomes saturated or decreased for a higher q-value. In cumulative variable space ln decreases linearly with increase of lnM. This indicates that no evidence of non-statistical multiplicity fluctuation is observed in our data sets. So, any fluctuation indicated in the results of normal variable space analysis is totally caused by the non-uniformity of the single-particle density distribution.

A mid-term analysis of progress toward international biodiversity targets.

PubMed

Tittensor, Derek P; Walpole, Matt; Hill, Samantha L L; Boyce, Daniel G; Britten, Gregory L; Burgess, Neil D; Butchart, Stuart H M; Leadley, Paul W; Regan, Eugenie C; Alkemade, Rob; Baumung, Roswitha; Bellard, Céline; Bouwman, Lex; Bowles-Newark, Nadine J; Chenery, Anna M; Cheung, William W L; Christensen, Villy; Cooper, H David; Crowther, Annabel R; Dixon, Matthew J R; Galli, Alessandro; Gaveau, Valérie; Gregory, Richard D; Gutierrez, Nicolas L; Hirsch, Tim L; Höft, Robert; Januchowski-Hartley, Stephanie R; Karmann, Marion; Krug, Cornelia B; Leverington, Fiona J; Loh, Jonathan; Lojenga, Rik Kutsch; Malsch, Kelly; Marques, Alexandra; Morgan, David H W; Mumby, Peter J; Newbold, Tim; Noonan-Mooney, Kieran; Pagad, Shyama N; Parks, Bradley C; Pereira, Henrique M; Robertson, Tim; Rondinini, Carlo; Santini, Luca; Scharlemann, Jörn P W; Schindler, Stefan; Sumaila, U Rashid; Teh, Louise S L; van Kolck, Jennifer; Visconti, Piero; Ye, Yimin

2014-10-10

In 2010, the international community, under the auspices of the Convention on Biological Diversity, agreed on 20 biodiversity-related "Aichi Targets" to be achieved within a decade. We provide a comprehensive mid-term assessment of progress toward these global targets using 55 indicator data sets. We projected indicator trends to 2020 using an adaptive statistical framework that incorporated the specific properties of individual time series. On current trajectories, results suggest that despite accelerating policy and management responses to the biodiversity crisis, the impacts of these efforts are unlikely to be reflected in improved trends in the state of biodiversity by 2020. We highlight areas of societal endeavor requiring additional efforts to achieve the Aichi Targets, and provide a baseline against which to assess future progress. Copyright © 2014, American Association for the Advancement of Science.

Time-reversal optical tomography: detecting and locating extended targets in a turbid medium

NASA Astrophysics Data System (ADS)

Wu, Binlin; Cai, W.; Xu, M.; Gayen, S. K.

2012-03-01

Time Reversal Optical Tomography (TROT) is developed to locate extended target(s) in a highly scattering turbid medium, and estimate their optical strength and size. The approach uses Diffusion Approximation of Radiative Transfer Equation for light propagation along with Time Reversal (TR) Multiple Signal Classification (MUSIC) scheme for signal and noise subspaces for assessment of target location. A MUSIC pseudo spectrum is calculated using the eigenvectors of the TR matrix T, whose poles provide target locations. Based on the pseudo spectrum contours, retrieval of target size is modeled as an optimization problem, using a "local contour" method. The eigenvalues of T are related to optical strengths of targets. The efficacy of TROT to obtain location, size, and optical strength of one absorptive target, one scattering target, and two absorptive targets, all for different noise levels was tested using simulated data. Target locations were always accurately determined. Error in optical strength estimates was small even at 20% noise level. Target size and shape were more sensitive to noise. Results from simulated data demonstrate high potential for application of TROT in practical biomedical imaging applications.

A Small-molecule Inhibitor, 5′-O-Tritylthymidine, targets FAK and Mdm-2 Interaction, and Blocks Breast and Colon Tumorigenesis in vivo

PubMed Central

Golubovskaya, Vita; Palma, Nadia L.; Zheng, Min; Ho, Baotran; Magis, Andrew; Ostrov, David; Cance, William G.

2013-01-01

Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays an important role in survival. We developed a novel approach, targeting FAK-protein interactions by computer modeling and screening of NCI small molecule drug database. In this report we targeted FAK and Mdm-2 protein interaction to decrease tumor growth. By macromolecular modeling we found a model of FAK and Mdm-2 interaction and performed screening of >200,000 small molecule compounds from NCI database with drug-like characteristics, targeting the FAK-Mdm-2 interaction. We identified 5′-O-Tritylthymidine, called M13 compound that significantly decreased viability in different cancer cells. M13 was docked into the pocket of FAK and Mdm-2 interaction and was directly bound to the FAK-N terminal domain by ForteBio Octet assay. In addition, M13 compound affected FAK and Mdm-2 levels and decreased complex of FAK and Mdm-2 proteins in breast and colon cancer cells. M13 re-activated p53 activity inhibited by FAK with Mdm-2 promoter. M13 decreased viability, clonogenicity, increased detachment and apoptosis in a dose-dependent manner in BT474 breast and in HCT116 colon cancer cells in vitro. M13 decreased FAK, activated p53 and caspase-8 in both cell lines. In addition, M13 decreased breast and colon tumor growth in vivo. M13 activated p53 and decreased FAK in tumor samples consistent with decreased tumor growth. The data demonstrate a novel approach for targeting FAK and Mdm-2 protein interaction, provide a model of FAK and Mdm-2 interaction, identify M13 compound targeting this interaction and decreasing tumor growth that is critical for future targeted therapeutics. PMID:22292771

Chondroprotective and anti-inflammatory role of melanocortin peptides in TNF-α activated human C-20/A4 chondrocytes

PubMed Central

Kaneva, Magdalena K; Kerrigan, Mark JP; Grieco, Paolo; Curley, G Paul; Locke, Ian C; Getting, Stephen J

2012-01-01

BACKGROUND AND PURPOSE Melanocortin MC1 and MC3 receptors, mediate the anti-inflammatory effects of melanocortin peptides. Targeting these receptors could therefore lead to development of novel anti-inflammatory therapeutic agents. We investigated the expression of MC1 and MC3 receptors on chondrocytes and the role of α-melanocyte-stimulating hormone (α-MSH) and the selective MC3 receptor agonist, [DTRP8]-γ-MSH, in modulating production of inflammatory cytokines, tissue-destructive proteins and induction of apoptotic pathway(s) in the human chondrocytic C-20/A4 cells. EXPERIMENTAL APPROACH Effects of α-MSH, [DTRP8]-γ-MSH alone or in the presence of the MC3/4 receptor antagonist, SHU9119, on TNF-α induced release of pro-inflammatory cytokines, MMPs, apoptotic pathway(s) and cell death in C-20/A4 chondrocytes were investigated, along with their effect on the release of the anti-inflammatory cytokine IL-10. KEY RESULTS C-20/A4 chondrocytes expressed functionally active MC1,3 receptors. α-MSH and [DTRP8]-γ-MSH treatment, for 30 min before TNF-α stimulation, provided a time-and-bell-shaped concentration-dependent decrease in pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) release and increased release of the chondroprotective and anti-inflammatory cytokine, IL-10, whilst decreasing expression of MMP1, MMP3, MMP13 genes.α-MSH and [DTRP8]-γ-MSH treatment also inhibited TNF-α-induced caspase-3/7 activation and chondrocyte death. The effects of [DTRP8]-γ-MSH, but not α-MSH, were abolished by the MC3/4 receptor antagonist, SHU9119. CONCLUSION AND IMPLICATIONS Activation of MC1/MC3 receptors in C-20/A4 chondrocytes down-regulated production of pro-inflammatory cytokines and cartilage-destroying proteinases, inhibited initiation of apoptotic pathways and promoted release of chondroprotective and anti-inflammatory cytokines. Developing small molecule agonists to MC1/MC3 receptors could be a viable approach for developing chondroprotective and anti

A novel multi-target ligand (JM-20) protects mitochondrial integrity, inhibits brain excitatory amino acid release and reduces cerebral ischemia injury in vitro and in vivo.

PubMed

Nuñez-Figueredo, Yanier; Ramírez-Sánchez, Jeney; Hansel, Gisele; Simões Pires, Elisa Nicoloso; Merino, Nelson; Valdes, Odalys; Delgado-Hernández, René; Parra, Alicia Lagarto; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Salbego, Christianne; Costa, Silvia L; Souza, Diogo O; Pardo-Andreu, Gilberto L

2014-10-01

We previously showed that JM-20, a novel 1,5-benzodiazepine fused to a dihydropyridine moiety, possessed an anxiolytic profile similar to diazepam and strong neuroprotective activity in different cell models relevant to cerebral ischemia. Here, we investigated whether JM-20 protects against ischemic neuronal damage in vitro and in vivo. The effects of JM-20 were evaluated on hippocampal slices subjected to oxygen and glucose deprivation (OGD). For in vivo studies, Wistar rats were subjected 90 min of middle cerebral artery occlusion (MCAo) and oral administration of JM-20 at 2, 4 and 8 mg/kg 1 h following reperfusion. Twenty-four hours after cerebral blood flow restoration, neurological deficits were scored, and the infarct volume, histopathological changes in cortex, number of hippocampal and striatal neurons, and glutamate/aspartate concentrations in the cerebrospinal fluid were measured. Susceptibility to brain mitochondrial swelling, membrane potential dissipation, H2O2 generation, cytochrome c release, Ca2+ accumulation, and morphological changes in the organelles were assessed 24 h post-ischemia. In vitro, JM-20 (1 and 10 μM) administered during reperfusion significantly reduced cell death in hippocampal slices subjected to OGD. In vivo, JM-20 treatment (4 and 8 mg/kg) significantly decreased neurological deficit scores, edema formation, total infarct volumes and histological alterations in different brain regions. JM-20 treatment also protected brain mitochondria from ischemic damage, most likely by preventing Ca2+ accumulation in organelles. Moreover, an 8-mg/kg JM-20 dose reduced glutamate and aspartate concentrations in cerebrospinal fluid and the deleterious effects of MCAo even when delivered 8 h after blood flow restoration. These results suggest that in rats, JM-20 is a robust neuroprotective agent against ischemia/reperfusion injury with a wide therapeutic window. Our findings support the further examination of potential clinical JM-20 use to treat

Target thrust measurement for applied-field magnetoplasmadynamic thruster

NASA Astrophysics Data System (ADS)

Wang, B.; Yang, W.; Tang, H.; Li, Z.; Kitaeva, A.; Chen, Z.; Cao, J.; Herdrich, G.; Zhang, K.

2018-07-01

In this paper, we present a flat target thrust stand which is designed to measure the thrust of a steady-state applied-field magnetoplasmadynamic thruster (AF-MPDT). In our experiments we varied target-thruster distances and target size to analyze their influence on the target thrust measurement results. The obtained thrust-distance curves increase to local maximum and then decreases with the increasing distance, which means that the plume of the AF-MPDT can still accelerate outside the thruster exit. The peak positions are related to the target sizes: larger targets can make the peak positions further from the thruster and decrease the measurement errors. To further improve the reliability of measurement results, a thermal equilibrium assumption combined with Knudsen’s cosine law is adapted to analyze the error caused by the back stream of plume particles. Under the assumption, the error caused by particle backflow is no more than 3.6% and the largest difference between the measured thrust and the theoretical thrust is 14%. Moreover, it was verified that target thrust measurement can disturb the working of the AF-MPD thruster, and the influence on the thrust measurement result is no more than 1% in our experiment.

Ground Beef High in Total Fat and Saturated Fatty Acids Decreases X Receptor Signaling Targets in Peripheral Blood Mononuclear Cells of Men and Women.

PubMed

Choi, Seong H; Gharahmany, Ghazal; Walzem, Rosemary L; Meade, Thomas H; Smith, Stephen B

2018-03-01

We hypothesized that consumption of saturated fatty acids in the form of high-fat ground beef for 5 weeks would depress liver X receptor signaling targets in peripheral blood mononuclear cells (PBMC) and that changes in gene expression would be associated with the corresponding changes in lipoprotein cholesterol (C) concentrations. Older men (n = 5, age 68.0 ± 4.6 years) and postmenopausal women (n = 7, age 60.9 ± 3.1 years) were assigned randomly to consume ground-beef containing 18% total fat (18F) or 25% total fat (25F), five patties per week for 5 weeks with an intervening 4-week washout period. The 25F and 18F ground-beef increased (p < 0.05) the intake of saturated fat, monounsaturated fat, palmitic acid, and stearic acid, but the 25F ground-beef increased only the intake of oleic acid (p < 0.05). The ground-beefs 18F and 25F increased the plasma concentration of palmitic acid (p < 0.05) and decreased the plasma concentrations of arachidonic, eicosapentaenoic, and docosahexaenic acids (p < 0.05). The interventions of 18F and 25F ground-beef decreased very low-density lipoprotein C concentrations and increased particle diameters and low-density lipoprotein (LDL)-I-C and LDL-II-C concentrations (p < 0.05). The ground-beef 25F decreased PBMC mRNA levels for the adenosine triphosphate (ATP) binding cassette A, ATP binding cassette G1, sterol regulatory element binding protein-1, and LDL receptor (LDLR) (p < 0.05). The ground-beef 18F increased mRNA levels for stearoyl-CoA desaturase-1 (p < 0.05). We conclude that the increased LDL particle size and LDL-I-C and LDL-II-C concentrations following the 25F ground-beef intervention may have been caused by decreased hepatic LDLR gene expression. © 2018 AOCS.

Targeting Sphingosine Kinase-1 To Inhibit Melanoma

PubMed Central

Madhunapantula, SubbaRao V.; Hengst, Jeremy; Gowda, Raghavendra; Fox, Todd E.; Yun, Jong K; Robertson, Gavin P.

2012-01-01

SUMMARY Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient’s tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID:22236408

Conformational stability as a design target to control protein aggregation.

PubMed

Costanzo, Joseph A; O'Brien, Christopher J; Tiller, Kathryn; Tamargo, Erin; Robinson, Anne Skaja; Roberts, Christopher J; Fernandez, Erik J

2014-05-01

Non-native protein aggregation is a prevalent problem occurring in many biotechnological manufacturing processes and can compromise the biological activity of the target molecule or induce an undesired immune response. Additionally, some non-native aggregation mechanisms lead to amyloid fibril formation, which can be associated with debilitating diseases. For natively folded proteins, partial or complete unfolding is often required to populate aggregation-prone conformational states, and therefore one proposed strategy to mitigate aggregation is to increase the free energy for unfolding (ΔGunf) prior to aggregation. A computational design approach was tested using human γD crystallin (γD-crys) as a model multi-domain protein. Two mutational strategies were tested for their ability to reduce/increase aggregation rates by increasing/decreasing ΔGunf: stabilizing the less stable domain and stabilizing the domain-domain interface. The computational protein design algorithm, RosettaDesign, was implemented to identify point variants. The results showed that although the predicted free energies were only weakly correlated with the experimental ΔGunf values, increased/decreased aggregation rates for γD-crys correlated reasonably well with decreases/increases in experimental ΔGunf, illustrating improved conformational stability as a possible design target to mitigate aggregation. However, the results also illustrate that conformational stability is not the sole design factor controlling aggregation rates of natively folded proteins.

Bone marrow adipocytes: a neglected target tissue for growth hormone.

PubMed

Gevers, Evelien F; Loveridge, Nigel; Robinson, Iain C A F

2002-10-01

Bone marrow (BM) contains numerous adipocytes. These share a common precursor with osteoblasts and chondrocytes, but their function is unknown. It is unclear what regulates the differentiation of these three different cell types, though their subsequent metabolic activity is under hormonal regulation. GH and estrogen stimulate bone growth and mineralization, by direct effects on chondrocytes and osteoblasts. GH also stimulates lipolysis in subcutaneous and visceral adipocytes. However, adipocytes in BM have largely been ignored as potential targets for GH or estrogen action. We have addressed this by measuring BM adipocyte number, perimeter and area as well as bone area and osteoblast activity in GH-deficient dwarf (dw/dw), normal, or ovariectomized (Ovx) rats, with or without GH, IGF-1, PTH, or estrogen treatment or high fat feeding. Marrow adipocyte numbers were increased 5-fold (P < 0.001) in dw/dw rats, and cell size was also increased by 20%. These values returned toward normal in dw/dw rats given GH but not when given IGF-1. Cancellous bone area and osteoblast number were significantly (P < 0.005) lower in dw/dw rats, though alkaline phosphatase (ALP) activity in individual osteoblasts was unchanged. GH treatment increased % osteoblast covered bone surface without affecting individual cell ALP activity. Ovariectomy in normal or dw/dw rats had no affect on marrow adipocyte number nor size, although estrogen treatment in ovariectomized (Ovx) normal rats did increase adipocyte number. Ovx decreased tibial cancellous bone area in normal rats (64%; P < 0.05) and decreased osteoblast ALP-activity (P < 0.01) but did not affect the percentage of osteoblast-covered bone surface. Estrogen replacement reversed these changes. While treatment with PTH by continuous sc infusion decreased cancellous bone (P < 0.05) and high fat feeding increased the size of BM adipocytes (P < 0.01), they did not affect BM adipocyte number. These results suggest that GH has a specific action

Contextual cost: when a visual-search target is not where it should be.

PubMed

Makovski, Tal; Jiang, Yuhong V

2010-02-01

Visual search is often facilitated when the search display occasionally repeats, revealing a contextual-cueing effect. According to the associative-learning account, contextual cueing arises from associating the display configuration with the target location. However, recent findings emphasizing the importance of local context near the target have given rise to the possibility that low-level repetition priming may account for the contextual-cueing effect. This study distinguishes associative learning from local repetition priming by testing whether search is directed toward a target's expected location, even when the target is relocated. After participants searched for a T among Ls in displays that repeated 24 times, they completed a transfer session where the target was relocated locally to a previously blank location (Experiment 1) or to an adjacent distractor location (Experiment 2). Results revealed that contextual cueing decreased as the target appeared farther away from its expected location, ultimately resulting in a contextual cost when the target swapped locations with a local distractor. We conclude that target predictability is a key factor in contextual cueing.

The Decreasing Prevalence of the Arcuate Foramen.

PubMed

Sanchis-Gimeno, Juan A; Llido, Susanna; Miquel-Feutch, Marcos; Quiles-Guinau, Laura; Rios, Luis; Murillo-Llorente, Mayte; Perez-Bermejo, Marcelino; Nalla, Shahed

2018-02-01

The arcuate foramen (AF), or ponticulus posticus, is an anatomic variant of the first cervical vertebra that consists of a complete or partial osseous bridge over the groove for the vertebral artery and extends from the posterior aspect of the superior articular facet to the superior lateral border of the posterior arch. The AF has been associated with clinical symptoms, such as headache, migraine, neck pain, shoulder pain, arm pain, and vertebral artery dissection. We aimed to test whether the prevalence of the AF has decreased in the modern human population over the past centuries as a result of reduction in inbreeding and endogamy. Possible reduction in the prevalence of the AF was assessed by comparing a 17th century rural sample (n = 108) with a 20th century modern urban sample (n = 192). When comparing the 17th and the 20th century samples, we found a statistically significant (P = 0.003) reduction of 14.5% (95% confidence interval 4.5-24.5) in the prevalence of the AF. Prevalence of the AF has been decreasing over the past centuries. Copyright © 2017 Elsevier Inc. All rights reserved.

A perspective on B-cell-targeting therapy for SLE.

PubMed

Looney, R John; Anolik, Jennifer; Sanz, Inaki

2010-02-01

In recent years, large controlled trials have tested several new agents for systemic lupus erythematosus (SLE). Unfortunately, none of these trials has met its primary outcome. This does not mean progress has not been made. In fact, a great deal has been learned about doing clinical trials in lupus and about the biological and clinical effects of the drugs being tested. Many of these drugs were designed to target B cells directly, e.g., rituximab, belimumab, epratuzumab, and transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig). The enthusiasm for targeting B cells derives from substantial evidence showing the critical role of B cells in murine models of SLE, as well promising results from multiple open trials with rituximab, a chimeric anti-CD20 monoclonal antibody that specifically depletes B cells (Martin and Chan in Immunity 20(5):517-527, 2004; Sobel et al. in J Exp Med 173:1441-1449, 1991; Silverman and Weisman in Arthritis Rheum 48:1484-1492, 2003; Silverman in Arthritis Rheum 52(4):1342, 2005; Shlomchik et al. in Nat Rev Immunol 1:147-153, 2001; Looney et al. in Arthritis Rheum 50:2580-2589, 2004; Lu et al. in Arthritis Rheum 61(4):482-487, 2009; Saito et al. in Lupus 12(10):798-800, 2003; van Vollenhoven et al. in Scand J Rheumatol 33(6):423-427, 2004; Sfikakis et al. Arthritis Rheum 52(2):501-513, 2005). Why have the controlled trials of B-cell-targeting therapies failed to demonstrate efficacy? Were there flaws in design or execution of these trials? Or, were promising animal studies and open trials misleading, as so often happens? This perspective discusses the current state of B-cell-targeting therapies for human lupus and the future development of these therapies.

Target Acquisition for Projectile Vision-Based Navigation

DTIC Science & Technology

2014-03-01

Future Work 20 8. References 21 Appendix A. Simulation Results 23 Appendix B. Derivation of Ground Resolution for a Diffraction-Limited Pinhole Camera...results for visual acquisition (left) and target recognition (right). ..........19 Figure B-1. Differential object and image areas for pinhole camera...projectile and target (measured in terms of the angle ) will depend on target heading. In particular, because we have aligned the x axis along the

Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20.

PubMed

Rexiati, Maimaiti; Sun, Mingming; Guo, Wei

2018-01-05

Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.

Target Acquisition: Human Observer Performance Studies and TARGAC Model Validation

DTIC Science & Technology

1994-06-01

complete Scenario I run were displayed on a monitor. A transparent sheet was attached to the face of the monitor, the approach route was sketched on...track, passed a mark on the monitor face , the target was at a stop-sign location. The IRIG-B time of that instance was noted, and, since the distance of...route right 100- 80- 60 - 40 C.) 20 [- ion, A20 recognitio 0 0 . identification,C.) . 1I . I - - -• , 4) 1000 2000 3000 4000 SP Target G Q Target I0

Multiple shell fusion targets

DOEpatents

Lindl, J.D.; Bangerter, R.O.

1975-10-31

Multiple shell fusion targets for use with electron beam and ion beam implosion systems are described. The multiple shell targets are of the low-power type and use a separate relatively low Z, low density ablator at large radius for the outer shell, which reduces the focusing and power requirements of the implosion system while maintaining reasonable aspect ratios. The targets use a high Z, high density pusher shell placed at a much smaller radius in order to obtain an aspect ratio small enough to protect against fluid instability. Velocity multiplication between these shells further lowers the power requirements. Careful tuning of the power profile and intershell density results in a low entropy implosion which allows breakeven at low powers. For example, with ion beams as a power source, breakeven at 10-20 Terrawatts with 10 MeV alpha particles for imploding a multiple shell target can be accomplished.

IL-20 is epigenetically regulated in NSCLC and down regulates the expression of VEGF.

PubMed

Baird, Anne-Marie; Gray, Steven G; O'Byrne, Kenneth J

2011-08-01

IL-20 is a pleiotrophic member of the IL-10 family and plays a role in skin biology and the development of haematopoietic cells. Recently, IL-20 has been demonstrated to have potential anti-angiogenic effects in non-small cell lung cancer (NSCLC) by down regulating COX-2. The expression of IL-20 and its cognate receptors (IL-20RA/B and IL-22R1) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of this family was examined in normal bronchial epithelial and NSCLC cell lines. Furthermore, the effect of IL-20 on VEGF family members was examined. The expression of IL-20 and its receptors are frequently dysregulated in NSCLC. IL-20RB mRNA was significantly elevated in NSCLC tumours (p<0.01). Protein levels of the receptors, IL-20RB and IL-22R1, were significantly increased (p<0.01) in the tumours of NSCLC patients. IL-20 and its receptors were found to be epigenetically regulated through histone post-translational modifications and DNA CpG residue methylation. In addition, treatment with recombinant IL-20 resulted in decreased expression of the VEGF family members at the mRNA level. This family of genes are dysregulated in NSCLC and are subject to epigenetic regulation. Whilst the anti-angiogenic properties of IL-20 require further clarification, targeting this family via epigenetic means may be a viable therapeutic option in lung cancer treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Immuno-biosensor for Detection of CD20-Positive Cells Using Surface Plasmon Resonance.

PubMed

Shanehbandi, Dariush; Majidi, Jafar; Kazemi, Tohid; Baradaran, Behzad; Aghebati-Maleki, Leili; Fathi, Farzaneh; Ezzati Nazhad Dolatabadi, Jafar

2017-06-01

Purpose: Surface plasmon resonance (SPR) sensing confers a real-time assessment of molecular interactions between biomolecules and their ligands. This approach is highly sensitive and reproducible and could be employed to confirm the successful binding of drugs to cell surface targets. The specific affinity of monoclonal antibodies (MAb) for their target antigens is being utilized for development of immuno-sensors and therapeutic agents. CD20 is a surface protein of B lymphocytes which has been widely employed for immuno-targeting of B-cell related disorders. In the present study, binding ability of an anti-CD20 MAb to surface antigens of intact target cells was investigated by SPR technique. Methods: Two distinct strategies were used for immobilization of the anti-CD20 MAb onto gold (Au) chips. MUA (11-mercaptoundecanoic acid) and Staphylococcus aureus protein A (SpA) were the two systems used for this purpose. A suspension of CD20-positive Raji cells was injected in the analyte phase and the resulting interactions were analyzed and compared to those of MOLT-4 cell line as CD20-negative control. Results: Efficient binding of anti-CD20 MAb to the surface antigens of Raji cell line was confirmed by both immobilizing methods, whereas this MAb had not a noticeable affinity to the MOLT-4 cells. Conclusion: According to the outcomes, the investigated MAb had acceptable affinity and specificity to the target antigens on the cell surface and could be utilized for immuno-detection of CD20-positive intact cells by SPR method.

Immuno-biosensor for Detection of CD20-Positive Cells Using Surface Plasmon Resonance

PubMed Central

Shanehbandi, Dariush; Majidi, Jafar; Kazemi, Tohid; Baradaran, Behzad; Aghebati-Maleki, Leili; Fathi, Farzaneh; Ezzati Nazhad Dolatabadi, Jafar

2017-01-01

Purpose: Surface plasmon resonance (SPR) sensing confers a real-time assessment of molecular interactions between biomolecules and their ligands. This approach is highly sensitive and reproducible and could be employed to confirm the successful binding of drugs to cell surface targets. The specific affinity of monoclonal antibodies (MAb) for their target antigens is being utilized for development of immuno-sensors and therapeutic agents. CD20 is a surface protein of B lymphocytes which has been widely employed for immuno-targeting of B-cell related disorders. In the present study, binding ability of an anti-CD20 MAb to surface antigens of intact target cells was investigated by SPR technique. Methods: Two distinct strategies were used for immobilization of the anti-CD20 MAb onto gold (Au) chips. MUA (11-mercaptoundecanoic acid) and Staphylococcus aureus protein A (SpA) were the two systems used for this purpose. A suspension of CD20-positive Raji cells was injected in the analyte phase and the resulting interactions were analyzed and compared to those of MOLT-4 cell line as CD20-negative control. Results: Efficient binding of anti-CD20 MAb to the surface antigens of Raji cell line was confirmed by both immobilizing methods, whereas this MAb had not a noticeable affinity to the MOLT-4 cells. Conclusion: According to the outcomes, the investigated MAb had acceptable affinity and specificity to the target antigens on the cell surface and could be utilized for immuno-detection of CD20-positive intact cells by SPR method. PMID:28761820

Mercury Handling for the Target System for a Muon Collider

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

Graves, Van B; Mcdonald, K; Kirk, H.

2012-01-01

The baseline target concept for a Muon Collider or Neutrino Factory is a free-stream mercury jet being impacted by an 8-GeV proton beam. The target is located within a 20-T magnetic field, which captures the generated pions that are conducted to a downstream decay channel. Both the mercury and the proton beam are introduced at slight downward angles to the magnetic axis. A pool of mercury serves as a receiving reservoir for the mercury and a dump for the unexpended proton beam. The impact energy of the remaining beam and jet are substantial, and it is required that splashes andmore » waves be controlled in order to minimize the potential for interference of pion production at the target. Design issues discussed in this paper include the nozzle, splash mitigation in the mercury pool, the mercury containment vessel, and the mercury recirculation system.« less

Trends in referral to a single encopresis clinic over 20 years.

PubMed

Fishman, Laurie; Rappaport, Leonard; Schonwald, Alison; Nurko, Samuel

2003-05-01

To compare the characteristics of children with encopresis referred to a single encopresis clinic over the course of 20 years, including symptoms, previous diagnostic and therapeutic interventions, and parental attitudes. A retrospective study was conducted of an encopresis clinic at a tertiary care pediatric hospital. Questionnaires at initial evaluation elicited information about bowel habits, soiling, previous evaluations, previous treatments, and parental attitudes. In 503 children with encopresis, the average age of referral dropped from 115 months during the earliest 5 years to 77 months during the most recent 5 years. Children who had soiling for >3 years before referral decreased from 63% to 12%. The use of barium enema before referral decreased from 14% to 5%, as did psychological evaluation, from 25% to 14%. Previous therapy with enemas decreased from 45% to 27%. Mineral oil use remained at approximately 50%, and 20% of children had no previous treatment. Symptoms at referral and parental attitudes did not change across the years. Children are now referred at an earlier age to our tertiary encopresis clinic. The number of invasive and psychological evaluations has decreased before referral. However, treatment by many primary care providers before the referral has not changed. These data may suggest that pediatricians have increased awareness of encopresis and greater appreciation of its primarily physical rather than psychological nature. Additional studies will be needed to determine how these factors affect outcome.

Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug.

PubMed

Murakami, Takashi; Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Zhang, Yong; Zhao, Ming; Hiroshima, Yukihiko; Nelson, Scott D; Dry, Sarah M; Li, Yunfeng; Yanagawa, Jane; Russell, Tara; Federman, Noah; Singh, Arun; Elliott, Irmina; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2017-01-31

Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p<0.001 compared to untreated control). The osteosarcoma was only partially sensitive to the molecular-targeting drug sorafenib, which did not arrest its growth. S. typhimurium A1-R was significantly more effective than sorafenib (P <0.001). S. typhimurium grew in the treated tumors and caused extensive necrosis of the tumor tissue. These data show that S. typhimurium A1-R is powerful therapy for an osteosarcoma patient-derived xenograft model.

Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug

PubMed Central

Murakami, Takashi; Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Zhang, Yong; Zhao, Ming; Hiroshima, Yukihiko; Nelson, Scott D.; Dry, Sarah M.; Li, Yunfeng; Yanagawa, Jane; Russell, Tara; Federman, Noah; Singh, Arun; Elliott, Irmina; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Endo, Itaru; Eilber, Fritz C.; Hoffman, Robert M.

2017-01-01

Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p<0.001 compared to untreated control). The osteosarcoma was only partially sensitive to the molecular-targeting drug sorafenib, which did not arrest its growth. S. typhimurium A1-R was significantly more effective than sorafenib (P <0.001). S. typhimurium grew in the treated tumors and caused extensive necrosis of the tumor tissue. These data show that S. typhimurium A1-R is powerful therapy for an osteosarcoma patient-derived xenograft model. PMID:28030831

Microstructural investigation of plastically deformed Ti{sub 20}Zr{sub 20}Hf{sub 20}Nb{sub 20}Ta{sub 20} high entropy alloy by X-ray diffraction and transmission electron microscopy

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

Dirras, G., E-mail: dirras@univ-paris13.fr; Gubicza, J.; Heczel, A.

2015-10-15

The microstructure evolution in body-centered cubic (bcc) Ti{sub 20}Zr{sub 20}Hf{sub 20}Nb{sub 20}Ta{sub 20} high entropy alloy during quasi-static compression test was studied by X-ray line profile analysis (XLPA) and transmission electron microscopy (TEM). The average lattice constant and other important parameters of the microstructure such as the mean crystallite size, the dislocation density and the edge/screw character of dislocations were determined by XLPA. The elastic anisotropy factor required for XLPA procedure was determined by nanoindentation. XLPA shows that the crystallite size decreased while the dislocation density increased with strain during compression, and their values reached about 39 nm and 15more » × 10{sup 14} m{sup −2}, respectively, at a plastic strain of ~ 20%. It was revealed that with increasing strain the dislocation character became more screw. This can be explained by the reduced mobility of screw dislocations compared to edge dislocations in bcc structures. These observations are in line with TEM investigations. The development of dislocation density during compression was related to the yield strength evolution. - Highlights: • Ti{sub 20}Zr{sub 20}Hf{sub 20}Nb{sub 20}Ta{sub 20} high entropy alloy was processed by arc-melting. • The mechanical was evaluated by RT compression test. • The microstructure evolution was studied by XLPA and TEM. • With increasing strain the dislocation character became more screw. • The yield strength was related to the development of the dislocation density.« less

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

PubMed

Hinze, Florian; Dieterich, Christoph; Radke, Michael H; Granzier, Henk; Gotthardt, Michael

2016-12-01

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.

Drug-induced amplification of nanoparticle targeting to tumors

PubMed Central

Lin, Kevin Y.; Kwon, Ester J.; Lo, Justin H.; Bhatia, Sangeeta N.

2018-01-01

Summary Nanomedicines have the potential to significantly impact cancer therapy by improving drug efficacy and decreasing off-target effects, yet our ability to efficiently home nanoparticles to disease sites remains limited. One frequently overlooked constraint of current active targeting schemes is the relative dearth of targetable antigens within tumors, which restricts the amount of cargo that can be delivered in a tumor-specific manner. To address this limitation, we exploit tumor-specific responses to drugs to construct a cooperative targeting system where a small molecule therapeutic modulates the disease microenvironment to amplify nanoparticle recruitment in vivo. We first administer a vascular disrupting agent, ombrabulin, which selectively affects tumors and leads to locally elevated presentation of the stress-related protein, p32. This increase in p32 levels provides more binding sites for circulating p32-targeted nanoparticles, enhancing their delivery of diagnostic or therapeutic cargos to tumors. We show that this cooperative targeting system recruits over five times higher doses of nanoparticles to tumors and decreases tumor burden when compared with non-cooperative controls. These results suggest that using nanomedicine in conjunction with drugs that enhance the presentation of target antigens in the tumor environment may be an effective strategy for improving the diagnosis and treatment of cancer. PMID:29731806

Open Targets: a platform for therapeutic target identification and validation

PubMed Central

Koscielny, Gautier; An, Peter; Carvalho-Silva, Denise; Cham, Jennifer A.; Fumis, Luca; Gasparyan, Rippa; Hasan, Samiul; Karamanis, Nikiforos; Maguire, Michael; Papa, Eliseo; Pierleoni, Andrea; Pignatelli, Miguel; Platt, Theo; Rowland, Francis; Wankar, Priyanka; Bento, A. Patrícia; Burdett, Tony; Fabregat, Antonio; Forbes, Simon; Gaulton, Anna; Gonzalez, Cristina Yenyxe; Hermjakob, Henning; Hersey, Anne; Jupe, Steven; Kafkas, Şenay; Keays, Maria; Leroy, Catherine; Lopez, Francisco-Javier; Magarinos, Maria Paula; Malone, James; McEntyre, Johanna; Munoz-Pomer Fuentes, Alfonso; O'Donovan, Claire; Papatheodorou, Irene; Parkinson, Helen; Palka, Barbara; Paschall, Justin; Petryszak, Robert; Pratanwanich, Naruemon; Sarntivijal, Sirarat; Saunders, Gary; Sidiropoulos, Konstantinos; Smith, Thomas; Sondka, Zbyslaw; Stegle, Oliver; Tang, Y. Amy; Turner, Edward; Vaughan, Brendan; Vrousgou, Olga; Watkins, Xavier; Martin, Maria-Jesus; Sanseau, Philippe; Vamathevan, Jessica; Birney, Ewan; Barrett, Jeffrey; Dunham, Ian

2017-01-01

We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org. PMID:27899665

Decreased expression of miR‑490‑3p in colorectal cancer predicts poor prognosis and promotes cell proliferation and invasion by targeting RAB14.

PubMed

Wang, Bo; Yin, Mujun; Cheng, Cheng; Jiang, Hongpeng; Jiang, Kewei; Shen, Zhanlong; Ye, Yingjiang; Wang, Shan

2018-06-19

Growing evidence indicates a potential role for miR‑490‑3p in tumorigenesis. However, its function in colorectal carcinoma (CRC) remains undefined. In this study, miR‑490‑3p was markedly downregulated in fifty colorectal cancer tissue samples compared with the corresponding adjacent non‑cancerous specimens, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of miR‑490‑3p were closely associated with tumor differentiation and distant metastasis. In addition, both Kaplan-Meier and multivariate analyses indicated CRC patients with elevated miR‑490‑3p amounts had prolonged overall survival. Overexpression of miR‑490‑3p markedly reduced proliferation, colony formation and invasion in CRC cells by enhancing apoptosis and promoting G2/M phase arrest. Furthermore, ectopic expression of miR‑490‑3p resulted in decreased expression of RAB14, which was directly targeted by miR‑490‑3p, as shown by the dual-luciferase reporter gene assay. Finally, in a nude mouse model, miR‑490‑3p overexpression significantly suppressed the growth of CRC cells. The above results indicated that miR‑490‑3p might constitute a prognostic indicator and a novel molecular target for miRNA-based CRC therapy.

Effects of Alzheimer's Disease on Visual Target Detection: A "Peripheral Bias".

PubMed

Vallejo, Vanessa; Cazzoli, Dario; Rampa, Luca; Zito, Giuseppe A; Feuerstein, Flurin; Gruber, Nicole; Müri, René M; Mosimann, Urs P; Nef, Tobias

2016-01-01

Visual exploration is an omnipresent activity in everyday life, and might represent an important determinant of visual attention deficits in patients with Alzheimer's Disease (AD). The present study aimed at investigating visual search performance in AD patients, in particular target detection in the far periphery, in daily living scenes. Eighteen AD patients and 20 healthy controls participated in the study. They were asked to freely explore a hemispherical screen, covering ±90°, and to respond to targets presented at 10°, 30°, and 50° eccentricity, while their eye movements were recorded. Compared to healthy controls, AD patients recognized less targets appearing in the center. No difference was found in target detection in the periphery. This pattern was confirmed by the fixation distribution analysis. These results show a neglect for the central part of the visual field for AD patients and provide new insights by mean of a search task involving a larger field of view.

Fractures in geriatric mice show decreased callus expansion and bone volume.

PubMed

Lopas, Luke A; Belkin, Nicole S; Mutyaba, Patricia L; Gray, Chancellor F; Hankenson, Kurt D; Ahn, Jaimo

2014-11-01

210.79±37.60 mg HA/cm3; p=0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279±46,755 square pixels versus 302,167±137,806 square pixels; p=0.013) and bone content (mean bone volume at 20 days postfracture, 11.68±3.18 mm3 versus 22.34±10.59 mm3; p<0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48±0.10 versus 0.50±0.13; p=0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135+25 versus 90±52; p=0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2±5.3 versus 18.7±5.2; p=0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25%±6.8% versus 42%±14.5%; p=0.047). Our findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude. Our study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.

Synthetic Aperture Sonar Imaging of Simple Finite Targets

DTIC Science & Technology

2011-03-15

again including the geometric spreading. The target strength of a sphere, as given by Urick [22], is TSs = 10 log10(a2/4), which yields TSs = −19.58...respectively. find TSis = 12.63− 52.04 + 20.00 = −19.41 dB, which compares favorably with Urick’s value. From Urick , the target strength of a finite cylinder...is now TSic = 9.08 − 27.51 + 20.00 = 1.57, which is again in good agreement with Urick . It is noted that a value of N = 21.7 reproduces TSc. The final

Light localization with low-contrast targets in a patient implanted with a suprachoroidal-transretinal stimulation retinal prosthesis.

PubMed

Endo, Takao; Fujikado, Takashi; Hirota, Masakazu; Kanda, Hiroyuki; Morimoto, Takeshi; Nishida, Kohji

2018-04-20

To evaluate the improvement in targeted reaching movements toward targets of various contrasts in a patient implanted with a suprachoroidal-transretinal stimulation (STS) retinal prosthesis. An STS retinal prosthesis was implanted in the right eye of a 42-year-old man with advanced Stargardt disease (visual acuity: right eye, light perception; left eye, hand motion). In localization tests during the 1-year follow-up period, the patient attempted to touch the center of a white square target (visual angle, 10°; contrast, 96, 85, or 74%) displayed at a random position on a monitor. The distance between the touched point and the center of the target (the absolute deviation) was averaged over 20 trials with the STS system on or off. With the left eye occluded, the absolute deviation was not consistently lower with the system on than off for high-contrast (96%) targets, but was consistently lower with the system on for low-contrast (74%) targets. With both eyes open, the absolute deviation was consistently lower with the system on than off for 85%-contrast targets. With the system on and 96%-contrast targets, we detected a shorter response time while covering the right eye, which was being implanted with the STS, compared to covering the left eye (2.41 ± 2.52 vs 8.45 ± 3.78 s, p < 0.01). Performance of a reaching movement improved in a patient with an STS retinal prosthesis implanted in an eye with residual natural vision. Patients with a retinal prosthesis may be able to improve their visual performance by using both artificial vision and their residual natural vision. Beginning date of the trial: Feb. 20, 2014 Date of registration: Jan. 4, 2014 Trial registration number: UMIN000012754 Registration site: UMIN Clinical Trials Registry (UMIN-CTR) http://www.umin.ac.jp/ctr/index.htm.

20 CFR 404.1642 - Processing time standards.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., whichever is earlier. (b) Target levels. The processing time target levels are: (1) 37 days for title II initial claims. (2) 43 days for title XVI initial claims. (c) Threshold levels. The processing time... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Processing time standards. 404.1642 Section...

20 CFR 416.1042 - Processing time standards.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., whichever is earlier. (b) Target levels. The processing time target levels are: (1) 37 days for title II initial claims. (2) 43 days for title XVI initial claims. (c) Threshold levels. The processing time... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Processing time standards. 416.1042 Section...

MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma

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

Zhang, Yuqin; Zheng, Lin; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province

2015-08-01

Purpose: To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment. Methods and Materials: The expression of miR-20a and PTEN were detected in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Aktmore » pathway. Results: MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a–induced radioresistance. Conclusion: MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR-20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC.« less

Hsp20 Interacting with Phosphorylated Akt Reduces Doxorubicin-Triggered Oxidative Stress and Cardiotoxicity

PubMed Central

Fan, Guo-Chang; Zhou, Xiaoyang; Wang, Xiaohong; Song, Guojie; Qian, Jiang; Nicolaou, Persoulla; Chen, Guoli; Ren, Xiaoping; Kranias, Evangelia G.

2009-01-01

Doxorubicin (DOX) is a widely used antitumor drug, but its application is limited due to its cardiotoxic side effects. Hsp20 has been recently shown to protect cardiomyocytes against apoptosis, induced by ischemia/reperfusion injury or by prolonged β-agonist stimulation. However, it is not clear whether Hsp20 would exert similar protective effects against DOX-induced cardiac injury. Actually, DOX-treatment was associated with down-regulation of Hsp20 in the heart. To elucidate the role of Hsp20 in DOX-triggered cardiac toxicity, Hsp20 was first overexpressed ex vivo by adenovirus-mediated gene delivery. Increased Hsp20 levels conferred higher resistance to DOX-induced cell death, compared to GFP-control. Furthermore, cardiac-specific overexpression of Hsp20 in vivo significantly ameliorated acute DOX-triggered cardiomyocyte apoptosis and animal mortality. Hsp20-transgenic mice also showed improved cardiac function and prolonged survival after chronic administration of DOX. The mechanisms underlying these beneficial effects were associated with preserved Akt phosphorylation/activity and attenuation of DOX-induced oxidative stress. Co-immunoprecipitation studies revealed an interaction between Hsp20 and phosphorylated Akt. Accordingly, BAD phosphorylation was preserved and cleaved caspase-3 was decreased in DOX-treated Hsp20-TG hearts, consistent with the Hsp20's anti-apoptotic effects. Parallel ex vivo experiments showed that either infection with a dominant-negative Akt adenovirus or pre-incubation of cardiomyocytes with the PI3-kinase inhibitors significantly attenuated the protective effects of Hsp20. Taken together, our findings indicate that overexpression of Hsp20 inhibits DOX-triggered cardiac injury, and these beneficial effects appear to be dependent on Akt activation. Thus, Hsp20 may constitute a new therapeutic target in ameliorating the cardiotoxic effects of DOX-treatment in cancer patients. PMID:18948619

Evaluation of Bar and Nightclub Intervention to Decrease Young Adult Smoking in New Mexico

PubMed Central

Kalkhoran, Sara; Lisha, Nadra E.; Neilands, Torsten B.; Jordan, Jeffrey W.; Ling, Pamela M.

2016-01-01

Purpose Over 20% of young adults in New Mexico currently smoke. We evaluated cigarette smoking prevalence of young adult bar patrons during an anti-tobacco Social Branding intervention. Methods The Social Branding intervention used a smoke-free brand, “HAVOC,” to compete with tobacco marketing within the “Partier” young adult peer crowd. A series of cross-sectional surveys were collected from adults aged 18–26 in bars and nightclubs in Albuquerque, New Mexico, from 2009 to 2013 using randomized time-location sampling. Multivariable multinomial regression using full information maximum likelihood estimation to account for missing data evaluated differences in daily and nondaily smoking during the intervention, controlling for demographics, other risk behaviors, and tobacco-related attitudes. Results Data were collected from 1,069 individuals at Time 1, and 720, 1,142, and 1,149 participants at Times 2, 3, and 4, respectively. Current smoking rates decreased from 47.5% at Time 1 to 37.5% at Time 4 (p < .001). Among Partiers, the odds of daily smoking decreased significantly, but nondaily smoking was unchanged. Partiers that recalled, liked, and understood the smoke-free message of HAVOC had lower odds of nondaily (odds ratio: .48, 95% CI: .31–.75) and daily (odds ratio: .31,95% CI: .14–.68) smoking than those who did not recall HAVOC. HAVOC recall was associated with attitudes that were also associated with smoking behavior. Conclusions The significant decrease in daily smoking among young adult Partiers in New Mexico was associated with HAVOC recall and understanding. Social Branding interventions efficiently target and may decrease tobacco use among young adult bar patrons. PMID:27265423

Evaluation of Bar and Nightclub Intervention to Decrease Young Adult Smoking in New Mexico.

PubMed

Kalkhoran, Sara; Lisha, Nadra E; Neilands, Torsten B; Jordan, Jeffrey W; Ling, Pamela M

2016-08-01

Over 20% of young adults in New Mexico currently smoke. We evaluated cigarette smoking prevalence of young adult bar patrons during an anti-tobacco Social Branding intervention. The Social Branding intervention used a smoke-free brand, "HAVOC," to compete with tobacco marketing within the "Partier" young adult peer crowd. A series of cross-sectional surveys were collected from adults aged 18-26 in bars and nightclubs in Albuquerque, New Mexico, from 2009 to 2013 using randomized time-location sampling. Multivariable multinomial regression using full information maximum likelihood estimation to account for missing data evaluated differences in daily and nondaily smoking during the intervention, controlling for demographics, other risk behaviors, and tobacco-related attitudes. Data were collected from 1,069 individuals at Time 1, and 720, 1,142, and 1,149 participants at Times 2, 3, and 4, respectively. Current smoking rates decreased from 47.5% at Time 1 to 37.5% at Time 4 (p < .001). Among Partiers, the odds of daily smoking decreased significantly, but nondaily smoking was unchanged. Partiers that recalled, liked, and understood the smoke-free message of HAVOC had lower odds of nondaily (odds ratio: .48, 95% CI: .31-.75) and daily (odds ratio: .31, 95% CI: .14-.68) smoking than those who did not recall HAVOC. HAVOC recall was associated with attitudes that were also associated with smoking behavior. The significant decrease in daily smoking among young adult Partiers in New Mexico was associated with HAVOC recall and understanding. Social Branding interventions efficiently target and may decrease tobacco use among young adult bar patrons. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia

PubMed Central

Yu, Bo; Mao, Yicheng; Bai, Li-Yuan; Herman, Sarah E. M.; Wang, Xinmei; Ramanunni, Asha; Jin, Yan; Mo, Xiaokui; Cheney, Carolyn; Chan, Kenneth K.; Jarjoura, David; Marcucci, Guido; Lee, Robert J.; Byrd, John C.

2013-01-01

Several RNA-targeted therapeutics, including antisense oligonucleotides (ONs), small interfering RNAs, and miRNAs, constitute immunostimulatory CpG motifs as an integral part of their design. The limited success with free antisense ONs in hematologic malignancies in recent clinical trials has been attributed to the CpG motif–mediated, TLR-induced prosurvival effects and inefficient target modulation in desired cells. In an attempt to diminish their off-target prosurvival and proinflammatory effects and specific delivery, as a proof of principle, in the present study, we developed an Ab-targeted liposomal delivery strategy using a clinically relevant CD20 Ab (rituximab)–conjugated lipopolyplex nanoparticle (RIT-INP)– and Bcl-2–targeted antisense G3139 as archetypical antisense therapeutics. The adverse immunostimulatory responses were abrogated by selective B cell–targeted delivery and early endosomal compartmentalization of G3139-encapsulated RIT-INPs, resulting in reduced NF-κB activation, robust Bcl-2 down-regulation, and enhanced sensitivity to fludarabine-induced cytotoxicity. Furthermore, significant in vivo therapeutic efficacy was noted after RIT-INP–G3139 administration in a disseminated xenograft leukemia model. The results of the present study demonstrate that CD20-targeted delivery overcomes the immunostimulatory properties of CpG-containing ON therapeutics and improves efficient gene silencing and in vivo therapeutic efficacy for B-cell malignancies. The broader implications of similar approaches in overcoming immunostimulatory properties of RNA-directed therapeutics in hematologic malignancies are also discussed. PMID:23165478

Reinforcement learning of targeted movement in a spiking neuronal model of motor cortex.

PubMed

Chadderdon, George L; Neymotin, Samuel A; Kerr, Cliff C; Lytton, William W

2012-01-01

Sensorimotor control has traditionally been considered from a control theory perspective, without relation to neurobiology. In contrast, here we utilized a spiking-neuron model of motor cortex and trained it to perform a simple movement task, which consisted of rotating a single-joint "forearm" to a target. Learning was based on a reinforcement mechanism analogous to that of the dopamine system. This provided a global reward or punishment signal in response to decreasing or increasing distance from hand to target, respectively. Output was partially driven by Poisson motor babbling, creating stochastic movements that could then be shaped by learning. The virtual forearm consisted of a single segment rotated around an elbow joint, controlled by flexor and extensor muscles. The model consisted of 144 excitatory and 64 inhibitory event-based neurons, each with AMPA, NMDA, and GABA synapses. Proprioceptive cell input to this model encoded the 2 muscle lengths. Plasticity was only enabled in feedforward connections between input and output excitatory units, using spike-timing-dependent eligibility traces for synaptic credit or blame assignment. Learning resulted from a global 3-valued signal: reward (+1), no learning (0), or punishment (-1), corresponding to phasic increases, lack of change, or phasic decreases of dopaminergic cell firing, respectively. Successful learning only occurred when both reward and punishment were enabled. In this case, 5 target angles were learned successfully within 180 s of simulation time, with a median error of 8 degrees. Motor babbling allowed exploratory learning, but decreased the stability of the learned behavior, since the hand continued moving after reaching the target. Our model demonstrated that a global reinforcement signal, coupled with eligibility traces for synaptic plasticity, can train a spiking sensorimotor network to perform goal-directed motor behavior.

Neuroprotection by JM-20 against oxygen-glucose deprivation in rat hippocampal slices: Involvement of the Akt/GSK-3β pathway.

PubMed

Ramírez-Sánchez, Jeney; Simões Pires, Elisa Nicoloso; Nuñez-Figueredo, Yanier; Pardo-Andreu, Gilberto L; Fonseca-Fonseca, Luis Arturo; Ruiz-Reyes, Alberto; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Delgado-Hernández, René; Souza, Diogo O; Salbego, Christianne

2015-11-01

Cerebral ischemia is the third most common cause of death and a major cause of disability worldwide. Beyond a shortage of essential metabolites, ischemia triggers many interconnected pathophysiological events, including excitotoxicity, oxidative stress, inflammation and apoptosis. Here, we investigated the neuroprotective mechanisms of JM-20, a novel synthetic molecule, focusing on the phosphoinositide-3-kinase (PI3K)/Akt survival pathway and glial cell response as potential targets of JM-20. For this purpose, we used organotypic hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD) to achieve ischemic/reperfusion damage in vitro. Treatment with JM-20 at 0.1 and 10 μM reduced PI incorporation (indicative of cell death) after OGD. OGD decreased the phosphorylation of Akt (pro-survival) and GSK 3β (pro-apoptotic), resulting in respective inhibition and activation of these proteins. Treatment with JM20 prevented the reduced phosphorylation of these proteins after OGD, representing a shift from pro-apoptotic to pro-survival signaling. The OGD-induced activation of caspase-3 was also attenuated by JM-20 treatment at 10 μM. Moreover, in cultures treated with JM-20 and exposed to OGD conditioning, we observed a decrease in activated microglia, as well as a decrease in interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α release into the culture medium, while the level of the anti-inflammatory IL-10 increased. GFAP immunostaining and IB4 labeling showed that JM-20 treatment significantly augmented GFAP immunoreactivity after OGD, when compared with cultures exposed to OGD only, suggesting the activation of astroglial cells. Our results confirm that JM-20 has a strong neuroprotective effect against ischemic injury and suggest that the mechanisms involved in this effect may include the modulation of reactive astrogliosis, as well as neuroinflammation and the anti-apoptotic cell signaling pathway. Copyright © 2015 Elsevier Ltd. All rights

A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations

PubMed Central

Orgun, Nural; Hamlin, Donald K.; Wilbur, D. Scott; Gooley, Theodore A.; Gopal, Ajay K.; Park, Steven I.; Green, Damian J.; Lin, Yukang; Press, Oliver W.

2009-01-01

Relapsed B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. Radiolabeled antibodies directed against B-cell surface antigens have emerged as effective and safe therapies for relapsed lymphomas. We therefore investigated the potential utility of both directly radiolabeled 1F5 (anti-CD20), HD39 (anti-CD22), and Lym-1 (anti-DR) antibodies (Abs) and of pretargeted radioimmunotherapy (RIT) using Ab-streptavidin (SA) conjugates, followed by an N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled DOTA-biotin, for treatment of lymphomas in mouse models using Ramos, Raji, and FL-18 human lymphoma xenografts. This study demonstrates the marked superiority of pretargeted RIT for each of the antigenic targets with more complete tumor regressions and longer mouse survival compared with conventional one-step RIT. The Ab-SA conjugate yielding the best tumor regression and progression-free survival after pretargeted RIT varied depending upon the lymphoma cell line used, with 1F5 Ab-SA and Lym-1 Ab-SA conjugates yielding the most promising results overall. Contrary to expectations, the best rates of mouse survival were obtained using optimal single Ab-SA conjugates rather than combinations of conjugates targeting different antigens. We hypothesize that clinical implementation of pretargeted RIT methods will provide a meaningful prolongation of survival for patients with relapsed lymphomas compared with currently available treatment strategies. PMID:19124831

DETANONOate, a nitric oxide donor, decreases amiloride-sensitive alveolar fluid clearance in rabbits.

PubMed

Nielsen, V G; Baird, M S; Chen, L; Matalon, S

2000-04-01

Inhaled nitric oxide (NO) has been administered to animals to selectively reduce pulmonary hypertension via NO donors such as the NONOates. However, vectorial Na(+) transport across confluent monolayers of alveolar type II (ATII) pneumocytes has been decreased by NO. We tested the hypothesis that administration of the NO donor, DETANONOate, would decrease alveolar fluid clearance (AFC) in the rabbit in vivo. We instilled a solution of 5% albumin in 0.9% NaCl with 3 mM DETANONOate into anesthetized rabbits. Two hours later, similar AFC values were measured in the presence and absence of 3 mM DETANONOate (38 +/- 12% versus 43 +/- 13%; mean +/- SD). However, animals coadministered 1 mM amiloride with one of three doses of DETANONOate (100 microM, 300 microM, or 3 mM) had significantly (p < 0.05) greater AFC values (23 +/- 8, 20 +/- 14, 28 +/- 12%, respectively) than those administered amiloride alone (10 +/- 7%). When 5% albumin in a Cl(-)-free solution was administered in the presence or absence of 100 microM DETANONOate, neither AFC values nor alveolar Cl(-) concentrations were different. DETANONOate decreases the amiloride-sensitive fraction of AFC but does not decrease total AFC. DETANONOate does not influence total AFC secondary to an increase in the amiloride-insensitive fraction of AFC that is not associated with a decrease in alveolar Cl(-) secretion.

miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth.

PubMed

Han, Yuyan; Meng, Fanyin; Venter, Julie; Wu, Nan; Wan, Ying; Standeford, Holly; Francis, Heather; Meininger, Cynthia; Greene, John; Trzeciakowski, Jerome P; Ehrlich, Laurent; Glaser, Shannon; Alpini, Gianfranco

2016-06-01

Disruption of circadian rhythm is associated with cancer development and progression. MicroRNAs (miRNAs) are a class of small non-coding RNAs that trigger mRNA translation inhibition. We aimed to evaluate the role of Per1 and related miRNAs in cholangiocarcinoma growth. The expression of clock genes was evaluated in human cholangiocarcinoma tissue arrays and cholangiocarcinoma lines. The rhythmic expression of clock genes was evaluated in cholangiocarcinoma cells and H69 (non-malignant cholangiocytes) by qPCR. We measured cell proliferation, cell cycle and apoptosis in Mz-ChA-1 cells after Per1 overexpression. We examined tumor growth in vivo after injection of Per1 overexpressing cells. We verified miRNAs that targets Per1. The circadian rhythm of miR-34a was evaluated in cholangiocarcinoma and H69 cells. We evaluated cell proliferation, apoptosis and invasion after inhibition of miR-34a in vitro, and the potential molecular mechanisms by mRNA profiling after overexpression of Per1. Expression of Per1 was decreased in cholangiocarcinoma. The circadian rhythm of Per1 expression was lost in cholangiocarcinoma cells. Decreased cell proliferation, lower G2/M arrest, and enhanced apoptosis were shown in Per1 overexpressing cells. An in vivo study revealed decreased tumor growth, decreased proliferation, angiogenesis and metastasis after overexpressing Per1. Per1 was verified as a target of miR-34a. miR-34a was rhythmically expressed in cholangiocarcinoma cells and H69. The inhibition of miR-34a decreased proliferation, migration and invasion in cholangiocarcinoma cells. mRNA profiling has shown that overexpression of Per1 inhibits cell growth through regulation of multiple cancer-related pathways, such as cell cycle, cell growth and apoptosis pathways. Disruption of circadian rhythms of clock genes contribute to the malignant phenotypes of human cholangiocarcinoma. The current study is about how biological clock and its regulators affect the bile duct tumor growth. The

Pilots' Attention Distributions Between Chasing a Moving Target and a Stationary Target.

PubMed

Li, Wen-Chin; Yu, Chung-San; Braithwaite, Graham; Greaves, Matthew

2016-12-01

Attention plays a central role in cognitive processing; ineffective attention may induce accidents in flight operations. The objective of the current research was to examine military pilots' attention distributions between chasing a moving target and a stationary target. In the current research, 37 mission-ready F-16 pilots participated. Subjects' eye movements were collected by a portable head-mounted eye-tracker during tactical training in a flight simulator. The scenarios of chasing a moving target (air-to-air) and a stationary target (air-to-surface) consist of three operational phases: searching, aiming, and lock-on to the targets. The findings demonstrated significant differences in pilots' percentage of fixation during the searching phase between air-to-air (M = 37.57, SD = 5.72) and air-to-surface (M = 33.54, SD = 4.68). Fixation duration can indicate pilots' sustained attention to the trajectory of a dynamic target during air combat maneuvers. Aiming at the stationary target resulted in larger pupil size (M = 27,105, SD = 6565), reflecting higher cognitive loading than aiming at the dynamic target (M = 23,864, SD = 8762). Pilots' visual behavior is not only closely related to attention distribution, but also significantly associated with task characteristics. Military pilots demonstrated various visual scan patterns for searching and aiming at different types of targets based on the research settings of a flight simulator. The findings will facilitate system designers' understanding of military pilots' cognitive processes during tactical operations. They will assist human-centered interface design to improve pilots' situational awareness. The application of an eye-tracking device integrated with a flight simulator is a feasible and cost-effective intervention to improve the efficiency and safety of tactical training.Li W-C, Yu C-S, Braithwaite G, Greaves M. Pilots' attention distributions between chasing a moving target and a stationary target. Aerosp Med

Oncogenic MicroRNA-20a is downregulated by the HIF-1α/c-MYC pathway in IDH1 R132H-mutant glioma.

PubMed

Xu, Qingfu; Ahmed, A Karim; Zhu, Yan; Wang, Kimberly; Lv, Shengqing; Li, Yunqing; Jiang, Yugang

2018-05-23

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified as one of the earliest events in gliomagenesis, occurring in over 70% of low grade gliomas and are present in the vast majority of secondary glioblastoma (GBM) that develop from these low-grade lesions. The aim of this study was to investigate whether the IDH1 R132H mutation influences the expression of oncogenic miR-20a and shed light on the underlying molecular mechanisms. The findings of the current study demonstrate presence of the IDH1 R132H mutation in primary human glioblastoma cell lines with upregulated HIF-1α expression, downregulating c-MYC activity and resulting in a consequential decrease in miR-20a, which is responsible for cell proliferation and resistance to standard temozolomide treatment. Elucidating the mechanism of oncogenic miR-20a activity introduces its role among well-established signaling pathways (i.e. HIF/c-MYC) and may be a meaningful prognostic biomarker or target for novel therapies among patients with IDH1-mutant glioma. Copyright © 2018 Elsevier Inc. All rights reserved.

Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer.

PubMed

Kim, Hye-Young; Cho, Yunhee; Kang, HyeokGu; Yim, Ye-Seal; Kim, Seok-Jun; Song, Jaewhan; Chun, Kyung-Hee

2016-08-02

Wee1 is a member of the Serine/Threonine protein kinase family and is a key regulator of cell cycle progression. It has been known that WEE1 is highly expressed and has oncogenic functions in various cancers, but it is not yet studied in gastric cancers. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in gastric cancer. At first, higher expression levels of WEE1 with lower survival probability were determined in stage 4 gastric cancer patients or male patients with accompanied lymph node metastasis. To determine the function of WEE1 in gastric cancer cells, we determined that WEE1 ablation decreased the proliferation, migration, and invasion, while overexpression of WEE1 increased these effects in gastric cancer cells. We also validated the clinical application of WEE1 targeting by a small molecule, AZD1775 (MK-1775), which is a WEE1 specific inhibitor undergoing clinical trials. AZD1775 significantly inhibited cell proliferation and induced apoptosis and cell cycle arrest in gastric cancer cells, which was more effective in WEE1 high-expressing gastric cancer cells. Moreover, we performed combination treatments with AZD1775 and anti-cancer agents, 5- fluorouracil or Paclitaxel in gastric cancer cells and in gastric cancer orthotopic-transplanted mice to maximize the therapeutic effect and safety of AZD1775. The combination treatments dramatically inhibited the proliferation of gastric cancer cells and tumor burdens in stomach orthotopic-transplanted mice. Taken together, we propose that WEE1 is over-expressed and could enhance gastric cancer cell proliferation and metastasis. Therefore, we suggest that WEE1 is a potent target for gastric cancer therapy.

Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer

PubMed Central

Kim, Hye-Young; Cho, Yunhee; Kang, HyeokGu; Yim, Ye-Seal; Kim, Seok-Jun; Song, Jaewhan; Chun, Kyung-Hee

2016-01-01

Wee1 is a member of the Serine/Threonine protein kinase family and is a key regulator of cell cycle progression. It has been known that WEE1 is highly expressed and has oncogenic functions in various cancers, but it is not yet studied in gastric cancers. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in gastric cancer. At first, higher expression levels of WEE1 with lower survival probability were determined in stage 4 gastric cancer patients or male patients with accompanied lymph node metastasis. To determine the function of WEE1 in gastric cancer cells, we determined that WEE1 ablation decreased the proliferation, migration, and invasion, while overexpression of WEE1 increased these effects in gastric cancer cells. We also validated the clinical application of WEE1 targeting by a small molecule, AZD1775 (MK-1775), which is a WEE1 specific inhibitor undergoing clinical trials. AZD1775 significantly inhibited cell proliferation and induced apoptosis and cell cycle arrest in gastric cancer cells, which was more effective in WEE1 high-expressing gastric cancer cells. Moreover, we performed combination treatments with AZD1775 and anti-cancer agents, 5- fluorouracil or Paclitaxel in gastric cancer cells and in gastric cancer orthotopic-transplanted mice to maximize the therapeutic effect and safety of AZD1775. The combination treatments dramatically inhibited the proliferation of gastric cancer cells and tumor burdens in stomach orthotopic-transplanted mice. Taken together, we propose that WEE1 is over-expressed and could enhance gastric cancer cell proliferation and metastasis. Therefore, we suggest that WEE1 is a potent target for gastric cancer therapy. PMID:27363019

Target development for diversified irradiations at a medical cyclotron.

PubMed

Spellerberg, S; Scholten, B; Spahn, I; Bolten, W; Holzgreve, M; Coenen, H H; Qaim, S M

2015-10-01

The irradiation facility at an old medical cyclotron (Ep=17 MeV; Ed=10 MeV) was upgraded by extending the beam line and incorporation of solid state targetry. Tests performed to check the quality of the available beam are outlined. Results on nuclear data measurements and improvement of radiochemical separations are described. Using solid targets, with the proton beam falling at a slanting angle of 20°, a few radionuclides, e.g. (75)Se, (120)I, (124)I, etc. were produced with medium currents (up to 20 µA) in no-carrier-added form in quantities sufficient for local use. The extended irradiation facility has considerably enhanced the utility of the medical cyclotron. Copyright © 2015 Elsevier Ltd. All rights reserved.

Apixaban decreases brain thrombin activity in a male mouse model of acute ischemic stroke.

PubMed

Bushi, Doron; Chapman, Joab; Wohl, Anton; Stein, Efrat Shavit; Feingold, Ekaterina; Tanne, David

2018-05-14

Factor Xa (FXa) plays a critical role in the coagulation cascade by generation of thrombin. During focal ischemia thrombin levels increase in the brain tissue and cause neural damage. This study examined the hypothesis that administration of the FXa inhibitor, apixaban, following focal ischemic stroke may have therapeutic potential by decreasing brain thrombin activity and infarct volume. Male mice were divided into a treated groups that received different doses of apixaban (2, 20, 100 mg/kg administered I.P.) or saline (controls) immediately after blocking the middle cerebral artery (MCA). Thrombin activity was measured by a fluorescence assay on fresh coronal slices taken from the mice brains 24 hr following the MCA occlusion. Infarct volume was assessed using triphenyltetrazolium chloride staining. A high dose of apixaban (100 mg/kg) significantly decreased thrombin activity levels in the ipsilateral hemisphere compared to the control group (Slice#5, p = .016; Slice#6, p = .016; Slice#7, p = .016; Slice#8, p = .036; by the nonparametric Mann-Whitney test). In addition, treatment with apixaban doses of both 100 mg/kg (32 ± 8% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .005 by the nonparametric Mann-Whitney test) and 20 mg/kg (43 ± 7% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .019 by the nonparametric Mann-Whitney test) decreased infarct volumes in areas surrounding the ischemic core (Slices #3 and #8). No brain hemorrhages were observed either in the treated or control groups. In summary, I.P. administration of high dose of apixaban immediately after MCA occlusion decreases brain thrombin activity and reduces infarct size. © 2018 Wiley Periodicals, Inc.

Commissioning and Operation of a Cryogenic Target at HI γS

NASA Astrophysics Data System (ADS)

Kendellen, David; Compton@HIγ Collaboration

2016-09-01

We have developed a cryogenic target for use at the High Intensity γ-ray Source (HI γS). The target system is able to liquefy helium-4 (LHe) at 4 K, hydrogen (LH2) at 20 K, or deuterium (LD2) at 23 K to fill a 0.3 L Kapton cell. Liquid temperatures and condenser pressures are recorded throughout each run in order to ensure that the target's areal density is known to 1 % . A low-temperature valve enables cycling between full and empty modes in less than 15 minutes. The target is being utilized in a series of experiments which probe the electromagnetic polarizabilities of the nucleon by Compton scattering high-energy photons from the liquid and detecting them with the HI γS NaI Detector Array (HINDA). During a 50-hour-long commissioning run last fall, the target held LHe at 3.17 K, followed by a 300-hour-long production run this spring with LD2 at 23.9 K. The design of the target will be presented and its performance during these two runs will be discussed. Work supported by US Department of Energy Contracts DE-FG02-97ER41033, DE-FG02-06ER41422, and DE-SCOO0536.

Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis.

PubMed

Watts, Rani; Johnsen, Virginia L; Shearer, Jane; Hittel, Dustin S

2013-05-15

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (-11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G(0)/G(1) phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.

Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner.

PubMed

Wu, Fei; Lin, Yun; Cui, Peng; Li, Hongyun; Zhang, Lechao; Sun, Zeqiang; Huang, Shengliang; Li, Shun; Huang, Shiming; Zhao, Qingli; Liu, Qingyong

2018-06-01

At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive. In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC. Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment. In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim

Commissioning and Operation of a Cryogenic Target at HI γS

NASA Astrophysics Data System (ADS)

Kendellen, David; Compton@HIγS Collaboration

2017-01-01

We have developed a cryogenic target for use at the High Intensity γ-ray Source (HI γS). The target system is able to liquefy helium-4 (LHe) at 4 K, hydrogen (LH2) at 20 K, or deuterium (LD2) at 23 K to fill a 0.3 L Kapton cell. Liquid temperatures and condenser pressures are recorded throughout each run in order to ensure that the target's areal density is known to 1%. A low-temperature valve enables cycling between full and empty modes in less than 15 minutes. The target is being utilized in a series of experiments which probe the electromagnetic polarizabilities of the nucleon by Compton scattering high-energy photons from the liquid and detecting them with the HI γS NaI Detector Array (HINDA). During a 50-hour-long commissioning run, the target held LHe at 3.17 K, followed by 600 hours of production running with LD2 at 23.9 K. The design of the target will be presented and its performance during these runs will be discussed. Work supported by US Department of Energy contracts DE-FG02-97ER41033, DE-FG02-06ER41422, and DE-SCOO0536

Target with a frozen nuclear polarization for experiments at low energies

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

Borisov, N.S.; Matafonov, V.N.; Neganov, A.B.

1995-09-01

The short history of the development of frozen spin polarized targets at the Laboratory of Nuclear Problems JINR is given. The latest development is the target with a frozen spin polarization of protons in 1,2- propanediol with a paramagnetic Cr{sup {ital V}} impurity, intended for polarization parameter studies in np-scattering at approximately 15 MeV neutron energy. The target of cylindrical shape of 2 cm diameter and 6 cm long with an initial polarization of 95{plus_minus}3{percent} obtainable by the dynamic polarization technique is placed at a temperature about 20 mK in a magnetic field of 0.37 T generated by a magneticmore » system, which provides a large aperture for scattered particles. The relaxation time for the spin polarization is about 1000 hours. {copyright} {ital 1995 American Institute of Physics.}« less

Overexpression of 20-Oxidase Confers a Gibberellin-Overproduction Phenotype in Arabidopsis

PubMed Central

Huang, Shihshieh; Raman, Anuradha S.; Ream, Joel E.; Fujiwara, Hideji; Cerny, R. Eric; Brown, Sherri M.

1998-01-01

In the gibberellin (GA) biosynthesis pathway, 20-oxidase catalyzes the oxidation and elimination of carbon-20 to give rise to C19-GAs. All bioactive GAs are C19-GAs. We have overexpressed a cDNA encoding 20-oxidase isolated from Arabidopsis seedlings in transgenic Arabidopsis plants. These transgenic plants display a phenotype that may be attributed to the overproduction of GA. The phenotype includes a longer hypocotyl, lighter-green leaves, increased stem elongation, earlier flowering, and decreased seed dormancy. However, the fertility of the transgenic plants is not affected. Increased levels of endogenous GA1, GA9, and GA20 were detected in seedlings of the transgenic line examined. GA4, which is thought to be the predominantly active GA in Arabidopsis, was not present at increased levels in this line. These results suggest that the overexpression of this 20-oxidase increases the levels of some endogenous GAs in transgenic seedlings, which causes the GA-overproduction phenotype. PMID:9808721

Inhibition of Steptococcus mutans biofilm formation by extracts of Tenacibaculum sp. 20J, a bacterium with wide-spectrum quorum quenching activity.

PubMed

Muras, Andrea; Mayer, Celia; Romero, Manuel; Camino, Tamara; Ferrer, Maria D; Mira, Alex; Otero, Ana

2018-01-01

Background : Previous studies have suggested the quorum sensing signal AI-2 as a potential target to prevent the biofilm formation by Streptococcus mutans , a pathogen involved in tooth decay. Objective : To obtain inhibition of biofilm formation by S. mutans by extracts obtained from the marine bacterium Tenacibaculum sp. 20J interfering with the AI-2 quorum sensing system. Design : The AI-2 inhibitory activity was tested with the biosensors Vibrio harveyi BB170 and JMH597. S. mutans ATCC25175 biofilm formation was monitored using impedance real-time measurements with the xCELLigence system®, confocal laser microscopy, and the crystal violet quantification method. Results : The addition of the cell extract from Tenacibaculum sp. 20J reduced biofilm formation in S. mutans ATCC25175 by 40-50% compared to the control without significantly affecting growth. A decrease of almost 40% was also observed in S. oralis DSM20627 and S. dentisani 7747 biofilms. Conclusions : The ability of Tenacibaculum sp. 20J to interfere with AI-2 and inhibit biofilm formation in S. mutans was demonstrated. The results indicate that the inhibition of quorum sensing processes may constitute a suitable strategy for inhibiting dental plaque formation, although additional experiments using mixed biofilm models would be required.

Inhibition of Steptococcus mutans biofilm formation by extracts of Tenacibaculum sp. 20J, a bacterium with wide-spectrum quorum quenching activity

PubMed Central

Muras, Andrea; Mayer, Celia; Romero, Manuel; Camino, Tamara; Ferrer, Maria D.; Mira, Alex; Otero, Ana

2018-01-01

ABSTRACT Background: Previous studies have suggested the quorum sensing signal AI-2 as a potential target to prevent the biofilm formation by Streptococcus mutans, a pathogen involved in tooth decay. Objective: To obtain inhibition of biofilm formation by S. mutans by extracts obtained from the marine bacterium Tenacibaculum sp. 20J interfering with the AI-2 quorum sensing system. Design: The AI-2 inhibitory activity was tested with the biosensors Vibrio harveyi BB170 and JMH597. S. mutans ATCC25175 biofilm formation was monitored using impedance real-time measurements with the xCELLigence system®, confocal laser microscopy, and the crystal violet quantification method. Results: The addition of the cell extract from Tenacibaculum sp. 20J reduced biofilm formation in S. mutans ATCC25175 by 40–50% compared to the control without significantly affecting growth. A decrease of almost 40% was also observed in S. oralis DSM20627 and S. dentisani 7747 biofilms. Conclusions: The ability of Tenacibaculum sp. 20J to interfere with AI-2 and inhibit biofilm formation in S. mutans was demonstrated. The results indicate that the inhibition of quorum sensing processes may constitute a suitable strategy for inhibiting dental plaque formation, although additional experiments using mixed biofilm models would be required. PMID:29410771

Molecular and Structural Characterization of the Tegumental 20.6-kDa Protein in Clonorchis sinensis as a Potential Druggable Target.

PubMed

Kim, Yu-Jung; Yoo, Won Gi; Lee, Myoung-Ro; Kang, Jung-Mi; Na, Byoung-Kuk; Cho, Shin-Hyeong; Park, Mi-Yeoun; Ju, Jung-Won

2017-03-04

The tegument, representing the membrane-bound outer surface of platyhelminth parasites, plays an important role for the regulation of the host immune response and parasite survival. A comprehensive understanding of tegumental proteins can provide drug candidates for use against helminth-associated diseases, such as clonorchiasis caused by the liver fluke Clonorchis sinensis . However, little is known regarding the physicochemical properties of C. sinensis teguments. In this study, a novel 20.6-kDa tegumental protein of the C. sinensis adult worm (CsTegu20.6) was identified and characterized by molecular and in silico methods. The complete coding sequence of 525 bp was derived from cDNA clones and encodes a protein of 175 amino acids. Homology search using BLASTX showed CsTegu20.6 identity ranging from 29% to 39% with previously-known tegumental proteins in C. sinensis . Domain analysis indicated the presence of a calcium-binding EF-hand domain containing a basic helix-loop-helix structure and a dynein light chain domain exhibiting a ferredoxin fold. We used a modified method to obtain the accurate tertiary structure of the CsTegu20.6 protein because of the unavailability of appropriate templates. The CsTegu20.6 protein sequence was split into two domains based on the disordered region, and then, the structure of each domain was modeled using I-TASSER. A final full-length structure was obtained by combining two structures and refining the whole structure. A refined CsTegu20.6 structure was used to identify a potential CsTegu20.6 inhibitor based on protein structure-compound interaction analysis. The recombinant proteins were expressed in Escherichia coli and purified by nickel-nitrilotriacetic acid affinity chromatography. In C. sinensis , CsTegu20.6 mRNAs were abundant in adult and metacercariae, but not in the egg. Immunohistochemistry revealed that CsTegu20.6 localized to the surface of the tegument in the adult fluke. Collectively, our results contribute to a

Endogenous opioid system: a promising target for future smoking cessation medications.

PubMed

Norman, Haval; D'Souza, Manoranjan S

2017-05-01

Nicotine addiction continues to be a health challenge across the world. Despite several approved medications, smokers continue to relapse. Several human and animal studies have evaluated the role of the endogenous opioid system as a potential target for smoking cessation medications. In this review, studies that have elucidated the role of the mu (MORs), delta (DORs), and kappa (KORs) opioid receptors in nicotine reward, nicotine withdrawal, and reinstatement of nicotine seeking will be discussed. Additionally, the review will discuss discrepancies in the literature and therapeutic potential of the endogenous opioid system, and suggest studies to address gaps in knowledge with respect to the role of the opioid receptors in nicotine dependence. Data available till date suggest that blockade of the MORs and DORs decreased the rewarding effects of nicotine, while activation of the MORs and DORs decreased nicotine withdrawal-induced aversive effects. In contrast, activation of the KORs decreased the rewarding effects of nicotine, while blockade of the KORs decreased nicotine withdrawal-induced aversive effects. Interestingly, blockade of the MORs and KORs attenuated reinstatement of nicotine seeking. In humans, MOR antagonists have shown benefits in select subpopulations of smokers and further investigation is required to realize their full therapeutic potential. Future work must assess the influence of polymorphisms in opioid receptor-linked genes in nicotine dependence, which will help in both identifying individuals vulnerable to nicotine addiction and the development of opioid-based smoking cessation medications. Overall, the endogenous opioid system continues to be a promising target for future smoking cessation medications.

Sudden collapse of vacuoles in Saintpaulia sp. palisade cells induced by a rapid temperature decrease.

PubMed

Kadohama, Noriaki; Goh, Tatsuaki; Ohnishi, Miwa; Fukaki, Hidehiro; Mimura, Tetsuro; Suzuki, Yoshihiro

2013-01-01

It is well known that saintpaulia leaf is damaged by the rapid temperature decrease when cold water is irrigated onto the leaf surface. We investigated this temperature sensitivity and the mechanisms of leaf damage in saintpaulia (Saintpaulia sp. cv. 'Iceberg') and other Gesneriaceae plants. Saintpaulia leaves were damaged and discolored when subjected to a rapid decrease in temperature, but not when the temperature was decreased gradually. Sensitivity to rapid temperature decrease increased within 10 to 20 min during pre-incubation at higher temperature. Injury was restricted to the palisade mesophyll cells, where there was an obvious change in the color of the chloroplasts. During a rapid temperature decrease, chlorophyll fluorescence monitored by a pulse amplitude modulated fluorometer diminished and did not recover even after rewarming to the initial temperature. Isolated chloroplasts were not directly affected by the rapid temperature decrease. Intracellular pH was monitored with a pH-dependent fluorescent dye. In palisade mesophyll cells damaged by rapid temperature decrease, the cytosolic pH decreased and the vacuolar membrane collapsed soon after a temperature decrease. In isolated chloroplasts, chlorophyll fluorescence declined when the pH of the medium was lowered. These results suggest that a rapid temperature decrease directly or indirectly affects the vacuolar membrane, resulting in a pH change in the cytosol that subsequently affects the chloroplasts in palisade mesophyll cells. We further confirmed that the same physiological damage occurs in other Gesneriaceae plants. These results strongly suggested that the vacuoles of palisade mesophyll cells collapsed during the initial phase of leaf injury.

Sudden Collapse of Vacuoles in Saintpaulia sp. Palisade Cells Induced by a Rapid Temperature Decrease

PubMed Central

Kadohama, Noriaki; Goh, Tatsuaki; Ohnishi, Miwa; Fukaki, Hidehiro; Mimura, Tetsuro; Suzuki, Yoshihiro

2013-01-01

It is well known that saintpaulia leaf is damaged by the rapid temperature decrease when cold water is irrigated onto the leaf surface. We investigated this temperature sensitivity and the mechanisms of leaf damage in saintpaulia (Saintpaulia sp. cv. ‘Iceberg’) and other Gesneriaceae plants. Saintpaulia leaves were damaged and discolored when subjected to a rapid decrease in temperature, but not when the temperature was decreased gradually. Sensitivity to rapid temperature decrease increased within 10 to 20 min during pre-incubation at higher temperature. Injury was restricted to the palisade mesophyll cells, where there was an obvious change in the color of the chloroplasts. During a rapid temperature decrease, chlorophyll fluorescence monitored by a pulse amplitude modulated fluorometer diminished and did not recover even after rewarming to the initial temperature. Isolated chloroplasts were not directly affected by the rapid temperature decrease. Intracellular pH was monitored with a pH-dependent fluorescent dye. In palisade mesophyll cells damaged by rapid temperature decrease, the cytosolic pH decreased and the vacuolar membrane collapsed soon after a temperature decrease. In isolated chloroplasts, chlorophyll fluorescence declined when the pH of the medium was lowered. These results suggest that a rapid temperature decrease directly or indirectly affects the vacuolar membrane, resulting in a pH change in the cytosol that subsequently affects the chloroplasts in palisade mesophyll cells. We further confirmed that the same physiological damage occurs in other Gesneriaceae plants. These results strongly suggested that the vacuoles of palisade mesophyll cells collapsed during the initial phase of leaf injury. PMID:23451194

Literature evidence in open targets - a target validation platform.

PubMed

Kafkas, Şenay; Dunham, Ian; McEntyre, Johanna

2017-06-06

We present the Europe PMC literature component of Open Targets - a target validation platform that integrates various evidence to aid drug target identification and validation. The component identifies target-disease associations in documents and ranks the documents based on their confidence from the Europe PMC literature database, by using rules utilising expert-provided heuristic information. The confidence score of a given document represents how valuable the document is in the scope of target validation for a given target-disease association by taking into account the credibility of the association based on the properties of the text. The component serves the platform regularly with the up-to-date data since December, 2015. Currently, there are a total number of 1168365 distinct target-disease associations text mined from >26 million PubMed abstracts and >1.2 million Open Access full text articles. Our comparative analyses on the current available evidence data in the platform revealed that 850179 of these associations are exclusively identified by literature mining. This component helps the platform's users by providing the most relevant literature hits for a given target and disease. The text mining evidence along with the other types of evidence can be explored visually through https://www.targetvalidation.org and all the evidence data is available for download in json format from https://www.targetvalidation.org/downloads/data .

Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cells.

PubMed

Han, Songhee; Jeong, Ae Jin; Yang, Heejung; Bin Kang, Kyo; Lee, Haeri; Yi, Eun Hee; Kim, Byung-Hak; Cho, Chung-Hyun; Chung, Jin Woong; Sung, Sang Hyun; Ye, Sang-Kyu

2016-12-24

Panax ginseng is one of the most well-known medicinal herbs in Korea and China, which has been used for treatment and prevention of cancer, obesity, diabetes, and cardiovascular diseases. Ginsenosides are the major components of P. ginseng, having a wide range of pharmacological activities. Among the ginsenosides, protopanaxadiol (PPD)-types reportedly have potent anti-cancer effects. Rh2 is PPD-type ginsenoside, and two stereoisomeric forms of Rh2 as 20(S)- and 20(R)-Rh2 were selectively isolated recently. The biological activities of Rh2 ginsenosides are known to depend on their differences in stereochemistry. Colorectal cancer (CRC) is one of the most lethal neoplasm, and cancer-related death is usually associated with metastasis to other organs. We aimed this study to investigate whether 20(S)- and 20(R)-Rh2 can suppress tumor invasion in human CRC cells. 20(S)- and 20(R)-Rh2 were isolated from the roots of ginseng. Human CRC cells were incubated with 20(S)- or 20(R)-Rh2 in the presence or absence of interleukin-6. An MTT assay was used to measure cell viability. Western blot and quantitative real-time PCR analyses were performed to determine levels of expression and phosphorylation. An invasion assay was performed using a Boyden chamber system with the Matrigel-coated membrane to measure cancer cell invasion. 20(S)- and 20(R)-Rh2 showed differential cytotoxic activity. Only 20(S)-Rh2 decreased cancer cell viability. Additionally, 20(S)-Rh2 effectively inhibited IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of matrix metalloproteinases (MMPs), including MMP-1, -2, and -9, resulting in inhibition of cancer cell invasion. Interestingly, these pharmacological activities of 20(S)-Rh2 were more potent than those of 20(R)-Rh2. Furthermore, combination treatment showed that 20(S)-Rh2 enhanced the sensitization of doxorubicin-treated anti-cancer activities in CRC cells. Our results demonstrated that

Particle production of a graphite target system for the intensity frontier

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

Ding, X.; Kirk, H.; McDonald, K. T.

2015-05-03

A solid graphite target system is considered for an intense muon and/or neutrino source in support of physics at the intensity frontier. We previously optimized the geometric parameters of the beam and target to maximize particle production at low energies by incoming protons with kinetic energy of 6.75 GeV and an rms geometric emittance of 5 mm-mrad using the MARS15(2014) code. In this study, we ran MARS15 with ROOT-based geometry and also considered a mercury-jet target as an upgrade option. The optimization was extended to focused proton beams with transverse emittances from 5 to 50 mm-mrad, showing that the particlemore » production decreases slowly with increasing emittance. We also studied beam-dump configurations to suppress the rate of undesirable high-energy secondary particles in the beam.« less

A longitudinal analysis of the effect of nonmedical exemption law and vaccine uptake on vaccine-targeted disease rates.

PubMed

Yang, Y Tony; Debold, Vicky

2014-02-01

We assessed how nonmedical exemption (NME) laws and annual uptake of vaccines required for school or daycare entry affect annual incidence rates for 5 vaccine-targeted diseases: pertussis, measles, mumps, Haemophilus influenzae type B, and hepatitis B. We employed longitudinal mixed-effects models to examine 2001-2008 vaccine-targeted disease data obtained from the National Notifiable Disease Surveillance System. Key explanatory variables were state-level vaccine-specific uptake rates from the National Immunization Survey and a state NME law restrictiveness level. NME law restrictiveness and vaccine uptake were not associated with disease incidence rate for hepatitis B, Haemophilus influenzae type B, measles, or mumps. Pertussis incidence rate, however, was negatively associated with NME law restrictiveness (b = -0.20; P = .03) and diphtheria-pertussis-tetanus vaccine uptake (b = -0.01; P = .05). State NME laws and vaccine uptake rates did not appear to influence lower-incidence diseases but may influence reported disease rates for higher-incidence diseases. If all states increased their NME law restrictiveness by 1 level and diphtheria-pertussis-tetanus uptake by 1%, national annual pertussis cases could decrease by 1.14% (171 cases) and 0.04% (5 cases), respectively.

Pressure control of a proton beam-irradiated water target through an internal flow channel-induced thermosyphon.

PubMed

Hong, Bong Hwan; Jung, In Su

2017-07-01

A water target was designed to enhance cooling efficiency using a thermosyphon, which is a system that uses natural convection to induce heat exchange. Two water targets were fabricated: a square target without any flow channel and a target with a flow channel design to induce a thermosyphon mechanism. These two targets had the same internal volume of 8 ml. First, visualization experiments were performed to observe the internal flow by natural convection. Subsequently, an experiment was conducted to compare the cooling performance of both water targets by measuring the temperature and pressure. A 30-MeV proton beam with a beam current of 20 μA was used to irradiate both targets. Consequently, the target with an internal flow channel had a lower mean temperature and a 50% pressure drop compared to the target without a flow channel during proton beam irradiation. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Computational Approach to Finding Novel Targets for Existing Drugs

PubMed Central

Li, Yvonne Y.; An, Jianghong; Jones, Steven J. M.

2011-01-01

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects. PMID:21909252

Immunologic properties and therapeutic efficacy of a multivalent epitope-based vaccine against four Helicobacter pylori adhesins (urease, Lpp20, HpaA, and CagL) in Mongolian gerbils.

PubMed

Guo, Le; Yin, Runting; Xu, Guangxian; Gong, Xiaojuan; Chang, Zisong; Hong, Dantong; Liu, Hongpeng; Ding, Shuqin; Han, Xuebo; Li, Yuan; Tang, Feng; Liu, Kunmei

2017-12-01

Therapeutic vaccination is a desirable alternative for controlling Helicobacter pylori (H. pylori) infection. Attachment to the gastric mucosa is the first step in establishing bacterial colonization, and adhesins, which are on the surface of H. pylori, play a pivotal role in binding to human gastric mucosa. In the present study, we constructed a multivalent epitope-based vaccine named CFAdE with seven carefully selected antigenic fragments from four H. pylori adhesins (urease, Lpp20, HpaA and CagL). The specificity, immunogenicity and ability to produce neutralizing antibodies of CFAdE were evaluated in BALB/c mice. After that, its therapeutic efficacy and protective immune mechanisms were explored in H. pylori-infected Mongolian gerbils. The results indicated that CFAdE could induce comparatively high levels of specific antibodies against urease, Lpp20, HpaA and CagL. Additionally, oral therapeutic immunization with CFAdE plus polysaccharide adjuvant (PA) significantly decreased H. pylori colonization compared with oral immunization with urease plus PA, and the protection was correlated with IgG and sIgA antibody and antigen-specific CD4 + T cells. This study indicated that the multivalent epitope-based vaccine, which targeted multiple adhesins in adherence of H. pylori to the gastric mucosa, is more effective than the univalent vaccine targeting urease only. This multivalent epitope-based vaccine may be a promising therapeutic candidate vaccine against H. pylori infection. © 2017 John Wiley & Sons Ltd.

A Track Initiation Method for the Underwater Target Tracking Environment

NASA Astrophysics Data System (ADS)

Li, Dong-dong; Lin, Yang; Zhang, Yao

2018-04-01

A novel efficient track initiation method is proposed for the harsh underwater target tracking environment (heavy clutter and large measurement errors): track splitting, evaluating, pruning and merging method (TSEPM). Track initiation demands that the method should determine the existence and initial state of a target quickly and correctly. Heavy clutter and large measurement errors certainly pose additional difficulties and challenges, which deteriorate and complicate the track initiation in the harsh underwater target tracking environment. There are three primary shortcomings for the current track initiation methods to initialize a target: (a) they cannot eliminate the turbulences of clutter effectively; (b) there may be a high false alarm probability and low detection probability of a track; (c) they cannot estimate the initial state for a new confirmed track correctly. Based on the multiple hypotheses tracking principle and modified logic-based track initiation method, in order to increase the detection probability of a track, track splitting creates a large number of tracks which include the true track originated from the target. And in order to decrease the false alarm probability, based on the evaluation mechanism, track pruning and track merging are proposed to reduce the false tracks. TSEPM method can deal with the track initiation problems derived from heavy clutter and large measurement errors, determine the target's existence and estimate its initial state with the least squares method. What's more, our method is fully automatic and does not require any kind manual input for initializing and tuning any parameter. Simulation results indicate that our new method improves significantly the performance of the track initiation in the harsh underwater target tracking environment.

S3 targets monitoring with an electron gun

NASA Astrophysics Data System (ADS)

Kallunkathariyil, J.; Stodel, Ch.; Marry, C.; Frémont, G.; Bastin, B.; Piot, J.; Clément, E.; Le Moal, S.; Morel, V.; Thomas, J.-C.; Kamalou, O.; Spitaëls, C.; Savajols, H.; Vostinar, M.; Pellemoine, F.; Mittig, W.

2018-05-01

The monitoring of targets under irradiation was investigated using a 20 keV electron beam. An integrated and automated electron beam deflection was developed allowing a monitoring over the whole surface of target materials. Thus, local defects could be identified on-line during an experiment performed at GANIL involving different materials irradiated with a focused krypton beam at 10.5 MeV/u. Performances of this target monitoring system are presented in this paper.

Impaired granulocyte oxidative burst and decreased expression of leucocyte adhesion molecule-1 (LAM-1) in patients with Wegener's granulomatosis.

PubMed Central

Riecken, B; Gutfleisch, J; Schlesier, M; Peter, H H

1994-01-01

Neutrophils are the target of autoantibodies in Wegener's granulomatosis (WG). In this study, granulocyte function and surface marker expression were investigated in patients with WG. The oxidative burst in response to phorbol myristate acetate (PMA) was tested with granulocytes of 25 patients with histologically proven WG. A significantly diminished percentage of oxygen radical-producing cells was found in patients with active disease. Surface antigen expression of CD11b and LAM-1 was analysed on granulocytes of 20 patients with WG. Whereas the expression of CD11b was normal, surface expression of LAM-1 was decreased in nine cases with WG. The decrease of LAM-1 correlated with disease activity. Phagocytosis of Escherichia coli was tested in 10 patients with WG, and normal values were found in all cases. We conclude that down-regulation of LAM-1 may be a marker of disease activity in WG. The altered response to PMA may indicate functional changes in granulocyte reactivity due to autoantibody-induced damage of the granulocyte membrane. PMID:7512009

Observation of a rapid decrease in the brightness of the coma of 2060 Chiron in 1990 January

NASA Technical Reports Server (NTRS)

Buratti, Bonnie J.; Dunbar, R. Scott

1991-01-01

Photometric observations of 2060 Chiron in the V and R filters were obtained with the 1.5-m telescope on Palomar Mountain during a 7-hr period on January 20, 1990 (UT). A general decrease of about 10 percent in integrated brightness occurred in both filters. No color dependence to the decrease was observed. A small (about 0.02 mag) rotational light curve, far smaller than the 0.09 mag (peak-to-peak) one observed by Bus et al. (1989) is superposed on the general decrease. On January 29, 1990, Luu and Jewitt (1990) observed an impulsive brightening of Chiron of approximately the same magnitude and time scale as the presently observed decrease in brightness. The combined results provide evidence that Chiron is currently exhibiting short-term fluctuations in the brightness of its coma, in addition to its well-established general decrease in brightness.

Observation of a rapid decrease in the brightness of the coma of 2060 Chiron in 1990 January

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

Buratti, B.J.; Dunbar, R.S.

Photometric observations of 2060 Chiron in the V and R filters were obtained with the 1.5-m telescope on Palomar Mountain during a 7-hr period on January 20, 1990 (UT). A general decrease of about 10 percent in integrated brightness occurred in both filters. No color dependence to the decrease was observed. A small (about 0.02 mag) rotational light curve, far smaller than the 0.09 mag (peak-to-peak) one observed by Bus et al. (1989) is superposed on the general decrease. On January 29, 1990, Luu and Jewitt (1990) observed an impulsive brightening of Chiron of approximately the same magnitude and timemore » scale as the presently observed decrease in brightness. The combined results provide evidence that Chiron is currently exhibiting short-term fluctuations in the brightness of its coma, in addition to its well-established general decrease in brightness. 14 refs.« less

Static and Dynamic Compaction of CL-20 Powders

NASA Astrophysics Data System (ADS)

Cooper, Marcia; Brundage, Aaron; Dudley, Evan

2009-06-01

Hexanitrohexaazaisowurtzitane (CL-20) powders were compacted under quasi-static and dynamic loading conditions. A uniaxial compression apparatus quasi-statically compressed the powders to 90% theoretical maximum density with applied stresses up to 0.5 GPa. Dynamic compaction measurements using low-density pressings (62-70% theoretical maximum density) were obtained in a single-stage gas gun at impact velocities between 0.17-0.70 km/s. Experiments were conducted in a reverse ballistic arrangement in which the CL-20 ladened projectile impacted a target consisting of an aluminized window. VISAR-measured particle velocities at the explosive-window interface determined the shock Hugoniot states for pressures up to 0.9 GPa. The powder compaction behavior is found to be stiffer under dynamic loading than under quasi-static loading. Additional gas gun tests were conducted in which the low-density CL-20 pressings were confined within a target cup by the aluminized window. This arrangement enabled temporal measurement of the transmitted wave profiles in which elastic wave precursors were observed.

Target-directed catalytic metallodrugs

PubMed Central

Joyner, J.C.; Cowan, J.A.

2013-01-01

Most drugs function by binding reversibly to specific biological targets, and therapeutic effects generally require saturation of these targets. One means of decreasing required drug concentrations is incorporation of reactive metal centers that elicit irreversible modification of targets. A common approach has been the design of artificial proteases/nucleases containing metal centers capable of hydrolyzing targeted proteins or nucleic acids. However, these hydrolytic catalysts typically provide relatively low rate constants for target inactivation. Recently, various catalysts were synthesized that use oxidative mechanisms to selectively cleave/inactivate therapeutic targets, including HIV RRE RNA or angiotensin converting enzyme (ACE). These oxidative mechanisms, which typically involve reactive oxygen species (ROS), provide access to comparatively high rate constants for target inactivation. Target-binding affinity, co-reactant selectivity, reduction potential, coordination unsaturation, ROS products (metal-associated vs metal-dissociated; hydroxyl vs superoxide), and multiple-turnover redox chemistry were studied for each catalyst, and these parameters were related to the efficiency, selectivity, and mechanism(s) of inactivation/cleavage of the corresponding target for each catalyst. Important factors for future oxidative catalyst development are 1) positioning of catalyst reduction potential and redox reactivity to match the physiological environment of use, 2) maintenance of catalyst stability by use of chelates with either high denticity or other means of stabilization, such as the square planar geometric stabilization of Ni- and Cu-ATCUN complexes, 3) optimal rate of inactivation of targets relative to the rate of generation of diffusible ROS, 4) targeting and linker domains that afford better control of catalyst orientation, and 5) general bio-availability and drug delivery requirements. PMID:23828584

Coffee consumption in aged mice increases energy production and decreases hepatic mTOR levels.

PubMed

Takahashi, Keita; Yanai, Shuichi; Shimokado, Kentaro; Ishigami, Akihito

2017-06-01

Coffee, one of the world's most consumed beverages, has many benefits. Some studies have reported the effects of coffee on aging. The aim of this study was to investigate the locomotor activity, energy metabolism, and lipid metabolism of aged (20-mo-old) mice given coffee. Aged C57 BL/6 NCr mice were divided into three groups: controls that were not given coffee (n = 9), a group that received 0.1% caffeinated coffee (n = 9), and a group that received 0.1% decaffeinated coffee (n = 9). This regimen continued for 17 wk until mice reached the age of 24 mo. Regular and decaffeinated coffee consumption decreased plasma-free fatty acid levels, increased hepatic adenosine triphosphate content, and decreased total mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) protein content in the liver. However, no differences were found in the protein or activity levels of Akt, adenosine monophosphate-activated protein kinase (AMPK), p70 S6 kinase, or sterol regulatory element-binding protein 1, proteins that are upstream or downstream of the mTOR complex 1 (mTORC1)-related pathways. Regular coffee consumption increased food and water intake, locomotor activity, the volume of carbon dioxide production, and the respiration exchange ratio. Regular and decaffeinated coffee consumption decreased hepatic total mTOR and p-mTOR levels independently of Akt and AMPK pathways in aged mice. Because decreased mTORC1 activity is known to have antiaging effects, coffee consumption during old age may retard aging. Moreover, coffee consumption by the aged population had a positive effect on behavioral energy and lipid metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of cationic liposome formulations designed to exhibit extended plasma residence times and tumor vasculature targeting properties.

PubMed

Ho, Emmanuel A; Ramsay, Euan; Ginj, Mihaela; Anantha, Malathi; Bregman, Isaiah; Sy, Jonathan; Woo, Janet; Osooly-Talesh, Maryam; Yapp, Donald T; Bally, Marcel B

2010-06-01

Cationic liposomes exhibit a propensity to selectively target tumor-associated blood vessels demonstrating potential value as anti-cancer drug delivery vehicles. Their utility however, is hampered by their biological instability and rapid elimination following i.v. administration. Efforts to circumvent rapid plasma elimination have, to date, focused on decreasing cationic lipid content and incorporating polyethylene glycol (PEG)-modified lipids. In this study we wanted to determine whether highly charged cationic liposomes with surface-associated PEG could be designed to exhibit extended circulation lifetimes, while retaining tumor vascular targeting properties in an HT29 colorectal cancer xenograft model. Cationic liposomes prepared of DSPC, cationic lipids (DODAC, DOTAP, or DC-CHOL), and DSPE-PEG(2000) were studied. Our results demonstrate that formulations prepared with 50 mol% DODAC or DC-CHOL, and 20 mol% DSPE-PEG(2000) exhibited circulation half-lives ranging from 6.5 to 12.5 h. Biodistribution studies demonstrated that DC-CHOL formulations prepared with DSPE-PEG(2000) accumulated threefold higher in s.c. HT29 tumors than its PEG-free counterpart. Fluorescence microscopy studies suggested that the presence of DSPE-PEG(2000) did not adversely affect liposomal tumor vasculature targeting. We show for the first time that it is achievable to design highly charged, highly pegylated (20 mol% DSPE-PEG(2000)) cationic liposomes which exhibit both extended circulation lifetimes and tumor vascular targeting properties. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice.

PubMed

Yan, Caifeng; Chen, Jinfeng; Li, Min; Xuan, Wenying; Su, Dongming; You, Hui; Huang, Yujie; Chen, Nuoqi; Liang, Xiubin

2016-07-01

MicroRNA-9 (miR-9) is involved in the regulation of pancreatic beta cell function. However, its role in gluconeogenesis is still unclear. Our objective was to investigate the role of miR-9 in hepatic glucose production (HGP). MiR-9 expression was measured in livers of high-fat diet (HFD) mice and ob/ob mice. The methylation status of the miR-9-3 promoter regions in hepatocytes was determined by the methylation-specific PCR procedure. The binding activity of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b on the miR-9-3 promoter was detected by chromatin immunoprecipitation (ChIP) and quantitative real-time PCR assays. HGP was evaluated in vitro and in vivo. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were also performed. Reduced miR-9 expression and hypermethylation of the miR-9-3 promoter were observed in the livers of obese mice. Further study showed that the binding of DNMT1, but not of DNMT3a and DNMT3b, to the miR-9-3 promoter was increased in hepatocytes from ob/ob mice. Knockdown of DNMT1 alleviated the decrease in hepatic miR-9 expression in vivo and in vitro. Overexpression of hepatic miR-9 improved insulin sensitivity in obese mice and inhibited HGP. In addition, deletion of hepatic miR-9 led to an increase in random and fasting blood glucose levels in lean mice. Importantly, silenced forkhead box O1 (FOXO1) expression reversed the gluconeogenesis and glucose production in hepatocytes induced by miR-9 deletion. Our observations suggest that the decrease in miR-9 expression contributes to an inappropriately activated gluconeogenesis in obese mice.

A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection

PubMed Central

Vereecke, Lars; Mc Guire, Conor; Sze, Mozes; Schuijs, Martijn J.; Willart, Monique; Itati Ibañez, Lorena; Hammad, Hamida; Lambrecht, Bart N.; Beyaert, Rudi; Saelens, Xavier; van Loo, Geert

2016-01-01

A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20AEC-KO mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20AEC-KO mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20AEC-KO mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20AEC-KO mice during later stages of infection. When A20AEC-KO mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20AEC-KO mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection. PMID:26815999

Three distinct suppressors of RNA silencing encoded by a 20-kb viral RNA genome

NASA Astrophysics Data System (ADS)

Lu, Rui; Folimonov, Alexey; Shintaku, Michael; Li, Wan-Xiang; Falk, Bryce W.; Dawson, William O.; Ding, Shou-Wei

2004-11-01

Viral infection in both plant and invertebrate hosts requires a virus-encoded function to block the RNA silencing antiviral defense. Here, we report the identification and characterization of three distinct suppressors of RNA silencing encoded by the 20-kb plus-strand RNA genome of citrus tristeza virus (CTV). When introduced by genetic crosses into plants carrying a silencing transgene, both p20 and p23, but not coat protein (CP), restored expression of the transgene. Although none of the CTV proteins prevented DNA methylation of the transgene, export of the silencing signal (capable of mediating intercellular silencing spread) was detected only from the F1 plants expressing p23 and not from the CP- or p20-expressing F1 plants, demonstrating suppression of intercellular silencing by CP and p20 but not by p23. Thus, intracellular and intercellular silencing are each targeted by a CTV protein, whereas the third, p20, inhibits silencing at both levels. Notably, CP suppresses intercellular silencing without interfering with intracellular silencing. The novel property of CP suggests a mechanism distinct to p20 and all of the other viral suppressors known to interfere with intercellular silencing and that this class of viral suppressors may not be consistently identified by Agrobacterium coinfiltration because it also induces RNA silencing against the infiltrated suppressor transgene. Our analyses reveal a sophisticated viral counter-defense strategy that targets the silencing antiviral pathway at multiple steps and may be essential for protecting CTV with such a large RNA genome from antiviral silencing in the perennial tree host. RNA interference | citrus tristeza virus | virus synergy | antiviral immunity

Chemical Feedback From Decreasing Carbon Monoxide Emissions

NASA Astrophysics Data System (ADS)

Gaubert, B.; Worden, H. M.; Arellano, A. F. J.; Emmons, L. K.; Tilmes, S.; Barré, J.; Martinez Alonso, S.; Vitt, F.; Anderson, J. L.; Alkemade, F.; Houweling, S.; Edwards, D. P.

2017-10-01

Understanding changes in the burden and growth rate of atmospheric methane (CH4) has been the focus of several recent studies but still lacks scientific consensus. Here we investigate the role of decreasing anthropogenic carbon monoxide (CO) emissions since 2002 on hydroxyl radical (OH) sinks and tropospheric CH4 loss. We quantify this impact by contrasting two model simulations for 2002-2013: (1) a Measurement of the Pollution in the Troposphere (MOPITT) CO reanalysis and (2) a Control-Run without CO assimilation. These simulations are performed with the Community Atmosphere Model with Chemistry of the Community Earth System Model fully coupled chemistry climate model with prescribed CH4 surface concentrations. The assimilation of MOPITT observations constrains the global CO burden, which significantly decreased over this period by 20%. We find that this decrease results to (a) increase in CO chemical production, (b) higher CH4 oxidation by OH, and (c) 8% shorter CH4 lifetime. We elucidate this coupling by a surrogate mechanism for CO-OH-CH4 that is quantified from the full chemistry simulations.

Atomic Force Microscopy Probing of Receptor–Nanoparticle Interactions for Riboflavin Receptor Targeted Gold–Dendrimer Nanocomposites

PubMed Central

2015-01-01

Riboflavin receptors are overexpressed in malignant cells from certain human breast and prostate cancers, and they constitute a group of potential surface markers important for cancer targeted delivery of therapeutic agents and imaging molecules. Here we report on the fabrication and atomic force microscopy (AFM) characterization of a core–shell nanocomposite consisting of a gold nanoparticle (AuNP) coated with riboflavin receptor-targeting poly(amido amine) dendrimer. We designed this nanocomposite for potential applications such as a cancer targeted imaging material based on its surface plasmon resonance properties conferred by AuNP. We employed AFM as a technique for probing the binding interaction between the nanocomposite and riboflavin binding protein (RfBP) in solution. AFM enabled precise measurement of the AuNP height distribution before (13.5 nm) and after chemisorption of riboflavin-conjugated dendrimer (AuNP–dendrimer; 20.5 nm). Binding of RfBP to the AuNP–dendrimer caused a height increase to 26.7 nm, which decreased to 22.8 nm when coincubated with riboflavin as a competitive ligand, supporting interaction of AuNP–dendrimer and its target protein. In summary, physical determination of size distribution by AFM imaging can serve as a quantitative approach to monitor and characterize the nanoscale interaction between a dendrimer-covered AuNP and target protein molecules in vitro. PMID:24571134

Recombinant cell lines expressing shRNA targeting herpes simplex virus 2 VP16 inhibit virus replication.

PubMed

Zhang, Rui; Wang, Yan; Song, Bo; Han, Zhi Qiang; Xu, Yu Ming

2012-01-01

To establish HSV2 VP16 targeting shRNA-expressing cell lines and investigate the antiviral effect of shRNA targeting HSV2 VP16. The cell lines Vero-shRNAs and negative-control Vero-shCON were established. Their inhibition effects on VP16 mRNA expression were tested by real-time fluorescent quantitative polymerase chain reaction (PCR) and their antiviral effects were evaluated by yield reduction assay. The influence of passage numbers on the inhibition ability of cell lines was researched. Vero-shRNA24 targeting the upper stream, Vero-shRNA642 targeting the lower stream and Vero-shCON were established. Vero-shRNA24, Vero-shRNA642 and Vero-shRNA24 + 642 could reduce the VP16 mRNA significantly. Vero-shRNA24 was the most efficient. The HSV2 titers in Vero and Vero-shCON were the highest at 72 h after infection, and started decreasing thereafter. The viral titers of the Vero-shRNA groups reached a peak after 84 h and the highest titers were lower than in the Vero group. The inhibiting effect on VP16 mRNA expression and viral replication of Vero-shRNA24 cell lines of passages 10 and 20 were not significantly different from the primary cell line. Although of no statistical significance, the passage 50 cell line showed decreased inhibiting ability. Recombinant cell lines expressing shRNA targeting HSV2 VP16 were established. They can stably inhibit HSV2 VP16 mRNA expression and viral replication within passage 50. Copyright © 2012 S. Karger AG, Basel.

3,3’-Diindolylmethane attenuates LPS-mediated acute liver failure by regulating miRNAs to target IRAK4 and suppress Toll-like receptor signalling

PubMed Central

Tomar, S; Nagarkatti, M; Nagarkatti, P S

2015-01-01

Background and Purpose Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. 3,3′-Diindolylmethane (DIM) is a natural plant-derived compound with anti-cancer activities. Recently, DIM has also been shown to have anti-inflammatory properties. Here, we tested the hypothesis that DIM would suppress endotoxin-induced ALF. Experimental Approach We investigated the therapeutic potential of DIM in a mouse model of D-galactosamine/Lipopolysaccharide (GalN/LPS)-induced ALF. The efficacy of DIM treatment was assessed by survival, liver histopathology, serum levels of alanine transaminase, pro-inflammatory cytokines and number of activated liver macrophages. Effects of DIM on the expression of two miRNAs, 106a and 20b, and their predicted target gene were measured by qRT-PCR and Western blotting. Effects of DIM on the release of TNF-α from RAW264.7 macrophages transfected with mimics of these miRNAs and activated by LPS was assessed by elisa. Key Results DIM treatment protected mice from ALF symptoms and reduced the number of activated liver macrophages. DIM increased expression of miR-106a and miR-20b in liver mononuclear cells and decreased expression of their predicted target gene IL-1 receptor-associated kinase 4 (IRAK4), involved in signalling from Toll-like receptor 4 (TLR4). In vitro transfection of RAW264.7 cells using miRNA mimics of miR-106a and 20b decreased expression of IRAK4 and of TNF-α secretion, following LPS stimulation. Conclusions and Implications DIM attenuated GalN/LPS-induced ALF by regulating the expression of unique miRNAs that target key molecules in the TLR4 inflammatory pathway. DIM may represent a potential novel hepatoprotective agent. PMID:25521277

Polyethylene Glycol Modified, Cross-Linked Starch Coated Iron Oxide Nanoparticles for Enhanced Magnetic Tumor Targeting

PubMed Central

Cole, Adam J.; David, Allan E.; Wang, Jianxin; Galbán, Craig J.; Hill, Hannah L.; Yang, Victor C.

2010-01-01

While successful magnetic tumor targeting of iron oxide nanoparticles has been achieved in a number of models, the rapid blood clearance of magnetically suitable particles by the reticuloendothelial system (RES) limits their availability for targeting. This work aimed to develop a long-circulating magnetic iron oxide nanoparticle (MNP) platform capable of sustained tumor exposure via the circulation and, thus, enhanced magnetic tumor targeting. Aminated, cross-linked starch (DN) and aminosilane (A) coated MNPs were successfully modified with 5 kDa (A5, D5) or 20 kDa (A20, D20) polyethylene glycol (PEG) chains using simple N-Hydroxysuccinimide (NHS) chemistry and characterized. Identical PEG-weight analogues between platforms (A5 & D5, A20 & D20) were similar in size (140–190 nm) and relative PEG labeling (1.5% of surface amines – A5/D5, 0.4% – A20/D20), with all PEG-MNPs possessing magnetization properties suitable for magnetic targeting. Candidate PEG-MNPs were studied in RES simulations in vitro to predict long-circulating character. D5 and D20 performed best showing sustained size stability in cell culture medium at 37°C and 7 (D20) to 10 (D5) fold less uptake in RAW264.7 macrophages when compared to previously targeted, unmodified starch MNPs (D). Observations in vitro were validated in vivo, with D5 (7.29 hr) and D20 (11.75 hr) showing much longer half-lives than D (0.12 hr). Improved plasma stability enhanced tumor MNP exposure 100 (D5) to 150 (D20) fold as measured by plasma AUC0-∞ Sustained tumor exposure over 24 hours was visually confirmed in a 9L-glioma rat model (12 mg Fe/kg) using magnetic resonance imaging (MRI). Findings indicate that both D5 and D20 are promising MNP platforms for enhanced magnetic tumor targeting, warranting further study in tumor models. PMID:21176955

Decreasing aqueous mercury concentrations to achieve safe levels in fish: examining the water-fish relationship in two point-source contaminated streams

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

Mathews, Teresa J; Southworth, George R; Peterson, Mark J

2013-01-01

East Fork Poplar Creek (EFPC) and White Oak Creek (WOC) are two mercury-contaminated streams located on the Department of Energy s Oak Ridge Reservation in east Tennessee. East Fork Poplar Creek is the larger and more contaminated of the two, with average aqueous mercury (Hg) concentrations exceeding those in reference streams by several hundred-fold. Remedial actions over the past 20 years have decreased aqueous Hg concentrations in EFPC by 85 %. Fish fillet concentrations, however, have not responded to this decrease in aqueous Hg and remain above the U.S. Environmental Protection Agency s ambient water quality criterion (AWQC) of 0.3more » mg/kg. The lack of correlation between aqueous and fish tissue Hg concentrations in this creek has led to questions regarding the usefulness of target aqueous Hg concentrations and strategies for future remediation efforts. White Oak Creek has a similar contamination history but aqueous Hg concentrations in WOC are an order of magnitude lower than in EFPC. Despite the lower aqueous Hg concentrations, fish fillet concentrations in WOC have also been above the AWQC, making the most recent aqueous Hg target of 200 ng/L in EFPC seem unlikely to result in an effective decrease in fillet Hg concentrations. Recent monitoring efforts in WOC, however, suggest an aqueous total Hg threshold above which Hg bioaccumulation in fish may not respond. This new information could be useful in guiding remedial actions in EFPC and in other point-source contaminated streams.« less

Simulation of cosmic irradiation conditions in thick target arrangements

NASA Technical Reports Server (NTRS)

Theis, S.; Englert, P.; Reedy, R. C.; Arnold, J. R.

1986-01-01

One approach to simulate 2-pi irradiation conditions of planetary surfaces which has been widely applied in the past are bombardments of so called thick targets. A very large thick target was exposed recently to 2.1 GeV protons at the Bevatron-Bevalac in Berkeley. In a 100x100x180 cm steel-surrounded granodiorite target radioactive medium and high energy spallation products of the incident primary and of secondary particles were analyzed along the beam axis down to depths of 140 g/cm(2) in targets such as Cu, Ni, Co, Fe, T, Si, SiO2 and Al. Activities of these nuclides were exclusively determined via instrumental gamma-ray spectroscopy. Relative yields of neutron capture and spallation products induced in Co and Cu targets during the thick target bombardment are shown as a function of depth. The majority of the medium energy products such as Co-58 from Co targets exhibit a maximum at shallow depths of 40-60 g/cm(2) and then decrease exponentially. In a comparable 600 MeV proton bombarded thick target such a slight maximum for medium energy products was not observed. Rather, Co-58 activities in Co decreased steadily with the highest activity at the surface. The activities of the n-capture product Co-60 increase steadily starting at the surface. This indicates the rapidly growing flux of low energy neutrons within the target.

IG20/MADD Plays a Critical Role in Glucose-Induced Insulin Secretion

PubMed Central

Li, Liang-cheng; Wang, Yong; Carr, Ryan; Haddad, Christine Samir; Li, Ze; Qian, Lixia; Oberholzer, Jose; Maker, Ajay V.; Wang, Qian; Prabhakar, Bellur S.

2014-01-01

Pancreatic β-cell dysfunction is a common feature of type 2 diabetes. Earlier, we had cloned IG20 cDNA from a human insulinoma and had shown that IG20/MADD can encode six different splice isoforms that are differentially expressed and have unique functions, but its role in β-cell function was unexplored. To investigate the role of IG20/MADD in β-cell function, we generated conditional knockout (KMA1ko) mice. Deletion of IG20/MADD in β-cells resulted in hyperglycemia and glucose intolerance associated with reduced and delayed glucose-induced insulin production. KMA1ko β-cells were able to process insulin normally but had increased insulin accumulation and showed a severe defect in glucose-induced insulin release. These findings indicated that IG20/MADD plays a critical role in glucose-induced insulin release from β-cells and that its functional disruption can cause type 2 diabetes. The clinical relevance of these findings is highlighted by recent reports of very strong association of the rs7944584 single nucleotide polymorphism (SNP) of IG20/MADD with fasting hyperglycemia/diabetes. Thus, IG20/MADD could be a therapeutic target for type 2 diabetes, particularly in those with the rs7944584 SNP. PMID:24379354

Targeting DYRK1B suppresses the proliferation and migration of liposarcoma cells

PubMed Central

Chen, Hua; Shen, Jacson; Choy, Edwin; Hornicek, Francis J.; Shan, Aijun; Duan, Zhenfeng

2018-01-01

Liposarcoma is a common subtype of soft tissue sarcoma and accounts for 20% of all sarcomas. Conventional chemotherapeutic agents have limited efficacy in liposarcoma patients. Expression and activation of serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B (DYRK1B) is associated with growth and survival of many types of cancer cells. However, the role of DYRK1B in liposarcoma remains unknown. In this study, we investigated the functional and therapeutic relevance of DYRK1B in liposarcoma. Tissue microarray and immunohistochemistry analysis showed that higher expression levels of DYRK1B correlated with a worse prognosis. RNA interference-mediated knockdown of DYRK1B or targeting DYRK1B with the kinase inhibitor AZ191 inhibited liposarcoma cell growth, decreased cell motility, and induced apoptosis. Moreover, combined AZ191 with doxorubicin demonstrated an increased anti-cancer effect on liposarcoma cells. These findings suggest that DYRK1B is critical for the growth of liposarcoma cells. Targeting DYRK1B provides a new rationale for treatment of liposarcoma. PMID:29568347

Gibberellin 20-oxidase gene OsGA20ox3 regulates plant stature and disease development in rice.

PubMed

Qin, Xue; Liu, Jun Hua; Zhao, Wen Sheng; Chen, Xu Jun; Guo, Ze Jian; Peng, You Liang

2013-02-01

Gibberellin (GA) 20-oxidase (GA20ox) catalyses consecutive steps of oxidation in the late part of the GA biosynthetic pathway. A T-DNA insertion mutant (17S-14) in rice, with an elongated phenotype, was isolated. Analysis of the flanking sequences of the T-DNA insertion site revealed that an incomplete T-DNA integration resulted in enhanced constitutively expression of downstream OsGA20ox3 in the mutant. The accumulation of bioactive GA(1) and GA(4) were increased in the mutant in comparison with the wild-type plant. Transgenic plants overexpressing OsGA20ox3 showed phenotypes similar to those of the 17S-14 mutant, and the RNA interference (RNAi) lines that had decreased OsGA20ox3 expression exhibited a semidwarf phenotype. Expression of OsGA20ox3 was detected in the leaves and roots of young seedlings, immature panicles, anthers, and pollens, based on β-glucuronidase (GUS) activity staining in transgenic plants expressing the OsGA20ox3 promoter fused to the GUS gene. The OsGA20ox3 RNAi lines showed enhanced resistance against rice pathogens Magnaporthe oryzae (causing rice blast) and Xanthomonas oryzae pv. oryzae (causing bacterial blight) and increased expression of defense-related genes. Conversely, OsGA20ox3-overexpressing plants were more susceptible to these pathogens comparing with the wild-type plants. The susceptibility of wild-type plants to X. oryzae pv. oryzae was increased by exogenous application of GA(3) and decreased by S-3307 treatment. Together, the results provide direct evidence for a critical role of OsGA20ox3 in regulating not only plant stature but also disease resistance in rice.

20-Hydroxyecdysone (20E) Primary Response Gene E93 Modulates 20E Signaling to Promote Bombyx Larval-Pupal Metamorphosis*

PubMed Central

Liu, Xi; Dai, Fangyin; Guo, Enen; Li, Kang; Ma, Li; Tian, Ling; Cao, Yang; Zhang, Guozheng; Palli, Subba R.; Li, Sheng

2015-01-01

As revealed in a previous microarray study to identify genes regulated by 20-hydroxyecdysone (20E) and juvenile hormone (JH) in the silkworm, Bombyx mori, E93 expression in the fat body was markedly low prior to the wandering stage but abundant during larval-pupal metamorphosis. Induced by 20E and suppressed by JH, E93 expression follows this developmental profile in multiple silkworm alleles. The reduction of E93 expression by RNAi disrupted 20E signaling and the 20E-induced autophagy, caspase activity, and cell dissociation in the fat body. Reducing E93 expression also decreased the expression of the 20E-induced pupal-specific cuticle protein genes and prevented growth and differentiation of the wing discs. Importantly, the two HTH domains in E93 are critical for inducing the expression of a subset of 20E response genes, including EcR, USP, E74, Br-C, and Atg1. By contrast, the LLQHLL and PLDLSAK motifs in E93 inhibit its transcriptional activity. E93 binds to the EcR-USP complex via a physical association with USP through its LLQHLL motif; and this association is enhanced by 20E-induced EcR-USP interaction, which attenuates the transcriptional activity of E93. E93 acts through the two HTH domains to bind to GAGA-containing motifs present in the Atg1 promoter region for inducing gene expression. In conclusion, E93 transcriptionally modulates 20E signaling to promote Bombyx larval-pupal metamorphosis. PMID:26378227

20-Hydroxyecdysone (20E) Primary Response Gene E93 Modulates 20E Signaling to Promote Bombyx Larval-Pupal Metamorphosis.

PubMed

Liu, Xi; Dai, Fangyin; Guo, Enen; Li, Kang; Ma, Li; Tian, Ling; Cao, Yang; Zhang, Guozheng; Palli, Subba R; Li, Sheng

2015-11-06

As revealed in a previous microarray study to identify genes regulated by 20-hydroxyecdysone (20E) and juvenile hormone (JH) in the silkworm, Bombyx mori, E93 expression in the fat body was markedly low prior to the wandering stage but abundant during larval-pupal metamorphosis. Induced by 20E and suppressed by JH, E93 expression follows this developmental profile in multiple silkworm alleles. The reduction of E93 expression by RNAi disrupted 20E signaling and the 20E-induced autophagy, caspase activity, and cell dissociation in the fat body. Reducing E93 expression also decreased the expression of the 20E-induced pupal-specific cuticle protein genes and prevented growth and differentiation of the wing discs. Importantly, the two HTH domains in E93 are critical for inducing the expression of a subset of 20E response genes, including EcR, USP, E74, Br-C, and Atg1. By contrast, the LLQHLL and PLDLSAK motifs in E93 inhibit its transcriptional activity. E93 binds to the EcR-USP complex via a physical association with USP through its LLQHLL motif; and this association is enhanced by 20E-induced EcR-USP interaction, which attenuates the transcriptional activity of E93. E93 acts through the two HTH domains to bind to GAGA-containing motifs present in the Atg1 promoter region for inducing gene expression. In conclusion, E93 transcriptionally modulates 20E signaling to promote Bombyx larval-pupal metamorphosis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Laser ``M'egajoule'' cryogenic target program: from target fabrication to conformation of the deuterium-tritium ice layer

NASA Astrophysics Data System (ADS)

Collier, Rémy; Durut, Frédéric; Reneaume, Benoît; Chicane, Cédric; Théobald, Marc; Breton, Olivier; Martin, Michel; Fleury, Emmanuel; Vincent-Viry, Olivier; Bachelet, Franck; Jeannot, Laurent; Geoffray, Isabelle; Botrel, Ronan; Dauteuil, Christophe; Hermerel, Cyril; Choux, Alexandre; Bednarczyk, Sophie; Legaie, Olivier

2008-11-01

For the French inertial confinement fusion (ICF) experiments, cryogenic target assemblies (CTAs) for the LMJ program are manufactured and filled at CEA Valduc (Dijon) in the cryogenic targets filling station (IRCC). They will be moved at about 20 K into a transport cryostat for cryogenic targets and will be driven from CEA/Valduc to CEA/CESTA (Bordeaux). Cryogenic targets will then be transferred by several cryogenic grippers on the cryogenic target positioner before shots. The CTA has to meet severe specifications and involves a lot of challenging tasks for its manufacture. To fill CTAs by permeation with deuterium-tritium (DT), the IRCC need to meet strict thermal, mechanical and dimensional specifications. To obtain a good combustion yield, a very homogenous DT ice layer and very smooth roughness at 1.5 K below the DT triple point are also required. This paper deals with the up to date main issues in the different fields of the LMJ cryogenic target program.

Decreasing the metastatic potential in cancers--targeting the heparan sulfate proteoglycans.

PubMed

Fjeldstad, K; Kolset, S O

2005-09-01

The heterogeneity of proteoglycans (PG)s contributes to their functional diversity. Many functions depend on their ability to bind and modulate the activity of components of the extracellular matrix (ECM). The ability of PGs to interact with other molecules, such as growth factors, is largely determined by the fine structure of the glycosaminoglycan (GAG) chains. Tumorigenesis is associated with changes in the PG synthesis. Heparan sulfate (HS) PGs are involved in several aspects of cancer biology including tumor progression, angiogenesis, and metastasis. PGs can have both tumor promoting and tumor suppressing activities depending on the protein core, the GAG attached, molecules they associate with, localization, the tumor subtype, stages, and degree of tumor differentiation. Perlecan is an angiogenic factor involved in tumor invasiveness. The C-terminal domain V of perlecan, named endorepellin, has however been shown to inhibit angiogenesis. Another angiogenic factor is endostatin, the COOH-terminal domain of the part-time PG collagen XVIII. Glypicans and syndecans may promote local cancer cell growth in some cancer tissues, but inhibit tissue invasion and metastasis in others. The GAG hyaluronan (HA) promotes cancer growth by providing a loose matrix for migrating tumor cells and mediates adhesion of cancer cells. HSPG degrading enzymes like heparanase, heparitinase, and other enzymes such as hyaluronidase and MMP are also important in tumor metastasis. Several different treatment strategies that target PGs have been developed. They have the potential to be effective in reducing tumor growth and inhibit the formation of metastases. PGs are also valuable tumor markers in several cancers.

NCI-MATCH Trial Links Targeted Drugs to Mutations

Cancer.gov

Investigators for the nationwide trial, NCI-MATCH: Molecular Analysis for Therapy Choice, announced that the trial will seek to determine whether targeted therapies for people whose tumors have specific gene mutations will be effective regardless of their cancer type. NCI-MATCH will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, in order to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor.

Brain glycogen decreases during prolonged exercise

PubMed Central

Matsui, Takashi; Soya, Shingo; Okamoto, Masahiro; Ichitani, Yukio; Kawanaka, Kentaro; Soya, Hideaki

2011-01-01

Abstract Brain glycogen could be a critical energy source for brain activity when the glucose supply from the blood is inadequate (hypoglycaemia). Although untested, it is hypothesized that during prolonged exhaustive exercise that induces hypoglycaemia and muscular glycogen depletion, the resultant hypoglycaemia may cause a decrease in brain glycogen. Here, we tested this hypothesis and also investigated the possible involvement of brain monoamines with the reduced levels of brain glycogen. For this purpose, we exercised male Wistar rats on a treadmill for different durations (30–120 min) at moderate intensity (20 m min−1) and measured their brain glycogen levels using high-power microwave irradiation (10 kW). At the end of 30 and 60 min of running, the brain glycogen levels remained unchanged from resting levels, but liver and muscle glycogen decreased. After 120 min of running, the glycogen levels decreased significantly by ∼37–60% in five discrete brain loci (the cerebellum 60%, cortex 48%, hippocampus 43%, brainstem 37% and hypothalamus 34%) compared to those of the sedentary control. The brain glycogen levels in all five regions after running were positively correlated with the respective blood and brain glucose levels. Further, in the cortex, the levels of methoxyhydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), potential involved in degradation of the brain glycogen, increased during prolonged exercise and negatively correlated with the glycogen levels. These results support the hypothesis that brain glycogen could decrease with prolonged exhaustive exercise. Increased monoamines together with hypoglycaemia should be associated with the development of decreased brain glycogen, suggesting a new clue towards the understanding of central fatigue during prolonged exercise. PMID:21521757

Novel targeted therapies for eosinophilic disorders

PubMed Central

Wechsler, Michael E.; Fulkerson, Patricia C.; Bochner, Bruce S.; Gauvreau, Gail M.; Gleich, Gerald J.; Henkel, Tim; Kolbeck, Roland; Mathur, Sameer K.; Ortega, Hector; Patel, Jatin; Prussin, Calman; Renzi, Paolo; Rothenberg, Marc E.; Roufosse, Florence; Simon, Dagmar; Simon, Hans-Uwe; Wardlaw, Andrew; Weller, Peter F.; Klion, Amy D.

2013-01-01

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders. PMID:22935585

Effects of target typicality on categorical search.

PubMed

Maxfield, Justin T; Stalder, Westri D; Zelinsky, Gregory J

2014-10-01

The role of target typicality in a categorical visual search task was investigated by cueing observers with a target name, followed by a five-item target present/absent search array in which the target images were rated in a pretest to be high, medium, or low in typicality with respect to the basic-level target cue. Contrary to previous work, we found that search guidance was better for high-typicality targets compared to low-typicality targets, as measured by both the proportion of immediate target fixations and the time to fixate the target. Consistent with previous work, we also found an effect of typicality on target verification times, the time between target fixation and the search judgment; as target typicality decreased, verification times increased. To model these typicality effects, we trained Support Vector Machine (SVM) classifiers on the target categories, and tested these on the corresponding specific targets used in the search task. This analysis revealed significant differences in classifier confidence between the high-, medium-, and low-typicality groups, paralleling the behavioral results. Collectively, these findings suggest that target typicality broadly affects both search guidance and verification, and that differences in typicality can be predicted by distance from an SVM classification boundary. © 2014 ARVO.

T-20 and Trimeris.

PubMed

James, J S

1998-04-17

Trimeris, Inc. is developing a new class of HIV treatment, T-20 (pentafuside), known as a fusion inhibitor. Using a viral sequence from the actual HIV virus, researchers developed T-20 (a 36-amino acid portion of gp41) to inhibit the virus from binding to, entering, and infecting healthy cells. T-20 also blocks infected cells from fusing with uninfected cells. T-20 shows a high degree of antiviral activity, no toxicity, and a low chance of developing cross resistance. It is effective against all known strains of HIV-1 and the technology may lead to development of drugs effective against other enveloped viruses. Viral resistance is not likely to develop because T-20 was produced from a segment of the HIV virus that is constant from one strain to another. Additionally, the T-20 sequence in gp41 has to bind to a complementary sequence in gp41, ruling out most mutations that cause resistance because they are unlikely to occur in matched pairs. T-20 is targeted to be dispensed continuously by a portable infusion pump, reducing how much T-20 is needed. A phase I trial of four patients showed increased CD4 counts for larger doses, 30 mg and 100mg doses, but not at smaller doses. A larger trial of forty patients who have failed at least one protease inhibitor is planned. Further trials are proposed for children, treatment-naive adults, and adults with high viral loads. T-20 can also be used for short-term treatment to reduce drug side effects or to prevent maternal/fetal transmission early in gestation. Trimeris will apply for marketing approval early in 2000.

Polyethylene glycol modified, cross-linked starch-coated iron oxide nanoparticles for enhanced magnetic tumor targeting.

PubMed

Cole, Adam J; David, Allan E; Wang, Jianxin; Galbán, Craig J; Hill, Hannah L; Yang, Victor C

2011-03-01

While successful magnetic tumor targeting of iron oxide nanoparticles has been achieved in a number of models, the rapid blood clearance of magnetically suitable particles by the reticuloendothelial system (RES) limits their availability for targeting. This work aimed to develop a long-circulating magnetic iron oxide nanoparticle (MNP) platform capable of sustained tumor exposure via the circulation and, thus, potentially enhanced magnetic tumor targeting. Aminated, cross-linked starch (DN) and aminosilane (A) coated MNPs were successfully modified with 5 kDa (A5, D5) or 20 kDa (A20, D20) polyethylene glycol (PEG) chains using simple N-Hydroxysuccinimide (NHS) chemistry and characterized. Identical PEG-weight analogues between platforms (A5 & D5, A20 & D20) were similar in size (140-190 nm) and relative PEG labeling (1.5% of surface amines - A5/D5, 0.4% - A20/D20), with all PEG-MNPs possessing magnetization properties suitable for magnetic targeting. Candidate PEG-MNPs were studied in RES simulations in vitro to predict long-circulating character. D5 and D20 performed best showing sustained size stability in cell culture medium at 37 °C and 7 (D20) to 10 (D5) fold less uptake in RAW264.7 macrophages when compared to previously targeted, unmodified starch MNPs (D). Observations in vitro were validated in vivo, with D5 (7.29 h) and D20 (11.75 h) showing much longer half-lives than D (0.12 h). Improved plasma stability enhanced tumor MNP exposure 100 (D5) to 150 (D20) fold as measured by plasma AUC(0-∞). Sustained tumor exposure over 24 h was visually confirmed in a 9L-glioma rat model (12 mg Fe/kg) using magnetic resonance imaging (MRI). Findings indicate that a polyethylene glycol modified, cross-linked starch-coated MNP is a promising platform for enhanced magnetic tumor targeting, warranting further study in tumor models. Copyright © 2010 Elsevier Ltd. All rights reserved.