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Sample records for activities showed significant

  1. Pomalidomide Shows Significant Therapeutic Activity against CNS Lymphoma with a Major Impact on the Tumor Microenvironment in Murine Models

    PubMed Central

    Li, Zhimin; Qiu, Yushi; Personett, David; Huang, Peng; Edenfield, Brandy; Katz, Jason; Babusis, Darius; Tang, Yang; Shirely, Michael A.; Moghaddam, Mehran F.; Copland, John A.; Tun, Han W.

    2013-01-01

    Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS

  2. Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication.

    PubMed

    Rothan, Hussin A; Bahrani, Hirbod; Mohamed, Zulqarnain; Abd Rahman, Noorsaadah; Yusof, Rohana

    2014-01-01

    Dengue virus (DENV) broadly disseminates in tropical and sub-tropical countries and there are no vaccine or anti-dengue drugs available. DENV outbreaks cause serious economic burden due to infection complications that requires special medical care and hospitalization. This study presents a new strategy for inexpensive production of anti-DENV peptide-fusion protein to prevent and/or treat DENV infection. Antiviral cationic peptides protegrin-1 (PG1) and plectasin (PLSN) were fused with MAP30 protein to produce recombinant antiviral peptide-fusion protein (PG1-MAP30-PLSN) as inclusion bodies in E. coli. High yield production of PG1-MAP30-PLSN protein was achieved by solubilization of inclusion bodies in alkaline buffer followed by the application of appropriate refolding techniques. Antiviral PG1-MAP30-PLSN protein considerably inhibited DENV protease (NS2B-NS3pro) with half-maximal inhibitory concentration (IC50) 0.5±0.1 μM. The real-time proliferation assay (RTCA) and the end-point proliferation assay (MTT assay) showed that the maximal-nontoxic dose of the peptide-fusion protein against Vero cells is approximately 0.67±0.2 μM. The cell-based assays showed considerable inhibition of the peptide-fusion protein against binding and proliferating stages of DENV2 into the target cells. The peptide-fusion protein protected DENV2-challeged mice with 100% of survival at the dose of 50 mg/kg. In conclusion, producing recombinant antiviral peptide-fusion protein by combining short antiviral peptide with a central protein owning similar activity could be useful to minimize the overall cost of short peptide production and take advantage of its synergistic antiviral activities. PMID:24722532

  3. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma.

    PubMed

    Patwardhan, Parag P; Ivy, Kathryn S; Musi, Elgilda; de Stanchina, Elisa; Schwartz, Gary K

    2016-01-26

    Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10-18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma. PMID:26675259

  4. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma

    PubMed Central

    Musi, Elgilda; de Stanchina, Elisa; Schwartz, Gary K.

    2016-01-01

    Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10–18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma. PMID:26675259

  5. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia

    PubMed Central

    Kay, Neil E.; Geyer, Susan M.; Call, Timothy G.; Shanafelt, Tait D.; Zent, Clive S.; Jelinek, Diane F.; Tschumper, Renee; Bone, Nancy D.; Dewald, Gordon W.; Lin, Thomas S.; Heerema, Nyla A.; Smith, Lisa; Grever, Michael R.; Byrd, John C.

    2007-01-01

    Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity. PMID:17008537

  6. 9. SITE MAP HIGHLIGHTING SIGNIFICANT BUILDINGS AND SHOWING LOCATION LOCATION ...

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

    9. SITE MAP HIGHLIGHTING SIGNIFICANT BUILDINGS AND SHOWING LOCATION LOCATION OF OUTPATIENT CLINIC ADDITION - U.S. Veterans Administration Medical Center, 600 South Seventieth Street, Lincoln, Lancaster County, NE

  7. Human-directed social behaviour in dogs shows significant heritability.

    PubMed

    Persson, M E; Roth, L S V; Johnsson, M; Wright, D; Jensen, P

    2015-04-01

    Through domestication and co-evolution with humans, dogs have developed abilities to attract human attention, e.g. in a manner of seeking assistance when faced with a problem solving task. The aims of this study were to investigate within breed variation in human-directed contact seeking in dogs and to estimate its genetic basis. To do this, 498 research beagles, bred and kept under standardized conditions, were tested in an unsolvable problem task. Contact seeking behaviours recorded included both eye contact and physical interactions. Behavioural data was summarized through a principal component analysis, resulting in four components: test interactions, social interactions, eye contact and physical contact. Females scored significantly higher on social interactions and physical contact and age had an effect on eye contact scores. Narrow sense heritabilities (h(2) ) of the two largest components were estimated at 0.32 and 0.23 but were not significant for the last two components. These results show that within the studied dog population, behavioural variation in human-directed social behaviours was sex dependent and that the utilization of eye contact seeking increased with age and experience. Hence, heritability estimates indicate a significant genetic contribution to the variation found in human-directed social interactions, suggesting that social skills in dogs have a genetic basis, but can also be shaped and enhanced through individual experiences. This research gives the opportunity to further investigate the genetics behind dogs' social skills, which could also play a significant part into research on human social disorders such as autism. PMID:25703740

  8. Metabolic syndrome showed significant relationship with carotid atherosclerosis.

    PubMed

    Kawada, Tomoyuki; Andou, Takeshi; Fukumitsu, Masayuki

    2016-05-01

    Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease. We assessed the associations between MetS and the indicators of carotid atherosclerosis as assessed by ultrasonography taking into consideration of confounders in the general population. A total of 1281 subjects (856 males, 425 females) were included in the present study. The total plaque score and maximum intima-media thickness (IMT) of the carotid arteries were measured as indicators of atherosclerosis. Cardiovascular risk factors were several metabolic components, serum uric acid, serum C-reactive protein (CRP), and lifestyle factors. MetS was defined according to the criteria of the National Cholesterol Education Program. The prevalences of an elevated total plaque score (≥5) and elevated IMT (>1 mm) of the carotid arteries were significantly higher in subjects with MetS as compared to subjects without MetS. Furthermore, a trend was observed towards higher prevalences of these indicators of atherosclerosis as the number of components of MetS increased. Logistic regression analysis revealed a significant association between elevated plaque score and MetS even after adjustments for age, serum uric acid, serum CRP and lifestyle factors in the males. Among the indicators of atherosclerosis assessed by carotid ultrasonography, a significant independent association was observed between the total plaque score and MetS in males in the general population. PMID:25810113

  9. GDF11/BMP11 activates both smad1/5/8 and smad2/3 signals but shows no significant effect on proliferation and migration of human umbilical vein endothelial cells

    PubMed Central

    Zhang, Yong-Hui; Cheng, Feng; Du, Xue-Ting; Gao, Jin-Lai; Xiao, Xiao-Lin; Li, Na; Li, Shan-Liang; Dong, De-Li

    2016-01-01

    GDF11/BMP11, a member of TGF-β superfamily, was reported to rejuvenate heart, skeletal muscle and blood vessel architecture in aged mice. However, the rejuvenative effects of GDF11 were questioned recently. Here, we investigated the effects of GDF11 on smad and non-smad signals in human umbilical vein endothelial cells (HUVECs) and the effects of GDF11 on proliferation and migration of HUVECs and primary rat aortic endothelial cells (RAECs). GDF11 factor purchased from two different companies (PeproTech and R&D Systems) was comparatively studied. Western blot was used to detect the protein expressions. The cell viability and migration were examined by using MTT and wound healing assays. Results showed that GDF11 activated both smad1/5/8 and smad2/3 signals in HUVECs. GDF11 increased protein expression of NADPH oxidase 4(NOX4) in HUVECs. GDF11 showed no significant effect on the protein level of p38, p-p38, ERK, p-ERK, Akt, p-Akt (Ser473) and p-Akt(Thr308), but increased the protein level of p-JNK and p-AMPK in HUVECs, and these increases were inhibited by antioxidant mitoTEMPO treatment. GDF11 slightly increased cell viability after short-term treatment and slightly decreased cell viability after long-term treatment. GDF11 showed no significant effect on cell proliferation and migration. These data indicated that the notion of GDF11 as a rejuvenation-related factor for endothelial cells needs to be cautious. PMID:26919250

  10. Surveys show support for green 'activities'.

    PubMed

    Baillie, Jonathan

    2012-03-01

    Two independently conducted surveys on sustainability - one into the 'views and values' of NHS 'leaders', and the other questioning the public about the importance of the 'green agenda' in the NHS, and their opinions on how the service might most effectively reduce its carbon footprint, form the basis of Sustainability in the NHS: Health Check 2012, a new NHS Sustainable Development Unit (NHS SDU) publication. As HEJ editor Jonathan Baillie reports, the new document also presents updated data on the 'size' of the carbon footprint of the NHS in England, showing that, although good work by a number of Trusts in the past two years has seen healthcare-generated carbon emissions start to 'level off', the biggest contributors have been the current health service spending review, and the increased national availability of renewable energy. PMID:22515017

  11. 47 CFR 76.54 - Significantly viewed signals; method to be followed for special showings.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 4 2013-10-01 2013-10-01 false Significantly viewed signals; method to be followed for special showings. 76.54 Section 76.54 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Carriage of...

  12. 47 CFR 76.54 - Significantly viewed signals; method to be followed for special showings.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 4 2012-10-01 2012-10-01 false Significantly viewed signals; method to be followed for special showings. 76.54 Section 76.54 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Carriage of...

  13. 47 CFR 76.54 - Significantly viewed signals; method to be followed for special showings.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 4 2011-10-01 2011-10-01 false Significantly viewed signals; method to be followed for special showings. 76.54 Section 76.54 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Carriage of...

  14. 47 CFR 76.54 - Significantly viewed signals; method to be followed for special showings.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 4 2014-10-01 2014-10-01 false Significantly viewed signals; method to be followed for special showings. 76.54 Section 76.54 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Carriage of...

  15. Croton grewioides Baill. (Euphorbiaceae) Shows Antidiarrheal Activity in Mice

    PubMed Central

    da Silva, Anne Dayse Soares; de Melo e Silva, Karoline; Neto, José Clementino; Costa, Vicente Carlos de Oliveira; Pessôa, Hilzeth de Luna F.; Tavares, Josean Fechine; da Silva, Marcelo Sobral; Cavalcante, Fabiana de Andrade

    2016-01-01

    Based on chemotaxonomy, we decided to investigate the possible antidiarrheal activity in mice of a crude ethanolic extract obtained from aerial parts of Croton grewioides (CG-EtOH). We tested for any possible toxicity in rat erythrocytes and acute toxicity in mice. Antidiarrheal activity was assessed by determining the effect of CG-EtOH on defecation frequency, liquid stool, intestinal motility and intestinal fluid accumulation. CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females. CG-EtOH produced a significant and equipotent antidiarrheal activity, both in defecation frequency (ED50 = 106.0 ± 8.1 mg/kg) and liquid stools (ED50 = 105.0 ± 9.2 mg/kg). However, CG-EtOH (125 mg/kg) decreased intestinal motility by only 22.7% ± 4.4%. Moreover, extract markedly inhibited the castor oil-induced intestinal contents (ED50 = 34.6 ± 5.4 mg/kg). We thus conclude that CG-EtOH is not orally lethal and contains active principles with antidiarrheal activity, and this effect seems to involve mostly changes in intestinal secretion. SUMMARY CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females.CG-EtOH probably contains active metabolites with antidiarrheal activity.CG-EtOH reduced the frequency and number of liquid stools.Metabolites presents in the CG-EtOH act mainly by reducing intestinal fluid and, to a lesser extent, reducing intestinal motility. Abbreviations Used: CG-EtOH: crude ethanolic extract obtained from the aerial parts of C. grewioides; WHO: World Health Organization; ED50: dose of a drug that produces 50% of its maximum effect; Emax: maximum effect PMID:27365990

  16. Why does precipitation in northwest China show a significant increasing trend from 1960 to 2010?

    NASA Astrophysics Data System (ADS)

    Li, Baofu; Chen, Yaning; Chen, Zhongsheng; Xiong, Heigang; Lian, Lishu

    2016-01-01

    Based on monthly precipitation data from 74 weather stations in the arid region of northwest China, we employed statistical methods to analyse the characteristics of precipitation and investigated the relationships between precipitation and 11 atmospheric circulations. The results showed that the precipitation in northwest China had a significantly increasing trend (P < 0.01), at a rate of 0.61 mm/year, which is higher than the average rate of China (- 0.16 mm/year) for the same period. Annual precipitation increased markedly after 1987, but the increase in precipitation gradually declined from north to south and from west to east. We found that the precipitation variation in spring, summer, autumn, and winter plays an important role in the yearly change, accounting for 21.6%, 42.4%, 18.4%, and 17.6%, respectively. The correlation analysis indicated that the annual precipitation revealed strong and significant associations with the West Pacific Subtropical High (WPSH, R = 0.60, P < 0.001) and the North America Subtropical High (NASH, R = 0.57, P < 0.001) from 1960 to 2010. We therefore suggest that the strengthening of the WPSH and NASH after the mid-1980s is probably the main cause for the significant increasing trend of precipitation in northwest China.

  17. Novel hexapeptide interacts with tubulin and microtubules, inhibits Aβ fibrillation, and shows significant neuroprotection.

    PubMed

    Biswas, Atanu; Kurkute, Prashant; Saleem, Suraiya; Jana, Batakrishna; Mohapatra, Saswat; Mondal, Prasenjit; Adak, Anindyasundar; Ghosh, Subhajit; Saha, Abhijit; Bhunia, Debmalya; Biswas, Subhash Chandra; Ghosh, Surajit

    2015-08-19

    Herein, we report a novel hexapeptide, derived from activity dependent neuroprotective protein (ADNP), that spontaneously self-assembles to form antiparallel β-sheet structure and produces nanovesicles under physiological conditions. This peptide not only strongly binds with β-tubulin in the taxol binding site but also binds with the microtubule lattice in vitro as well as in intracellular microtubule networks. Interestingly, it shows inhibition of amyloid fibril formation upon co-incubation with Aβ peptide following an interesting mechanistic pathway and excellent neuroprotection in PC12 cells treated with anti-nerve growth factor (NGF). The potential of this hexapeptide opens up a new paradigm in design and development of novel therapeutics for AD. PMID:26147391

  18. Chromosome 2p shows significant linkage to antihypertensive response in the British Genetics of Hypertension Study.

    PubMed

    Padmanabhan, Sandosh; Wallace, Chris; Munroe, Patricia B; Dobson, Richard; Brown, Morris; Samani, Nilesh; Clayton, David; Farrall, Martin; Webster, John; Lathrop, Mark; Caulfield, Mark; Dominiczak, Anna F; Connell, John M

    2006-03-01

    There is a lack of consistently linked loci influencing blood pressure and hypertension status, and this may be because of genetic or phenotypic heterogeneity. We hypothesize that stratification of subjects by response to antihypertensive drug groups could be used to stringently define subsets that will have reduced genetic and etiologic heterogeneity, by partitioning contrasting mechanisms of hypertension and, thus, enhancing gene finding. We investigated the British Genetics of Hypertension Study population, which is composed of 2142 severely hypertensive white affected sibling pairs. Nonresponse to antihypertensive therapy was defined as an on-treatment blood pressure of >140/90 mm Hg or a difference between prediagnosis and on-treatment blood pressure of <20 mm Hg. Of the nonresponders, there were 89 sibling pairs (AB) who were both on antihypertensive therapy that inhibit the renin-angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, or beta-blockers), and 76 sibling pairs (CD) who were both on drugs that do not (calcium channel blockers or diuretics). Nonparametric linkage analysis carried out using markers from a 10-cM genome scan and additional "grid tightening" markers showed significant linkage in the AB group on chromosome 2p (logarithm of odds=4.84 at 90.68 Kosambi cM) and suggestive linkage for the CD group on chromosome 10q (logarithm of odds=2.83 at 125.96 Kosambi cM). The AB linkage locus attained genomewide significance after simulation using 10,000 replicates (P=0.005). This locus may contain a gene for the salt-sensitive form of hypertension and/or a pharmacogenetic locus affecting drug response. We have demonstrated for the first time identification of a significant locus by partitioning different pathways of hypertension using drug response. PMID:16391175

  19. Neurons in cat V1 show significant clustering by degree of tuning

    PubMed Central

    Ziskind, Avi J.; Emondi, Al A.; Kurgansky, Andrei V.; Rebrik, Sergei P.

    2015-01-01

    Neighboring neurons in cat primary visual cortex (V1) have similar preferred orientation, direction, and spatial frequency. How diverse is their degree of tuning for these properties? To address this, we used single-tetrode recordings to simultaneously isolate multiple cells at single recording sites and record their responses to flashed and drifting gratings of multiple orientations, spatial frequencies, and, for drifting gratings, directions. Orientation tuning width, spatial frequency tuning width, and direction selectivity index (DSI) all showed significant clustering: pairs of neurons recorded at a single site were significantly more similar in each of these properties than pairs of neurons from different recording sites. The strength of the clustering was generally modest. The percent decrease in the median difference between pairs from the same site, relative to pairs from different sites, was as follows: for different measures of orientation tuning width, 29–35% (drifting gratings) or 15–25% (flashed gratings); for DSI, 24%; and for spatial frequency tuning width measured in octaves, 8% (drifting gratings). The clusterings of all of these measures were much weaker than for preferred orientation (68% decrease) but comparable to that seen for preferred spatial frequency in response to drifting gratings (26%). For the above properties, little difference in clustering was seen between simple and complex cells. In studies of spatial frequency tuning to flashed gratings, strong clustering was seen among simple-cell pairs for tuning width (70% decrease) and preferred frequency (71% decrease), whereas no clustering was seen for simple-complex or complex-complex cell pairs. PMID:25652921

  20. The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.

    PubMed

    Carvalho, Luis; Martínez-García, Marta; Pérez-Victoria, Ignacio; Manzano, José Ignacio; Yardley, Vanessa; Gamarro, Francisco; Pérez-Victoria, José M

    2015-10-01

    The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. PMID:26195527

  1. The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei

    PubMed Central

    Carvalho, Luis; Martínez-García, Marta; Pérez-Victoria, Ignacio; Manzano, José Ignacio; Yardley, Vanessa

    2015-01-01

    The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca2+, and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. PMID:26195527

  2. Cytochrome bd Displays Significant Quinol Peroxidase Activity

    PubMed Central

    Al-Attar, Sinan; Yu, Yuanjie; Pinkse, Martijn; Hoeser, Jo; Friedrich, Thorsten; Bald, Dirk; de Vries, Simon

    2016-01-01

    Cytochrome bd is a prokaryotic terminal oxidase that catalyses the electrogenic reduction of oxygen to water using ubiquinol as electron donor. Cytochrome bd is a tri-haem integral membrane enzyme carrying a low-spin haem b558, and two high-spin haems: b595 and d. Here we show that besides its oxidase activity, cytochrome bd from Escherichia coli is a genuine quinol peroxidase (QPO) that reduces hydrogen peroxide to water. The highly active and pure enzyme preparation used in this study did not display the catalase activity recently reported for E. coli cytochrome bd. To our knowledge, cytochrome bd is the first membrane-bound quinol peroxidase detected in E. coli. The observation that cytochrome bd is a quinol peroxidase, can provide a biochemical basis for its role in detoxification of hydrogen peroxide and may explain the frequent findings reported in the literature that indicate increased sensitivity to hydrogen peroxide and decreased virulence in mutants that lack the enzyme. PMID:27279363

  3. A novel nucleic acid analogue shows strong angiogenic activity

    SciTech Connect

    Tsukamoto, Ikuko; Sakakibara, Norikazu; Maruyama, Tokumi; Igarashi, Junsuke; Kosaka, Hiroaki; Kubota, Yasuo; Tokuda, Masaaki; Ashino, Hiromi; Hattori, Kenichi; Tanaka, Shinji; Kawata, Mitsuhiro; Konishi, Ryoji

    2010-09-03

    Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.

  4. Motivationally Significant Stimuli Show Visual Prior Entry: Evidence for Attentional Capture

    ERIC Educational Resources Information Center

    West, Greg L.; Anderson, Adam A. K.; Pratt, Jay

    2009-01-01

    Previous studies that have found attentional capture effects for stimuli of motivational significance do not directly measure initial attentional deployment, leaving it unclear to what extent these items produce attentional capture. Visual prior entry, as measured by temporal order judgments (TOJs), rests on the premise that allocated attention…

  5. 47 CFR 76.54 - Significantly viewed signals; method to be followed for special showings.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... (CONTINUED) BROADCAST RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Carriage of Television... and order on reconsideration of the Cable Television Report and Order (Docket 18397 et al.), FCC 72... website of the Federal Communications Commission. (b) Significant viewing in a cable television...

  6. Significant Quantum Effects in Hydrogen Activation

    SciTech Connect

    Kyriakou, Georgios; Davidson, Erlend R.; Peng, Guowen; Roling, Luke T.; Singh, Suyash; Boucher, Matthew B.; Marcinkowski, Matthew D.; Mavrikakis, Manos; Michaelides, Angelos; Sykes, E. Charles H.

    2014-03-31

    Dissociation of molecular hydrogen is an important step in a wide variety of chemical, biological, and physical processes. Due to the light mass of hydrogen, it is recognized that quantum effects are often important to its reactivity. However, understanding how quantum effects impact the reactivity of hydrogen is still in its infancy. Here, we examine this issue using a well-defined Pd/Cu(111) alloy that allows the activation of hydrogen and deuterium molecules to be examined at individual Pd atom surface sites over a wide range of temperatures. Experiments comparing the uptake of hydrogen and deuterium as a function of temperature reveal completely different behavior of the two species. The rate of hydrogen activation increases at lower sample temperature, whereas deuterium activation slows as the temperature is lowered. Density functional theory simulations in which quantum nuclear effects are accounted for reveal that tunneling through the dissociation barrier is prevalent for H2 up to 190 K and for D2 up to 140 K. Kinetic Monte Carlo simulations indicate that the effective barrier to H2 dissociation is so low that hydrogen uptake on the surface is limited merely by thermodynamics, whereas the D2 dissociation process is controlled by kinetics. These data illustrate the complexity and inherent quantum nature of this ubiquitous and seemingly simple chemical process. Examining these effects in other systems with a similar range of approaches may uncover temperature regimes where quantum effects can be harnessed, yielding greater control of bond-breaking processes at surfaces and uncovering useful chemistries such as selective bond activation or isotope separation.

  7. Significant Quantum Effects in Hydrogen Activation

    PubMed Central

    2014-01-01

    Dissociation of molecular hydrogen is an important step in a wide variety of chemical, biological, and physical processes. Due to the light mass of hydrogen, it is recognized that quantum effects are often important to its reactivity. However, understanding how quantum effects impact the reactivity of hydrogen is still in its infancy. Here, we examine this issue using a well-defined Pd/Cu(111) alloy that allows the activation of hydrogen and deuterium molecules to be examined at individual Pd atom surface sites over a wide range of temperatures. Experiments comparing the uptake of hydrogen and deuterium as a function of temperature reveal completely different behavior of the two species. The rate of hydrogen activation increases at lower sample temperature, whereas deuterium activation slows as the temperature is lowered. Density functional theory simulations in which quantum nuclear effects are accounted for reveal that tunneling through the dissociation barrier is prevalent for H2 up to ∼190 K and for D2 up to ∼140 K. Kinetic Monte Carlo simulations indicate that the effective barrier to H2 dissociation is so low that hydrogen uptake on the surface is limited merely by thermodynamics, whereas the D2 dissociation process is controlled by kinetics. These data illustrate the complexity and inherent quantum nature of this ubiquitous and seemingly simple chemical process. Examining these effects in other systems with a similar range of approaches may uncover temperature regimes where quantum effects can be harnessed, yielding greater control of bond-breaking processes at surfaces and uncovering useful chemistries such as selective bond activation or isotope separation. PMID:24684530

  8. Honey shows potent inhibitory activity against the bovine testes hyaluronidase.

    PubMed

    Kolayli, Sevgi; Sahin, Huseyin; Can, Zehra; Yildiz, Oktay; Sahin, Kübra

    2016-08-01

    The purpose of this study was to investigate the anti-hyaluronidase activities of honeys from different botanical origins honeys in order to determine their anti-inflammatory properties. The total phenolic contents, total flavonoids and total tannin levels of six types of honey, chestnut, oak, heather, pine, buckwheat and mixed blossom, were determined. Concentration-related inhibition values were tested turbidimetrically on bovine testis hyaluronidase (BTHase) as IC50 (mg/mL). All honeys exhibited various concentration-dependent degrees of inhibition against BTHase. Inhibition values varied significantly depending on honeys' levels of phenolic contents, flavonoid and tannin. The honeys with the highest anti-hyaluronidase activity were oak, chestnut and heather. In conclusion, polyphenol-rich honeys have high anti-hyaluronidase activity, and these honeys have high protective and complementary potential against hyaluronidase-induced anti-inflammatory failures. PMID:26076195

  9. Silver nanoparticles synthesised using plant extracts show strong antibacterial activity.

    PubMed

    Kumari, Avnesh; Guliani, Anika; Singla, Rubbel; Yadav, Ramdhan; Yadav, Sudesh Kumar

    2015-06-01

    In this study, three plants Populus alba, Hibiscus arboreus and Lantana camara were explored for the synthesis of silver nanoparticles (SNPs). The effect of reaction temperature and leaf extract (LE) concentration of P. alba, H. arboreus and L. camara was evaluated on the synthesis and size of SNPs. The SNPs were characterised by ultra-violet-visible spectroscopy, scanning electron microscopy and atomic force microscopy. The synthesis rate of SNPs was highest with LE of L. camara followed by H. arboreus and P. alba under similar conditions. L. camara LE showed maximum potential of smaller size SNPs synthesis, whereas bigger particles were formed by H. arboreous LE. The size and shape of L. camara LE synthesised SNPs were analysed by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX). TEM analysis revealed the formation of SNPs of average size 17±9.5 nm with 5% LE of L. camara. The SNPs synthesised by LE of L. camara showed strong antibacterial activity against Escherichia coli. The results document that desired size SNPs can be synthesised using these plant LEs at a particular temperature for applications in the biomedical field. PMID:26023158

  10. High-Resolution Observations of a Filament showing Activated Barb

    NASA Astrophysics Data System (ADS)

    Joshi, Anand; Martin, Sara F.; Mathew, Shibu; Srivastava, Nandita

    2012-07-01

    Analysis of a filament showing an activated barb using observations from the Dutch Open Telescope (DOT) on 2010 August 20 are presented. The DOT takes Doppler images in Hα, among other wavelengths, in a region about 110 × 110 arcsec^{2} in area, at a cadence of 30~seconds. The offline image restoration technique of speckle reconstruction is applied to obtain diffraction limited images. The filament developed a new barb in 10~minutes, which disappeared within the next 35~minutes. Such a rapid formation and disappearance of a filament barb is unusual, and has not been reported earlier. Line-of-sight velocity maps were constructed from the Doppler images of the target filament. We observe flows in the filament spine towards the barb location prior to its formation, and flows in the barb towards the spine during its disappearance. Photospheric magnetograms from Heliospheric Magnetic Imager on board the Solar Dynamics Observatory, at a cadence of 45~seconds, were used to determine the changes in magnetic flux in the region surrounding the barb location. The variation of magnetic flux in this duration supports the view that barbs are rooted in minor magnetic polarity. Our analysis shows that barbs can be short-lived and formation and disappearance of the barb was associated with cancellation of magnetic flux.

  11. NASA's Fermi Shows How Active Galaxies Can Be

    NASA Video Gallery

    Active galaxies called blazars make up the largest class of objects detected by Fermi's Large Area Telescope (LAT). Massive black holes in the hearts of these galaxies fire particle jets in our dir...

  12. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning

    PubMed Central

    Schultz, Douglas H.; Balderston, Nicholas L.; Baskin-Sommers, Arielle R.; Larson, Christine L.; Helmstetter, Fred J.

    2016-01-01

    Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into “primary” and “secondary” psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional “fearlessness,” while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths. PMID:27014154

  13. China's Changbaishan volcano showing signs of increased activity

    NASA Astrophysics Data System (ADS)

    Schultz, Colin

    2012-10-01

    Roughly 1100 years ago, the Changbaishan volcano that lies along the border between northeastern China and North Korea erupted, sending pyroclastic flows dozens of kilometers and blasting a 5-kilometer-wide chunk off of the tip of the stratovolcano. The eruption, known as the Millennium eruption because of its proximity to the turn of the first millennium, was one of the largest volcanic events in the Common Era. In the subsequent period, there have been three smaller eruptions, the most recent of which took place in 1903. Starting in 1999, spurred by signs of resumed activity, scientists established the Changbaishan Volcano Observatory, a network to track changing gas compositions, seismic activity, and ground deformation. Reporting on the data collected over the past 12 years, Xu et al. found that these volcanic indices each leapt during a period of heightened activity from 2002 to 2006.

  14. Ultraviolet imaging spectroscopy shows an active saturnian system.

    PubMed

    Esposito, Larry W; Colwell, Joshua E; Larsen, Kristopher; McClintock, William E; Stewart, A Ian F; Hallett, Janet Tew; Shemansky, Donald E; Ajello, Joseph M; Hansen, Candice J; Hendrix, Amanda R; West, Robert A; Keller, H Uwe; Korth, Axel; Pryor, Wayne R; Reulke, Ralf; Yung, Yuk L

    2005-02-25

    Neutral oxygen in the saturnian system shows variability, and the total number of oxygen atoms peaks at 4 x 10(34). Saturn's aurora brightens in response to solar-wind forcing, and the auroral spectrum resembles Jupiter's. Phoebe's surface shows variable water-ice content, and the data indicate it originated in the outer solar system. Saturn's rings also show variable water abundance, with the purest ice in the outermost A ring. This radial variation is consistent with initially pure water ice bombarded by meteors, but smaller radial structures may indicate collisional transport and recent renewal events in the past 10(7) to 10(8) years. PMID:15604361

  15. Insurance Applications of Active Fault Maps Showing Epistemic Uncertainty

    NASA Astrophysics Data System (ADS)

    Woo, G.

    2005-12-01

    Insurance loss modeling for earthquakes utilizes available maps of active faulting produced by geoscientists. All such maps are subject to uncertainty, arising from lack of knowledge of fault geometry and rupture history. Field work to undertake geological fault investigations drains human and monetary resources, and this inevitably limits the resolution of fault parameters. Some areas are more accessible than others; some may be of greater social or economic importance than others; some areas may be investigated more rapidly or diligently than others; or funding restrictions may have curtailed the extent of the fault mapping program. In contrast with the aleatory uncertainty associated with the inherent variability in the dynamics of earthquake fault rupture, uncertainty associated with lack of knowledge of fault geometry and rupture history is epistemic. The extent of this epistemic uncertainty may vary substantially from one regional or national fault map to another. However aware the local cartographer may be, this uncertainty is generally not conveyed in detail to the international map user. For example, an area may be left blank for a variety of reasons, ranging from lack of sufficient investigation of a fault to lack of convincing evidence of activity. Epistemic uncertainty in fault parameters is of concern in any probabilistic assessment of seismic hazard, not least in insurance earthquake risk applications. A logic-tree framework is appropriate for incorporating epistemic uncertainty. Some insurance contracts cover specific high-value properties or transport infrastructure, and therefore are extremely sensitive to the geometry of active faulting. Alternative Risk Transfer (ART) to the capital markets may also be considered. In order for such insurance or ART contracts to be properly priced, uncertainty should be taken into account. Accordingly, an estimate is needed for the likelihood of surface rupture capable of causing severe damage. Especially where a

  16. What Fraction of Active Galaxies Actually Show Outflows?

    NASA Astrophysics Data System (ADS)

    Ganguly, Rajib; Brotherton, M. S.

    2007-12-01

    Outflows from active galactic nuclei (AGNs) seem to be common and are thought to be important from a variety of perspectives: as an agent of chemical enhancement of the interstellar and intergalactic media, as an agent of angular momentum removal from the accreting central engine, and as an agent limiting star formation in starbursting systems by blowing out gas and dust from the host galaxy. To understand these processes, we must determine what fraction of AGNs feature outflows and understand what forms they take. We examine recent surveys of outflows detected in ultraviolet absorption over the entire range of velocities and velocity widths (i.e., broad absorption lines, associated absorption lines, and high-velocity narrow absorption lines). While the fraction of specific forms of outflows depends on AGN properties, the overall fraction displaying outflows is fairly constant, approximately 60%, over many orders of magnitude in luminosity. We discuss implications of this result and ways to refine our understanding of outflows. We acknowledge support from the US National Science Foundation through grant AST 05-07781.

  17. Trajectory Hunting: Analysis of UARS Measurements Showing Rapid Chlorine Activation

    NASA Technical Reports Server (NTRS)

    Danilin, M. Y.; Santee, M. L.; Rodriquez, J. M.; Ko, M. K. W.; Mergenthaler, J. M.; Kumer, J. B.; Tabazadeh, A.

    1998-01-01

    Trajectory hunting (i.e., a technique to find air parcels sampled at least twice over the course of a few days) is applied to analyze Upper Atmosphere Research Satellite (UARS) measurements in conjunction with the AER photochemical box model. In this study, we investigate rapid chlorine activation in the Arctic lower stratosphere on 29 Dec. 1992 associated with a polar stratospheric cloud (PSC) event. Six air parcels that have been sampled twice were followed along 5-day trajectories at the 465 K (approx. 46 mb) and 585 K (approxi. 22 mb) levels. A detailed sensitivity study with the AER photochemical box model along these trajectories leads to the following conclusions for the episode considered: 1) model results are in better agreement with UARS measurements at these levels if the U.K. Meteorological Office (UKMO) temperature is decreased by at least 1-2 K; 2) the NAT (nitric acid trihydrate) PSC formation scheme produces results in better agreement with observations than the STS (supercooled ternary solution) scheme; 3) the model can explain the UARS measurements at 585 K, but under-estimates the ClO abundance at 465 K, suggesting some inconsistency between the UARS measurements at this level.

  18. Trajectory Hunting: Analysis of UARS Measurements showing Rapid Chlorine Activation

    NASA Technical Reports Server (NTRS)

    Danilin, M.Y.; Santee, M. L.; Rodriquez, J. M.; Ko, M. K. W.; Mergenthaler, J. M.; Kumer, J. B.; Tabazadeh, A.

    1998-01-01

    Trajectory hunting (i.e., a technique to find air parcels sampled at least twice over the course of a few days) is applied to analyze Upper Atmosphere Research Satellite (UARS) measurements in conjunction with the AER photochemical box model. In this study, we investigate rapid chlorine activation in the Arctic lower stratosphere on 29 Dec 1992 associated with a polar stratospheric cloud (PSC) event. Six air parcels that have been sampled twice were followed along 5-day trajectories at the 465 K (approximately 46 mb) and 585 K (approximately 22 mb) levels. A detailed sensitivity study with the AER. photochemical box model along these trajectories leads to the following conclusions for the episode considered: (1) model results are in better agreement with UARS measurements at these levels if the UKMO temperature is decreased by at least 1-2 K; (2) the NAT (nitric acid trihydrate) PSC formation scheme produces results in better agreement with observations than the STS (supercooled ternary solution) scheme; (3) the model can explain the UARS measurements at 585 K, but under-estimates the ClO abundance at 465 K, suggesting some inconsistency between the UARS measurements at this level.

  19. Sulfur dioxide - Episodic injection shows evidence for active Venus volcanism

    NASA Technical Reports Server (NTRS)

    Esposito, L. W.

    1984-01-01

    Pioneer Venus ultraviolet spectra from the first 5 years of operation show a decline (by more than a factor of 10) in sulfur dioxide abundance at the cloud tops and in the amount of submicron haze above the clouds. At the time of the Pioneer Venus encounter, the values for both parameters greatly exceeded earlier upper limits. However, Venus had a similar appearance in the late 1950's, implying the episodic injection of sulfur dioxide possibly caused by episodic volcanism. The amount of haze in the Venus middle atmosphere is about ten times that found in earth's stratosphere after the most recent major volcanic eruptions, and the thermal energy required for this injection on Venus is greater by about an order of magnitude than the largest of these recent earth eruptions and about as large as the Krakatoa eruption of 1883. The episodic behavior of sulfur dioxide implies that steady-state models of the chemistry and dynamics of cloud-top regions may be of limited use.

  20. The cosmopolitan maternal heritage of the Thoroughbred racehorse breed shows a significant contribution from British and Irish native mares.

    PubMed

    Bower, M A; Campana, M G; Whitten, M; Edwards, C J; Jones, H; Barrett, E; Cassidy, R; Nisbet, R E R; Hill, E W; Howe, C J; Binns, M

    2011-04-23

    The paternal origins of Thoroughbred racehorses trace back to a handful of Middle Eastern stallions, imported to the British Isles during the seventeenth century. Yet, few details of the foundation mares were recorded, in many cases not even their names (several different maternal lineages trace back to 'A Royal Mare'). This has fuelled intense speculation over their origins. We examined mitochondrial DNA from 1929 horses to determine the origin of Thoroughbred foundation mares. There is no evidence to support exclusive Arab maternal origins as some historical records have suggested, or a significant importation of Oriental mares (the term used in historic records to refer to Middle East and western Asian breeds including Arab, Akhal-Teke, Barb and Caspian). Instead, we show that Thoroughbred foundation mares had a cosmopolitan European heritage with a far greater contribution from British and Irish Native mares than previously recognized. PMID:20926431

  1. The cosmopolitan maternal heritage of the Thoroughbred racehorse breed shows a significant contribution from British and Irish native mares

    PubMed Central

    Bower, M. A.; Campana, M. G.; Whitten, M.; Edwards, C. J.; Jones, H.; Barrett, E.; Cassidy, R.; Nisbet, R. E. R.; Hill, E. W.; Howe, C. J.; Binns, M.

    2011-01-01

    The paternal origins of Thoroughbred racehorses trace back to a handful of Middle Eastern stallions, imported to the British Isles during the seventeenth century. Yet, few details of the foundation mares were recorded, in many cases not even their names (several different maternal lineages trace back to ‘A Royal Mare’). This has fuelled intense speculation over their origins. We examined mitochondrial DNA from 1929 horses to determine the origin of Thoroughbred foundation mares. There is no evidence to support exclusive Arab maternal origins as some historical records have suggested, or a significant importation of Oriental mares (the term used in historic records to refer to Middle East and western Asian breeds including Arab, Akhal-Teke, Barb and Caspian). Instead, we show that Thoroughbred foundation mares had a cosmopolitan European heritage with a far greater contribution from British and Irish Native mares than previously recognized. PMID:20926431

  2. Prognostic significance of intraoperative macroscopic serosal invasion finding when it shows a discrepancy in pathologic result gastric cancer

    PubMed Central

    Kang, Sang Yull; Park, Ho Sung

    2016-01-01

    Purpose Depth of wall invasion is an important prognostic factor in patients with gastric cancer, whereas the prognostic significance of intraoperative macroscopic serosal invasion (mSE) findings remain unclear when they show a discrepancy in pathologic findings. This study, therefore, assessed the prognostic significance of mSE. Methods Data from cohort of 2,835 patients with resectable gastric cancer who underwent surgery between 1990 and 2010 were retrospectively reviewed. Results The overall accuracy of mSE and pathologic results was 83.4%. The accuracy of mSE was 75.5% in pT2. On the other hand, the accuracy of pT3 dropped to 24.5%. According to mSE findings (+/–), the 5-year disease-specific survival (DSS) rate differed significantly in patients with pT2 (+; 74.2% vs. –; 92.0%), pT3 (+; 76.7% vs. –; 91.8%) and pT4a (+; 51.3% vs. –; 72.8%) (P < 0.001 each), but not in patients with T1 tumor. Multivariate analysis showed that mSE findings (hazard ratio [HR], 2.275; 95% confidence interval [CI], 1.148–4.509), tumor depth (HR, 6.894; 95% CI, 2.325–20.437), nodal status (HR, 5.206; 95% CI, 2.298–11.791), distant metastasis (HR, 2.881; 95% CI, 1.388–6.209), radical resection (HR, 2.002; 95% CI, 1.017–3.940), and lymphatic invasion (HR, 2.713; 95% CI, 1.424–5.167) were independent predictors of 5-year DSS rate. Conclusion We observed considerable discrepancies between macroscopic and pathologic diagnosis of serosal invasion. However, macroscopic diagnosis of serosal invasion was independently prognostic of 5-year DSS. It suggests that because the pathologic results could not be perfect and the local inflammatory change with mSE(+) could affect survival, a combination of mSE(+/–) and pathologic depth may be predictive of prognosis in patients with gastric cancer. PMID:27186569

  3. Comparisons between Murine Polyomavirus and Simian Virus 40 Show Significant Differences in Small T Antigen Function ▿

    PubMed Central

    Andrabi, Shaida; Hwang, Justin H.; Choe, Jennifer Kean; Roberts, Thomas M.; Schaffhausen, Brian S.

    2011-01-01

    Although members of a virus family produce similar gene products, those products may have quite different functions. Simian virus 40 (SV40) large T antigen (LT), for example, targets p53 directly, but murine polyomavirus LT does not. SV40 small T antigen (SVST) has received considerable attention because of its ability to contribute to transformation of human cells. Here, we show that there are major differences between SVST and polyomavirus small T antigen (POLST) in their effects on differentiation, transformation, and cell survival. Both SVST and POLST induce cell cycle progression. However, POLST also inhibits differentiation of 3T3-L1 preadipocytes and C2C12 myoblasts. Additionally, POLST induces apoptosis of mouse embryo fibroblasts. SVST reduces the proapoptotic transcriptional activity of FOXO1 through phosphorylation. On the other hand, SVST complements large T antigen and Ras for the transformation of human mammary epithelial cells (HMECs), but POLST does not. Mechanistically, the differences between SVST and POLST may lie in utilization of protein phosphatase 2A (PP2A). POLST binds both Aα and Aβ scaffolding subunits of PP2A while SVST binds only Aα. Knockdown of Aβ could mimic POLST-induced apoptosis. The two small T antigens can target different proteins for dephosphorylation. POLST binds and dephosphorylates substrates, such as lipins, that SVST does not. PMID:21835797

  4. Analysis of a large dataset of mycorrhiza inoculation field trials on potato shows highly significant increases in yield.

    PubMed

    Hijri, Mohamed

    2016-04-01

    An increasing human population requires more food production in nutrient-efficient systems in order to simultaneously meet global food needs while reducing the environmental footprint of agriculture. Arbuscular mycorrhizal fungi (AMF) have the potential to enhance crop yield, but their efficiency has yet to be demonstrated in large-scale crop production systems. This study reports an analysis of a dataset consisting of 231 field trials in which the same AMF inoculant (Rhizophagus irregularis DAOM 197198) was applied to potato over a 4-year period in North America and Europe under authentic field conditions. The inoculation was performed using a liquid suspension of AMF spores that was sprayed onto potato seed pieces, yielding a calculated 71 spores per seed piece. Statistical analysis showed a highly significant increase in marketable potato yield (ANOVA, P < 0.0001) for inoculated fields (42.2 tons/ha) compared with non-inoculated controls (38.3 tons/ha), irrespective of trial year. The average yield increase was 3.9 tons/ha, representing 9.5 % of total crop yield. Inoculation was profitable with a 0.67-tons/ha increase in yield, a threshold reached in almost 79 % of all trials. This finding clearly demonstrates the benefits of mycorrhizal-based inoculation on crop yield, using potato as a case study. Further improvements of these beneficial inoculants will help compensate for crop production deficits, both now and in the future. PMID:26403242

  5. Hybrid [FeFe]-hydrogenases with modified active sites show remarkable residual enzymatic activity.

    PubMed

    Siebel, Judith F; Adamska-Venkatesh, Agnieszka; Weber, Katharina; Rumpel, Sigrun; Reijerse, Edward; Lubitz, Wolfgang

    2015-02-24

    [FeFe]-hydrogenases are to date the only enzymes for which it has been demonstrated that the native inorganic binuclear cofactor of the active site Fe2(adt)(CO)3(CN)2 (adt = azadithiolate = [S-CH2-NH-CH2-S](2-)) can be synthesized on the laboratory bench and subsequently inserted into the unmaturated enzyme to yield fully functional holo-enzyme (Berggren, G. et al. (2013) Nature 499, 66-70; Esselborn, J. et al. (2013) Nat. Chem. Biol. 9, 607-610). In the current study, we exploit this procedure to introduce non-native cofactors into the enzyme. Mimics of the binuclear subcluster with a modified bridging dithiolate ligand (thiodithiolate, N-methylazadithiolate, dimethyl-azadithiolate) and three variants containing only one CN(-) ligand were inserted into the active site of the enzyme. We investigated the activity of these variants for hydrogen oxidation as well as proton reduction and their structural accommodation within the active site was analyzed using Fourier transform infrared spectroscopy. Interestingly, the monocyanide variant with the azadithiolate bridge showed ∼50% of the native enzyme activity. This would suggest that the CN(-) ligands are not essential for catalytic activity, but rather serve to anchor the binuclear subsite inside the protein pocket through hydrogen bonding. The inserted artificial cofactors with a propanedithiolate and an N-methylazadithiolate bridge as well as their monocyanide variants also showed residual activity. However, these activities were less than 1% of the native enzyme. Our findings indicate that even small changes in the dithiolate bridge of the binuclear subsite lead to a rather strong decrease of the catalytic activity. We conclude that both the Brønsted base function and the conformational flexibility of the native azadithiolate amine moiety are essential for the high catalytic activity of the native enzyme. PMID:25633077

  6. Gedunin and photogedunin of Xylocarpus granatum show significant anti-secretory effects and protect the gastric mucosa of peptic ulcer in rats.

    PubMed

    Lakshmi, V; Singh, N; Shrivastva, S; Mishra, S K; Dharmani, P; Mishra, V; Palit, G

    2010-07-01

    In the present study, the gastroprotective mechanism of Xylocarpus granatum fruit and its active constituents gedunin and photogedunin was investigated. Chloroform fraction (Fr-CHCl(3)) of X. granatum fruit was evaluated against cold restraint (CRU), aspirin (AS), alcohol (AL) and pyloric ligation (PL) induced gastric ulcer models in rats and histamine (HA) induced duodenal ulcer model in guinea pigs. Potential anti-ulcer activity of Fr-CHCl(3) was observed against CRU (58.28%), AS (67.81%), AL (84.38%), PL (65.66%) and HA (61.93%) induced ulcer models. The standard drug omeprazole (10mg/kg, p.o.) showed 68.25% protection against CRU, 57.08% against AS and 69.42% against PL model and 70.79% against HA induced duodenal ulcer. Sucralfate, another standard drug (500 mg/kg, p.o.) showed 62.72% protection in AL induced ulcer model. Fr-CHCl(3) significantly reduced free acidity (51.42%), total acidity (30.76%) and upregulated mucin secretion by 58.37% respectively. Phytochemical investigations of Fr-CHCl(3) yielded gedunin (36%), photogedunin (2%). Further, Fr-CHCl(3) and its compounds gedunin and photogedunin significantly inhibited H(+) K(+)-ATPase activity in vitro with IC(50) of 89.37, 56.86 and 66.54 microg/ml respectively as compared to the IC(50) value of omeprazole (30.24 microg/ml) confirming their anti-secretory activity. Conclusively, Fr-CHCl(3) of Xylocarpus granatum was found to possess anti-ulcerogenic activity which might be due to its anti-secretory activity and subsequent strengthening of the defensive mechanism. This study is the first of its kind to show significant anti-secretory effect of gedunin and photogedunin. Therefore it could act as a potent therapeutic agent against peptic ulcer disease. PMID:19962286

  7. Distribution and significance of heterotrophic marine bacteria with antibacterial activity.

    PubMed Central

    Nair, S; Simidu, U

    1987-01-01

    Bacteria with antibacterial activity were isolated from seawater, sediments, phytoplankton, and zooplankton of Suruga, Sagami, and Tokyo Bays and from soft corals and sponges collected from the Taiwan coast. Of the 726 strains isolated, 37 showed antibacterial activity against either Vibrio parahaemolyticus (ATCC 17802) or Staphylococcus aureus (P209). Sediment harbored the lowest number of these forms of bacteria, and those from Tokyo Bay did not show any activity. Attached isolates showed greater activity compared with free-living forms. Relatively high numbers of strains with antibacterial activity were associated with phytoplankton. Among the zooplankton isolates, cladocerans harbored the maximum number of antibacterial strains. Isolates were more inhibitory to gram-positive test cultures. Autoinhibition was observed only among 8% of the isolates. Marine nonproducers were more susceptible. Pseudomonas/Alteromonas species made up 81.0% of isolates, of which 30% were pigmented strains. The absence or reduction in number of bacteria with antibacterial activity in Tokyo Bay is attributed to its eutrophic nature, which may tend to moderate the production of antibacterial compounds. PMID:3435149

  8. Satellite microglia show spontaneous electrical activity that is uncorrelated with activity of the attached neuron.

    PubMed

    Wogram, Emile; Wendt, Stefan; Matyash, Marina; Pivneva, Tatyana; Draguhn, Andreas; Kettenmann, Helmut

    2016-06-01

    Microglia are innate immune cells of the brain. We have studied a subpopulation of microglia, called satellite microglia. This cell type is defined by a close morphological soma-to-soma association with a neuron, indicative of a direct functional interaction. Indeed, ultrastructural analysis revealed closely attached plasma membranes of satellite microglia and neurons. However, we found no apparent morphological specializations of the contact, and biocytin injection into satellite microglia showed no dye-coupling with the apposed neurons or any other cell. Likewise, evoked local field potentials or action potentials and postsynaptic potentials of the associated neuron did not lead to any transmembrane currents or non-capacitive changes in the membrane potential of the satellite microglia in the cortex and hippocampus. Both satellite and non-satellite microglia, however, showed spontaneous transient membrane depolarizations that were not correlated with neuronal activity. These events could be divided into fast-rising and slow-rising depolarizations, which showed different characteristics in satellite and non-satellite microglia. Fast-rising and slow-rising potentials differed with regard to voltage dependence. The frequency of these events was not affected by the application of tetrodotoxin, but the fast-rising event frequency decreased after application of GABA. We conclude that microglia show spontaneous electrical activity that is uncorrelated with the activity of adjacent neurons. PMID:27060918

  9. The Significance of Ras Activity in Pancreatic Cancer Initiation

    PubMed Central

    Logsdon, Craig D.; Lu, Weiqin

    2016-01-01

    The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Rasmt alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Rasmt. Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Rasmt is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Rasmt activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Rasmt. Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Rasmt activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease. PMID:26929740

  10. Meropenem-Clavulanic Acid Shows Activity against Mycobacterium tuberculosis In Vivo

    PubMed Central

    England, Kathleen; Boshoff, Helena I. M.; Arora, Kriti; Weiner, Danielle; Dayao, Emmanuel; Schimel, Daniel; Via, Laura E.

    2012-01-01

    The carbapenems imipenem and meropenem in combination with clavulanic acid reduced the bacterial burden in Mycobacterium tuberculosis-infected macrophages by 2 logs over 6 days. Despite poor stability in solution and a short half-life in rodents, treatment of chronically infected mice revealed significant reductions of bacterial burden in the lungs and spleens. Our results show that meropenem has activity in two in vivo systems, but stability and pharmacokinetics of long-term administration will offer significant challenges to clinical evaluation. PMID:22450968

  11. Age distribution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution.

    PubMed

    Gu, Xun; Wang, Yufeng; Gu, Jianying

    2002-06-01

    The classical (two-round) hypothesis of vertebrate genome duplication proposes two successive whole-genome duplication(s) (polyploidizations) predating the origin of fishes, a view now being seriously challenged. As the debate largely concerns the relative merits of the 'big-bang mode' theory (large-scale duplication) and the 'continuous mode' theory (constant creation by small-scale duplications), we tested whether a significant proportion of paralogous genes in the contemporary human genome was indeed generated in the early stage of vertebrate evolution. After an extensive search of major databases, we dated 1,739 gene duplication events from the phylogenetic analysis of 749 vertebrate gene families. We found a pattern characterized by two waves (I, II) and an ancient component. Wave I represents a recent gene family expansion by tandem or segmental duplications, whereas wave II, a rapid paralogous gene increase in the early stage of vertebrate evolution, supports the idea of genome duplication(s) (the big-bang mode). Further analysis indicated that large- and small-scale gene duplications both make a significant contribution during the early stage of vertebrate evolution to build the current hierarchy of the human proteome. PMID:12032571

  12. Human and Animal Isolates of Yersinia enterocolitica Show Significant Serotype-Specific Colonization and Host-Specific Immune Defense Properties

    PubMed Central

    Schaake, Julia; Kronshage, Malte; Uliczka, Frank; Rohde, Manfred; Knuuti, Tobias; Strauch, Eckhard; Fruth, Angelika; Wos-Oxley, Melissa

    2013-01-01

    Yersinia enterocolitica is a human pathogen that is ubiquitous in livestock, especially pigs. The bacteria are able to colonize the intestinal tract of a variety of mammalian hosts, but the severity of induced gut-associated diseases (yersiniosis) differs significantly between hosts. To gain more information about the individual virulence determinants that contribute to colonization and induction of immune responses in different hosts, we analyzed and compared the interactions of different human- and animal-derived isolates of serotypes O:3, O:5,27, O:8, and O:9 with murine, porcine, and human intestinal cells and macrophages. The examined strains exhibited significant serotype-specific cell binding and entry characteristics, but adhesion and uptake into different host cells were not host specific and were independent of the source of the isolate. In contrast, survival and replication within macrophages and the induced proinflammatory response differed between murine, porcine, and human macrophages, suggesting a host-specific immune response. In fact, similar levels of the proinflammatory cytokine macrophage inflammatory protein 2 (MIP-2) were secreted by murine bone marrow-derived macrophages with all tested isolates, but the equivalent interleukin-8 (IL-8) response of porcine bone marrow-derived macrophages was strongly serotype specific and considerably lower in O:3 than in O:8 strains. In addition, all tested Y. enterocolitica strains caused a considerably higher level of secretion of the anti-inflammatory cytokine IL-10 by porcine than by murine macrophages. This could contribute to limiting the severity of the infection (in particular of serotype O:3 strains) in pigs, which are the primary reservoir of Y. enterocolitica strains pathogenic to humans. PMID:23959720

  13. Isolation of Lactic Acid Bacteria Showing Antioxidative and Probiotic Activities from Kimchi and Infant Feces.

    PubMed

    Ji, Keunho; Jang, Na Young; Kim, Young Tae

    2015-09-01

    The purpose of this study was to investigate lactic acid bacteria with antioxidative and probiotic activities isolated from Korean healthy infant feces and kimchi. Isolates A1, A2, S1, S2, and S3 were assigned to Lactobacillus sp. and isolates A3, A4, E1, E2, E3, and E4 were assigned to Leuconostoc sp. on the basis of their physiological properties and 16S ribosomal DNA sequence analysis. Most strains were confirmed as safe bioresources through nonhemolytic activities and non-production of harmful enzymes such as β-glucosidase, β- glucuronidase and tryptophanase. The 11 isolates showed different resistance to acid and bile acids. In addition, they exhibited antibacterial activity against foodborne bacteria, especially Bacillus cereus, Listeria monocytogenes, and Escherichia coli. Furthermore, all strains showed significantly high levels of hydrophobicity. The antioxidant effects of culture filtrates of the 11 strains included 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging capacity, 2.2'- azino-bis (2-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical cation scavenging activity, and superoxide dismutase activity. The results revealed that most of the culture filtrates have effective scavenging activity for DPPH and ABTS radicals. All strains appeared to have effective superoxide dismutase activity. In conclusion, the isolated strains A1, A3, S1, and S3 have significant probiotic activities applicable to the development of functional foods and health-related products. These strains might also contribute to preventing and controlling several diseases associated with oxidative stress, when used as probiotics. PMID:25951843

  14. Pilomyxoid Astrocytoma (PMA) Shows Significant Differences in Gene Expression vs. Pilocytic Astrocytoma (PA) and Variable Tendency Toward Maturation to PA.

    PubMed

    Kleinschmidt-DeMasters, Bette K; Donson, Andrew M; Vogel, Hannes; Foreman, Nicholas K

    2015-07-01

    Pilomyxoid astrocytomas (PMAs) manifest a more aggressive clinical course than pilocytic astrocytomas (PAs). Development of effective therapies demands a better biological understanding of PMA. We first conducted gene expression microarray analysis of 9 PMA and 13 PA from infra- and supratentorial sites. Unsupervised hierarchical clustering analysis demonstrated that tumors are grouped according to anatomic site, not diagnosis. Gene expression profiles were then contrasted between eight PMAs and six PAs, all supratentorial/hypothalamic/chiasmal. Clinical outcome of PMAs varied, with four out of four patients with diencephalic syndrome succumbing to disease, one of whom showed bulky metastatic leptomeningeal spread at autopsy, with bimodal maturation to PA in some areas and de-differentiation to glioblastoma in others. A surviving child has undergone multiple surgical debulking, with progressive maturation to PA over time. Ontology-enrichment analysis identified overexpression in PMAs of extracellular matrix and mitosis-related genes. Genes overexpressed in PMA vs. PA, ranked according to fold-change, included developmental genes H19, DACT2, extracellular matrix collagens (COL2A1; COL1A1) and IGF2BP3 (IMP3), the latter previously identified as an adverse prognostic factor in PMA and PA. PMID:25521223

  15. Pilomyxoid astrocytoma (PMA) shows significant differences in gene expression versus pilocytic astrocytoma (PA) and variable tendency toward maturation to PA

    PubMed Central

    Kleinschmidt-DeMasters, B.K.; Donson, Andrew M.; Vogel, Hannes; Foreman, Nicholas K.

    2015-01-01

    Pilomyxoid astrocytomas (PMAs) manifest a more aggressive clinical course than pilocytic astrocytomas (PAs). Development of effective therapies demands a better biological understanding of PMA. We first conducted gene expression microarray analysis of 9 PMA and 13 PA from infra- and supra-tentorial sites. Unsupervised hierarchical clustering analysis demonstrated that tumors grouped according to anatomic site, not diagnosis. Gene expression profiles were then contrasted between 8 PMAs and 6 PAs, all supratentorial/hypothalamic/chiasmal. Clinical outcome of PMAs varied, with 4/4 patients with diencephalic syndrome succumbing to disease, one of whom showed bulky metastatic leptomeningeal spread at autopsy, with bimodal maturation to PA in some areas and de-differentiation to glioblastoma in others. A surviving child has undergone multiple surgical debulkings, with progressive maturation to PA over time. Ontology-enrichment analysis identified overexpression in PMAs of extracellular matrix and mitosis-related genes. Genes overexpressed in PMA versus PA, ranked according to fold-change, included developmental genes H19, DACT2, extracellular matrix collagens (COL2A1;COL1A1) and IGF2BP3 (IMP3), the latter previously identified as an adverse prognostic factor in PMA and PA. PMID:25521223

  16. Commercial runs show TiO/sub 2/ Claus catalyst retains activity

    SciTech Connect

    Nougayrede, J.; Philippe, A.; Quesmerel, E.; Vermeersch, R.

    1987-08-10

    Commercial data are given for the CRS 31 Claus catalyst, jointly developed by Rhone Poulenc and Societe Nationale Elf Aquitane (Production) (SNEA). The data confirm laboratory results that show the catalyst's ability to deliver more complete hydrolysis in the first reactor of Claus sulfur recovery plants, and its ability to maintain activity in the second and third reactors. The most important losses in sulfur yields in Claus plants generally come from COS and CS/sub 2/ formed in the thermal steps of the process in the first reactor, and from the low Claus activity of alumina-based catalysts in the second and third reactors. In the first reactor, loaded with alumina-based catalyst, hydrolysis is only partial. Low Claus activity in second and third reactors is caused by the inevitable sulfation of the alumina. Catalytic-activity decrease of aluminas is caused particularly by the presence of oxygen, even in trace amounts, in the Claus gases. Therefore, in the first reactor, the CS/sub 2/ hydrolysis rate is lowered in the subsequent reactors, the H/sub 2/ + SO/sub 2/ conversion significantly drops. The chemical composition of CRS 31, TiO/sub 2/ only, in the same operating conditions, causes a significant improvement in activity because of its increased resistance to sulfation. The economics of the process are given.

  17. Psychoacoustic Tinnitus Loudness and Tinnitus-Related Distress Show Different Associations with Oscillatory Brain Activity

    PubMed Central

    Balkenhol, Tobias; Wallhäusser-Franke, Elisabeth; Delb, Wolfgang

    2013-01-01

    Background The phantom auditory perception of subjective tinnitus is associated with aberrant brain activity as evidenced by magneto- and electroencephalographic studies. We tested the hypotheses (1) that psychoacoustically measured tinnitus loudness is related to gamma oscillatory band power, and (2) that tinnitus loudness and tinnitus-related distress are related to distinct brain activity patterns as suggested by the distinction between loudness and distress experienced by tinnitus patients. Furthermore, we explored (3) how hearing impairment, minimum masking level, and (4) psychological comorbidities are related to spontaneous oscillatory brain activity in tinnitus patients. Methods and Findings Resting state oscillatory brain activity recorded electroencephalographically from 46 male tinnitus patients showed a positive correlation between gamma band oscillations and psychoacoustic tinnitus loudness determined with the reconstructed tinnitus sound, but not with the other psychoacoustic loudness measures that were used. Tinnitus-related distress did also correlate with delta band activity, but at electrode positions different from those associated with tinnitus loudness. Furthermore, highly distressed tinnitus patients exhibited a higher level of theta band activity. Moreover, mean hearing loss between 0.125 kHz and 16 kHz was associated with a decrease in gamma activity, whereas minimum masking levels correlated positively with delta band power. In contrast, psychological comorbidities did not express significant correlations with oscillatory brain activity. Conclusion Different clinically relevant tinnitus characteristics show distinctive associations with spontaneous brain oscillatory power. Results support hypothesis (1), but exclusively for the tinnitus loudness derived from matching to the reconstructed tinnitus sound. This suggests to preferably use the reconstructed tinnitus spectrum to determine psychoacoustic tinnitus loudness. Results also support

  18. A Paradox of Syntactic Priming: Why Response Tendencies Show Priming for Passives, and Response Latencies Show Priming for Actives

    PubMed Central

    Segaert, Katrien; Menenti, Laura; Weber, Kirsten; Hagoort, Peter

    2011-01-01

    Speakers tend to repeat syntactic structures across sentences, a phenomenon called syntactic priming. Although it has been suggested that repeating syntactic structures should result in speeded responses, previous research has focused on effects in response tendencies. We investigated syntactic priming effects simultaneously in response tendencies and response latencies for active and passive transitive sentences in a picture description task. In Experiment 1, there were priming effects in response tendencies for passives and in response latencies for actives. However, when participants' pre-existing preference for actives was altered in Experiment 2, syntactic priming occurred for both actives and passives in response tendencies as well as in response latencies. This is the first investigation of the effects of structure frequency on both response tendencies and latencies in syntactic priming. We discuss the implications of these data for current theories of syntactic processing. PMID:22022352

  19. 26 CFR 1.513-3 - Qualified convention and trade show activity.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Qualified convention and trade show activity. 1... Organizations § 1.513-3 Qualified convention and trade show activity. (a) Introduction—(1) In general. Section 513(d) and § 1.513-3(b) provide that convention and trade show activities carried on by a...

  20. 26 CFR 1.513-3 - Qualified convention and trade show activity.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Qualified convention and trade show activity. 1... Organizations § 1.513-3 Qualified convention and trade show activity. (a) Introduction—(1) In general. Section 513(d) and § 1.513-3(b) provide that convention and trade show activities carried on by a...

  1. Bipolar I disorder and major depressive disorder show similar brain activation during depression

    PubMed Central

    Cerullo, Michael A; Eliassen, James C; Smith, Christopher T; Fleck, David E; Nelson, Erik B; Strawn, Jeffrey R; Lamy, Martine; DelBello, Melissa P; Adler, Caleb M; Strakowski, Stephen M

    2014-01-01

    Objectives Despite different treatments and course of illness, depressive symptoms appear similar in major depressive disorder (MDD) and bipolar I disorder (BP-I). This similarity of depressive symptoms suggests significant overlap in brain pathways underlying neurovegetative, mood, and cognitive symptoms of depression. These shared brain regions might be expected to exhibit similar activation in individuals with MDD and BP-I during functional magnetic resonance imaging (fMRI). Methods fMRI was used to compare regional brain activation in participants with BP-I (n = 25) and MDD (n = 25) during a depressive episode as well as 25 healthy comparison (HC) participants. During the scans, participants performed an attentional task that incorporated emotional pictures. Results During the viewing of emotional images, subjects with BP-I showed decreased activation in the middle occipital gyrus, lingual gyrus, and middle temporal gyrus compared to both subjects with MDD and HC participants. During attentional processing, participants with MDD had increased activation in the parahippocampus, parietal lobe, and postcentral gyrus. However, among these regions, only the postcentral gyrus also showed differences between MDD and HC participants. Conclusions No differences in cortico-limbic regions were found between participants with BP-I and MDD during depression. Instead, the major differences occurred in primary and secondary visual processing regions with decreased activation in these regions in BP-I compared to major depression. These differences were driven by abnormal decreases in activation seen in the participants with BP-I. Posterior activation changes are a common finding in studies across mood states in participants with BP-I. PMID:24990479

  2. Hoarding disorder and obsessive-compulsive disorder show different patterns of neural activity during response inhibition

    PubMed Central

    Tolin, David F.; Witt, Suzanne T.; Stevens, Michael C.

    2014-01-01

    Although hoarding disorder (HD) has been historically conceptualized as a subtype or dimension of obsessive-compulsive disorder (OCD), preliminary evidence suggests that these two disorders have distinct neural underpinnings. The aim of the present study was to compare the hemodynamic responses of HD patients, OCD patients, and healthy controls (HC) during response inhibition on a high-conflict Go/NoGo task that has previously proved sensitive to OCD. Participants comprised 24 HD patients, 24 OCD patients, and 24 HCs who completed a Go/NoGo task during functional magnetic resonance imaging (fMRI). Although behavioral data showed no difference among the groups in Go/NoGo task performance, significant differences in hemodynamic activity were noted. During correct rejects (successful response inhibition), HD patients showed greater right precentral gyrus activation, whereas OCD patients exhibited greater right orbitofrontal activation, as assessed using a region of interest approach. During errors of commission (response inhibition failures), OCD patients, but not HD patients, were characterized by excessive activity in left and right orbitofrontal gyrus. The present results lend further support to the biological distinction between HD and OCD, and they are consistent with previous research suggesting frontal hypoactivity in HD patients during hoarding-unrelated tasks. PMID:24389161

  3. A human intervention study with foods containing natural Ah-receptor agonists does not significantly show AhR-mediated effects as measured in blood cells and urine.

    PubMed

    de Waard, Pim W J; Peijnenburg, Ad A C M; Baykus, Hakan; Aarts, Jac M M J G; Hoogenboom, Ron L A P; van Schooten, Frederik J; de Kok, Theo M C M

    2008-10-22

    Binding and activation of the aryl hydrocarbon receptor (AhR) is thought to be an essential step in the toxicity of the environmental pollutants dioxins and dioxin-like PCBs. However, also a number of natural compounds, referred to as NAhRAs (natural Ah-receptor agonists), which are present in, for example, fruits and vegetables, can bind and activate this receptor. To study their potential effects in humans, we first investigated the effect of the prototypical AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression in ex vivo exposed freshly isolated human lymphocytes, and compared the resulting gene expression profile with those caused by the well-known NAhRA indolo[3,2-b]carbazole (ICZ), originating from cruciferous vegetables, and by a hexane extract of NAhRA-containing grapefruit juice (GJE). Only ICZ induced a gene expression profile similar to TCDD in the lymphocytes, and both significantly up-regulated CYP1B1 and TIPARP (TCDD-inducible poly (ADP-ribose) polymerase) mRNA. Next, we performed a human intervention study with NAhRA-containing cruciferous vegetables and grapefruit juice. The expression of the prototypical AhR-responsive genes CYP1A1, CYP1B1 and NQO1 in whole blood cells and in freshly isolated lymphocytes was not significantly affected. Also enzyme activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), as judged by caffeine metabolites in urine, were unaffected, except for a small down-regulation of NAT2 activity by grapefruit juice. Examination of blood plasma with DR CALUX showed a 12% increased AhR agonist activity 3 and 24 h after consumption of cruciferous vegetables, but did not show a significant effect of grapefruit juice consumption. We conclude that intake of NAhRAs from food may result in minor AhR-related effects measurable in human blood and urine. PMID:18762178

  4. Water Extract of Fructus Hordei Germinatus Shows Antihyperprolactinemia Activity via Dopamine D2 Receptor

    PubMed Central

    Wang, Xiong; Ma, Li; Zhang, En-jing; Zou, Ji-li; Guo, Hao; Peng, Si-wei; Wu, Jin-hu

    2014-01-01

    Objective. Fructus Hordei Germinatus is widely used in treating hyperprolactinemia (hyperPRL) as a kind of Chinese traditional herb in China. In this study, we investigated the anti-hyperPRL activity of water extract of Fructus Hordei Germinatus (WEFHG) and mechanism of action. Methods. Effect of WEFHG on serum prolactin (PRL), estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and hypothalamus protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) levels of hyperPRL rats were investigated. And effect of WEFHG on PRL secretion, D2 receptors, and dopamine transporters (DAT) was studied in MMQ, GH3, and PC12 cells, respectively. Results. WEFHG reduced the secretion of PRL in hyperPRL rats effectively. In MMQ cell, treatment with WEFHG at 1–5 mg/mL significantly suppressed PRL secretion and synthesis. Consistent with a D2-action, WEFHG did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D2 receptor expression but significantly increased the expression of D2 receptors and DAT in PC12 cells. In addition, WEFHG reduced the cAMP and PKA levels of hypothalamus in hyperPRL rats significantly. Conclusions. WEFHG showed anti-hyperPRL activity via dopamine D2 receptor, which was related to the second messenger cAMP and PKA. PMID:25254056

  5. A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy

    PubMed Central

    Sciorati, Clara; Miglietta, Daniela; Buono, Roberta; Pisa, Viviana; Cattaneo, Dario; Azzoni, Emanuele; Brunelli, Silvia; Clementi, Emilio

    2011-01-01

    A resolutive therapy for muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration and in the severe forms to death, is still lacking. Since inflammation and defects in nitric oxide generation are recognized key pathogenic events in muscular dystrophy, we have analysed the effects of a derivative of ibuprofen, NCX 320, belonging to the class of cyclooxygenase inhibiting nitric oxide donator (CINOD), in the α-sarcoglycan null mice, a severe mouse model of dystrophy. NCX 320 was administered daily in the diet for 8 months starting 1 month from weaning. Muscle functional recovery was evaluated by free wheel and treadmill tests at 8 months. Serum creatine kinase activity, as well as the number of diaphragm inflammatory infiltrates and necrotic fibres, was measured as indexes of skeletal muscle damage. Muscle regeneration was evaluated in diaphragm and tibialis anterior muscles, measuring the numbers of centronucleated fibres and of myogenic precursor cells. NCX 320 mitigated muscle damage, reducing significantly serum creatine kinase activity, the number of necrotic fibres and inflammatory infiltrates. Moreover, NCX 320 stimulated muscle regeneration increasing significantly the number of myogenic precursor cells and regenerating fibres. All these effects concurred in inducing a significant improvement of muscle function, as assessed by both free wheel and treadmill tests. These results describe the properties of a new compound incorporating nitric oxide donation together with anti-inflammatory properties, showing that it is effective in slowing muscle dystrophy progression long term. Of importance, this new compound deserves specific attention for its potential in the therapy of muscular dystrophy given that ibuprofen is well tolerated in paediatric patients and with a profile of safety that makes it suitable for chronic treatment such as the one required in muscular dystrophies. PMID:21609764

  6. Photocytotoxic oxovanadium(IV) complexes showing light-induced DNA and protein cleavage activity.

    PubMed

    Sasmal, Pijus K; Saha, Sounik; Majumdar, Ritankar; Dighe, Rajan R; Chakravarty, Akhil R

    2010-02-01

    Oxovanadium(IV) complexes [VO(L)(B)]Cl(2) (1-3), where L is bis(2-benzimidazolylmethyl)amine and B is 1,10-phenanthroline (phen), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) or dipyrido[3,2-a:2',3'-c]phenazine (dppz), have been prepared, characterized, and their photo-induced DNA and protein cleavage activity studied. The photocytotoxicity of complex 3 has been studied using adenocarcinoma A549 cells. The phen complex 1, structurally characterized by single-crystal X-ray crystallography, shows the presence of a vanadyl group in six-coordinate VON(5) coordination geometry. The ligands L and phen display tridentate and bidentate N-donor chelating binding modes, respectively. The complexes exhibit a d-d band near 740 nm in 15% DMF-Tris-HCl buffer (pH 7.2). The phen and dpq complexes display an irreversible cathodic cyclic voltammetric response near -0.8 V in 20% DMF-Tris-HCl buffer having 0.1 M KCl as supporting electrolyte. The dppz complex 3 exhibits a quasi-reversible voltammogram near -0.6 V (vs SCE) that is assignable to the V(IV)-V(III) couple. The complexes bind to calf thymus DNA giving binding constant values in the range of 6.6 x 10(4)-2.9 x 10(5) M(-1). The binding site size, thermal melting and viscosity binding data suggest DNA surface and/or groove binding nature of the complexes. The complexes show poor "chemical nuclease" activity in dark in the presence of 3-mercaptopropionic acid or hydrogen peroxide. The dpq and dppz complexes are efficient photocleavers of plasmid DNA in UV-A light of 365 nm via a mechanistic pathway that involves formation of both singlet oxygen and hydroxyl radicals. The complexes show significant photocleavage of DNA in near-IR light (>750 nm) via hydroxyl radical pathway. Among the three complexes, the dppz complex 3 shows significant BSA and lysozyme protein cleavage activity in UV-A light of 365 nm via hydroxyl radical pathway. The dppz complex 3 also exhibits photocytotoxicity in non-small cell lung carcinoma/human lung

  7. [Synthetic peptides -- analogs of biologically active fragment of the differentiation factor from HL-60 cells show radioprotective and adaptogenic activities].

    PubMed

    Goncharenko, E N; Deev, L I; Kostanian, I A; Astapova, M V; Akhalaia, M Ia; Kudriashova, N Iu; Surina, E A

    2002-01-01

    It was shown that the addition of synthetic six-membered peptide (HLDF-6) and its Tyr-analog (HLDF-Y) to cultural medium significantly increased the survival of cells HL-60, treated by cold shock. The prophylactic administration of HDLF-Y (1 mg/kg, 4 hours prior to applied actions) decreased the response of hypothalamushypophysis-adrenal glands system and sympathicoadrenal system of rat males on supercooling and also increased the resistance of mouse males to supercooling and X-irradiation. In the experiences with females HDLF-Y did not show the similar biological activity. PMID:12004612

  8. Cysteamine, the natural metabolite of pantetheinase, shows specific activity against Plasmodium.

    PubMed

    Min-Oo, Gundula; Ayi, Kodjo; Bongfen, Silayuv E; Tam, Mifong; Radovanovic, Irena; Gauthier, Susan; Santiago, Helton; Rothfuchs, Antonio Gigliotti; Roffê, Ester; Sher, Alan; Mullick, Alaka; Fortin, Anny; Stevenson, Mary M; Kain, Kevin C; Gros, Philippe

    2010-08-01

    In mice, loss of pantetheinase activity causes susceptibility to infection with Plasmodium chabaudi AS. Treatment of mice with the pantetheinase metabolite cysteamine reduces blood-stage replication of P. chabaudi and significantly increases survival. Similarly, a short exposure of Plasmodium to cysteamine ex vivo is sufficient to suppress parasite infectivity in vivo. This effect of cysteamine is specific and not observed with a related thiol (dimercaptosuccinic acid) or with the pantethine precursor of cysteamine. Also, cysteamine does not protect against infection with the parasite Trypanosoma cruzi or the fungal pathogen Candida albicans, suggesting cysteamine acts directly against the parasite and does not modulate host inflammatory response. Cysteamine exposure also blocks replication of P. falciparum in vitro; moreover, these treated parasites show higher levels of intact hemoglobin. This study highlights the in vivo action of cysteamine against Plasmodium and provides further evidence for the involvement of pantetheinase in host response to this infection. PMID:20219464

  9. Cysteamine, the natural metabolite of pantetheinase, shows specific activity against Plasmodium

    PubMed Central

    Min-Oo, Gundula; Ayi, Kodjo; Bongfen, Silayuv E.; Tam, Mifong; Radovanovic, Irena; Gauthier, Susan; Santiago, Helton; Rothfuchs, Antonio Gigliotti; Roffê, Ester; Sher, Alan; Mullick, Alaka; Fortin, Anny; Stevenson, Mary M.; Kain, Kevin C.; Gros, Philippe

    2016-01-01

    In mice, loss of pantetheinase activity causes susceptibility to infection with Plasmodium chabaudi AS. Treatment of mice with the pantetheinase metabolite cysteamine reduces blood-stage replication of P. chabaudi and significantly increases survival. Similarly, a short exposure of Plasmodium to cysteamine ex vivo is sufficient to suppress parasite infectivity in vivo. This effect of cysteamine is specific and not observed with a related thiol (dimercaptosuccinic acid) or with the pantethine precursor of cysteamine. Also, cysteamine does not protect against infection with the parasite Trypanosoma cruzi or the fungal pathogen Candida albicans, suggesting cysteamine acts directly against the parasite and does not modulate host inflammatory response. Cysteamine exposure also blocks replication of P. falciparum in vitro; moreover, these treated parasites show higher levels of intact hemoglobin. This study highlights the in vivo action of cysteamine against Plasmodium and provides further evidence for the involvement of pantetheinase in host response to this infection. PMID:20219464

  10. Adaptive significance of right hemisphere activation in aphasic language comprehension.

    PubMed

    Meltzer, Jed A; Wagage, Suraji; Ryder, Jennifer; Solomon, Beth; Braun, Allen R

    2013-06-01

    Aphasic patients often exhibit increased right hemisphere activity during language tasks. This may represent takeover of function by regions homologous to the left-hemisphere language networks, maladaptive interference, or adaptation of alternate compensatory strategies. To distinguish between these accounts, we tested language comprehension in 25 aphasic patients using an online sentence-picture matching paradigm while measuring brain activation with MEG. Linguistic conditions included semantically irreversible ("The boy is eating the apple") and reversible ("The boy is pushing the girl") sentences at three levels of syntactic complexity. As expected, patients performed well above chance on irreversible sentences, and at chance on reversible sentences of high complexity. Comprehension of reversible non-complex sentences ranged from nearly perfect to chance, and was highly correlated with offline measures of language comprehension. Lesion analysis revealed that comprehension deficits for reversible sentences were predicted by damage to the left temporal lobe. Although aphasic patients activated homologous areas in the right temporal lobe, such activation was not correlated with comprehension performance. Rather, patients with better comprehension exhibited increased activity in dorsal fronto-parietal regions. Correlations between performance and dorsal network activity occurred bilaterally during perception of sentences, and in the right hemisphere during a post-sentence memory delay. These results suggest that effortful reprocessing of perceived sentences in short-term memory can support improved comprehension in aphasia, and that strategic recruitment of alternative networks, rather than homologous takeover, may account for some findings of right hemisphere language activation in aphasia. PMID:23566891

  11. Combined MEG and EEG show reliable patterns of electromagnetic brain activity during natural viewing.

    PubMed

    Chang, Wei-Tang; Jääskeläinen, Iiro P; Belliveau, John W; Huang, Samantha; Hung, An-Yi; Rossi, Stephanie; Ahveninen, Jyrki

    2015-07-01

    Naturalistic stimuli such as movies are increasingly used to engage cognitive and emotional processes during fMRI of brain hemodynamic activity. However, movies have been little utilized during magnetoencephalography (MEG) and EEG that directly measure population-level neuronal activity at a millisecond resolution. Here, subjects watched a 17-min segment from the movie Crash (Lionsgate Films, 2004) twice during simultaneous MEG/EEG recordings. Physiological noise components, including ocular and cardiac artifacts, were removed using the DRIFTER algorithm. Dynamic estimates of cortical activity were calculated using MRI-informed minimum-norm estimation. To improve the signal-to-noise ratio (SNR), principal component analyses (PCA) were employed to extract the prevailing temporal characteristics within each anatomical parcel of the Freesurfer Desikan-Killiany cortical atlas. A variety of alternative inter-subject correlation (ISC) approaches were then utilized to investigate the reliability of inter-subject synchronization during natural viewing. In the first analysis, the ISCs of the time series of each anatomical region over the full time period across all subject pairs were calculated and averaged. In the second analysis, dynamic ISC (dISC) analysis, the correlation was calculated over a sliding window of 200 ms with 3.3 ms steps. Finally, in a between-run ISC analysis, the between-run correlation was calculated over the dynamic ISCs of the two different runs after the Fisher z-transformation. Overall, the most reliable activations occurred in occipital/inferior temporal visual and superior temporal auditory cortices as well as in the posterior cingulate, precuneus, pre- and post-central gyri, and right inferior and middle frontal gyri. Significant between-run ISCs were observed in superior temporal auditory cortices and inferior temporal visual cortices. Taken together, our results show that movies can be utilized as naturalistic stimuli in MEG/EEG similarly as

  12. Rural Enterprises, Incorporated report of significant activities and accomplishments

    NASA Technical Reports Server (NTRS)

    1985-01-01

    The ongoing activities of Rural Enterprises, Inc. are presented. The function of Rural Enterprises is to bring innovation from its rudimentary conceptual stages to useful and productive ends by means of cooperation with government, business, and educational institutions.

  13. Routine activities and victimization at school: the significance of gender.

    PubMed

    Popp, Ann Marie; Peguero, Anthony A

    2011-08-01

    Routine activities theory has not fully considered the role of gender in shaping victimization and yet, the research literature clearly demonstrates that gender is associated with an individual's risk of victimization. In addition to the pervasive effect of gender on victimization, gender shapes an individual's daily routines and thus may create a gender-specific relationship with victimization. This article explores the importance of gender in understanding the relationship between student's participation in extracurricular routine activities (e.g., student government, clubs, sports, and etc.) and the risk of victimization. From the Education Longitudinal Study of 2002, a sample of 10th-grade students was drawn for analyses. Hierarchical Generalized Linear Modeling was employed to explore the role of gender in the relationship between extracurricular routine activities and victimization at school. The results reveal that students' gender indeed interacts with several of the extracurricular routine activities creating gender-specific risks of victimization. This article highlights the importance of gender in explaining victimization and suggests researchers should consider how gender may interact with other routine activities and victimization. PMID:20956442

  14. Hydroxyeicosapentaenoic acids from the Pacific krill show high ligand activities for PPARs[S

    PubMed Central

    Yamada, Hidetoshi; Oshiro, Eriko; Kikuchi, Sayaka; Hakozaki, Mayuka; Takahashi, Hideyuki; Kimura, Ken-ichi

    2014-01-01

    PPARs regulate the expression of genes for energy metabolism in a ligand-dependent manner. PPARs can influence fatty acid oxidation, the level of circulating triglycerides, glucose uptake and insulin sensitivity. Here, we demonstrate that 5-hydroxyeicosapentaenoic acid (HEPE), 8-HEPE, 9-HEPE, 12-HEPE and 18-HEPE (hydroxylation products of EPA) obtained from methanol extracts of Pacific krill (Euphausia pacifica) can act as PPAR ligands. Two of these products, 8-HEPE and 9-HEPE, enhanced the transcription levels of GAL4-PPARs to a significantly greater extent than 5-HEPE, 12-HEPE, 18-HEPE, EPA, and EPA ethyl-ester. 8-HEPE also activated significantly higher transcription of GAL4-PPARα, GAL4-PPARγ, and GAL4-PPARδ than EPA at concentrations greater than 4, 64, and 64 μM, respectively. We also demonstrated that 8-HEPE increased the expression levels of genes regulated by PPARs in FaO, 3T3-F442A, and C2C12 cells. Furthermore, 8-HEPE enhanced adipogenesis and glucose uptake. By contrast, at the same concentrations, EPA showed weak or little effect, indicating that 8-HEPE was the more potent inducer of physiological effects. PMID:24668940

  15. Routine Activities and Victimization at School: The Significance of Gender

    ERIC Educational Resources Information Center

    Popp, Ann Marie; Peguero, Anthony A.

    2011-01-01

    Routine activities theory has not fully considered the role of gender in shaping victimization and yet, the research literature clearly demonstrates that gender is associated with an individual's risk of victimization. In addition to the pervasive effect of gender on victimization, gender shapes an individual's daily routines and thus may create a…

  16. A modified HSP70 inhibitor shows broad activity as an anticancer agent

    PubMed Central

    Balaburski, Gregor M.; Leu, Julia I-Ju; Beeharry, Neil; Hayik, Seth; Andrake, Mark D.; Zhang, Gao; Herlyn, Meenhard; Villanueva, Jessie; Dunbrack, Roland L.; Yen, Tim; George, Donna L.; Murphy, Maureen E.

    2013-01-01

    The stress-induced heat shock protein 70 (HSP70) is an ATP-dependent molecular chaperone that plays a key role in refolding misfolded proteins and promoting cell survival following stress. HSP70 is marginally expressed in non-transformed cells, but is greatly overexpressed in tumor cells. Silencing HSP70 is uniformly cytotoxic to tumor but not normal cells; therefore, there has been great interest in the development of HSP70 inhibitors for cancer therapy. Here we report that the HSP70 inhibitor 2-phenylethynesulfonamide (PES) binds to the substrate-binding domain of HSP70, and requires the C-terminal helical ‘lid’ of this protein (amino acids 573-616) in order to bind. Using molecular modeling and in silico docking, we have identified a candidate binding site for PES in this region of HSP70, and we identify point mutants that fail to interact with PES. A preliminary structure-activity relationship analysis has revealed a derivative of PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), which shows increased cytotoxicity and ability to inhibit autophagy, along with significantly improved ability to extend the life of mice with pre-B cell lymphoma, compared to the parent compound (p=0.015). Interestingly, we also show that these HSP70 inhibitors impair the activity of the Anaphase Promoting Complex/Cyclosome (APC/C) in cell-free extracts, and induce G2/M arrest and genomic instability in cancer cells. PES-Cl is thus a promising new anti-cancer compound with several notable mechanisms of action. PMID:23303345

  17. Finding Significant Correlates of Conscious Activity in Rhythmic EEG

    NASA Astrophysics Data System (ADS)

    Durka, Piotr J.

    2005-12-01

    One of the important issues in designing an EEG-based brain-computer interface is an exact delineation of the rhythms, related to the intended or performed action. Traditionally, related bands were found by trial and error procedures seeking maximum reactivity. Even then, large values of ERD/ERS did not imply the statistical significance of the results. This paper presents complete methodology, allowing for a high-resolution presentation of the whole time-frequency picture of event-related changes in the energy density of signals, revealing the microstructure of rhythms, and determination of the time-frequency regions of energy changes, which are related to the intentions in a statistically significant way.

  18. Active tectonics west of New Zealand's Alpine Fault: South Westland Fault Zone activity shows Australian Plate instability

    NASA Astrophysics Data System (ADS)

    De Pascale, Gregory P.; Chandler-Yates, Nicholas; Dela Pena, Federico; Wilson, Pam; May, Elijah; Twiss, Amber; Cheng, Che

    2016-04-01

    The 300 km long South Westland Fault Zone (SWFZ) is within the footwall of the Central Alpine Fault (<20 km away) and has 3500 m of dip-slip displacement, but it has been unknown if the fault is active. Here the first evidence for SWFZ thrust faulting in the "stable" Australian Plate is shown with cumulative dip-slip displacements up to 5.9 m (with 3 m throw) on Pleistocene and Holocene sediments and gentle hanging wall anticlinal folding. Cone penetration test (CPT) stratigraphy shows repeated sequences within the fault scarp (consistent with thrusting). Optically stimulated luminescence (OSL) dating constrains the most recent rupture post-12.1 ± 1.7 ka with evidence for three to four events during earthquakes of at least Mw 6.8. This study shows significant deformation is accommodated on poorly characterized Australian Plate structures northwest of the Alpine Fault and demonstrates that major active and seismogenic structures remain uncharacterized in densely forested regions on Earth.

  19. Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy.

    PubMed

    Bahia El Idrissi, N; Hakobyan, S; Ramaglia, V; Geluk, A; Morgan, B Paul; Das, P Kumar; Baas, F

    2016-06-01

    Mycobacterium leprae infection gives rise to the immunologically and histopathologically classified spectrum of leprosy. At present, several tools for the stratification of patients are based on acquired immunity markers. However, the role of innate immunity, particularly the complement system, is largely unexplored. The present retrospective study was undertaken to explore whether the systemic levels of complement activation components and regulators can stratify leprosy patients, particularly in reference to the reactional state of the disease. Serum samples from two cohorts were analysed. The cohort from Bangladesh included multi-bacillary (MB) patients with (n = 12) or without (n = 46) reaction (R) at intake and endemic controls (n = 20). The cohort from Ethiopia included pauci-bacillary (PB) (n = 7) and MB (n = 23) patients without reaction and MB (n = 15) patients with reaction. The results showed that the activation products terminal complement complex (TCC) (P ≤ 0·01), C4d (P ≤ 0·05) and iC3b (P ≤ 0·05) were specifically elevated in Bangladeshi patients with reaction at intake compared to endemic controls. In addition, levels of the regulator clusterin (P ≤ 0·001 without R; P < 0·05 with R) were also elevated in MB patients, irrespective of a reaction. Similar analysis of the Ethiopian cohort confirmed that, irrespective of a reaction, serum TCC levels were increased significantly in patients with reactions compared to patients without reactions (P ≤ 0·05). Our findings suggests that serum TCC levels may prove to be a valuable tool in diagnosing patients at risk of developing reactions. PMID:26749503

  20. A humanized anti-M2 scFv shows protective in vitro activity against influenza

    SciTech Connect

    Bradbury, Andrew M; Velappan, Nileena; Schmidt, Jurgen G

    2008-01-01

    M2 is one of the most conserved influenza proteins, and has been widely prospected as a potential universal vaccine target, with protection predominantly mediated by antibodies. In this paper we describe the creation of a humanized single chain Fv from 14C2, a potent monoclonal antibody against M2. We show that the humanized scFv demonstrates similar activity to the parental mAb: it is able to recognize M2 in its native context on cell surfaces and is able to show protective in vitro activity against influenza, and so represents a potential lead antibody candidate for universal prophylactic or therapeutic intervention in influenza.

  1. 26 CFR 1.513-3 - Qualified convention and trade show activity.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Qualified convention and trade show activity. 1.513-3 Section 1.513-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.513-3 Qualified convention...

  2. Distributive Education--Fashion Show. Kit No. 88. Instructor's Manual [and] Student Learning Activity Guide.

    ERIC Educational Resources Information Center

    Walters, Brenda B.

    An instructor's manual and student activity guide on fashion shows are provided in this set of prevocational education materials which focuses on the vocational area of distributive education. (This set of materials is one of ninety-two prevocational education sets arranged around a cluster of seven vocational offerings: agriculture, home…

  3. Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the hemagglutinin of influenza virus.

    PubMed

    Yamamoto, Nobuto; Urade, Masahiro

    2005-04-01

    Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The precursor activity of serum Gc protein was reduced in all influenza virus-infected patients. These patient sera contained alpha-N-acetylgalactosaminidase (Nagalase) that deglycosylates Gc protein. Deglycosylated Gc protein cannot be converted to MAF, thus it loses the MAF precursor activity, leading to immunosuppression. An influenza virus stock contained a large amount of Nagalase activity. A sucrose gradient centrifugation analysis of the virus stock showed that the profile of Nagalase activity corresponds to that of hemagglutinating activity. When these gradient fractions were treated with 0.01% trypsin for 30 min, the Nagalase activity of each fraction increased significantly, suggesting that the Nagalase activity resides on an outer envelope protein of the influenza virion and is enhanced by the proteolytic process. After disruption of influenza virions with sodium deoxycholate, fractionation of the envelope proteins with mannose-specific lectin affinity column along with electrophoretic analysis of the Nagalase peak fraction revealed that Nagalase is the intrinsic component of the hemagglutinin (HA). Cloned HA protein exhibited Nagalase activity only if treated with trypsin. Since both fusion capacity and Nagalase activity of HA protein are expressed by proteolytic cleavage, Nagalase activity appears to be an enzymatic basis for the fusion process. Thus, Nagalase plays dual roles in regulating both infectivity and immunosuppression. PMID:15848273

  4. Plant crude extracts could be the solution: extracts showing in vivo antitumorigenic activity.

    PubMed

    Amara, A A; El-Masry, M H; Bogdady, H H

    2008-04-01

    Screening active compounds from plants lead to discover new medicinal drugs which have efficient protection and treatment roles against various diseases including cancer. In our study, extracts from different plants represent seeds of: Gossypium barbadense, Ricinus communis, Sesamum indicum, Nigella sativa, Vinca rosea and Melia azedarah; fruits of: Xanthium occidental; flowers of: Atriplex nummularia; barks of: Cinnamomum zeylanicum; latex of: Ficus carica and rhizomes of: Curcuma longa and Zingiber officinale were tested in vivo using three subsequent bioassays: the BST (Brine Shrimp Toxicity bioassay), AWD (Agar well diffusion antimicrobial bioassay) and AtPDT (Agrobacterium tumefaciens Potato Disc Tumor bioassay). AWD technique omitted any extracts have antimicrobial activities while BST omitted any extract did not has physiological activity and determined the various LC(50) of each plant extract. For the first time, using a range of concentrations in the AtPDT modified protocol allowed the detection of tumor promotion caused by extract represented by A. nummularia. Using cluster analysis leads to classifying the different plant extracts activities to six groups regarding to their toxicity, antitumor activities and both of them. The extracts from edible plants represent 50% of the first and the second group which have the highest antitumor activities represented in F. caraica (group 1) and C. longa (group 2) as well as the non-edible plant extracts of Gossypium barbadense and Ricinus communis. A comparison study between the edible and herbaceous plants different extracts for their antitumor activities was performed. We recommended using the modified protocols used in this study for investigating more plants and using crude plant extracts which have antitumor activities in cancer treatment. Edible plants, which show in vivo antitumor activities, are recommended as save sources for antitumor compounds. PMID:18390447

  5. Functional characterization of a Plagiochasma appendiculatum flavone synthase I showing flavanone 2-hydroxylase activity.

    PubMed

    Han, Xiao-Juan; Wu, Yi-Feng; Gao, Shuai; Yu, Hai-Na; Xu, Rui-Xue; Lou, Hong-Xiang; Cheng, Ai-Xia

    2014-06-27

    FNS I is a 2-oxoglutarate dependent dioxygenase (2-ODD) found mainly in species of the Apiaceae family. Here, an FNS I cDNA sequence was isolated from the liverwort Plagiochasma appendiculatum (Aytoniaceae) and characterized. The recombinant protein exhibited high FNS I activity catalyzing the conversion of naringenin to apigenin and 2-hydroxynaringenin. The critical residue for flavanone-2-hydroxylation activity was Tyr240, as identified from homology modeling and site-directed mutagenesis. The recombinant protein also showed some flavonol synthase activity, as it can convert dihydrokaempferol to kaempferol. When the Leu311 residue was mutated to Phe, the enzyme's capacity to convert dihydrokaempferol to kaempferol was substantially increased. PaFNS I represents a 2-ODD in which a hydrophobic π-stacking interaction between the key residue and the naringenin A-ring determines 2-hydroxyflavanone formation. PMID:24859082

  6. The three catalases in Deinococcus radiodurans: Only two show catalase activity.

    PubMed

    Jeong, Sun-Wook; Jung, Jong-Hyun; Kim, Min-Kyu; Seo, Ho Seong; Lim, Heon-Man; Lim, Sangyong

    2016-01-15

    Deinococcus radiodurans, which is extremely resistant to ionizing radiation and oxidative stress, is known to have three catalases (DR1998, DRA0146, and DRA0259). In this study, to investigate the role of each catalase, we constructed catalase mutants (Δdr1998, ΔdrA0146, and ΔdrA0259) of D. radiodurans. Of the three mutants, Δdr1998 exhibited the greatest decrease in hydrogen peroxide (H2O2) resistance and the highest increase in intracellular reactive oxygen species (ROS) levels following H2O2 treatments, whereas ΔdrA0146 showed no change in its H2O2 resistance or ROS level. Catalase activity was not attenuated in ΔdrA0146, and none of the three bands detected in an in-gel catalase activity assay disappeared in ΔdrA0146. The purified His-tagged recombinant DRA0146 did not show catalase activity. In addition, the phylogenetic analysis of the deinococcal catalases revealed that the DR1998-type catalase is common in the genus Deinococcus, but the DRA0146-type catalase was found in only 4 of 23 Deinococcus species. Taken together, these results indicate that DR1998 plays a critical role in the anti-oxidative system of D. radiodurans by detoxifying H2O2, but DRA0146 does not have catalase activity and is not involved in the resistance to H2O2 stress. PMID:26692481

  7. Sterols from Mytilidae Show Anti-Aging and Neuroprotective Effects via Anti-Oxidative Activity

    PubMed Central

    Sun, Yujuan; Lin, Yanfei; Cao, Xueli; Xiang, Lan; Qi, Jianhua

    2014-01-01

    For screening anti-aging samples from marine natural products, K6001 yeast strain was employed as a bioassay system. The active mussel extract was separated to give an active sterol fraction (SF). SF was further purified, and four sterol compounds were obtained. Their structures were determined to be cholesterol (CHOL), brassicasterol, crinosterol, and 24-methylenecholesterol. All compounds showed similar anti-aging activity. To understand the action mechanism involved, anti-oxidative experiments, reactive oxygen species (ROS) assays, and malondialdehyde (MDA) tests were performed on the most abundant compound, CHOL. Results indicated that treatment with CHOL increases the survival rate of yeast under oxidative stress and decreases ROS and MDA levels. In addition, mutations of uth1, skn7, sod1, and sod2, which feature a K6001 background, were employed and the lifespans of the mutations were not affected by CHOL. These results demonstrate that CHOL exerts anti-aging effects via anti-oxidative stress. Based on the connection between neuroprotection and anti-aging, neuroprotective experiments were performed in PC12 cells. Paraquat was used to induce oxidative stress and the results showed that the CHOL and SF protect the PC12 cells from the injury induced by paraquat. In addition, these substance exhibited nerve growth factor (NGF) mimic activities again confirmed their neuroprotective function. PMID:25429428

  8. Bovine serum albumin with glycated carboxyl groups shows membrane-perturbing activities.

    PubMed

    Yang, Shin-Yi; Chen, Ying-Jung; Kao, Pei-Hsiu; Chang, Long-Sen

    2014-12-15

    The aim of the present study aimed to investigate whether glycated bovine serum albumin (BSA) showed novel activities on the lipid-water interface. Mannosylated BSA (Man-BSA) was prepared by modification of the carboxyl groups with p-aminophenyl α-d-mannopyranoside. In contrast to BSA, Man-BSA notably induced membrane permeability of egg yolk phosphatidylcholine (EYPC)/egg yolk sphingomyelin (EYSM)/cholesterol (Chol) and EYPC/EYSM vesicles. Noticeably, Man-BSA induced the fusion of EYPC/EYSM/Chol vesicles, but not of EYPC/EYSM vesicles. Although BSA and Man-BSA showed similar binding affinity for lipid vesicles, the lipid-bound conformation of Man-BSA was distinct from that of BSA. Moreover, Man-BSA adopted distinct structure upon binding with the EYPC/EYSM/Chol and EYPC/EYSM vesicles. Man-BSA could induce the fusion of EYPC/EYSM/Chol vesicles with K562 and MCF-7 cells, while Man-BSA greatly induced the leakage of Chol-depleted K562 and MCF-7 cells. The modified BSA prepared by conjugating carboxyl groups with p-aminophenyl α-d-glucopyranoside also showed membrane-perturbing activities. Collectively, our data indicate that conjugation of carboxyl groups with monosaccharide generates functional BSA with membrane-perturbing activities on the lipid-water interface. PMID:25449061

  9. Evolution of EF-hand calcium-modulated proteins. III. Exon sequences confirm most dendrograms based on protein sequences: calmodulin dendrograms show significant lack of parallelism

    NASA Technical Reports Server (NTRS)

    Nakayama, S.; Kretsinger, R. H.

    1993-01-01

    In the first report in this series we presented dendrograms based on 152 individual proteins of the EF-hand family. In the second we used sequences from 228 proteins, containing 835 domains, and showed that eight of the 29 subfamilies are congruent and that the EF-hand domains of the remaining 21 subfamilies have diverse evolutionary histories. In this study we have computed dendrograms within and among the EF-hand subfamilies using the encoding DNA sequences. In most instances the dendrograms based on protein and on DNA sequences are very similar. Significant differences between protein and DNA trees for calmodulin remain unexplained. In our fourth report we evaluate the sequences and the distribution of introns within the EF-hand family and conclude that exon shuffling did not play a significant role in its evolution.

  10. Vv-AMP1, a ripening induced peptide from Vitis vinifera shows strong antifungal activity

    PubMed Central

    de Beer, Abré; Vivier, Melané A

    2008-01-01

    Background Latest research shows that small antimicrobial peptides play a role in the innate defense system of plants. These peptides typically contribute to preformed defense by developing protective barriers around germinating seeds or between different tissue layers within plant organs. The encoding genes could also be upregulated by abiotic and biotic stimuli during active defense processes. The peptides display a broad spectrum of antimicrobial activities. Their potent anti-pathogenic characteristics have ensured that they are promising targets in the medical and agricultural biotechnology sectors. Results A berry specific cDNA sequence designated Vv-AMP1, Vitis vinifera antimicrobial peptide 1, was isolated from Vitis vinifera. Vv-AMP1 encodes for a 77 amino acid peptide that shows sequence homology to the family of plant defensins. Vv-AMP1 is expressed in a tissue specific, developmentally regulated manner, being only expressed in berry tissue at the onset of berry ripening and onwards. Treatment of leaf and berry tissue with biotic or abiotic factors did not lead to increased expression of Vv-AMP1 under the conditions tested. The predicted signal peptide of Vv-AMP1, fused to the green fluorescent protein (GFP), showed that the signal peptide allowed accumulation of its product in the apoplast. Vv-AMP1 peptide, produced in Escherichia coli, had a molecular mass of 5.495 kDa as determined by mass spectrometry. Recombinant Vv-AMP1 was extremely heat-stable and showed strong antifungal activity against a broad spectrum of plant pathogenic fungi, with very high levels of activity against the wilting disease causing pathogens Fusarium oxysporum and Verticillium dahliae. The Vv-AMP1 peptide did not induce morphological changes on the treated fungal hyphae, but instead strongly inhibited hyphal elongation. A propidium iodide uptake assay suggested that the inhibitory activity of Vv-AMP1 might be associated with altering the membrane permeability of the fungal

  11. A novel cathelicidin from Bufo bufo gargarizans Cantor showed specific activity to its habitat bacteria.

    PubMed

    Sun, Tongyi; Zhan, Bo; Gao, Yuanyuan

    2015-10-25

    Toad Bufo bufo gargarizans Cantor is still used in China as traditional Chinese medicine. However, present investigations on its skin secretions were mainly focused on the bufadienolides, the proteins/peptides contained in the secretions are largely unknown. A cDNA encoding a novel cathelicidin termed BG-CATH was identified by analysis of the toad skin transcriptome. The BG-CATH precursor was predicted to have 2 possible cleavage sites following dibasic cleavage signals at its C-terminal, which will generate two mature peptides, BG-CATH37 and BG-CATH(5-37). Phylogenetic analysis suggests that amphibian cathelicidins might evolve from common ancestors. The two predicted mature cathelicidins from B. bufo gargarizans were synthesized and both of them showed weak antimicrobial activities against human pathogenic bacteria Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus (MIC ≥ 200 μg/mL). However, BG-CATH37 and BG-CATH(5-37) had strong antimicrobial activities against aquatic bacteria of Vibrio splendidus, Streptococcus iniae and Aeromorus hydrophila, which were common microorganisms in the habitat of B. bufo gargarizans (MIC 3.125-40 μg/mL). BG-CATH37 and BG-CATH(5-37) showed no hemolytic activity even at high concentrations (400 μg/mL). CD spectra analysis suggested that structure rigidity of BG-CATH37 and BG-CATH(5-37) might play an important role to regulate their biological activities. Selective antimicrobial activity against habitat microorganisms might reflect the adaptation of amphibians to their living environments. PMID:26091834

  12. [Significance of mTOR (mammalian target of rapamycin) activity in human lymphomas].

    PubMed

    Márk, Ágnes

    2014-06-01

    Neoplastic processes, tumor growth, and tumor cell proliferation and survival are often due to the altered activation of different signaling pathways. The increased activity of PI3K/AKT/mTOR signaling has been shown to be an important regulator of tumor growth in several solid tumors and in mantle cell lymphomas. The active form of mTOR kinase (mammalian target of rapamycin) is a key signaling molecule, and it exists in two different complexes, mTORC1 and mTORC2. In the present work, mTOR activity was investigated in different lymphoma types, in parallel with clinical data. We also examined in Hodgkin lymphomas (HL) the role of mTOR activity in survival mechanisms such as antiapoptotic protein expression and alterations in the microenvironment. We determined which lymphoma types display characteristic high mTOR activity in our TMA (tissue microarray) study. We observed that mTOR activity is increased in mitotic lymphoid cells compared to interphasic cells. The number of diffuse large B cell lymphoma (DLBCL) and HL cases was extended in a further set of TMA. We observed significantly higher mTOR activity in the non-centrum germinativum derived subtype of DLBCL than in the centrum germinativum derived subtype, which was a prognostic marker; 63% of mTOR active cases showed Rictor overexpression, indicating mTORC2 activity. High mTOR activity was also established in 92% of HL cases, which was linked to mTORC1. This finding was not a prognostic marker, however, it can be useful in targeted therapy. We observed the overexpression of the antiapoptotic protein BCL-xL and NFκB-p50 in the majority of mTOR active HLs. HLs showed high numbers of regulatory T cells in the microenvironment and high expression of galectin-1 in tumor cells and in the extracellular matrix, when compared to reactive lymph nodes. We confirmed that mTOR inhibition had significant antiproliferative and antiapoptotic effects in lymphoma cell lines and in lymphoma xenografts (HL, DLBCL, Burkitt lymphoma

  13. Pinelliae rhizoma, a toxic chinese herb, can significantly inhibit CYP3A activity in rats.

    PubMed

    Wu, Jinjun; Cheng, Zaixing; He, Shugui; Shi, Jian; Liu, Shuqiang; Zhang, Guiyu; Zhu, Lijun; Liu, Liang; Liu, Zhongqiu; Lin, Na; Lu, Linlin

    2015-01-01

    Raw Pinelliae Rhizoma (RPR) is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP) and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA), are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes) and buspirone (BP) were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug-drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions. PMID:25574821

  14. Variegation of comet 67P/Churyumov-Gerasimenko in regions showing activity

    NASA Astrophysics Data System (ADS)

    Oklay, N.; Vincent, J.-B.; Fornasier, S.; Pajola, M.; Besse, S.; Davidsson, B. J. R.; Lara, L. M.; Mottola, S.; Naletto, G.; Sierks, H.; Barucci, A. M.; Scholten, F.; Preusker, F.; Pommerol, A.; Masoumzadeh, N.; Lazzarin, M.; Barbieri, C.; Lamy, P. L.; Rodrigo, R.; Koschny, D.; Rickman, H.; A'Hearn, M. F.; Bertaux, J.-L.; Bertini, I.; Bodewits, D.; Cremonese, G.; Da Deppo, V.; Debei, S.; De Cecco, M.; Fulle, M.; Groussin, O.; Gutiérrez, P. J.; Güttler, C.; Hall, I.; Hofmann, M.; Hviid, S. F.; Ip, W.-H.; Jorda, L.; Keller, H. U.; Knollenberg, J.; Kovacs, G.; Kramm, J.-R.; Kührt, E.; Küppers, M.; Lin, Z.-Y.; Lopez Moreno, J. J.; Marzari, F.; Moreno, F.; Shi, X.; Thomas, N.; Toth, I.; Tubiana, C.

    2016-02-01

    Aims.We carried out an investigation of the surface variegation of comet 67P/Churyumov-Gerasimenko, the detection of regions showing activity, the determination of active and inactive surface regions of the comet with spectral methods, and the detection of fallback material. Methods: We analyzed multispectral data generated with Optical, Spectroscopic, and Infrared Remote Imaging System (OSIRIS) narrow angle camera (NAC) observations via spectral techniques, reflectance ratios, and spectral slopes in order to study active regions. We applied clustering analysis to the results of the reflectance ratios, and introduced the new technique of activity thresholds to detect areas potentially enriched in volatiles. Results: Local color inhomogeneities are detected over the investigated surface regions. Active regions, such as Hapi, the active pits of Seth and Ma'at, the clustered and isolated bright features in Imhotep, the alcoves in Seth and Ma'at, and the large alcove in Anuket, have bluer spectra than the overall surface. The spectra generated with OSIRIS NAC observations are dominated by cometary emissions of around 700 nm to 750 nm as a result of the coma between the comet's surface and the camera. One of the two isolated bright features in the Imhotep region displays an absorption band of around 700 nm, which probably indicates the existence of hydrated silicates. An absorption band with a center between 800-900 nm is tentatively observed in some regions of the nucleus surface. This absorption band can be explained by the crystal field absorption of Fe2+, which is a common spectral feature seen in silicates.

  15. Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects

    PubMed Central

    Johannesson, Elisabet; Ringström, Gisela; Abrahamsson, Hasse; Sadik, Riadh

    2015-01-01

    AIM: To assess the long-term effects of physical activity on irritable bowel syndrome (IBS) symptoms and on quality of life, fatigue, depression and anxiety. METHODS: Seventy-six patients from a previous randomized controlled interventional study on increased physical activity in IBS were asked to participate in this long-term follow-up study. The included patients attended one visit in which they filled out questionnaires and they underwent a submaximal cycle ergometer test. The primary end point was the change in the IBS Severity Scoring System (IBS-SSS) at baseline, i.e., before the intervention and at follow-up. The secondary endpoints were changes in quality of life, fatigue, depression and anxiety. RESULTS: A total of 39 [32 women, median age 45 (28-61) years] patients were included in this follow-up. Median follow-up time was 5.2 (range: 3.8-6.2) years. The IBS symptoms were improved compared with baseline [IBS-SSS: 276 (169-360) vs 218 (82-328), P = 0.001]. This was also true for the majority of the dimensions of psychological symptoms such as disease specific quality of life, fatigue, depression and anxiety. The reported time of physical activity during the week before the visit had increased from 3.2 (0.0-10.0) h at baseline to 5.2 (0.0-15.0) h at follow-up, P = 0.019. The most common activities reported were walking, aerobics and cycling. There was no significant difference in the oxygen uptake 31.8 (19.7-45.8) mL per min per kg at baseline vs 34.6 (19.0-54.6) mL/min per kg at follow-up. CONCLUSION: An intervention to increase physical activity has positive long-term effects on IBS symptoms and psychological symptoms. PMID:25593485

  16. Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

    PubMed Central

    2013-01-01

    Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development. PMID:24304150

  17. An NGR-integrated and enediyne-energized apoprotein shows CD13-targeting antitumor activity.

    PubMed

    Zheng, Yan-Bo; Shang, Bo-Yang; Li, Yi; Zhen, Yong-Su

    2013-03-01

    Targeting and inhibiting angiogenesis is a promising strategy for treatment of cancer. NGR peptide motif is a tumor-homing peptide, which could bind with CD13 expressed on tumor blood vessels. Lidamycin is a highly potent antitumor antibiotic, which is composed of an apoprotein (LDP) and an active enediyne chromophore (AE). Here, an NGR-integrated and enediyne-energized apoprotein composed of cyclic NGR peptide and lidamycin was developed by a two-step procedure. Firstly, we prepared the fusion protein composed of NGR peptide and LDP by recombinant DNA technology. Then, AE was reloaded to the fusion protein to get NGR-LDP-AE. Our experiments showed that NGR-LDP could bind to CD13-expressing HT-1080 cells, whereas the recombinant LDP (rLDP) showed weak binding. NGR-LDP-AE exerted highly potent cytotoxicity to cultured tumor cells in vitro. In vivo antitumor activity was evaluated in murine hepatoma 22 (H22) model and human fibrosarcoma HT-1080 model. At the tolerable dose, NGR-LDP-AE and lidamycin inhibited H22 tumor growth by 94.8 and 66.9%, and the median survival time of the mice was 62 and 37 days, respectively. In the HT-1080 model, NGR-LDP-AE inhibited tumor growth by 88.6%, which was statistically different from that of lidamycin (74.5%). Immunohistochemical study showed that NGR-LDP could bind to tumor blood vessels. Conclusively, these results demonstrate that fusion of LDP with CNGRC peptide delivers AE to tumor blood vessels and improves its antitumor activity. PMID:23206754

  18. Synovial sarcoma cell lines showed reduced DNA repair activity and sensitivity to a PARP inhibitor.

    PubMed

    Yamasaki, Hiroyuki; Miyamoto, Mamiko; Yamamoto, Yuki; Kondo, Tadashi; Watanabe, Toshiki; Ohta, Tsutomu

    2016-08-01

    Synovial sarcoma is a soft-tissue sarcoma and a rare type of cancer. Unfortunately, effective chemotherapies for synovial sarcomas have not been established. In this report, we show that synovial sarcoma cell lines have reduced repair activity for DNA damage induced by ionizing radiation (IR) and a topoisomerase II inhibitor (etoposide). We also observed reduced recruitment of RAD51 homologue (S. cerevisiae; RAD51) at sites of double-strand breaks (DSBs) in synovial sarcoma cell lines that had been exposed to IR. These findings showed that synovial sarcoma cell lines are defective in homologous recombination (HR) repair. Furthermore, we found that a poly-(ADP-ribose) polymerase (PARP) inhibitor (AZD2281; olaparib) effectively reduced the growth of synovial sarcoma cell lines in the presence of an alkylating agent (temozolomide). Our findings offer evidence that treatment combining a PARP inhibitor and an alkylating agent could have therapeutic benefits in the treatment of synovial sarcoma. PMID:27353471

  19. Children with High Functioning Autism show increased prefrontal and temporal cortex activity during error monitoring

    PubMed Central

    Goldberg, Melissa C.; Spinelli, Simona; Joel, Suresh; Pekar, James J.; Denckla, Martha B.; Mostofsky, Stewart H.

    2010-01-01

    Evidence exists for deficits in error monitoring in autism. These deficits may be particularly important because they may contribute to excessive perseveration and repetitive behavior in autism. We examined the neural correlates of error monitoring using fMRI in 8–12-year-old children with high-functioning autism (HFA, n=11) and typically developing children (TD, n=15) during performance of a Go/No-Go task by comparing the neural correlates of commission errors versus correct response inhibition trials. Compared to TD children, children with HFA showed increased BOLD fMRI signal in the anterior medial prefrontal cortex (amPFC) and the left superior temporal gyrus (STempG) during commission error (versus correct inhibition) trials. A follow-up region-of-interest analysis also showed increased BOLD signal in the right insula in HFA compared to TD controls. Our findings of increased amPFC and STempG activity in HFA, together with the increased activity in the insula, suggest a greater attention towards the internally-driven emotional state associated with making an error in children with HFA. Since error monitoring occurs across different cognitive tasks throughout daily life, an increased emotional reaction to errors may have important consequences for early learning processes. PMID:21151713

  20. Tannic acid modified silver nanoparticles show antiviral activity in herpes simplex virus type 2 infection.

    PubMed

    Orlowski, Piotr; Tomaszewska, Emilia; Gniadek, Marianna; Baska, Piotr; Nowakowska, Julita; Sokolowska, Justyna; Nowak, Zuzanna; Donten, Mikolaj; Celichowski, Grzegorz; Grobelny, Jaroslaw; Krzyzowska, Malgorzata

    2014-01-01

    The interaction between silver nanoparticles and herpesviruses is attracting great interest due to their antiviral activity and possibility to use as microbicides for oral and anogenital herpes. In this work, we demonstrate that tannic acid modified silver nanoparticles sized 13 nm, 33 nm and 46 nm are capable of reducing HSV-2 infectivity both in vitro and in vivo. The antiviral activity of tannic acid modified silver nanoparticles was size-related, required direct interaction and blocked virus attachment, penetration and further spread. All tested tannic acid modified silver nanoparticles reduced both infection and inflammatory reaction in the mouse model of HSV-2 infection when used at infection or for a post-infection treatment. Smaller-sized nanoparticles induced production of cytokines and chemokines important for anti-viral response. The corresponding control buffers with tannic acid showed inferior antiviral effects in vitro and were ineffective in blocking in vivo infection. Our results show that tannic acid modified silver nanoparticles are good candidates for microbicides used in treatment of herpesvirus infections. PMID:25117537

  1. CpG oligodeoxynucleotides with double stem-loops show strong immunostimulatory activity.

    PubMed

    Yang, Liang; Wu, Xiuli; Wan, Min; Yu, Yue; Yu, Yongli; Wang, Liying

    2013-01-01

    Based on the current understanding of TLR9 recognition of CpG ODN, we have tried to design a series of CpG ODNs that display double stem-loops when being analyzed for their secondary structures using 'mfold web server'. Proliferation of human PBMC and bioassay for IFN production were used as technical platforms in primary screening. Interestingly, two of them, designated as DSL01 and D-SL03, belonging to B class CpG ODN and C class CpG ODN respectively, showed vigorous immunostimulatory activity and were chosen for further tests. Flow cytometry analysis showed that both of them could activate human B cells, NK cells, mononuclear cells and T cells and up-regulate expression of CD80, CD86 and HLA-DR on the surface of subsets in human PBMCs. Furthermore, we demonstrated that those two ODNs potently stimulated proliferation of PBMC/splenocytes obtained from diverse vertebrate species. Noticeably, both of them displayed anti-breast cancer effect in mice when administered by peritumoral injection. PMID:23142503

  2. Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61.

    PubMed

    Huang, Kuan-Chun; Chen, Zhihong; Jiang, Yimin; Akare, Sandeep; Kolber-Simonds, Donna; Condon, Krista; Agoulnik, Sergei; Tendyke, Karen; Shen, Yongchun; Wu, Kuo-Ming; Mathieu, Steven; Choi, Hyeong-Wook; Zhu, Xiaojie; Shimizu, Hajime; Kotake, Yoshihiko; Gerwick, William H; Uenaka, Toshimitsu; Woodall-Jappe, Mary; Nomoto, Kenichi

    2016-06-01

    Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A-treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a (3)H-labeled apratoxin A probe and specific Sec 61α/β antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure. Mol Cancer Ther; 15(6); 1208-16. ©2016 AACR. PMID:27196783

  3. The alkylphospholipid edelfosine shows activity against Strongyloides venezuelensis and induces apoptosis-like cell death.

    PubMed

    Legarda-Ceballos, Ana L; Rojas-Caraballo, Jose; López-Abán, Julio; Ruano, Ana Lucía; Yepes, Edward; Gajate, Consuelo; Mollinedo, Faustino; Muro, Antonio

    2016-10-01

    Strongyloidiasis is widely distributed in the tropical and subtropical areas. Ivermectin is the drug of choice for the treatment. However, the concerns about relying treatment on a single drug make identification of new molecules a priority. Alkylphospholipid analogues, including edelfosine, are a group of synthetic compounds that have shown activity against some parasites. The objective was to assess the in vitro and in vivo activity of edelfosine, miltefosine, perifosine against Strongyloides venezuelensis. Moreover, apoptosis-like mechanism in larvae after treatment was studied. Edelfosine displayed the highest activity and the best selectivity index (LD50=49.6 ± 5.4μM, SI=1.1) compared to miltefosine or perifosine. Third stage larvae after culture with edelfosine were not able to develop an infection in mice. Treatment of mice with edelfosine showed reduction of 47% in parasitic females allocated in the gut. Moreover, DNA fragmentation was observed by TUNEL staining in larvae treated with edelfosine. These results suggest that edelfosine could be an effective drug against strongyloidiasis, probably through induction of apoptosis-like cell death. PMID:27394030

  4. Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells.

    PubMed

    Tynell, Janne; Westenius, Veera; Rönkkö, Esa; Munster, Vincent J; Melén, Krister; Österlund, Pamela; Julkunen, Ilkka

    2016-02-01

    In this study we assessed the ability of Middle East respiratory syndrome coronavirus (MERS-CoV) to replicate and induce innate immunity in human monocyte-derived macrophages and dendritic cells (MDDCs), and compared it with severe acute respiratory syndrome coronavirus (SARS-CoV). Assessments of viral protein and RNA levels in infected cells showed that both viruses were impaired in their ability to replicate in these cells. Some induction of IFN-λ1, CXCL10 and MxA mRNAs in both macrophages and MDDCs was seen in response to MERS-CoV infection, but almost no such induction was observed in response to SARS-CoV infection. ELISA and Western blot assays showed clear production of CXCL10 and MxA in MERS-CoV-infected macrophages and MDDCs. Our data suggest that SARS-CoV and MERS-CoV replicate poorly in human macrophages and MDDCs, but MERS-CoV is nonetheless capable of inducing a readily detectable host innate immune response. Our results highlight a clear difference between the viruses in activating host innate immune responses in macrophages and MDDCs, which may contribute to the pathogenesis of infection. PMID:26602089

  5. Isolation and functional characterization of chicken intestinal intra-epithelial lymphocytes showing natural killer cell activity against tumour target cells.

    PubMed Central

    Chai, J Y; Lillehoj, H S

    1988-01-01

    Intestinal intra-epithelial lymphocytes (IEL) of SC or FP chickens were isolated and examined for their natural killer (NK)-cell activity against chicken tumour cell lines, LSCC-RP9 (RP9), LSCC-RP12 (RP12), MDCC-MSB-1 (MSB-1) and MDCC-CU36 (CU36). In general, IEL of satisfactory yield and of good viability were obtained with EDTA treatment of the gut tissues, followed by rapid passages of the resultant cells through nylon-wool columns and centrifugation on two-step Percoll density gradients (45% and 80%). In 4-hr and 16-hr 51Cr-release assays, the NK-cell activity of chicken IEL depended not only upon the type of target cells but also upon the incubation time and the host genetic background. RP9, MSB-1 and CU36 were susceptible to NK lysis by IEL and by spleen cells, while RP12 was resistant to lysis even after a prolonged incubation. In kinetic studies the cytotoxicity was detactable from 2 hr after incubation and progressively increased up to 16 or 18 hr. The IEL of SC chickens revealed significantly higher levels of NK-cell activity against RP9 than FP-strain chickens, whereas their splenic NK-cell activity was not significantly different. Against MSB-1 targets, however, IEL of SC and FP chickens showed similar levels of NK-cell activity while their spleens did not (being higher in FP). When tested in FP chickens, IEL NK-cell activity was inhibited by the addition of unlabelled homologous target cells. In general, NK-cell activity was higher in the jejunum and ileum than in the duodenum and caecum. Efforts to enrich IEL NK-effector cells by discontinuous Percoll gradients were not successful. The results of the present study show that IEL of chicken intestine contain effector cells that can mediate NK-cell activity against chicken tumour cells. PMID:3338816

  6. Activity in ventromedial prefrontal cortex during self-related processing: positive subjective value or personal significance?

    PubMed

    Kim, Kyungmi; Johnson, Marcia K

    2015-04-01

    Well-being and subjective experience of a coherent world depend on our sense of 'self' and relations between the self and the environment (e.g. people, objects and ideas). The ventromedial prefrontal cortex (vMPFC) is involved in self-related processing, and disrupted vMPFC activity is associated with disruptions of emotional/social functioning (e.g. depression and autism). Clarifying precise function(s) of vMPFC in self-related processing is an area of active investigation. In this study, we sought to more specifically characterize the function of vMPFC in self-related processing, focusing on two alternative accounts: (i) assignment of positive subjective value to self-related information and (ii) assignment of personal significance to self-related information. During functional magnetic resonance imaging (fMRI), participants imagined owning objects associated with either their perceived ingroup or outgroup. We found that for ingroup-associated objects, vMPFC showed greater activity for objects with increased than decreased post-ownership preference. In contrast, for outgroup-associated objects, vMPFC showed greater activity for objects with decreased than increased post-ownership preference. Our findings support the idea that the function of vMPFC in self-related processing may not be to represent/evaluate the 'positivity' or absolute preference of self-related information but to assign personal significance to it based on its meaning/function for the self. PMID:24837477

  7. Native and recombinant Pg-AMP1 show different antibacterial activity spectrum but similar folding behavior.

    PubMed

    Porto, William F; Nolasco, Diego O; Franco, Octavio L

    2014-05-01

    Glycine-rich proteins (GRPs) derived from plants compose a family of proteins and peptides that share a glycine repeat domain and they can perform diverse functions. Two structural conformations have been proposed for GRPs: glycine loops arranged as a Velcro and an anti-parallel β-sheet with several β-strands. The antimicrobial peptide Pg-AMP1 is the only plant GRP with antibacterial activity reported so far and its structure remains unclear. Recently, its recombinant expression was reported, where the recombinant peptide had an additional methionine residue at the N-terminal and a histidine tag at the C-terminal (His6-tag). These changes seem to change the peptide's activity, generating a broader spectrum of antibacterial activity. In this report, through ab initio molecular modelling and molecular dynamics, it was observed that both native and recombinant peptide structures were composed of an N-terminal α-helix and a dynamic loop that represents two-thirds of the protein. In contrast to previous reports, it was observed that there is a tendency to adopt a globular fold instead of an extended one, which could be in both, glycine loops or anti-parallel β-sheet conformation. The recombinant peptide showed a slightly higher solvated potential energy compared to the native form, which could be related to the His6-tag exposition. In fact, the His6-tag could be mainly responsible for the broader spectrum of activity, but it does not seem to cause great structural changes. However, novel studies are needed for a better characterization of its pharmacological properties so that in the future novel drugs may be produced based on this peptide. PMID:24582624

  8. Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models.

    PubMed

    Tsimafeyeu, Ilya; Ludes-Meyers, John; Stepanova, Evgenia; Daeyaert, Frits; Kochenkov, Dmitry; Joose, Jean-Baptiste; Solomko, Eliso; Van Akene, Koen; Peretolchina, Nina; Yin, Wei; Ryabaya, Oxana; Byakhov, Mikhail; Tjulandin, Sergei

    2016-07-01

    Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers. PMID:27136102

  9. Are secular correlations between sunspots, geomagnetic activity, and global temperature significant?

    USGS Publications Warehouse

    Love, J.J.; Mursula, K.; Tsai, V.C.; Perkins, D.M.

    2011-01-01

    Recent studies have led to speculation that solar-terrestrial interaction, measured by sunspot number and geomagnetic activity, has played an important role in global temperature change over the past century or so. We treat this possibility as an hypothesis for testing. We examine the statistical significance of cross-correlations between sunspot number, geomagnetic activity, and global surface temperature for the years 1868-2008, solar cycles 11-23. The data contain substantial autocorrelation and nonstationarity, properties that are incompatible with standard measures of cross-correlational significance, but which can be largely removed by averaging over solar cycles and first-difference detrending. Treated data show an expected statistically- significant correlation between sunspot number and geomagnetic activity, Pearson p < 10-4, but correlations between global temperature and sunspot number (geomagnetic activity) are not significant, p = 0.9954, (p = 0.8171). In other words, straightforward analysis does not support widely-cited suggestions that these data record a prominent role for solar-terrestrial interaction in global climate change. With respect to the sunspot-number, geomagnetic-activity, and global-temperature data, three alternative hypotheses remain difficult to reject: (1) the role of solar-terrestrial interaction in recent climate change is contained wholly in long-term trends and not in any shorter-term secular variation, or, (2) an anthropogenic signal is hiding correlation between solar-terrestrial variables and global temperature, or, (3) the null hypothesis, recent climate change has not been influenced by solar-terrestrial interaction. ?? 2011 by the American Geophysical Union.

  10. Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model.

    PubMed

    Maswadeh, Hamzah M; Aljarbou, Ahmad N; Alorainy, Mohammed S; Alsharidah, Mansour S; Khan, Masood A

    2015-01-01

    Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs. PMID:25821817

  11. Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries

    PubMed Central

    Zhang, Hua; Zheng, Wenjing; Shen, Yan; Adhikari, Deepak; Ueno, Hiroo; Liu, Kui

    2012-01-01

    It has been generally accepted for more than half a century that, in most mammalian species, oocytes cannot renew themselves in postnatal or adult life, and that the number of oocytes is already fixed in fetal or neonatal ovaries. This assumption, however, has been challenged over the past decade. In this study, we have taken an endogenous genetic approach to this question and generated a multiple fluorescent Rosa26rbw/+;Ddx4-Cre germline reporter mouse model for in vivo and in vitro tracing of the development of female germline cell lineage. Through live cell imaging and de novo folliculogenesis experiments, we show that the Ddx4-expressing cells from postnatal mouse ovaries did not enter mitosis, nor did they contribute to oocytes during de novo folliculogenesis. Our results provide evidence that supports the traditional view that no postnatal follicular renewal occurs in mammals, and no mitotically active Ddx4-expressing female germline progenitors exist in postnatal mouse ovaries. PMID:22778414

  12. Acidophilic actinobacteria synthesised silver nanoparticles showed remarkable activity against fungi-causing superficial mycoses in humans.

    PubMed

    Anasane, N; Golińska, P; Wypij, M; Rathod, D; Dahm, H; Rai, M

    2016-03-01

    Superficial mycoses are limited to the most external part of the skin and hair and caused by Malassezia sp., Trichophyton sp. and Candida sp. We report extracellular biosynthesis of silver nanoparticles (AgNPs) by acidophilic actinobacteria (SF23, C9) and its in vitro antifungal activity against fungi-causing superficial mycoses. The phylogenetic analysis based on the 16S rRNA gene sequence of strains SF23 and C9 showed that they are most closely related to Pilimelia columellifera subsp. pallida GU269552(T) . The detection of AgNPs was confirmed by visual observation of colour changes from colourless to brown, and UV-vis spectrophotometer analysis, which showed peaks at 432 and 427 nm, respectively. These AgNPs were further characterised by nanoparticle tracking analysis (NTA), Zeta potential, Fourier-transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM). The FTIR analysis exhibited the presence of proteins as capping agents. The TEM analysis revealed the formation of spherical and polydispersed nanoparticles in the size range of 4-36 nm and 8-60 nm, respectively. The biosynthesised AgNPs were screened against fungi-causing superficial mycoses viz., Malassezia furfur, Trichophyton rubrum, Candida albicans and C. tropicalis. The highest antifungal activity of AgNPs from SF23 and C9 against T. rubrum and the least against M. furfur and C. albicans was observed as compared to other tested fungi. The biosynthesised AgNPs were found to be potential anti-antifungal agent against fungi-causing superficial mycoses. PMID:26671603

  13. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

    PubMed Central

    Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

    2016-01-01

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554

  14. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase.

    PubMed

    Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

    2015-10-01

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 µM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl(-) and the decreased HCO3 (-) concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na-K-2Cl electroneutral cotransporter or Cl(-)/HCO3 (-) anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554

  15. Boehmenan, a lignan from Hibiscus ficulneus, showed Wnt signal inhibitory activity.

    PubMed

    Shono, Takumi; Ishikawa, Naoki; Toume, Kazufumi; Arai, Midori A; Ahmed, Firoj; Sadhu, Samir K; Ishibashi, Masami

    2015-07-15

    The Wnt signal pathway modulates numerous biological processes, and its aberrant activation is related to various diseases. Therefore, inhibition of the Wnt signal may provide an effective (or efficient) strategy for these diseases. Cell-based luciferase assay targeting the Wnt signal (TOP assay) revealed that Hibiscus ficulneus extract inhibited the Wnt signal. The activity-guided isolation of the MeOH extract of H. ficulneus stems yielded four known (1-4) lignans along with myriceric acid (5). Compounds 1-4 potently inhibited the Wnt signal with TOPflash IC50 values of 1.0, 4.5, 6.3, and 1.9 μM, respectively. Compound 1 exhibited cytotoxicity against both Wnt-dependent (HCT116) and Wnt-independent (RKO) cells. Western blot analysis showed that 1 decreased the expression of full, cytosolic and nuclear β-catenin along with c-myc in STF/293 cells. Our results suggested that 1 may have inhibited the Wnt signal by decreasing β-catenin levels. PMID:26026364

  16. Piper betle shows antioxidant activities, inhibits MCF-7 cell proliferation and increases activities of catalase and superoxide dismutase

    PubMed Central

    2012-01-01

    Background Breast cancer is the most common form of cancer and the focus on finding chemotherapeutic agents have recently shifted to natural products. Piper betle is a medicinal plant with various biological activities. However, not much data is available on the anti-cancer effects of P. betle on breast cancer. Due to the current interest in the potential effects of antioxidants from natural products in breast cancer treatment, we investigated the antioxidant activities of the leaves of P. betle and its inhibitory effect on the proliferation of the breast cancer cell line, MCF-7. Methods The leaves of P. betle were extracted with solvents of varying polarities (water, methanol, ethyl acetate and hexane) and their phenolic and flavonoid content were determined using colorimetric assays. Phenolic composition was characterized using HPLC. Antioxidant activities were measured using FRAP, DPPH, superoxide anion, nitric oxide and hyroxyl radical scavenging assays. Biological activities of the extracts were analysed using MTT assay and antioxidant enzyme (catalase, superoxide dismutase, glutathione peroxidase) assays in MCF-7 cells. Results Overall, the ethyl acetate extract showed the highest ferric reducing activity and radical scavenging activities against DPPH, superoxide anion and nitric oxide radicals. This extract also contained the highest phenolic content implying the potential contribution of phenolics towards the antioxidant activities. HPLC analyses revealed the presence of catechin, morin and quercetin in the leaves. The ethyl acetate extract also showed the highest inhibitory effect against the proliferation of MCF-7 cells (IC50=65 μg/ml). Treatment of MCF-7 cells with the plant extract increased activities of catalase and superoxide dismutase. Conclusions Ethyl acetate is the optimal solvent for the extraction of compounds with antioxidant and anti-proliferative activities. The increased activities of catalase and superoxide dismutase in the treated cells

  17. Trefoil factor 3 shows anti-inflammatory effects on activated microglia.

    PubMed

    Arnold, Philipp; Rickert, Uta; Helmers, Ann-Kristin; Spreu, Jessica; Schneppenheim, Janna; Lucius, Ralph

    2016-07-01

    Microglial cells are a major source of pro-inflammatory cytokines during central nervous system (CNS) inflammation. They can develop a pro-inflammatory M1 phenotype and an anti-inflammatory M2 phenotype. Shifting the phenotype from M1 to M2 might be an important mechanism to overcome CNS inflammation and to prevent or reduce neuronal damage. Here, we demonstrate that the anti-inflammatory protein trefoil factor 3 (TFF3) is secreted by astrocytes and that its transcription is significantly reduced after incubation with lipopolysaccharide (LPS). Moreover, we demonstrate that microglial cells cultured in the presence of TFF3 show reduced expression and secretion of pro-inflammatory cytokines after LPS stimulation. PMID:26899249

  18. Structural variants of yeast prions show conformer-specific requirements for chaperone activity

    PubMed Central

    Stein, Kevin C.; True, Heather L.

    2016-01-01

    Summary Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1, and its human ortholog Hdj1, had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation. PMID:25060529

  19. Crystal structure of plant light-harvesting complex shows the active, energy-transmitting state

    PubMed Central

    Barros, Tiago; Royant, Antoine; Standfuss, Jörg; Dreuw, Andreas; Kühlbrandt, Werner

    2009-01-01

    Plants dissipate excess excitation energy as heat by non-photochemical quenching (NPQ). NPQ has been thought to resemble in vitro aggregation quenching of the major antenna complex, light harvesting complex of photosystem II (LHC-II). Both processes are widely believed to involve a conformational change that creates a quenching centre of two neighbouring pigments within the complex. Using recombinant LHC-II lacking the pigments implicated in quenching, we show that they have no particular role. Single crystals of LHC-II emit strong, orientation-dependent fluorescence with an emission maximum at 680 nm. The average lifetime of the main 680 nm crystal emission at 100 K is 1.31 ns, but only 0.39 ns for LHC-II aggregates under identical conditions. The strong emission and comparatively long fluorescence lifetimes of single LHC-II crystals indicate that the complex is unquenched, and that therefore the crystal structure shows the active, energy-transmitting state of LHC-II. We conclude that quenching of excitation energy in the light-harvesting antenna is due to the molecular interaction with external pigments in vitro or other pigment–protein complexes such as PsbS in vivo, and does not require a conformational change within the complex. PMID:19131972

  20. Membrane Active Small Molecules Show Selective Broad Spectrum Antibacterial Activity with No Detectable Resistance and Eradicate Biofilms.

    PubMed

    Hoque, Jiaul; Konai, Mohini M; Gonuguntla, Spandhana; Manjunath, Goutham B; Samaddar, Sandip; Yarlagadda, Venkateswarlu; Haldar, Jayanta

    2015-07-23

    Treating bacterial biofilms with conventional antibiotics is limited due to ineffectiveness of the drugs and higher propensity to develop bacterial resistance. Development of new classes of antibacterial therapeutics with alternative mechanisms of action has become imperative. Herein, we report the design, synthesis, and biological evaluations of novel membrane-active small molecules featuring two positive charges, four nonpeptidic amide groups, and variable hydrophobic/hydrophilic (amphiphilic) character. The biocides synthesized via a facile methodology not only displayed good antibacterial activity against wild-type bacteria but also showed high activity against various drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactam-resistant Klebsiella pneumoniae. Further, these biocides not only inhibited the formation of biofilms but also disrupted the established S. aureus and E. coli biofilms. The membrane-active biocides hindered the propensity to develop bacterial resistance. Moreover, the biocides showed negligible toxicity against mammalian cells and thus bear potential to be used as therapeutic agents. PMID:26102297

  1. Neural activation in the "reward circuit" shows a nonlinear response to facial attractiveness.

    PubMed

    Liang, Xiaoyun; Zebrowitz, Leslie A; Zhang, Yi

    2010-01-01

    Positive behavioral responses to attractive faces have led neuroscientists to investigate underlying neural mechanisms in a "reward circuit" that includes brain regions innervated by dopamine pathways. Using male faces ranging from attractive to extremely unattractive, disfigured ones, this study is the first to demonstrate heightened responses to both rewarding and aversive faces in numerous areas of this putative reward circuit. Parametric analyses employing orthogonal linear and nonlinear regressors revealed positive nonlinear effects in anterior cingulate cortex, lateral orbital frontal cortex (LOFC), striatum (nucleus accumbens, caudate, putamen), and ventral tegmental area, in addition to replicating previously documented linear effects in medial orbital frontal cortex (MOFC) and LOFC and nonlinear effects in amygdala and MOFC. The widespread nonlinear responses are consistent with single cell recordings in animals showing responses to both rewarding and aversive stimuli, and with some human fMRI investigations of non-face stimuli. They indicate that the reward circuit does not process face valence with any simple dissociation of function across structures. Perceiver gender modulated some responses to our male faces: Women showed stronger linear effects, and men showed stronger nonlinear effects, which may have functional implications. Our discovery of nonlinear responses to attractiveness throughout the reward circuit echoes the history of amygdala research: Early work indicated a linear response to threatening stimuli, including faces; later work also revealed a nonlinear response with heightened activation to affectively salient stimuli regardless of valence. The challenge remains to determine how such dual coding influences feelings, such as pleasure and pain, and guides goal-related behavioral responses, such as approach and avoidance. PMID:20221946

  2. Neural Activation in the ‘Reward Circuit’ Shows a Nonlinear Response to Facial Attractiveness

    PubMed Central

    Liang, Xiaoyun; Zebrowitz, Leslie A.; Zhang, Yi

    2010-01-01

    Positive behavioral responses to attractive faces have led neuroscientists to investigate underlying neural mechanisms in a ‘reward circuit’ that includes brain regions innervated by dopamine pathways. Using male faces ranging from attractive to extremely unattractive, disfigured ones, this study is the first to demonstrate heightened responses to both rewarding and aversive faces in numerous areas of this putative reward circuit. Parametric analyses employing orthogonal linear and nonlinear regressors revealed positive nonlinear effects in anterior cingulate cortex (ACC), lateral orbitofrontal cortex (LOFC), striatum (nucleus accumbens (NAC), caudate, putamen), and ventral tegmental area (VTA), in addition to replicating previously documented linear effects in MOFC and LOFC and nonlinear effects in AMY and MOFC. The widespread nonlinear responses are consistent both with single cell recordings in animals showing responses to both rewarding and aversive stimuli and some human fMRI investigations of non-face stimuli. They indicate that the reward circuit does not process face valence with any simple dissociation of function across structures. Perceiver gender modulated some responses to our male faces: women showed stronger linear effects, and men showed stronger nonlinear effects, which may have functional implications. Our discovery of nonlinear responses to attractiveness throughout the reward circuit echoes the history of amygdala research: early work indicated a linear response to threatening stimuli, including faces; later work also revealed a nonlinear response with heightened activation to affectively salient stimuli regardless of valence. The challenge remains to determine how such dual coding influences feelings, like pleasure and pain, and guides goal-related behavioral responses, like approach and avoidance. PMID:20221946

  3. Backbone cyclised peptides from plants show molluscicidal activity against the rice pest Pomacea canaliculata (golden apple snail).

    PubMed

    Plan, Manuel Rey R; Saska, Ivana; Cagauan, Arsenia G; Craik, David J

    2008-07-01

    Golden apple snails ( Pomacea canaliculata) are serious pests of rice in South East Asia. Cyclotides are backbone cyclized peptides produced by plants from Rubiaceae and Violaceae. In this study, we investigated the molluscicidal activity of cyclotides against golden apple snails. Crude cyclotide extracts from both Oldenlandia affinis and Viola odorata plants showed molluscicidal activity comparable to the synthetic molluscicide metaldehyde. Individual cyclotides from each extract demonstrated a range of molluscicidal activities. The cyclotides cycloviolacin O1, kalata B1, and kalata B2 were more toxic to golden apple snails than metaldehyde, while kalata B7 and kalata B8 did not cause significant mortality. The toxicity of the cyclotide kalata B2 on a nontarget species, the Nile tilapia ( Oreochromis niloticus), was three times lower than the common piscicide rotenone. Our findings suggest that the existing diversity of cyclotides in plants could be used to develop natural molluscicides. PMID:18557620

  4. A cry in the dark: depressed mothers show reduced neural activation to their own infant’s cry

    PubMed Central

    Ablow, Jennifer C.

    2012-01-01

    This study investigated depression-related differences in primiparous mothers’ neural response to their own infant’s distress cues. Mothers diagnosed with major depressive disorder (n = 11) and comparison mothers with no diagnosable psychopathology (n = 11) were exposed to their own 18-months-old infant’s cry sound, as well as unfamiliar infant’s cry and control sound, during functional neuroimaging. Depressed mothers’ response to own infant cry greater than other sounds was compared to non-depressed mothers’ response in the whole brain [false discovery rate (FDR) corrected]. A continuous measure of self-reported depressive symptoms (CESD) was also tested as a predictor of maternal response. Non-depressed mothers activated to their own infant’s cry greater than control sound in a distributed network of para/limbic and prefrontal regions, whereas depressed mothers as a group failed to show activation. Non-depressed compared to depressed mothers showed significantly greater striatal (caudate, nucleus accumbens) and medial thalamic activation. Additionally, mothers with lower depressive symptoms activated more strongly in left orbitofrontal, dorsal anterior cingulate and medial superior frontal regions. Non-depressed compared to depressed mothers activated uniquely to own infant greater than other infant cry in occipital fusiform areas. Disturbance of these neural networks involved in emotional response and regulation may help to explain parenting deficits in depressed mothers. PMID:21208990

  5. HATS-2b: A transiting extrasolar planet orbiting a K-type star showing starspot activity

    NASA Astrophysics Data System (ADS)

    Mohler-Fischer, M.; Mancini, L.; Hartman, J. D.; Bakos, G. Á.; Penev, K.; Bayliss, D.; Jordán, A.; Csubry, Z.; Zhou, G.; Rabus, M.; Nikolov, N.; Brahm, R.; Espinoza, N.; Buchhave, L. A.; Béky, B.; Suc, V.; Csák, B.; Henning, T.; Wright, D. J.; Tinney, C. G.; Addison, B. C.; Schmidt, B.; Noyes, R. W.; Papp, I.; Lázár, J.; Sári, P.; Conroy, P.

    2013-10-01

    We report the discovery of HATS-2b, the second transiting extrasolar planet detected by the HATSouth survey. HATS-2b is moving on a circular orbit around a V = 13.6 mag, K-type dwarf star (GSC 6665-00236), at a separation of 0.0230 ± 0.0003 AU and with a period of 1.3541 days. The planetary parameters have been robustly determined using a simultaneous fit of the HATSouth, MPG/ESO 2.2 m/GROND, Faulkes Telescope South/Spectral transit photometry, and MPG/ESO 2.2 m/FEROS, Euler 1.2 m/CORALIE, AAT 3.9 m/CYCLOPS radial-velocity measurements. HATS-2b has a mass of 1.37 ± 0.16 MJ, a radius of 1.14 ± 0.03 RJ, and an equilibrium temperature of 1567 ± 30 K. The host star has a mass of 0.88 ± 0.04 M⊙ and a radius of 0.89 ± 0.02 R⊙, and it shows starspot activity. We characterized the stellar activity by analyzing two photometric follow-up transit light curves taken with the GROND instrument, both obtained simultaneously in four optical bands (covering the wavelength range of 3860-9520 Å). The two light curves contain anomalies compatible with starspots on the photosphere of the host star along the same transit chord. Tables of the individual photometric measurements are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/558/A55

  6. A cell penetrating peptide-integrated and enediyne-energized fusion protein shows potent antitumor activity.

    PubMed

    Ru, Qin; Shang, Bo-Yang; Miao, Qing-Fang; Li, Liang; Wu, Shu-Ying; Gao, Rui-Juan; Zhen, Yong-Su

    2012-11-20

    Arginine-rich peptides belong to a subclass of cell penetrating peptides that are taken up by living cells and can be detected freely diffusing inside the cytoplasm and nucleoplasm. This phenomenon has been attributed to either an endocytotic mode of uptake and a subsequent release from vesicles or a direct membrane penetration. Lidamycin is an antitumor antibiotic, which consists of an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). In the present study, a fusion protein (Arg)(9)-LDP composed of cell penetrating peptide (Arg)(9) and LDP was prepared by DNA recombination, and the enediyne-energized fusion protein (Arg)(9)-LDP-AE was prepared by molecular reconstitution. The data in fixed cells demonstrated that (Arg)(9)-LDP could rapidly enter cells, and the results based on fluorescence activated cell sorting indicated that the major route for (Arg)(9)-mediated cellular uptake of protein molecules was endocytosis. (Arg)(9)-LDP-AE demonstrated more potent cytotoxicity against different carcinoma cell lines than lidamycin in vitro. In the mouse hepatoma 22 model, (Arg)(9)-LDP-AE (0.3mg/kg) suppressed the tumor growth by 89.2%, whereas lidamycin (0.05 mg/kg) by 74.6%. Furthermore, in the glioma U87 xenograft model in nude mice, (Arg)(9)-LDP-AE at 0.2mg/kg suppressed tumor growth by 88.8%, compared with that of lidamycin by 62.9% at 0.05 mg/kg. No obvious toxic effects were observed in all groups during treatments. The results showed that energized fusion protein (Arg)(9)-LDP-AE was more effective than lidamycin and would be a promising candidate for glioma therapy. In addition, this approach to manufacturing fusion proteins might serve as a technology platform for the development of new cell penetrating peptides-based drugs. PMID:22982402

  7. Quercetin and quercetin 3-O-glycosides from Bauhinia longifolia (Bong.) Steud. show anti-Mayaro virus activity

    PubMed Central

    2014-01-01

    Background The arthropod-borne Mayaro virus (MAYV) causes ‘Mayaro fever’, a disease of medical significance, primarily affecting individuals in permanent contact with forested areas in tropical South America. Recently, MAYV has attracted attention due to its likely urbanization. Currently, there are no licensed drugs against most mosquito-transmitted viruses. Here, we investigated the in vitro anti-MAYV activity of the flavonoids quercetin and its derivatives from the Brazilian shrub Bauhinia longifolia (Bong.) Steud. Methods Flavonoids were purified by chromatographic fractionation from leaf extracts of B. longifolia and chemically identified as quercetin and quercetin glycosides using spectroscopic techniques. Cytotoxicity of purified flavonoids and of EtOAc- and n-BuOH-containing flavonoid mixtures was measured by the dye-uptake assay while their antiviral activity was evaluated by a virus yield inhibition assay. Results The following flavonoids were purified from B. longifolia leaves: non-glycosylated quercetin and its glycosides guaijaverin, quercitrin, isoquercitrin, and hyperin. EtOAc and n-BuOH fractions containing these flavonoids demonstrated the highest antiviral activity of all tested substances, while quercetin had the highest antiviral activity amongst purified flavonoids. Quercetin, EtOAc, or n-BuOH fractions inhibited MAYV production by more than 90% at 25 μg/mL, displaying a stronger antiviral effect than the licensed antiviral ribavirin. A mixture of the isomers isoquercitrin and hyperin had a modest antiviral effect (IC90 = 104.9), while guaijaverin and quercitrin did not show significant antiviral activity. Conclusions B. longifolia is a good source of flavonoids with anti-Mayaro virus activity. This is the first report of the activity of quercetin and its derivatives against an alphavirus. PMID:24678592

  8. Novel Peptides from Skins of Amphibians Showed Broad-Spectrum Antimicrobial Activities.

    PubMed

    Wang, Ying; Zhang, Yue; Lee, Wen-Hui; Yang, Xinwang; Zhang, Yun

    2016-03-01

    Peptide agents are often considered as potential biomaterials for developing new drugs that can overcome the rising resistance of pathogenic micro-organisms to classic antibiotic treatments. One key source of peptide agents is amphibian skin, as they provide a great deal of naturally occurring antimicrobial peptide (AMP) templates awaiting further exploitation and utilization. In this study, 12 novel AMPs from the skins of 3 ranid frogs, Rana limnocharis, R. exilispinosa, and Amolops afghanus, were identified using a 5' PCR primer. A total of 11 AMPs exhibited similarities with currently known AMP families, including brevinin-1, brevinin-2, esculentin-1, and nigrocin, besides, one AMP, named as Limnochariin, represented a novel AMP family. All 12 AMPs contain a C-terminus cyclic motif and most of them show obvious antimicrobial activities against 18 standard and clinically isolated strains of bacteria, including 4 Gram-positive bacteria, 11 Gram-negative bacteria, and 3 fungus. These findings provide helpful insight that will be useful in the design of anti-infective peptide agents. PMID:26452973

  9. Using analogy role-play activity in an undergraduate biology classroom to show central dogma revision.

    PubMed

    Takemura, Masaharu; Kurabayashi, Mario

    2014-01-01

    For the study of biology in an undergraduate classroom, a classroom exercise was developed: an analogy role-play to learn mechanisms of gene transcription and protein translation (central dogma). To develop the central dogma role-play exercise, we made DNA and mRNA using paper sheets, tRNA using a wire dress hanger, and amino acids using Lego® blocks (Lego System A/S, Denmark). Students were studying in the course of mathematics, physics, or chemistry, so biology was not among their usual studies. In this exercise, students perform the central dogma role-play and respectively act out nuclear matrix proteins, a transcription factor, an RNA polymerase II, an mRNA transport protein, nuclear pore proteins, a large ribosomal subunit, a small ribosomal subunit, and several amino-acyl tRNA synthetases. Questionnaire results obtained after the activity show that this central dogma role-play analogy holds student interest in the practical molecular biological processes of transcription and translation. PMID:24898113

  10. A randomized trial in a massive online open course shows people don't know what a statistically significant relationship looks like, but they can learn.

    PubMed

    Fisher, Aaron; Anderson, G Brooke; Peng, Roger; Leek, Jeff

    2014-01-01

    Scatterplots are the most common way for statisticians, scientists, and the public to visually detect relationships between measured variables. At the same time, and despite widely publicized controversy, P-values remain the most commonly used measure to statistically justify relationships identified between variables. Here we measure the ability to detect statistically significant relationships from scatterplots in a randomized trial of 2,039 students in a statistics massive open online course (MOOC). Each subject was shown a random set of scatterplots and asked to visually determine if the underlying relationships were statistically significant at the P < 0.05 level. Subjects correctly classified only 47.4% (95% CI [45.1%-49.7%]) of statistically significant relationships, and 74.6% (95% CI [72.5%-76.6%]) of non-significant relationships. Adding visual aids such as a best fit line or scatterplot smooth increased the probability a relationship was called significant, regardless of whether the relationship was actually significant. Classification of statistically significant relationships improved on repeat attempts of the survey, although classification of non-significant relationships did not. Our results suggest: (1) that evidence-based data analysis can be used to identify weaknesses in theoretical procedures in the hands of average users, (2) data analysts can be trained to improve detection of statistically significant results with practice, but (3) data analysts have incorrect intuition about what statistically significant relationships look like, particularly for small effects. We have built a web tool for people to compare scatterplots with their corresponding p-values which is available here: http://glimmer.rstudio.com/afisher/EDA/. PMID:25337457

  11. A randomized trial in a massive online open course shows people don’t know what a statistically significant relationship looks like, but they can learn

    PubMed Central

    Fisher, Aaron; Anderson, G. Brooke; Peng, Roger

    2014-01-01

    Scatterplots are the most common way for statisticians, scientists, and the public to visually detect relationships between measured variables. At the same time, and despite widely publicized controversy, P-values remain the most commonly used measure to statistically justify relationships identified between variables. Here we measure the ability to detect statistically significant relationships from scatterplots in a randomized trial of 2,039 students in a statistics massive open online course (MOOC). Each subject was shown a random set of scatterplots and asked to visually determine if the underlying relationships were statistically significant at the P < 0.05 level. Subjects correctly classified only 47.4% (95% CI [45.1%–49.7%]) of statistically significant relationships, and 74.6% (95% CI [72.5%–76.6%]) of non-significant relationships. Adding visual aids such as a best fit line or scatterplot smooth increased the probability a relationship was called significant, regardless of whether the relationship was actually significant. Classification of statistically significant relationships improved on repeat attempts of the survey, although classification of non-significant relationships did not. Our results suggest: (1) that evidence-based data analysis can be used to identify weaknesses in theoretical procedures in the hands of average users, (2) data analysts can be trained to improve detection of statistically significant results with practice, but (3) data analysts have incorrect intuition about what statistically significant relationships look like, particularly for small effects. We have built a web tool for people to compare scatterplots with their corresponding p-values which is available here: http://glimmer.rstudio.com/afisher/EDA/. PMID:25337457

  12. Syzyguim guineense Extracts Show Antioxidant Activities and Beneficial Activities on Oxidative Stress Induced by Ferric Chloride in the Liver Homogenate.

    PubMed

    Pieme, Constant Anatole; Ngoupayo, Joseph; Nkoulou, Claude Herve Khou-Kouz; Moukette, Bruno Moukette; Nono, Borgia Legrand Njinkio; Moor, Vicky Jocelyne Ama; Minkande, Jacqueline Ze; Ngogang, Jeanne Yonkeu

    2014-01-01

    The aim of this study was to determine the in vitro antioxidant activity, free radical scavenging property and the beneficial effects of extracts of various parts of Syzygium guineense in reducing oxidative stress damage in the liver. The effects of extracts on free radicals were determined on radicals DPPH, ABTS, NO and OH followed by the antioxidant properties using Ferric Reducing Antioxidant Power assay (FRAP) and hosphomolybdenum (PPMB). The phytochemical screening of these extracts was performed by determination of the phenolic content. The oxidative damage inhibition in the liver was determined by measuring malondialdehyde (MDA) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and peroxidase. Overall, the bark extract of the ethanol/water or methanol showed the highest radical scavenging activities against DPPH, ABTS and OH radicals compared to the other extracts. This extract also contained the highest phenolic content implying the potential contribution of phenolic compounds towards the antioxidant activities. However, the methanol extract of the root demonstrated the highest protective effects of SOD and CAT against ferric chloride while the hydro-ethanol extract of the leaves exhibited the highest inhibitory effects on lipid peroxidation. These findings suggest that antioxidant properties of S. guineense extracts could be attributed to phenolic compounds revealed by phytochemical studies. Thus, the present results indicate clearly that the extracts of S. guineense possess antioxidant properties and could serve as free radical inhibitors or scavengers, acting possibly as primary antioxidants. The antioxidant properties of the bark extract may thus sustain its various biological activities. PMID:26785075

  13. Syzyguim guineense Extracts Show Antioxidant Activities and Beneficial Activities on Oxidative Stress Induced by Ferric Chloride in the Liver Homogenate

    PubMed Central

    Pieme, Constant Anatole; Ngoupayo, Joseph; Khou-Kouz Nkoulou, Claude Herve; Moukette Moukette, Bruno; Njinkio Nono, Borgia Legrand; Ama Moor, Vicky Jocelyne; Ze Minkande, Jacqueline; Yonkeu Ngogang, Jeanne

    2014-01-01

    The aim of this study was to determine the in vitro antioxidant activity, free radical scavenging property and the beneficial effects of extracts of various parts of Syzygium guineense in reducing oxidative stress damage in the liver. The effects of extracts on free radicals were determined on radicals DPPH, ABTS, NO and OH followed by the antioxidant properties using Ferric Reducing Antioxidant Power assay (FRAP) and hosphomolybdenum (PPMB). The phytochemical screening of these extracts was performed by determination of the phenolic content. The oxidative damage inhibition in the liver was determined by measuring malondialdehyde (MDA) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and peroxidase. Overall, the bark extract of the ethanol/water or methanol showed the highest radical scavenging activities against DPPH, ABTS and OH radicals compared to the other extracts. This extract also contained the highest phenolic content implying the potential contribution of phenolic compounds towards the antioxidant activities. However, the methanol extract of the root demonstrated the highest protective effects of SOD and CAT against ferric chloride while the hydro-ethanol extract of the leaves exhibited the highest inhibitory effects on lipid peroxidation. These findings suggest that antioxidant properties of S. guineense extracts could be attributed to phenolic compounds revealed by phytochemical studies. Thus, the present results indicate clearly that the extracts of S. guineense possess antioxidant properties and could serve as free radical inhibitors or scavengers, acting possibly as primary antioxidants. The antioxidant properties of the bark extract may thus sustain its various biological activities. PMID:26785075

  14. The temporal structures and functional significance of scale-free brain activity

    PubMed Central

    He, Biyu J.; Zempel, John M.; Snyder, Abraham Z.; Raichle, Marcus E.

    2010-01-01

    SUMMARY Scale-free dynamics, with a power spectrum following P ∝ f-β, are an intrinsic feature of many complex processes in nature. In neural systems, scale-free activity is often neglected in electrophysiological research. Here, we investigate scale-free dynamics in human brain and show that it contains extensive nested frequencies, with the phase of lower frequencies modulating the amplitude of higher frequencies in an upward progression across the frequency spectrum. The functional significance of scale-free brain activity is indicated by task performance modulation and regional variation, with β being larger in default network and visual cortex and smaller in hippocampus and cerebellum. The precise patterns of nested frequencies in the brain differ from other scale-free dynamics in nature, such as earth seismic waves and stock market fluctuations, suggesting system-specific generative mechanisms. Our findings reveal robust temporal structures and behavioral significance of scale-free brain activity and should motivate future study on its physiological mechanisms and cognitive implications. PMID:20471349

  15. The temporal structures and functional significance of scale-free brain activity.

    PubMed

    He, Biyu J; Zempel, John M; Snyder, Abraham Z; Raichle, Marcus E

    2010-05-13

    Scale-free dynamics, with a power spectrum following P proportional to f(-beta), are an intrinsic feature of many complex processes in nature. In neural systems, scale-free activity is often neglected in electrophysiological research. Here, we investigate scale-free dynamics in human brain and show that it contains extensive nested frequencies, with the phase of lower frequencies modulating the amplitude of higher frequencies in an upward progression across the frequency spectrum. The functional significance of scale-free brain activity is indicated by task performance modulation and regional variation, with beta being larger in default network and visual cortex and smaller in hippocampus and cerebellum. The precise patterns of nested frequencies in the brain differ from other scale-free dynamics in nature, such as earth seismic waves and stock market fluctuations, suggesting system-specific generative mechanisms. Our findings reveal robust temporal structures and behavioral significance of scale-free brain activity and should motivate future study on its physiological mechanisms and cognitive implications. PMID:20471349

  16. Mice lacking brain-type creatine kinase activity show defective thermoregulation

    PubMed Central

    Streijger, Femke; Pluk, Helma; Oerlemans, Frank; Beckers, Gaby; Bianco, Antonio C.; Ribeiro, Miriam O.; Wieringa, Bé; Van der Zee, Catharina E.E.M.

    2010-01-01

    The cytosolic brain-type creatine kinase and mitochondrial ubiquitous creatine kinase (CK-B and UbCKmit) are expressed during the prepubescent and adult period of mammalian life. These creatine kinase (CK) isoforms are present in neural cell types throughout the central and peripheral nervous system and in smooth muscle containing tissues, where they have an important role in cellular energy homeostasis. Here, we report on the coupling of CK activity to body temperature rhythm and adaptive thermoregulation in mice. With both brain-type CK isoforms being absent, the body temperature reproducibly drops ~1.0°C below normal during every morning (inactive) period in the daily cycle. Facultative non-shivering thermogenesis is also impaired, since CK−−/−− mice develop severe hypothermia during 24 h cold exposure. A relationship with fat metabolism was suggested because comparison of CK−−/−− mice with wildtype controls revealed decreased weight gain associated with less white and brown fat accumulation and smaller brown adipocytes. Also, circulating levels of glucose, triglycerides and leptin are reduced. Extensive physiological testing and uncoupling protein1 analysis showed, however, that the thermogenic problems are not due to abnormal responsiveness of brown adipocytes, since noradrenaline infusion produced a normal increase of body temperature. Moreover, we demonstrate that the cyclic drop in morning temperature is also not related to altered rhythmicity with reduced locomotion, diminished food intake or increased torpor sensitivity. Although several integral functions appear altered when CK is absent in the brain, combined findings point into the direction of inefficient neuronal transmission as the dominant factor in the thermoregulatory defect. PMID:19419668

  17. Diversity of copper(I) complexes showing thermally activated delayed fluorescence: basic photophysical analysis.

    PubMed

    Czerwieniec, Rafał; Yersin, Hartmut

    2015-05-01

    A comparison of three copper(I) compounds [1, Cu(dppb)(pz2Bph2); 2, Cu(pop)(pz2Bph2); 3, Cu(dmp)(phanephos)(+)] that show pronounced thermally activated delayed fluorescence (TADF) at ambient temperature demonstrates a wide diversity of emission behavior. In this study, we focus on compound 1. A computational density functional theory (DFT)/time-dependent DFT approach allows us to predict detailed photophysical properties, while experimental emission studies over a wide temperature range down to T = 1.5 K lead to better insight into the electronic structures even with respect to spin-orbit coupling efficiencies, radiative rates, and zero-field splitting of the triplet state. All three compounds, with emission quantum yields higher than ϕPL = 70%, are potentially well suited as emitters for organic light-emitting diodes (OLEDs) based on the singlet-harvesting mechanism. Interestingly, compound 1 is by far the most attractive one because of a very small energy separation between the lowest excited singlet S1 and triplet T1 state of ΔE(S1-T1) = 370 cm(-1) (46 meV). Such a small value has not been reported so far. It is responsible for the very short decay time of τ(TADF, 300 K) = 3.3 μs. Hence, if focused on the requirements of a short TADF decay time for reduction of the saturation effects in OLEDs, copper(I) complexes are well comparable or even slightly better than the best purely organic TADF emitters. PMID:25894718

  18. Functional significance of complex fluctuations in brain activity: from resting state to cognitive neuroscience

    PubMed Central

    Papo, David

    2014-01-01

    Behavioral studies have shown that human cognition is characterized by properties such as temporal scale invariance, heavy-tailed non-Gaussian distributions, and long-range correlations at long time scales, suggesting models of how (non observable) components of cognition interact. On the other hand, results from functional neuroimaging studies show that complex scaling and intermittency may be generic spatio-temporal properties of the brain at rest. Somehow surprisingly, though, hardly ever have the neural correlates of cognition been studied at time scales comparable to those at which cognition shows scaling properties. Here, we analyze the meanings of scaling properties and the significance of their task-related modulations for cognitive neuroscience. It is proposed that cognitive processes can be framed in terms of complex generic properties of brain activity at rest and, ultimately, of functional equations, limiting distributions, symmetries, and possibly universality classes characterizing them. PMID:24966818

  19. Trends in space activities in 2014: The significance of the space activities of governments

    NASA Astrophysics Data System (ADS)

    Paikowsky, Deganit; Baram, Gil; Ben-Israel, Isaac

    2016-01-01

    This article addresses the principal events of 2014 in the field of space activities, and extrapolates from them the primary trends that can be identified in governmental space activities. In 2014, global space activities centered on two vectors. The first was geopolitical, and the second relates to the matrix between increasing commercial space activities and traditional governmental space activities. In light of these two vectors, the article outlines and analyzes trends of space exploration, human spaceflights, industry and technology, cooperation versus self-reliance, and space security and sustainability. It also reviews the space activities of the leading space-faring nations.

  20. Antisecretory and antimotility activity of Aconitum heterophyllum and its significance in treatment of diarrhea

    PubMed Central

    Prasad, Satyendra K.; Jain, Divya; Patel, Dinesh K.; Sahu, Alakh N.; Hemalatha, Siva

    2014-01-01

    Aim: The roots of the plant Aconitum heterophyllum (EAH) are traditionally used for curing hysteria, throat infection, dyspepsia, abdominal pain, diabetes, and diarrhea. Therefore, the present study was undertaken to determine the mechanism involved in the anti-diarrheal activity of roots of A. heterophyllum. Materials and Methods: Ant-diarrheal activity of ethanol extract at 50, 100, and 200 mg/kg p.o. was evaluated using fecal excretion and castor oil-induced diarrhea models, while optimized dose, that is, 100 mg/kg p.o. was further subjected to small intestinal transit, intestinal fluids accumulation, PGE2-induced enteropooling and gastric emptying test. To elucidate the probable mechanism, various biochemical parameters and Na+, K+ concentration in intestinal fluids were also determined. Further, antibacterial activity of extract along with its standardization using aconitine as a marker with the help of HPLC was carried out. Results: The results depicted a significant (P < 0.05) reduction in normal fecal output at 100 and 200 mg/kg p.o. of extract after 5th and 7th h of treatment. Castor oil-induced diarrhea model demonstrated a ceiling effect at 100 mg/kg p.o. with a protection of 60.185% from diarrhea. EAH at 100 mg/kg p.o. also showed significant activity in small intestinal transit, fluid accumulation, and PGE2-induced enteropooling models, which also restored the altered biochemical parameters and prevented Na+ and K+ loss. The extract with 0.0833% w/w of aconitine depicted a potential antibacterial activity of extract against microbes implicated in diarrhea. Conclusion: The study concluded antisecretory and antimotility effect of A. heterophyllum, which mediates through nitric oxide path way. PMID:24550590

  1. Systems of meaning and transference: Implicit significant-other activation evokes shared reality.

    PubMed

    Przybylinski, Elizabeth; Andersen, Susan M

    2015-10-01

    Evidence shows that representations of significant others (SOs) are used in interpersonal relations-for example, in the social-cognitive process of transference (see Andersen & Chen, 2002), a process that is assumed to serve meaning-making functions (Glassman & Andersen, 1999b). Five studies tested the more specific notion that implicit activation of an SO representation in transference should indirectly activate the worldview shared with the SO, leading to its active pursuit, validation, and protection. Shared worldviews were assessed beforehand, both idiographically, as values (Studies 1 and 4), and nomothetically, as political ideology or religious beliefs (Studies 2, 3, and 5). In each experiment, participants learned about new persons, one subtly resembling their own SO. Transference was assessed (memory bias; positive evaluation; see Andersen, Reznik, & Manzella, 1996) and, crucially, as predicted, when considering the new person resembling their SO (vs. the control persons), participants showed faster response latencies in a lexical decision task to words reflecting the worldview shared with the SO (vs. held only personally, Studies 1-3, or only by the SO, Study 3). With this person, they also anticipated a more meaningful interaction and actively socially tuned to the SO-shared worldview, selecting conversation topics reflecting the SO-shared worldview (vs. personally held or SO-held topics, Studies 1-3). Finally, threatening the SO-shared worldview with this person (vs. threatening personally held, SO-held, or irrelevant worldviews) prompted goal activation to restore the disrupted meaning (Studies 4 and 5), assessed by response latency in a lexical decision task. Transference thus evokes shared meaning systems and serves epistemic functions. PMID:26414844

  2. A Defined Terminal Region of the E. coli Chromosome Shows Late Segregation and High FtsK Activity

    PubMed Central

    Meile, Jean-Christophe; Stouf, Mathieu; Capiaux, Hervé; Mercier, Romain; Lesterlin, Christian; Hallet, Bernard; Cornet, François

    2011-01-01

    Background The FtsK DNA-translocase controls the last steps of chromosome segregation in E. coli. It translocates sister chromosomes using the KOPS DNA motifs to orient its activity, and controls the resolution of dimeric forms of sister chromosomes by XerCD-mediated recombination at the dif site and their decatenation by TopoIV. Methodology We have used XerCD/dif recombination as a genetic trap to probe the interaction of FtsK with loci located in different regions of the chromosome. This assay revealed that the activity of FtsK is restricted to a ∼400 kb terminal region of the chromosome around the natural position of the dif site. Preferential interaction with this region required the tethering of FtsK to the division septum via its N-terminal domain as well as its translocation activity. However, the KOPS-recognition activity of FtsK was not required. Displacement of replication termination outside the FtsK high activity region had no effect on FtsK activity and deletion of a part of this region was not compensated by its extension to neighbouring regions. By observing the fate of fluorescent-tagged loci of the ter region, we found that segregation of the FtsK high activity region is delayed compared to that of its adjacent regions. Significance Our results show that a restricted terminal region of the chromosome is specifically dedicated to the last steps of chromosome segregation and to their coupling with cell division by FtsK. PMID:21799784

  3. SYNTHESIS AND BIOLOGICAL ACTIVITY OF SULFUR COMPOUNDS SHOWING STRUCTURAL ANALOGY WITH COMBRETASTATIN A-4

    PubMed Central

    dos Santos, Edson dos A.; Prado, Paulo C.; de Carvalho, Wanderley R.; de Lima, Ricardo V.; Beatriz e, Adilson; de Lima, Dênis P.; Hamel, Ernest; Dyba, Marzena A.; Albuquerque, Sergio

    2013-01-01

    We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15). PMID:23766547

  4. A single domain of human prostatic acid phosphatase shows antibody-mediated restoration of catalytic activity.

    PubMed Central

    Choe, B K; Dong, M K; Walz, D; Gleason, S; Rose, N R

    1982-01-01

    By limited proteolysis with mouse submaxillaris protease, human prostatic acid phosphatase (EC 3.1.3.2) was cleaved into three fragments, Sp1, Sp2, and Sp3, which individually had no enzymatic activity. One of the fragments, Sp3, regained enzymatic activity after interaction with rabbit antibody to prostatic acid phosphatase. The Sp3 fragment was purified and characterized as to its molecular weight, amino acid composition, and carbohydrate content. The Sp3 fragment behaved like the parent molecule in L(+)-tartrate affinity and in trapping of a phosphoryl intermediate. The same Sp3 fragment also bears the most prominent antigenic determinants. This evidence suggest that Sp3 is the enzymatically active domain of prostatic acid phosphatase. Images PMID:6193513

  5. A transgenic apple callus showing reduced polyphenol oxidase activity and lower browning potential.

    PubMed

    Murata, M; Nishimura, M; Murai, N; Haruta, M; Homma, S; Itoh, Y

    2001-02-01

    Polyphenol oxidase (PPO) is responsible for enzymatic browning of apples. Apples lacking PPO activity might be useful not only for the food industry but also for studies of the metabolism of polyphenols and the function of PPO. Transgenic apple calli were prepared by using Agrobacterium tumefaciens carrying the kanamycin (KM) resistant gene and antisense PPO gene. Four KM-resistant callus lines were obtained from 356 leaf explants. Among these transgenic calli, three calli grew on the medium containing KM at the same rate as non-transgenic callus on the medium without KM. One callus line had an antisense PPO gene, in which the amount and activity of PPO were reduced to half the amount and activity in non-transgenic callus. The browning potential of this line, which was estimated by adding chlorogenic acid, was also half the browning potential of non-transgenic callus. PMID:11302173

  6. Isolation and analysis of polysaccharide showing high hyaluronidase inhibitory activity in Nostochopsis lobatus MAC0804NAN.

    PubMed

    Yamaguchi, Yuji; Koketsu, Mamoru

    2016-03-01

    An active substance with high hyaluronidase inhibitory effect was isolated from the edible cyanobacterium Nostochopsis lobatus MAC0804NAN strain and characterized. The active component in the hot water extract was purified by anion exchange and gel filtration chromatography and was found to be a polysaccharide. The IC(50) against hyaluronidase of the purified polysaccharide was 7.18 μg/ml whose inhibitory activity is 14.5 times stronger than that of disodium cromoglycate (DSCG), an anti-allergy medication. The carbohydrate composition which was analyzed by GC-MS and NMR was found to be composed mainly of glucose, glucuronic acid, fucose, 2-O-methylfucose, mannose, galactose and xylose. PMID:26296532

  7. Initiation of insulin aspart to Indian subjects on OADs show significant improvement in glycaemic outcomes: the A1chieve observational study.

    PubMed

    Rao, P V; Bhattacharyya, A; Sahay, R K

    2013-01-01

    The prevalence of diabetes is increasing worldwide and India stands second next only to china. The management of diabetes in real life settings needs to be evaluated for deriving better management practices. A1chieve observational study evaluated the use of modern insulin in real life settings. This was a 24-week, international, prospective, multicenter, non-interventional, observational study of people with type 2 diabetes. India recruited with 20,554 subjects and a total of 1815 patients were enrolled to receive insulin aspart as bolus insulin therapy of whom 1450 (79.9%) were insulin naïve and 365 (20.1%) were insulin users. At the end of 24 weeks, only one SAE was reported in this study and overall hypoglycemia events per patient year decreased from 2.49 (348 episodes) to 0.17 (20 episodes). There were no major hypoglycemic episodes reported in either insulin naive or insulin treated subjects. There was a significant improvement in the HbA(1c) values from the baseline in both insulin naive and insulin users. The mean HbA(1c) value was reduced from 9.5 to 7.4 (p < 0.001) for insulin naïve subjects and from 9.2 to 7.7 (p < 0.001) in insulin experienced subjects. Fasting plasma glucose values decreased by 70 mg/dL and 50 mg/dL in insulin naive and insulin experienced, respectively and the difference from baseline was statistically significant (P < 0.001). The post prandial glucose value was also significantly (p < 0.001) reduced by 105 mg/dL for insulin naïve subjects and 55 mg/dL for insulin experienced subjects. The composite end point was achieved by 46.6% of insulin naive and 38.1% of insulin-experienced subjects. The study concluded with good HbA(1c) reduction along with lower incidence of hypoglycemia and better health related quality of life outcomes in both in insulin naive and insulin experienced subjects who used insulin aspart as bolus insulin treatment. PMID:24482983

  8. Systematic Review Shows Only Few Reliable Studies of Physical Activity Intervention in Adolescents

    PubMed Central

    Soares, Nara Michelle Moura; Leão, Arley Santos; Santos, Josivan Rosa; Monteiro, Glauber Rocha; dos Santos, Jorge Rollemberg; Thomazzi, Sara Maria; Silva, Roberto Jerônimo dos Santos

    2014-01-01

    Introduction. Several studies have pointed to the high prevalence of low levels of physical activity in adolescents, suggesting the need for more effective interventions for this group. The aim of this study was to present evidence of intervention programs for efficacy of physical activity for adolescents. Methods. Surveys in PubMed, SportDiscus, LiLacs, and SciELO databases were conducted using keywords to identify population, intervention, and outcome, as well as DeCS and MeSH terms in English, Portuguese, and Spanish, whenever appropriate. The review included observational studies with minimal intervention of six months, minimum sample size of 100 adolescents, written in any language, and those who have reached STROBE score greater than 70%. Results. Only seven studies met all inclusion criteria. Of these, five were pre- and postintervention and two had n > 2000 participants. Interventions were of several types, durations, and strategies for physical activity implementation. Behavior change was assessed in 43% of studies and three reported success in some way. Conclusion. Due to heterogeneity in their contents and methodologies, as well as the lack of jobs that accompany adolescents after the intervention period, one cannot draw conclusions about the actual effects of the intervention programs of physical activity on the behavior of young people. PMID:25152903

  9. Water Works: A Great Show on Earth. Classroom Activities for Third and Fourth Grades.

    ERIC Educational Resources Information Center

    McClure, Judy; Clark, Neil

    This curriculum guide is divided into five lessons, each containing several activities that reflect the natural path of inquiry that third or fourth grade students might take in considering the water that arrives in their bathroom sinks each morning. Starting from the familiar faucet, the students are encouraged to reflect on their own habits and…

  10. Eighteen-Month-Old Infants Show False Belief Understanding in an Active Helping Paradigm

    ERIC Educational Resources Information Center

    Buttelmann, David; Carpenter, Malinda; Tomasello, Michael

    2009-01-01

    Recently, several studies have claimed that soon after their first birthday infants understand others' false beliefs. However, some have questioned these findings based on criticisms of the looking-time paradigms used. Here we report a new paradigm to test false belief understanding in infants using a more active behavioral response: helping.…

  11. Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells

    PubMed Central

    Tjon, A S W; Tha-In, T; Metselaar, H J; van Gent, R; van der Laan, L J W; Groothuismink, Z M A; te Boekhorst, P A W; van Hagen, P M; Kwekkeboom, J

    2013-01-01

    Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n = 12) or high-dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4+CD25+forkhead box protein 3 (FoxP3+) Tregs and of conventional CD4+FoxP3− T-helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating Tregs, as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high-dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders. PMID:23607448

  12. Left-handers show no self-advantage in detecting a delay in visual feedback concerning an active movement.

    PubMed

    Hoover, Adria E N; Elzein, Yasmeenah; Harris, Laurence R

    2016-07-01

    Right-handed people show an advantage in detecting a delay in visual feedback concerning an active movement of their right hand when it is viewed in a natural perspective compared to when it is seen as if viewing another person's hand (Hoover and Harris in Exp Brain Res 233:1053-1060, 2012. doi: 10.1007/s00221-014-4181-9 ; Exp Brain Res 222:389-397, 2015a. doi: 10.1007/s00221-012-3224-3 ). This self-advantage is unique to their dominant hand and may reflect an enhanced sense of ownership which contributes to how right-handed people relate to the world. Here we asked whether left-handers show the same pattern of performance for their dominant hand. We measured the minimum delay that could be detected by 29 left-handers when viewing either their dominant or non-dominant hand from 'self' or 'other' perspectives and compared their thresholds to an age-matched sample of 22 right-handers. Right-handers showed a significant signature self-advantage of 19 ms when viewing their dominant hand in an expected 'self' perspective compared to 'other' perspectives. Left-handers, however, showed no such advantage for either their dominant or non-dominant hand. This lack of self-advantage in detecting delayed visual feedback might indicate a less secure sense of body ownership amongst left-handers. PMID:26914478

  13. Declassified American Government Documents Show a Broad and In-Depth Interest in Soviet Space Activities

    NASA Astrophysics Data System (ADS)

    Pesavento, P.

    Back in 1993, when this author was able to acquire one of the first US National Intelligence Estimate (NIE) documents declassified on the Soviet Space Program [1], there was a dearth of materials concerning the USSR's space activities from a US intelligence perspective. Now, a decade on, the situation has dramatically changed. As a plethora of US government agencies labor to disgorge their materials from the era of the Cold War, space historians and observers now have access to many new documents, which shed both exciting and new light on Soviet space activities, and how the US viewed as well as interpreted them. Coupled with the fact that many of these are now available to be read via the Internet, and with most of the documents available only recently, a new era in space history research is now in hand. This article is intended to provide a broad overview of what is now available, and mention some highlights.

  14. Arginine kinase shows nucleoside diphosphate kinase-like activity toward deoxythymidine diphosphate.

    PubMed

    Lopez-Zavala, Alonso A; Sotelo-Mundo, Rogerio R; Hernandez-Flores, Jose M; Lugo-Sanchez, Maria E; Sugich-Miranda, Rocio; Garcia-Orozco, Karina D

    2016-06-01

    Arginine kinase (AK) (ATP: L-arginine phosphotransferase, E.C. 2.7.3.3) catalyzes the reversible transfer of ATP γ-phosphate group to L-arginine to synthetize phospho-arginine as a high-energy storage. Previous studies suggest additional roles for AK in cellular processes. Since AK is found only in invertebrates and it is homologous to creatine kinase from vertebrates, the objective of this work was to demonstrate nucleoside diphosphate kinase-like activity for shrimp AK. For this, AK from marine shrimp Litopenaeus vannamei (LvAK) was purified and its activity was assayed for phosphorylation of TDP using ATP as phosphate donor. Moreover, by using high-pressure liquid chromatography (HPLC) the phosphate transfer reaction was followed. Also, LvAK tryptophan fluorescence emission changes were detected by dTDP titration, suggesting that the hydrophobic environment of Trp 221, which is located in the top of the active site, is perturbed upon dTDP binding. The kinetic constants for both substrates Arg and dTDP were calculated by isothermal titration calorimetry (ITC). Besides, docking calculations suggested that dTDP could bind LvAK in the same cavity where ATP bind, and LvAK basic residues (Arg124, 126 and 309) stabilize the dTDP phosphate groups and the pyrimidine base interact with His284 and Ser122. These results suggest that LvAK bind and phosphorylate dTDP being ATP the phosphate donor, thus describing a novel alternate nucleoside diphosphate kinase-like activity for this enzyme. PMID:27072556

  15. Continuous infusion interleukin-2 and antihistamines in melanoma: a retrospective review showing activity of this combination.

    PubMed

    Evangelista-Dean, Maria; Khan, Nawazish; Quan, Walter

    2004-12-01

    A recent randomized trial suggests that there may be an advantage in terms of survival with the combination of histamine and subcutaneous interleukin-2 (IL-2), compared to IL-2 alone. It has been postulated, then, that antihistamines may actually be antagonistic to IL-2 and, therefore, interfere with its antitumor activity. Because antihistamines such as cimetidine and ranitidine are commonly used as prophylaxis against gastrointestinal toxicity commonly seen with IL-2, and, because antihistamines may increase natural killer cell activity, it is reasonable to examine the response rate for this combination. An OVID Medline literature search between 1985 and 2003 was done. Continuous infusion (CIV) interleukin- 2 was used as the reference therapy because of the relatively constant IL-2 levels generated by this approach. Included studies were those in which either cimetidine, ranitidine, or famotidine were regularly scheduled and administered concurrently with IL-2, typically for gastrointestinal ulcer prophylaxis. Six (6) studies were identified. A total of 21 patients responded to therapy. Total response rate was 11%, with a 95% Confidence Interval: 7-17%. Four (4) complete responses were noted. Complete response rate was 2%, with a 95% Confidence Interval: 1-6%. These response rates are consistent with previously noted IL-2 response rates. In this retrospective review of CIV IL-2 and antihistamines, this combination appears to be active in melanoma. There appears to be no deleterious effect of routine antihistamine on the CIV IL-2 response rate. PMID:15665623

  16. A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses

    PubMed Central

    Sharafeldin, Tamer A.; Mor, Sunil K.; Sobhy, Nader M.; Xing, Zheng; Reed, Kent M.; Goyal, Sagar M.; Porter, Robert E.

    2015-01-01

    Newly emergent turkey arthritis reoviruses (TARV) were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O’Neil strain). Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi). Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1–2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ) at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV. PMID:26659460

  17. Fine Resolution Analysis of Lake Malawi Sediment Record Shows No Significant Climatic Impacts from the Mount Toba Super-Eruption of ~75ky

    NASA Astrophysics Data System (ADS)

    Jackson, L. J.; Stone, J.; Cohen, A. S.

    2014-12-01

    Debate over long, and short-term climatic impacts of the Mt. Toba super-eruption circa 75ky is often focused on East Africa. A severe drop in anatomically modern human populations has been hypothesized to be synchronous with a volcanic winter caused by the Toba super-eruption. If the Toba eruption caused a volcanic winter in East Africa, climatologically-sensitive ecosystems, such as Lake Malawi and its immediate watershed should show a direct and observable response in the sediment record. Cooler temperatures would cause a reduction of density contrast between epilimnion and hypolimnion waters, allowing for increased mixing and oxygenation of normally anoxic bottom waters. Enhanced mixing would cause noticeable changes in lake fly and algal communities. Cooler temperatures might also affect precipitation and the fire regime in the surrounding watershed. We analyzed two Lake Malawi cores at the finest practical resolution. Core 2A-10H-2 was analyzed in less than 6-year intervals and core 1C-8H-1 in 7-year intervals surrounding the Youngest Toba Tephra (YTT) for microfaunal abundance and variability, sediment composition, and evidence of changes in the occurrence of fires or watershed precipitation. Our analysis included point counts of diatoms and other algae, lake flies, charcoal, and siliciclastics. Changes in microfossil assemblage, variability, and abundance, as well as sediment composition around the YTT in Core 2A and 1C do not indicate that increased mixing or cooler temperatures occurred in either the central or northern basins of Lake Malawi. Similarly, charcoal counts do not suggest a change in fire regime. Our results indicate that at a subdecadal scale there was no substantial response in Lake Malawi or its immediate watershed to the Mt. Toba super-eruption, in contrast to predictions from the volcanic winter hypothesis.

  18. Bacillus cereus strain S2 shows high nematicidal activity against Meloidogyne incognita by producing sphingosine

    PubMed Central

    Gao, Huijuan; Qi, Gaofu; Yin, Rong; Zhang, Hongchun; Li, Chenggang; Zhao, Xiuyun

    2016-01-01

    Plant-parasitic nematodes cause serious crop losses worldwidely. This study intended to discover the antagonistic mechanism of Bacillus cereus strain S2 against Meloidogyne incognita. Treatment with B. cereus strain S2 resulted in a mortality of 77.89% to Caenorhabditis elegans (a model organism) and 90.96% to M. incognita. In pot experiment, control efficiency of B. cereus S2 culture or supernatants were 81.36% and 67.42% towards M. incognita, respectively. In field experiment, control efficiency was 58.97% towards M. incognita. Nematicidal substances were isolated from culture supernatant of B. cereus S2 by polarity gradient extraction, silica gel column chromatography and HPLC. Two nematicidal compounds were identified as C16 sphingosine and phytosphingosine by LC-MS. The median lethal concentration of sphingosine was determined as 0.64 μg/ml. Sphingosine could obviously inhibit reproduction of C. elegans, with an inhibition rate of 42.72% for 24 h. After treatment with sphingosine, ROS was induced in intestinal tract, and genital area disappeared in nematode. Furthermore, B. cereus S2 could induce systemic resistance in tomato, and enhance activity of defense-related enzymes for biocontrol of M. incognita. This study demonstrates the nematicidal activity of B. cereus and its product sphingosine, as well provides a possibility for biocontrol of M. incognita. PMID:27338781

  19. X-ray microtomography shows pore structure and tortuosity in alkali-activated binders

    SciTech Connect

    Provis, John L.; Myers, Rupert J.; White, Claire E.; Rose, Volker; Deventer, Jannie S.J. van

    2012-06-15

    Durability of alkali-activated binders is of vital importance in their commercial application, and depends strongly on microstructure and pore network characteristics. X-ray microtomography ({mu}CT) offers, for the first time, direct insight into microstructural and pore structure characteristics in three dimensions. Here, {mu}CT is performed on a set of sodium metasilicate-activated fly ash/slag blends, using a synchrotron beamline instrument. Segmentation of the samples into pore and solid regions is then conducted, and pore tortuosity is calculated by a random walker method. Segmented porosity and diffusion tortuosity are correlated, and vary as a function of slag content (slag addition reduces porosity and increases tortuosity), and sample age (extended curing gives lower porosity and higher tortuosity). This is particularly notable for samples with {>=} 50% slag content, where a space-filling calcium (alumino)silicate hydrate gel provides porosity reductions which are not observed for the sodium aluminosilicate ('geopolymer') gels which do not chemically bind water of hydration.

  20. Bacillus cereus strain S2 shows high nematicidal activity against Meloidogyne incognita by producing sphingosine.

    PubMed

    Gao, Huijuan; Qi, Gaofu; Yin, Rong; Zhang, Hongchun; Li, Chenggang; Zhao, Xiuyun

    2016-01-01

    Plant-parasitic nematodes cause serious crop losses worldwidely. This study intended to discover the antagonistic mechanism of Bacillus cereus strain S2 against Meloidogyne incognita. Treatment with B. cereus strain S2 resulted in a mortality of 77.89% to Caenorhabditis elegans (a model organism) and 90.96% to M. incognita. In pot experiment, control efficiency of B. cereus S2 culture or supernatants were 81.36% and 67.42% towards M. incognita, respectively. In field experiment, control efficiency was 58.97% towards M. incognita. Nematicidal substances were isolated from culture supernatant of B. cereus S2 by polarity gradient extraction, silica gel column chromatography and HPLC. Two nematicidal compounds were identified as C16 sphingosine and phytosphingosine by LC-MS. The median lethal concentration of sphingosine was determined as 0.64 μg/ml. Sphingosine could obviously inhibit reproduction of C. elegans, with an inhibition rate of 42.72% for 24 h. After treatment with sphingosine, ROS was induced in intestinal tract, and genital area disappeared in nematode. Furthermore, B. cereus S2 could induce systemic resistance in tomato, and enhance activity of defense-related enzymes for biocontrol of M. incognita. This study demonstrates the nematicidal activity of B. cereus and its product sphingosine, as well provides a possibility for biocontrol of M. incognita. PMID:27338781

  1. A Note on Derivatives of Isoniazid, Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis.

    PubMed

    Nusrath Unissa, Ameeruddin; Hanna, Luke Elizabeth; Swaminathan, Soumya

    2016-04-01

    Drug-resistant tuberculosis (DR-TB) is a serious problem that impedes the success of the TB control program. Of note, multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB have certainly complicated the scenario. One of the possible strategies to overcome drug resistance in an economic and simple manner would involve modification of existing anti-TB drugs to obtain derivatives that can work on resistant TB bacilli. These may have improved half-life and increased bioavailability, be more efficacious, and serve as cost-effective alternatives, as compared to new drugs identified through conventional methods of drug discovery and development. Although extensive literature is available on the activity of various derivatives of first-line drugs (isoniazid, rifampicin and pyrazinamide) on drug-susceptible Mycobacterium tuberculosis (MTB), reports on the activity of derivatives on resistant MTB are very limited, to our knowledge. In light of this, the present review aims to provide a concise report on the derivatives of first-line drugs that have the potential to overcome the resistance to the parental drug and could thus serve as effective alternatives. PMID:26613382

  2. Primary nasal epithelium exposed to house dust mite extract shows activated expression in allergic individuals.

    PubMed

    Vroling, Aram B; Jonker, Martijs J; Luiten, Silvia; Breit, Timo M; Fokkens, Wytske J; van Drunen, Cornelis M

    2008-03-01

    Nasal epithelial cells form the outermost protective layer against environmental factors. However, this defense is not just physical; it has been shown that epithelial cells respond by the production of inflammatory mediators that may affect local immune responses. In this research we set out to characterize potential differences between the responses of nasal epithelium from healthy and allergic individuals to house dust mite (HDM) allergen. These differences will help us to define local mechanisms that could contribute to allergic disease expression. Epithelial cells were cultured from nasal biopsies taken from five healthy and five allergic individuals. These cultures were exposed for 24 hours to culture medium containing HDM allergen, or to culture medium alone. Isolated RNA was used for microarray analysis. Gene-ontology of the response in healthy epithelium revealed mainly up-regulation of chemokines, growth factors, and structural proteins. Moreover, we saw increased expression of two transcription factors (NF-kappaB and AP-1) and their regulatory members. The expression pattern of epithelium from allergic individuals in the absence of the HDM stimulus suggests that it is already in an activated state. Most striking is that, while the already activated NF-kappaB regulatory pathway remained unchanged in allergic epithelium, the AP-1 pathway is down-regulated upon exposure to HDM allergen; this is contrary to what we see in healthy epithelium. Clear differences in the expression pattern exist between epithelial cells isolated from healthy and allergic individuals at baseline and between their responses to allergen exposure; these differences may contribute to the inflammatory response. PMID:17901406

  3. Arsenic trioxide and resveratrol show synergistic anti-leukemia activity and neutralized cardiotoxicity.

    PubMed

    Fan, Yuhua; Chen, Meng; Meng, Jia; Yu, Lei; Tu, Yingfeng; Wan, Lin; Fang, Kun; Zhu, Wenliang

    2014-01-01

    Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac-friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 µM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co-administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 µM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity. PMID:25144547

  4. Jejuna of patients with insulin-dependent diabetes mellitus (IDDM) show signs of immune activation

    PubMed Central

    SAVILAHTI, E; ÖRMÄLÄ, T; SAUKKONEN, T; SANDINI-POHJAVUORI, U; KANTELE, J M; ARATO, A; ILONEN, J; ÅKERBLOM, H K

    1999-01-01

    The roles of enteric viruses and food antigens as possible triggers in human insulin-dependent diabetes mellitus and the evidence that mucosal-associated homing receptors are important in both human and experimental diabetes prompted us to undertake an immunohistochemical study of intestinal specimens from patients with IDDM. We studied jejunal morphology and immunohistochemistry in 26 patients with IDDM, 13 of whom had the HLA-DQB1*0201 gene and therefore a higher risk of coeliac disease. The findings were compared with those in specimens from age-matched controls. Villous structure and the density of the intraepithelial lymphocytes were normal in every biopsy specimen. The extent of positivity with anti-DR and -DP antibodies in the villous epithelium was significantly greater in the specimens from patients than in those from controls (P = 0.0002 in both comparisons). The crypts were also more positive: for DR P = 0.0001, and for DP P = 0.002. The densities of T cells, CD4+, CD8+, and T cell receptor α/β+ and γ/δ+ cells in the epithelium and lamina propria were similar in patients and controls, but the patients had significantly more α4/β7 integrin+ cells in the lamina propria (P = 0.006). No difference was seen between HLA-DQB1*0201-positive and -negative patients. These findings reflect a stage of inflammation in the structurally normal intestines of patients with IDDM and suggest secretion of inflammatory Th1-type cytokines in the intestine. PMID:10209507

  5. Montmorillonite enhanced ciprofloxacin transport in saturated porous media with sorbed ciprofloxacin showing antibiotic activity

    NASA Astrophysics Data System (ADS)

    Chen, Hao; Gao, Bin; Yang, Liu-Yan; Ma, Lena Q.

    2015-02-01

    Antibiotic ciprofloxacin (CIP) is immobile in the subsurface but it has been frequently detected in the aquatic system. Therefore it is important to investigate the factors impacting CIP's mobilization in aquifer. Laboratory columns packed with sand were used to test colloid-facilitated CIP transport by 1) using kaolinite or montmorillonite to mobilize presorbed-CIP in a column or 2) co-transporting with CIP by pre-mixing them before transport. The Langmuir model showed that CIP sorption by montmorillonite (23 g kg- 1) was 100 times more effective than sand or kaolinite. Even with strong CIP complexation ability to Fe/Al coating on sand surface, montmorillonite promoted CIP transport, but not kaolinite. All presorbed-CIP by sand was mobilized by montmorillonite after 3 pore volumes through co-transporting of CIP with montmorillonite. The majority of CIP was fixed onto the montmorillonite interlayer but still showed inhibition of bacteria growth. Our results suggested that montmorillonite with high CIP sorption ability can act as a carrier to enhance CIP's mobility in aquifer.

  6. Indonesian fire activity and smoke pollution in 2015 show persistent nonlinear sensitivity to El Niño-induced drought.

    PubMed

    Field, Robert D; van der Werf, Guido R; Fanin, Thierry; Fetzer, Eric J; Fuller, Ryan; Jethva, Hiren; Levy, Robert; Livesey, Nathaniel J; Luo, Ming; Torres, Omar; Worden, Helen M

    2016-08-16

    The 2015 fire season and related smoke pollution in Indonesia was more severe than the major 2006 episode, making it the most severe season observed by the NASA Earth Observing System satellites that go back to the early 2000s, namely active fire detections from the Terra and Aqua Moderate Resolution Imaging Spectroradiometers (MODIS), MODIS aerosol optical depth, Terra Measurement of Pollution in the Troposphere (MOPITT) carbon monoxide (CO), Aqua Atmospheric Infrared Sounder (AIRS) CO, Aura Ozone Monitoring Instrument (OMI) aerosol index, and Aura Microwave Limb Sounder (MLS) CO. The MLS CO in the upper troposphere showed a plume of pollution stretching from East Africa to the western Pacific Ocean that persisted for 2 mo. Longer-term records of airport visibility in Sumatra and Kalimantan show that 2015 ranked after 1997 and alongside 1991 and 1994 as among the worst episodes on record. Analysis of yearly dry season rainfall from the Tropical Rainfall Measurement Mission (TRMM) and rain gauges shows that, due to the continued use of fire to clear and prepare land on degraded peat, the Indonesian fire environment continues to have nonlinear sensitivity to dry conditions during prolonged periods with less than 4 mm/d of precipitation, and this sensitivity appears to have increased over Kalimantan. Without significant reforms in land use and the adoption of early warning triggers tied to precipitation forecasts, these intense fire episodes will reoccur during future droughts, usually associated with El Niño events. PMID:27482096

  7. Nutritional significance of a rice bran concentrate with trypsin inhibitor activity.

    PubMed

    Maki, Z; Tashiro, M

    1983-06-01

    A rice bran protein concentrate (RBPC) was prepared from de-fatted rice bran by extraction with a 1% sodium chloride solution and by acetone-precipitation. This protein concentrate contained 45% protein, which was as good as casein in terms of protein quality being judged from the results of amino acid analysis. On the other hand, RBPC possessed the trypsin inhibitor activity corresponding to the complete inhibition of about 6 mg of bovine trypsin per 1 g of dry material. The activity was, however, completely destroyed by autoclaving RBPC for 30 min at 121 degrees C. In vitro digestion tests showed that RBPC was easily digested by pepsin but was resistant to the attack by trypsin, compared with autoclaved RBPC. Concerning in vivo digestion, however, there was no significant difference in apparent nitrogen digestibility between RBPC and the heated RBPC. In growth experiments with weanling rats fed a 10% level of protein diet, growth depression and the tendency of slight pancreatic hypertrophy were observed in rats receiving a RBPC diet. It is presumed that one of the reasons which explains these phenomena is the presence of trypsin inhibitor in RBPC. PMID:6619992

  8. Comparison of the activities of the lantibiotics nisin and lacticin 3147 against clinically significant mycobacteria.

    PubMed

    Carroll, James; Draper, Lorraine A; O'Connor, Paula M; Coffey, Aidan; Hill, Colin; Ross, R Paul; Cotter, Paul D; O'Mahony, Jim

    2010-08-01

    The aim of this study was to use the microtitre alamarBlue assay to investigate and compare the antimycobacterial potential of the lantibiotics nisin and lacticin 3147 against a representative cohort of clinically significant mycobacteria, i.e. Mycobacterium tuberculosis H37Ra, Mycobacterium avium subsp. paratuberculosis (MAP) ATCC 19698 and Mycobacterium kansasii CIT11/06. Lacticin 3147 displayed potent activity against all strains of mycobacteria, with MIC(90) values (lowest concentration of lantibiotic that prevented growth of >90% of the bacterial population) of 60 mg/L and 15 mg/L for M. kansasii and MAP, respectively. Lacticin 3147 was particularly effective against M. tuberculosis H37Ra, with a MIC(90) value of 7.5mg/L. Nisin, although inhibitory, was generally less potent against all strains of mycobacteria, with MIC(90) values of 60 mg/L for M. kansasii and >60 mg/L for MAP and M. tuberculosis H37Ra. Thus, lacticin 3147 is a potent antimycobacterial peptide that shows superior activity compared with nisin at physiological pH. PMID:20547041

  9. Downscaling CMIP5 climate models shows increased tropical cyclone activity over the 21st century

    PubMed Central

    Emanuel, Kerry A.

    2013-01-01

    A recently developed technique for simulating large [O(104)] numbers of tropical cyclones in climate states described by global gridded data is applied to simulations of historical and future climate states simulated by six Coupled Model Intercomparison Project 5 (CMIP5) global climate models. Tropical cyclones downscaled from the climate of the period 1950–2005 are compared with those of the 21st century in simulations that stipulate that the radiative forcing from greenhouse gases increases by over preindustrial values. In contrast to storms that appear explicitly in most global models, the frequency of downscaled tropical cyclones increases during the 21st century in most locations. The intensity of such storms, as measured by their maximum wind speeds, also increases, in agreement with previous results. Increases in tropical cyclone activity are most prominent in the western North Pacific, but are evident in other regions except for the southwestern Pacific. The increased frequency of events is consistent with increases in a genesis potential index based on monthly mean global model output. These results are compared and contrasted with other inferences concerning the effect of global warming on tropical cyclones. PMID:23836646

  10. Downscaling CMIP5 climate models shows increased tropical cyclone activity over the 21st century.

    PubMed

    Emanuel, Kerry A

    2013-07-23

    A recently developed technique for simulating large [O(10(4))] numbers of tropical cyclones in climate states described by global gridded data is applied to simulations of historical and future climate states simulated by six Coupled Model Intercomparison Project 5 (CMIP5) global climate models. Tropical cyclones downscaled from the climate of the period 1950-2005 are compared with those of the 21st century in simulations that stipulate that the radiative forcing from greenhouse gases increases by over preindustrial values. In contrast to storms that appear explicitly in most global models, the frequency of downscaled tropical cyclones increases during the 21st century in most locations. The intensity of such storms, as measured by their maximum wind speeds, also increases, in agreement with previous results. Increases in tropical cyclone activity are most prominent in the western North Pacific, but are evident in other regions except for the southwestern Pacific. The increased frequency of events is consistent with increases in a genesis potential index based on monthly mean global model output. These results are compared and contrasted with other inferences concerning the effect of global warming on tropical cyclones. PMID:23836646

  11. B chromosomes showing active ribosomal RNA genes contribute insignificant amounts of rRNA in the grasshopper Eyprepocnemis plorans.

    PubMed

    Ruiz-Estévez, Mercedes; Badisco, Liesbeth; Broeck, Jozef Vanden; Perfectti, Francisco; López-León, María Dolores; Cabrero, Josefa; Camacho, Juan Pedro M

    2014-12-01

    The genetic inertness of supernumerary (B) chromosomes has recently been called into question after finding several cases of gene activity on them. The grasshopper Eyprepocnemis plorans harbors B chromosomes containing large amounts of ribosomal DNA (rDNA) units, some of which are eventually active, but the amount of rRNA transcripts contributed by B chromosomes, compared to those of the standard (A) chromosomes, is unknown. Here, we address this question by means of quantitative PCR (qPCR) for two different ITS2 amplicons, one coming from rDNA units located in both A and B chromosomes (ITS2(A+B)) and the other being specific to B chromosomes (ITS2(B)). We analyzed six body parts in nine males showing rDNA expression in their B chromosomes in the testis. Amplification of the ITS2(B) amplicon was successful in RNA extracted from all six body parts analyzed, but showed relative quantification (RQ) values four orders of magnitude lower than those obtained for the ITS(A+B) amplicon. RQ values differed significantly between body parts for the two amplicons, with testis, accessory gland and wing muscle showing threefold higher values than head, gastric cecum and hind leg. We conclude that the level of B-specific rDNA expression is extremely low even in individuals where B chromosome rDNA is not completely silenced. Bearing in mind that B chromosomes carry the largest rDNA cluster in the E. plorans genome, we also infer that the relative contribution of B chromosome rRNA genes to ribosome biogenesis is insignificant, at least in the body parts analyzed. PMID:24997085

  12. Totally synthetic peptide-based immunocontraceptive vaccines show activity in dogs of different breeds.

    PubMed

    Walker, John; Ghosh, Souravi; Pagnon, Joanne; Colantoni, Caterina; Newbold, Andrea; Zeng, Weiguang; Jackson, David C

    2007-10-10

    In this study we examine the immunogenicity of totally synthetic peptide-based immunocontraceptive vaccines in dogs. Seven individual epitope-based vaccines were assembled in which a different T helper (T(H)) cell epitope derived from the sequence of F protein of canine distemper virus was synthesized in tandem with a peptide representing luteinising hormone releasing hormone (LHRH). Each of the individual T(H)-LHRH peptide vaccines was inoculated subcutaneously into dogs. The results demonstrate that five of the seven peptide vaccines were able to elicit strong anti-LHRH antibody responses in beagle foxhounds accompanied by a concomitant suppression in the levels of the hormones testosterone and progesterone in the majority of the animals. A pool of these five peptides was then used to inoculate five different breeds of dogs. All animals responded with high levels of anti-LHRH antibody. An investigation of the proliferative responses of peripheral blood mononuclear cells (PBMC) obtained from inoculated dogs showed that the majority of breeds responded to each of the individual T helper cell epitope tested. The results provide a strategy for development of an immunocontraceptive vaccine for use in multiple breeds of dogs. PMID:17825958

  13. Appalachian Population and Income Show Significant Gains

    ERIC Educational Resources Information Center

    Pickard, Jerome

    1978-01-01

    Presenting statistical data, this article indicates that the population of Appalachia has grown nearly as fast as that of the nation between 1970 and 1976, while Appalachian per capita money income has continued to approach that of the national level. (JC)

  14. Novel triterpenoid saponins from residual seed cake of Camellia oleifera Abel. show anti-proliferative activity against tumor cells.

    PubMed

    Zong, Jianfa; Wang, Ruilong; Bao, Guanhu; Ling, Tiejun; Zhang, Liang; Zhang, Xinfu; Hou, Ruyan

    2015-07-01

    Four oleanane-type triterpenoid saponins were isolated from the seed cake of Camellia oleifera Abel.: camelliasaponin B1 and three new saponins, oleiferasaponin C1-C3 (1-3). Their structures were identified as 22-O-angeloyl-camelliagenin B 3-O-[β-d-galactopyranosyl-(1→2)]-[β-d-galactopyranosyl-(1→2)-α-l-arabinopyranosyl-(1→3)]-β-d-glucopyranosiduronic acid methyl ester (1); 22-O-angeloyl-camelliagenin A 3-O-[β-d-galactopyranosyl-(1→2)]-[β-d-glucopyranosyl-(1→2)-β-d-galactopyranosyl-(1→3)]-β-d-glucopyranosiduronic acid methyl ester (2); and 28-O-cinnamoyl-camelliagenin B 3-O-[β-d-galactopyranosylz-(1→2)] [β-d-galactopyranosyl(1→2)-α-l-arabinopyranosyl-(1→3)]-β-d-glucopyranosiduronic acid methyl ester (3) through 1D and 2D NMR, HR-ESI-MS, as well as GC-MS spectroscopic methods. The anti-proliferative activities of these four compounds were investigated on five human tumor cell lines (BEL-7402, BGC-823, MCF-7, HL-60 and KB). Compounds 1 and 2 and camelliasaponin B1 showed significant cytotoxic activities. PMID:25958771

  15. Carbonic anhydrase activators: gold nanoparticles coated with derivatized histamine, histidine, and carnosine show enhanced activatory effects on several mammalian isoforms.

    PubMed

    Saada, Mohamed-Chiheb; Montero, Jean-Louis; Vullo, Daniela; Scozzafava, Andrea; Winum, Jean-Yves; Supuran, Claudiu T

    2011-03-10

    Lipoic acid moieties were attached to amine or amino acids showing activating properties against the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). The obtained lipoic acid conjugates of histamine, L-histidine methyl ester, and L-carnosine methyl ester were attached to gold nanoparticles (NPs) by reaction with Au(III) salts in reducing conditions. The CA activators (CAAs)-coated NPs showed low nanomolar activation (K(A)s of 1-9 nM) of relevant cytosolic, membrane-bound, mitochondrial, and transmembrane CA isoforms, such as CA I, II, IV, VA, VII, and XIV. These NPs also effectively activated CAs ex vivo, in whole blood experiments, with an increase of 200-280% of the CA activity. This is the first example of enzyme activation with nanoparticles and may lead to biomedical applications for conditions in which the CA activity is diminished, such as aging, Alzheimer's disease, or CA deficiency syndrome. PMID:21291238

  16. Immunomodulatory Activity of Dietary Fiber: Arabinoxylan and Mixed-Linked Beta-Glucan Isolated from Barley Show Modest Activities in Vitro

    PubMed Central

    Samuelsen, Anne Berit; Rieder, Anne; Grimmer, Stine; Michaelsen, Terje E.; Knutsen, Svein H.

    2011-01-01

    High intake of dietary fiber is claimed to protect against development of colorectal cancer. Barley is a rich source of dietary fiber, and possible immunomodulatory effects of barley polysaccharides might explain a potential protective effect. Dietary fiber was isolated by extraction and enzyme treatment. A mixed-linked β-glucan (WSM-TPX, 96.5% β-glucan, Mw 886 kDa), an arabinoxylan (WUM-BS-LA, 96.4% arabinoxylan, Mw 156 kDa), a mixed-linked β-glucan rich fraction containing 10% arabinoxylan (WSM-TP) and an arabinoxylan rich fraction containing 30% mixed-linked β-glucan (WUM-BS) showed no significant effect on IL-8 secretion and proliferation of two intestinal epithelial cell lines, Caco-2 and HT-29, and had no significant effect on the NF-κB activity in the monocytic cell line U937-3κB-LUC. Further enriched arabinoxylan fractions (WUM-BS-LA) from different barley varieties (Tyra, NK96300, SB94897 and CDCGainer) were less active than the mixed-linked β-glucan rich fractions (WSM-TP and WSM-TPX) in the complement-fixing test. The mixed-linked β-glucan rich fraction from NK96300 and CDCGainer showed similar activities as the positive control while mixed-linked β-glucan rich fractions from Tyra and SB94897 were less active. From these results it is concluded that the isolated high molecular weight mixed-linked β-glucans and arabinoxylans from barley show low immunological responses in selected in vitro test systems and thus possible anti-colon cancer effects of barley dietary fiber cannot be explained by our observations. PMID:21340001

  17. Hydrogenase activity in aged, nonviable Desulfovibrio vulgaris cultures and its significance in anaerobic biocorrosion

    SciTech Connect

    Chatelus, C.; Carrier, P.; Saignes, P.; Libert, M.F.; Berlier, Y.; Lespinat, P.A.; Fauque, G.; Legall, J.

    1987-07-01

    Batch cultures of Desulfovibrio vulgaris stored at 32 degrees C for 10 months have been found to retain 50% of the hydrogenase activity of a 1-day culture. The hydrogenase found in old cultures needs reducing conditions for its activation. Viable cell counts are negative after 6 months, showing that the hydrogenase activity does not depend on the presence of viable cells. These observations are of importance in the understanding of anaerobic biocorrosion of metals caused by depolarization phenomena. (Refs. 16).

  18. Future role and significance of space activities in reflection of global social, technological and economic trends

    NASA Astrophysics Data System (ADS)

    Diekmann, Andreas; Richarz, Hans.-Peter

    The paper describes the interrelation of space activities and global socio-economic trends like "globalisation of markets" and "renaissance of fine arts". The interrelation reveals the economic strategic, technological and scientific dimension of space activities and their benefits to mankind. Then, the significance and perspectives of space activities in these dimensions are examined in more detail. The paper calls (1) for a more visible initiative to employ space activities to tackle urgent questions of global change and development, and (2) for a stronger impetus to secure European economic position in space sector as a key industry of the 21st century.

  19. Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

    PubMed Central

    Bazzola, L; Foroni, C; Andreis, D; Zanoni, V; R Cappelletti, M; Allevi, G; Aguggini, S; Strina, C; Milani, M; Venturini, S; Ferrozzi, F; Giardini, R; Bertoni, R; Turley, H; Gatter, K; Petronini, P G; Fox, S B; Harris, A L; Martinotti, M; Berruti, A; Bottini, A; Reynolds, A R; Generali, D

    2015-01-01

    Purpose: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). Methods: Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. Results: Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by 18FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively). Conclusions: The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is

  20. Paraoxonase-1 activity determination via paraoxon substrate yields no significant difference in mild hyperhomocysteinemia.

    PubMed

    Türkeli, Hatice; Caycı, Tuncer; Akgül, Emin Özgür; Macit, Enis; Yaman, Halil; Aydın, Ibrahim; Demirin, Hilmi; Alacam, Hasan; Ozkan, Esin; Cakır, Erdinç; Deren, Ozgür; Erbil, Mehmet Kemal; Kunak, Z Ilker; Burat, Kutlay; Akman, Serif

    2010-11-01

    Elevated plasma homocystein (Hcy) level has been recognized as an important risk factor for a number of cardiovascular diseases, peripheral arterial occlusive disease and venous thrombosis. A part of Hcy in the organism is turned to homocysteine thiolactone (HcyT) via a ring closure reaction, which gains rate in hyperhomocysteinemia, and in turn undergoes a hydrolytic reaction back to Hcy by paraoxonase enzyme (PON). Since this is a protective reflex action enzyme against hyperhomocysteinemia, we investigated how a mild hyperhomocysteinemic nutritional habit affected serum PON activity in a population-based study. The difference detected via enzymatic activity using the paraoxon substrate was statistically non-significant (p=0.19), suggesting a defective performance to reflect the expected significance. Determination of serum PON activity via substrate paraoxon yielded no significant difference in an acute mild hyperhomocysteinemic diet model in humans. PMID:19419786

  1. An Acute Lateral Ankle Sprain Significantly Decreases Physical Activity across the Lifespan

    PubMed Central

    Hubbard-Turner, Tricia; Wikstrom, Erik A.; Guderian, Sophie; Turner, Michael J.

    2015-01-01

    We do not know the impact an ankle sprain has on physical activity levels across the lifespan. With the negative consequences of physical inactivity well established, understanding the effect of an ankle sprain on this outcome is critical. The objective of this study was to measure physical activity across the lifespan after a single ankle sprain in an animal model. Thirty male mice (CBA/J) were randomly placed into one of three groups: the transected calcaneofibular ligament (CFL) group, the transected anterior talofibular ligament (ATFL)/CFL group, and a SHAM group. Three days after surgery, all of the mice were individually housed in a cage containing a solid surface running wheel. Physical activity levels were recorded and averaged every week across the mouse’s lifespan. The SHAM mice ran significantly more distance each day compared to the remaining two running groups (post hoc p = 0.011). Daily duration was different between the three running groups (p = 0.048). The SHAM mice ran significantly more minutes each day compared to the remaining two running groups (post hoc p=0.046) while the ATFL/CFL mice ran significantly less minutes each day (post hoc p = 0.028) compared to both the SHAM and CFL only group. The SHAM mice ran at a faster daily speed versus the remaining two groups of mice (post hoc p = 0.019) and the ATFL/CFL mice ran significantly slower each day compared to the SHAM and CFL group (post hoc p = 0.005). The results of this study indicate that a single ankle sprain significantly decreases physical activity across the lifespan in mice. This decrease in physical activity can potentially lead to the development of numerous chronic diseases. An ankle sprain thus has the potential to lead to significant long term health risks if not treated appropriately. Key points A single ankle significantly decreased physical activity levels in mice across the lifespan. Decreased physical activity could significantly negatively impact overall health if not

  2. Latent myostatin has significant activity and this activity is controlled more efficiently by WFIKKN1 than by WFIKKN2.

    PubMed

    Szláma, György; Trexler, Mária; Patthy, László

    2013-08-01

    Myostatin, a negative regulator of skeletal muscle growth, is produced from myostatin precursor by multiple steps of proteolytic processing. After cleavage by a furin-type protease, the propeptide and growth factor domains remain associated, forming a noncovalent complex, the latent myostatin complex. Mature myostatin is liberated from latent myostatin by bone morphogenetic protein 1/tolloid proteases. Here, we show that, in reporter assays, latent myostatin preparations have significant myostatin activity, as the noncovalent complex dissociates at an appreciable rate, and both mature and semilatent myostatin (a complex in which the dimeric growth factor domain interacts with only one molecule of myostatin propeptide) bind to myostatin receptor. The interaction of myostatin receptor with semilatent myostatin is efficiently blocked by WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 or growth and differentiation factor-associated serum protein 2 (WFIKKN1), a large extracellular multidomain protein that binds both mature myostatin and myostatin propeptide [Kondás et al. (2008) J Biol Chem 283, 23677-23684]. Interestingly, the paralogous protein WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 or growth and differentiation factor-associated serum protein 1 (WFIKKN2) was less efficient than WFIKKN1 as an antagonist of the interactions of myostatin receptor with semilatent myostatin. Our studies have shown that this difference is attributable to the fact that only WFIKKN1 has affinity for the propeptide domain, and this interaction increases its potency in suppressing the receptor-binding activity of semilatent myostatin. As the interaction of WFIKKN1 with various forms of myostatin permits tighter control of myostatin activity until myostatin is liberated from latent myostatin by bone morphogenetic protein 1/tolloid proteases, WFIKKN1 may have greater potential as an antimyostatic agent than WFIKKN2. PMID:23829672

  3. Significant bone microarchitecture impairment in premenopausal women with active celiac disease.

    PubMed

    Zanchetta, María Belén; Costa, Florencia; Longobardi, Vanesa; Longarini, Gabriela; Mazure, Roberto Martín; Moreno, María Laura; Vázquez, Horacio; Silveira, Fernando; Niveloni, Sonia; Smecuol, Edgardo; Temprano, María de la Paz; Hwang, Hui Jer; González, Andrea; Mauriño, Eduardo César; Bogado, Cesar; Zanchetta, Jose R; Bai, Julio César

    2015-07-01

    Patients with active celiac disease (CD) are more likely to have osteoporosis and increased risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) permits three-dimensional exploration of bone microarchitectural characteristics measuring separately cortical and trabecular compartments, and giving a more profound insight into bone disease pathophysiology and fracture. We aimed to determine the volumetric and microarchitectural characteristics of peripheral bones-distal radius and tibia-in an adult premenopausal cohort with active CD assessed at diagnosis. We prospectively enrolled 31 consecutive premenopausal women with newly diagnosed CD (median age 29 years, range: 18-49) and 22 healthy women of similar age (median age 30 years, range 21-41) and body mass index. Compared with controls, peripheral bones of CD patients were significantly lower in terms of total volumetric density mg/cm(3) (mean ± SD: 274.7 ± 51.7 vs. 324.7 ± 45.8, p 0.0006 at the radius; 264.4 ± 48.7 vs. 307 ± 40.7, p 0.002 at the tibia), trabecular density mg/cm(3) (118.6 ± 31.5 vs. 161.9 ± 33.6, p<0.0001 at the radius; 127.9 ± 28.7 vs. 157.6 ± 15.6, p < 0.0001 at the tibia); bone volume/trabecular volume ratio % (9.9 ± 2.6 vs. 13.5 ± 2.8, p<0.0001 at the radius; 10.6 ± 2.4 vs. 13.1 ± 1.3, p < 0.0001 at the tibia); number of trabeculae 1/mm (1.69 ± 0.27 vs. 1.89 ± 0.26, p 0.009 at the radius; 1.53 ± 0.32 vs. 1.80 ± 0.26, p 0.002 at the tibia); and trabecular thickness mm (0.058 ± 0.010 vs. 0.071 ± 0.008, p < 0.0001 at the radius with no significant difference at the tibia). Cortical density was significantly lower in both regions (D comp mg/cm(3) 860 ± 57.2 vs. 893.9 ± 43, p 0.02; 902.7 ± 48.7 vs. 932.6 ± 32.6, p 0.01 in radius and tibia respectively). Although cortical thickness was lower in CD patients, it failed to show any significant inter-group difference (a-8% decay with p 0.11 in both bones). Patients with symptomatic CD (n = 22) had

  4. TRAIL-CM4 fusion protein shows in vitro antibacterial activity and a stronger antitumor activity than solo TRAIL protein.

    PubMed

    Sang, Ming; Zhang, Jiaxin; Li, Bin; Chen, Yuqing

    2016-06-01

    A TRAIL-CM4 fusion protein in soluble form with tumor selective apoptosis and antibacterial functions was expressed in the Escherichia coli expression system and isolated through dialysis refolding and histidine-tag Nickel-affinity purification. Fresh Jurkat cells were treated with the TRAIL-CM4 fusion protein. Trypan blue staining and MTT analyses showed that, similar to a TRAIL positive control, Jurkat cell proliferation was significantly inhibited. Flow cytometry analyses using Annexin V-fluorescein revealed that Jurkat cells treated with the TRAIL-CM4 fusion protein exhibited increased apoptosis. Laser confocal microscopy showed that APB-CM4 and the fusion protein TRAIL-CM4 can bind to Jurkat cell membranes and initiate their destruction. ABP-CM4 enhances the antitumor activity of TRAIL by targeting and damaging the tumor cell membrane. In antibacterial experiments, agar well diffusion and bacterial growth inhibition curve assays revealed concentration-dependent TRAIL-CM4 antibacterial activity against Escherichia coli K12D31. The expressed TRAIL-CM4 fusion protein exhibited enhanced antitumor and antibacterial activities. Fusion protein expression allowed the two different proteins to function in combination. PMID:26926590

  5. A measles virus selectively blind to signaling lymphocytic activation molecule shows anti-tumor activity against lung cancer cells.

    PubMed

    Fujiyuki, Tomoko; Yoneda, Misako; Amagai, Yosuke; Obayashi, Kunie; Ikeda, Fusako; Shoji, Koichiro; Murakami, Yoshinori; Sato, Hiroki; Kai, Chieko

    2015-09-22

    Lung cancer cells, particularly those of non-small-cell lung cancer, are known to express Nectin-4. We previously generated a recombinant measles virus that uses Nectin-4 as its receptor but cannot bind its original principal receptor, signaling lymphocyte activation molecule (SLAM). This virus (rMV-SLAMblind) infects and kills breast cancer cells in vitro and in a subcutaneous xenograft model. However, it has yet to be determined whether rMV-SLAMblind is effective against other cancer types and in other tumor models that more closely represent disease. In this study, we analyzed the anti-tumor activity of this virus towards lung cancer cells using a modified variant that encodes green fluorescent protein (rMV-EGFP-SLAMblind). We found that rMV-EGFP-SLAMblind efficiently infected nine, human, lung cancer cell lines, and its infection resulted in reduced cell viability of six cell lines. Administration of the virus into subcutaneous tumors of xenotransplanted mice suppressed tumor growth. In addition, rMV-EGFP-SLAMblind could target scattered tumor masses grown in the lungs of xenotransplanted mice. These results suggest that rMV-SLAMblind is oncolytic for lung cancer and that it represents a promising tool for the treatment of this disease. PMID:26317644

  6. Risk Factors for Clinically Significant Intimate Partner Violence among Active-Duty Members

    ERIC Educational Resources Information Center

    Smith Slep, Amy M.; Foran, Heather M.; Heyman, Richard E.; Snarr, Jeffery D.

    2011-01-01

    Hypothesized risk factors for men's and women's clinically significant intimate partner violence (CS-IPV) from four ecological levels (i.e., individual, family, workplace, community) were tested in a representative sample of active-duty U.S. Air Force members (N = 42,744). When considered together, we expected only individual and family factors to…

  7. Subjective Significance Shapes Arousal Effects on Modified Stroop Task Performance: A Duality of Activation Mechanisms Account.

    PubMed

    Imbir, Kamil K

    2016-01-01

    Activation mechanisms such as arousal are known to be responsible for slowdown observed in the Emotional Stroop and modified Stroop tasks. Using the duality of mind perspective, we may conclude that both ways of processing information (automatic or controlled) should have their own mechanisms of activation, namely, arousal for an experiential mind, and subjective significance for a rational mind. To investigate the consequences of both, factorial manipulation was prepared. Other factors that influence Stroop task processing such as valence, concreteness, frequency, and word length were controlled. Subjective significance was expected to influence arousal effects. In the first study, the task was to name the color of font for activation charged words. In the second study, activation charged words were, at the same time, combined with an incongruent condition of the classical Stroop task around a fixation point. The task was to indicate the font color for color-meaning words. In both studies, subjective significance was found to shape the arousal impact on performance in terms of the slowdown reduction for words charged with subjective significance. PMID:26869974

  8. Subjective Significance Shapes Arousal Effects on Modified Stroop Task Performance: A Duality of Activation Mechanisms Account

    PubMed Central

    Imbir, Kamil K.

    2016-01-01

    Activation mechanisms such as arousal are known to be responsible for slowdown observed in the Emotional Stroop and modified Stroop tasks. Using the duality of mind perspective, we may conclude that both ways of processing information (automatic or controlled) should have their own mechanisms of activation, namely, arousal for an experiential mind, and subjective significance for a rational mind. To investigate the consequences of both, factorial manipulation was prepared. Other factors that influence Stroop task processing such as valence, concreteness, frequency, and word length were controlled. Subjective significance was expected to influence arousal effects. In the first study, the task was to name the color of font for activation charged words. In the second study, activation charged words were, at the same time, combined with an incongruent condition of the classical Stroop task around a fixation point. The task was to indicate the font color for color-meaning words. In both studies, subjective significance was found to shape the arousal impact on performance in terms of the slowdown reduction for words charged with subjective significance. PMID:26869974

  9. Sequential treatment with betulinic acid followed by 5-fluorouracil shows synergistic cytotoxic activity in ovarian cancer cells

    PubMed Central

    Wang, Ying-Jian; Liu, Jun-Bao; Dou, Yu-Chang

    2015-01-01

    Betulinic acid selectively inhibits the growth of ovarian carcinoma cell lines without affecting the normal cells. In the present study, the effect of 5-fluorouracil (5-FU) and betulinic acid (BA) combination on ovarian carcinoma cells was studied. The results demonstrated that ovarian carcinoma cells on concurrent or 5-FU followed by BA treatment show increased Sub-G1 cell population, increased rate of cell apoptosis and morphological changes in mitochondrial membrane. In OVCAR 432 cells treatment with sequential combination of 5-FU and BA increased the Sub-G1 cell population to 51.3% and growth inhibition rate of > 72%. However, exposure to BA before 5-FU treatment caused a decrease in rate of inhibition to < 35%. Treatment with combination of 5 μM of 5-FU and 1 μM of BA for 48 h, led to an induction of apoptosis in 79.7% and induced morphological changes in OVCAR 432 cells. The Western blot results showed high concentration of cytochrome c in the cell cytosol after 24 h of 5-FU and BA combination treatment. Treatment of BA-responsive RMS-13 cells with 5-FU and BA combination resulted in inhibition of GLI1, GLI2, PTCH1, and IGF2 genes. In addition, we found a significant reduction in hedgehog activity of RMS-13 cells after 5-FU and BA combination treatment by means of a hedgehog-responsive reporter assay. Therefore, 5-FU and BA combination can be a promising regimen for the treatment of ovarian carcinoma. PMID:25755712

  10. A psychrotrophic Burkholderia cepacia strain isolated from refrigerated raw milk showing proteolytic activity and adhesion to stainless steel.

    PubMed

    Nörnberg, Maria de Fátima Barros Leal; Mentges, Marilene Lenz; Silveira, Silvana Terra; Tondo, Eduardo César; Brandelli, Adriano

    2011-08-01

    The proteolytic activity of a psychrotrophic strain of Burkholderia cepacia isolated from refrigerated raw milk was characterized. Bur. cepacia produced proteolytic activity during growth at refrigeration temperature, with maximum activity at pH 6-7. The enzyme showed relative thermal stability in the range 40-50°C during 25 min, and maintained 80% its initial activity at 76°C/30 s. Milk coagulation assay showed that the crude protease from Bur. cepacia caused coagulation from day 2 for skimmed milk, whereas coagulation was observed from day 5 for whole milk. The adherence of this strain to stainless steel was evaluated, and the substrata had around 107 CFU/cm2 after 15 to 60 min incubation. Results on biofilm development suggest that this bacterium could adhere and to form biofilms even at refrigeration temperatures. These results indicate that Bur. cepacia may represent a potential hazardous to milk and dairy products. PMID:21457588

  11. Significance probability mapping: an aid in the topographic analysis of brain electrical activity.

    PubMed

    Duffy, F H; Bartels, P H; Burchfiel, J L

    1981-05-01

    We illustrate the application of significance probability mapping (SPM) to the analysis of topographic maps of spectral analyzed EEG and visual evoked potential (VEP) activity from patients with brain tumors, boys with dyslexia, and control subjects. When the VEP topographic plots of tumor patients were displayed as number of standard deviations from a reference mean, more subjects were correctly identified than by inspection of the underlying raw data. When topographic plots of EEG alpha activity obtained while listening to speech or music were compared by t statistic to plots of resting alpha activity, regions of cortex presumably activated by speech or music were delineated. DIfferent regions were defined in dyslexic boys and controls. We propose that SPM will prove valuable in the regional localization of normal and abnormal functions in other clinical situations. PMID:6165544

  12. Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice.

    PubMed

    Shaw, Maureen A; Kombrinck, Keith W; McElhinney, Kathryn E; Sweet, David R; Flick, Matthew J; Palumbo, Joseph S; Cheng, Mei; Esmon, Naomi L; Esmon, Charles T; Brill, Alexander; Wagner, Denisa D; Degen, Jay L; Mullins, Eric S

    2016-08-01

    Thrombin-mediated proteolysis is central to hemostatic function but also plays a prominent role in multiple disease processes. The proteolytic conversion of fII to α-thrombin (fIIa) by the prothrombinase complex occurs through 2 parallel pathways: (1) the inactive intermediate, prethrombin; or (2) the proteolytically active intermediate, meizothrombin (fIIa(MZ)). FIIa(MZ) has distinct catalytic properties relative to fIIa, including diminished fibrinogen cleavage and increased protein C activation. Thus, fII activation may differentially influence hemostasis and disease depending on the pathway of activation. To determine the in vivo physiologic and pathologic consequences of restricting thrombin generation to fIIa(MZ), mutations were introduced into the endogenous fII gene, resulting in expression of prothrombin carrying 3 amino acid substitutions (R157A, R268A, and K281A) to limit activation events to yield only fIIa(MZ) Homozygous fII(MZ) mice are viable, express fII levels comparable with fII(WT) mice, and have reproductive success. Although in vitro studies revealed delayed generation of fIIa(MZ) enzyme activity, platelet aggregation by fII(MZ) is similar to fII(WT) Consistent with prior analyses of human fIIa(MZ), significant prolongation of clotting times was observed for fII(MZ) plasma. Adult fII(MZ) animals displayed significantly compromised hemostasis in tail bleeding assays, but did not demonstrate overt bleeding. More notably, fII(MZ) mice had 2 significant phenotypic advantages over fII(WT) animals: protection from occlusive thrombosis after arterial injury and markedly diminished metastatic potential in a setting of experimental tumor metastasis to the lung. Thus, these novel animals will provide a valuable tool to assess the role of both fIIa and fIIa(MZ) in vivo. PMID:27252233

  13. Novel nuclear targeting coiled-coil protein of Helicobacter pylori showing Ca(2+)-independent, Mg(2+)-dependent DNase I activity.

    PubMed

    Kwon, Young Chul; Kim, Sinil; Lee, Yong Seok; Lee, Je Chul; Cho, Myung-Je; Lee, Woo-Kon; Kang, Hyung-Lyun; Song, Jae-Young; Baik, Seung Chul; Ro, Hyeon Su

    2016-05-01

    HP0059, an uncharacterized gene of Helicobacter pylori, encodes a 284-aa-long protein containing a nuclear localization sequence (NLS) and multiple leucine-rich heptad repeats. Effects of HP0059 proteins in human stomach cells were assessed by incubation of recombinant HP0059 proteins with the AGS human gastric carcinoma cell line. Wild-type HP0059 proteins showed cytotoxicity in AGS cells in a concentration-dependent manner, whereas NLS mutant protein showed no effect, suggesting that the cytotoxicity is attributed to host nuclear localization. AGS cells transfected with pEGFP-HP0059 plasmid showed strong GFP signal merged to the chromosomal DNA region. The chromosome was fragmented into multiple distinct dots merged with the GFP signal after 12 h of incubation. The chromosome fragmentation was further explored by incubation of AGS chromosomal DNA with recombinant HP0059 proteins, which leaded to complete degradation of the chromosomal DNA. HP0059 protein also degraded circular plasmid DNA without consensus, being an indication of DNase I activity. The DNase was activated by MgCl2, but not by CaCl2. The activity was completely blocked by EDTA. The optimal pH and temperature for DNase activity were 7.0-8.0 and 55°C, respectively. These results indicate that HP0059 possesses a novel DNase I activity along with a role in the genomic instability of human gastric cells, which may result in the transformation of gastric cells. PMID:27095458

  14. Healthy children show gender differences in correlations between nonverbal cognitive ability and brain activation during visual perception.

    PubMed

    Asano, Kohei; Taki, Yasuyuki; Hashizume, Hiroshi; Sassa, Yuko; Thyreau, Benjamin; Asano, Michiko; Takeuchi, Hikaru; Kawashima, Ryuta

    2014-08-01

    Humans perceive textual and nontextual information in visual perception, and both depend on language. In childhood education, students exhibit diverse perceptual abilities, such that some students process textual information better and some process nontextual information better. These predispositions involve many factors, including cognitive ability and learning preference. However, the relationship between verbal and nonverbal cognitive abilities and brain activation during visual perception has not yet been examined in children. We used functional magnetic resonance imaging to examine the relationship between nonverbal and verbal cognitive abilities and brain activation during nontextual visual perception in large numbers of children. A significant positive correlation was found between nonverbal cognitive abilities and brain activation in the right temporoparietal junction, which is thought to be related to attention reorienting. This significant positive correlation existed only in boys. These findings suggested that male brain activation differed from female brain activation, and that this depended on individual cognitive processes, even if there was no gender difference in behavioral performance. PMID:24937269

  15. [Clinical significance of telomerase activity in precancerous lesion of the liver (adenomatous hyperplasia)].

    PubMed

    Nishimoto, A; Miura, N; Oshimura, M

    1998-05-01

    To understand the role of telomere dynamics in hepatocellular carcinogenesis, we examined the lengths of terminal restriction fragments (TRFs) in hepatocellular carcinoma (HCC) and surrounding tissues with chronic active hepatitis (CAH), liver cirrhosis (LC) and atypical adenomatous hyperplasia (AAH). The peak TRFs in all HCCs were significantly shorter than those of the surrounding tissues (CAH, LC). TRF in AAH was shortened and similar to that of HCC. Telomerase was examined in CAH, LC, AH, and HCC, and detected in high levels almost exclusively in HCCs. Interestingly, the intensity of telomerase activity in the AH was similar to that of HCC. Thus, the progressive shortening of telomere and the activation of telomerase may be a useful marker for the early detection of malignant progression in liver disease. PMID:9613131

  16. The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.

    PubMed

    Anyanwu, Ebere; Campbell, Andrew W; Jones, Joseph; Ehiri, John E; Akpan, Akpan I

    2003-11-13

    Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range

  17. Peep show establishments, police activity, public place, and time: a study of secondary effects in San Diego, California.

    PubMed

    Linz, Daniel; Paul, Bryant; Yao, Mike

    2006-05-01

    An empirical study was undertaken in San Diego, California, to test assumptions made by the government and by conservative religious policy advocates that there is a greater incidence of crime in the vicinity of peep show establishments. We asked two questions: (a) Is criminal activity in San Diego particularly acute at peep show establishments compared to surrounding control locations? and (b) Is criminal activity in San Diego disproportionately greater at or near peep show establishments between the hours of 2 a.m. and 6 a.m. compared to other times of the day? The levels of crime activity and the expenditure of police resources were examined by measuring the number of calls-for-service (CFSs) to the police within a 1,000-ft. area on either side of the peep show establishments and comparably-sized control areas beyond the immediate 1,000-foot area. A more focused late-night (2 a.m. to 6 a.m.) analysis was also undertaken. The results showed no reliable evidence of differences in crime levels between the control and test areas, nor was there any evidence of disproportionately greater amounts of crime within the 2 a.m. to 6 a.m. time period in the areas surrounding the peep show establishments. We concluded that San Diego does not have a problem with crime at the peep show establishments generally, nor is there a heightened problem with crime during the 2 a.m. to 6 a.m. period. We discuss the implications of assuming that peep show establishments are associated with negative effects in the community and the possibility of viewpoint discrimination against sex communication. PMID:16817065

  18. Significant others and contingencies of self-worth: activation and consequences of relationship-specific contingencies of self-worth.

    PubMed

    Horberg, E J; Chen, Serena

    2010-01-01

    Three studies tested the activation and consequences of contingencies of self-worth associated with specific significant others, that is, relationship-specific contingencies of self-worth. The results showed that activating the mental representation of a significant other with whom one strongly desires closeness led participants to stake their self-esteem in domains in which the significant other wanted them to excel. This was shown in terms of self-reported contingencies of self-worth (Study 1), in terms of self-worth after receiving feedback on a successful or unsatisfactory performance in a relationship-specific contingency domain (Study 2), and in terms of feelings of reduced self-worth after thinking about a failure in a relationship-specific contingency domain (Study 3). Across studies, a variety of contingency domains were examined. Furthermore, Study 3 showed that failing in an activated relationship-specific contingency domain had negative implications for current feelings of closeness and acceptance in the significant-other relationship. Overall, the findings suggest that people's contingencies of self-worth depend on the social situation and that performance in relationship-specific contingency domains can influence people's perceptions of their relationships. PMID:20053033

  19. A chimeric protein of aluminum-activated malate transporter generated from wheat and Arabidopsis shows enhanced response to trivalent cations.

    PubMed

    Sasaki, Takayuki; Tsuchiya, Yoshiyuki; Ariyoshi, Michiyo; Ryan, Peter R; Yamamoto, Yoko

    2016-07-01

    TaALMT1 from wheat (Triticum aestivum) and AtALMT1 from Arabidopsis thaliana encode aluminum (Al)-activated malate transporters, which confer acid-soil tolerance by releasing malate from roots. Chimeric proteins from TaALMT1 and AtALMT1 (Ta::At, At::Ta) were previously analyzed in Xenopus laevis oocytes. Those studies showed that Al could activate malate efflux from the Ta::At chimera but not from At::Ta. Here, functions of TaALMT1, AtALMT1 and the chimeric protein Ta::At were compared in cultured tobacco BY-2 cells. We focused on the sensitivity and specificity of their activation by trivalent cations. The activation of malate efflux by Al was at least two-fold greater in the chimera than the native proteins. All proteins were also activated by lanthanides (erbium, ytterbium, gadolinium, and lanthanum), but the chimera again released more malate than TaALMT1 or AtALMT1. In Xenopus oocytes, Al, ytterbium, and erbium activated inward currents from the native TaALMT1 and the chimeric protein, but gadolinium only activated currents from the chimera. Lanthanum inhibited currents from both proteins. These results demonstrated that function of the chimera protein was altered compared to the native proteins and was more responsive to a range of trivalent cations when expressed in plant cells. PMID:27039280

  20. Significant Enhancement of Water Splitting Activity of N-Carbon Electrocatalyst by Trace Level Co Doping.

    PubMed

    Bayatsarmadi, Bita; Zheng, Yao; Tang, Youhong; Jaroniec, Mietek; Qiao, Shi-Zhang

    2016-07-01

    Replacement of precious metal electrocatalysts with highly active and cost efficient alternatives for complete water splitting at low voltage has attracted a growing attention in recent years. Here, this study reports a carbon-based composite co-doped with nitrogen and trace amount of metallic cobalt (1 at%) as a bifunctional electrocatalyst for water splitting at low overpotential and high current density. An excellent electrochemical activity of the newly developed electrocatalyst originates from its graphitic nanostructure and highly active Co-Nx sites. In the case of carefully optimized sample of this electrocatalyst, 10 mA cm(-2) current density can be achieved for two half reactions in alkaline solutions-hydrogen evolution reaction and oxygen evolution reaction-at low overpotentials of 220 and 350 mV, respectively, which are smaller than those previously reported for nonprecious metal and metal-free counterparts. Based on the spectroscopic and electrochemical investigations, the newly identified Co-Nx sites in the carbon framework are responsible for high electrocatalytic activity of the Co,N-doped carbon. This study indicates that a trace level of the introduced Co into N-doped carbon can significantly enhance its electrocatalytic activity toward water splitting. PMID:27246288

  1. Increased expression of β-glucosidase A in Clostridium thermocellum 27405 significantly increases cellulase activity

    PubMed Central

    Maki, Miranda L.; Armstrong, Lachlan; Leung, Kam Tin; Qin, Wensheng

    2013-01-01

    β-glucosidase A (bglA) in Clostridium thermocellum 27405 was increased by expression from shuttle vector pIBglA in attempts to increase cellulase activity and ethanol titer by lowering the end product inhibition of cellulase. Through a modified electrotransformation protocol C. thermocellum transformant (+MCbglA) harbouring pIBglA was produced. The β-glucosidase activity of +MCbglA was 2.3- and 1.6-fold greater than wild-type (WT) during late log and stationary phases of growth. Similarly, total cellulase activity of +MCbglA was shown to be 1.7-, 2.3- and 1.6-fold greater than WT during, log, late log and stationary phases of growth. However, there was no significant correlation found between increased cellulase activity and increased ethanol titers for +MCbglA compared with the WT. C. thermocellum has industrial potential for consolidated bioprocessing (CBP) to make a more cost effective production of biofuels; however, the hydrolysis rate of the strain is still hindered by end product inhibition. We successfully increased total cellulase activity by increased expression of bglA and thereby increased the productivity of C. thermocellum during the hydrolysis stage in CBP. Our work also lends insights into the complex metabolism of C. thermocellum for future improvement of this strain. PMID:22922214

  2. In vitro analysis of albendazole sulfoxide enantiomers shows that (+)-(R)-albendazole sulfoxide is the active enantiomer against Taenia solium.

    PubMed

    Paredes, Adriana; de Campos Lourenço, Tiago; Marzal, Miguel; Rivera, Andrea; Dorny, Pierre; Mahanty, Siddhartha; Guerra-Giraldez, Cristina; García, Hector H; Nash, Theodore E; Cass, Quezia B

    2013-02-01

    Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with Taenia solium cysts. However, drug levels of its active metabolite, albendazole sulfoxide (ABZSO), are erratic, likely resulting in decreased efficacy and suboptimal cure rates in NCC. Racemic albendazole sulfoxide is composed of ABZSO (+)-(R)- and (-)-(S) enantiomers that have been shown to differ in pharmacokinetics and activity against other helminths. The antiparasitic activities of racemic ABZSO and its (+)-(R)- and (-)-(S) enantiomers against T. solium cysts were evaluated in vitro. Parasites were collected from naturally infected pigs, cultured, and exposed to the racemic mixture or to each enantiomer (range, 10 to 500 ng/ml) or to praziquantel as a reference drug. The activity of each compound against cysts was assayed by measuring the ability to evaginate and inhibition of alkaline phosphatase (AP) and parasite antigen release. (+)-(R)-ABZSO was significantly more active than (-)-(S)-ABZSO in suppressing the release of AP and antigen into the supernatant in a dose- and time-dependent manner, indicating that most of the activity of ABZSO resides in the (+)-(R) enantiomer. Use of this enantiomer alone may lead to increased efficacy and/or less toxicity compared to albendazole. PMID:23229490

  3. In Vitro Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-(R)-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium

    PubMed Central

    Paredes, Adriana; de Campos Lourenço, Tiago; Marzal, Miguel; Rivera, Andrea; Dorny, Pierre; Mahanty, Siddhartha; Guerra-Giraldez, Cristina; García, Hector H.; Cass, Quezia B.

    2013-01-01

    Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with Taenia solium cysts. However, drug levels of its active metabolite, albendazole sulfoxide (ABZSO), are erratic, likely resulting in decreased efficacy and suboptimal cure rates in NCC. Racemic albendazole sulfoxide is composed of ABZSO (+)-(R)- and (−)-(S) enantiomers that have been shown to differ in pharmacokinetics and activity against other helminths. The antiparasitic activities of racemic ABZSO and its (+)-(R)- and (−)-(S) enantiomers against T. solium cysts were evaluated in vitro. Parasites were collected from naturally infected pigs, cultured, and exposed to the racemic mixture or to each enantiomer (range, 10 to 500 ng/ml) or to praziquantel as a reference drug. The activity of each compound against cysts was assayed by measuring the ability to evaginate and inhibition of alkaline phosphatase (AP) and parasite antigen release. (+)-(R)-ABZSO was significantly more active than (−)-(S)-ABZSO in suppressing the release of AP and antigen into the supernatant in a dose- and time-dependent manner, indicating that most of the activity of ABZSO resides in the (+)-(R) enantiomer. Use of this enantiomer alone may lead to increased efficacy and/or less toxicity compared to albendazole. PMID:23229490

  4. Electrophysiological evidence showing muscarinic agonist-antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons.

    PubMed

    Sugawara, Yuto; Kikuchi, Yui; Yoneda, Mitsugu; Ohno-Shosaku, Takako

    2016-07-01

    The atypical antipsychotic clozapine is widely used for treatment-resistant schizophrenic patients. Clozapine and its major active metabolite, N-desmethylclozapine (NDMC), have complex pharmacological properties, and interact with various neurotransmitter receptors. There are several biochemical studies reporting that NDMC exhibits a partial agonist profile at the human recombinant M1 muscarinic receptors. However, direct electrophysiological evidence showing the ability of NDMC to activate native M1 receptors in intact neurons is poor. Using rat hippocampal neurons, we previously demonstrated that activation of muscarinic receptors by a muscarinic agonist, oxotremorine M (oxo-M), induces a decrease in outward K(+)current at -40mV. In the present study, using this muscarinic current response we assessed agonist and antagonist activities of clozapine and NDMC at native muscarinic receptors in intact hippocampal excitatory and inhibitory neurons. Suppression of the oxo-M-induced current response by the M1 antagonist pirenzepine was evident only in excitatory neurons, while the M3 antagonist darifenacin was effective in both types of neurons. Muscarinic agonist activity of NDMC was higher than that of clozapine, higher in excitatory neurons than in inhibitory neurons, sensitive to pirenzepine, and partially masked when co-applied with clozapine. Muscarinic antagonist activity of clozapine as well as NDMC was not different between excitatory and inhibitory neurons, but clozapine was more effective than NDMC. These results demonstrate that NDMC has the ability to activate native M1 receptors expressed in hippocampal excitatory neurons, but its agonist activity might be limited in clozapine-treated patients because of the presence of excessive clozapine with muscarinic antagonist activity. PMID:27048752

  5. Active Hemovigilance Significantly Improves Reporting of Acute Non-infectious Adverse Reactions to Blood Transfusion.

    PubMed

    Agnihotri, Naveen; Agnihotri, Ajju

    2016-09-01

    One of the key purposes of a hemovigilance program is to improve reporting of transfusion related adverse events and subsequent data-driven improvement in blood transfusion (BT) practices. We conducted a study over 3 years to assess the impact of healthcare worker training and an active feedback programme on reporting of adverse reactions to BTs. All hospitalized patients who required a BT were included in the study. Healthcare workers involved in BT to patients were sensitized and trained in adverse reaction reporting by conducting training sessions and meetings. All the transfused patients were 'actively' monitored for any acute adverse reaction by using a uniquely coded blood issue form. A total of 18,914 blood components transfused to 5785 different patients resulted in 61 adverse reaction episodes. This incidence of 0.32 % in our study was found to be significantly higher (p < 0.005) than that reported from the same region in the past. Red blood cell units were the most frequently transfused component and thus most commonly involved in an adverse reaction (42.6 %), however apheresis platelets had the highest chance of reaction per unit transfused (0.66 %). There was no mortality associated with the BT during the study period. An active surveillance program significantly improves reporting and management of adverse reactions to BTs. PMID:27429527

  6. The crowded sea: incorporating multiple marine activities in conservation plans can significantly alter spatial priorities.

    PubMed

    Mazor, Tessa; Possingham, Hugh P; Edelist, Dori; Brokovich, Eran; Kark, Salit

    2014-01-01

    Successful implementation of marine conservation plans is largely inhibited by inadequate consideration of the broader social and economic context within which conservation operates. Marine waters and their biodiversity are shared by a host of stakeholders, such as commercial fishers, recreational users and offshore developers. Hence, to improve implementation success of conservation plans, we must incorporate other marine activities while explicitly examining trade-offs that may be required. In this study, we test how the inclusion of multiple marine activities can shape conservation plans. We used the entire Mediterranean territorial waters of Israel as a case study to compare four planning scenarios with increasing levels of complexity, where additional zones, threats and activities were added (e.g., commercial fisheries, hydrocarbon exploration interests, aquaculture, and shipping lanes). We applied the marine zoning decision support tool Marxan to each planning scenario and tested a) the ability of each scenario to reach biodiversity targets, b) the change in opportunity cost and c) the alteration of spatial conservation priorities. We found that by including increasing numbers of marine activities and zones in the planning process, greater compromises are required to reach conservation objectives. Complex plans with more activities incurred greater opportunity cost and did not reach biodiversity targets as easily as simplified plans with less marine activities. We discovered that including hydrocarbon data in the planning process significantly alters spatial priorities. For the territorial waters of Israel we found that in order to protect at least 10% of the range of 166 marine biodiversity features there would be a loss of ∼15% of annual commercial fishery revenue and ∼5% of prospective hydrocarbon revenue. This case study follows an illustrated framework for adopting a transparent systematic process to balance biodiversity goals and economic

  7. The Crowded Sea: Incorporating Multiple Marine Activities in Conservation Plans Can Significantly Alter Spatial Priorities

    PubMed Central

    Mazor, Tessa; Possingham, Hugh P.; Edelist, Dori; Brokovich, Eran; Kark, Salit

    2014-01-01

    Successful implementation of marine conservation plans is largely inhibited by inadequate consideration of the broader social and economic context within which conservation operates. Marine waters and their biodiversity are shared by a host of stakeholders, such as commercial fishers, recreational users and offshore developers. Hence, to improve implementation success of conservation plans, we must incorporate other marine activities while explicitly examining trade-offs that may be required. In this study, we test how the inclusion of multiple marine activities can shape conservation plans. We used the entire Mediterranean territorial waters of Israel as a case study to compare four planning scenarios with increasing levels of complexity, where additional zones, threats and activities were added (e.g., commercial fisheries, hydrocarbon exploration interests, aquaculture, and shipping lanes). We applied the marine zoning decision support tool Marxan to each planning scenario and tested a) the ability of each scenario to reach biodiversity targets, b) the change in opportunity cost and c) the alteration of spatial conservation priorities. We found that by including increasing numbers of marine activities and zones in the planning process, greater compromises are required to reach conservation objectives. Complex plans with more activities incurred greater opportunity cost and did not reach biodiversity targets as easily as simplified plans with less marine activities. We discovered that including hydrocarbon data in the planning process significantly alters spatial priorities. For the territorial waters of Israel we found that in order to protect at least 10% of the range of 166 marine biodiversity features there would be a loss of ∼15% of annual commercial fishery revenue and ∼5% of prospective hydrocarbon revenue. This case study follows an illustrated framework for adopting a transparent systematic process to balance biodiversity goals and economic

  8. Significant correlation between refractive index and activity of mitochondria: single mitochondrion study

    PubMed Central

    Haseda, Keisuke; Kanematsu, Keita; Noguchi, Keiichi; Saito, Hiromu; Umeda, Norihiro; Ohta, Yoshihiro

    2015-01-01

    Measurements of refractive indices (RIs) of intracellular components can provide useful information on the structure and function of cells. The present study reports, for the first time, determination of the RI of an isolated mitochondrion in isotonic solution using retardation-modulated differential interference contrast microscopy. The value was 1.41 ± 0.01, indicating that mitochondria are densely packed with molecules having high RIs. Further, the RIs of each mitochondrion were significantly correlated with the mitochondrial membrane potential, an index of mitochondrial activity. These results will provide useful information on the structures and functions of cells based on the intracellular distribution of RIs. PMID:25798310

  9. Actinobacteria from Termite Mounds Show Antiviral Activity against Bovine Viral Diarrhea Virus, a Surrogate Model for Hepatitis C Virus

    PubMed Central

    Padilla, Marina Aiello; Rodrigues, Rodney Alexandre Ferreira; Bastos, Juliana Cristina Santiago; Martini, Matheus Cavalheiro; Barnabé, Ana Caroline de Souza; Kohn, Luciana Konecny; Uetanabaro, Ana Paula Trovatti; Bomfim, Getúlio Freitas; Afonso, Rafael Sanches; Fantinatti-Garboggini, Fabiana; Arns, Clarice Weis

    2015-01-01

    Extracts from termite-associated bacteria were evaluated for in vitro antiviral activity against bovine viral diarrhea virus (BVDV). Two bacterial strains were identified as active, with percentages of inhibition (IP) equal to 98%. Both strains were subjected to functional analysis via the addition of virus and extract at different time points in cell culture; the results showed that they were effective as posttreatments. Moreover, we performed MTT colorimetric assays to identify the CC50, IC50, and SI values of these strains, and strain CDPA27 was considered the most promising. In parallel, the isolates were identified as Streptomyces through 16S rRNA gene sequencing analysis. Specifically, CDPA27 was identified as S. chartreusis. The CDPA27 extract was fractionated on a C18-E SPE cartridge, and the fractions were reevaluated. A 100% methanol fraction was identified to contain the compound(s) responsible for antiviral activity, which had an SI of 262.41. GC-MS analysis showed that this activity was likely associated with the compound(s) that had a peak retention time of 5 min. Taken together, the results of the present study provide new information for antiviral research using natural sources, demonstrate the antiviral potential of Streptomyces chartreusis compounds isolated from termite mounds against BVDV, and lay the foundation for further studies on the treatment of HCV infection. PMID:26579205

  10. Protopanaxadiol, an Active Ginseng Metabolite, Significantly Enhances the Effects of Fluorouracil on Colon Cancer

    PubMed Central

    Wang, Chong-Zhi; Zhang, Zhiyu; Wan, Jin-Yi; Zhang, Chun-Feng; Anderson, Samantha; He, Xin; Yu, Chunhao; He, Tong-Chuan; Qi, Lian-Wen; Yuan, Chun-Su

    2015-01-01

    In this study, we evaluated the effects of protopanaxadiol (PPD), a gut microbiome induced ginseng metabolite, in increasing the anticancer effects of a chemotherapeutic agent fluorouracil (5-FU) on colorectal cancer. An in vitro HCT-116 colorectal cancer cell proliferation test was conducted to observe the effects of PPD, 5-FU and their co-administration and the related mechanisms of action. Then, an in vivo xenografted athymic mouse model was used to confirm the in vitro data. Our results showed that the human gut microbiome converted ginsenoside compound K to PPD as a metabolite. PPD and 5-FU significantly inhibited HCT-116 cell proliferation in a concentration-dependent manner (both p < 0.01), and the effects of 5-FU were very significantly enhanced by combined treatment with PPD (p < 0.01). Cell cycle evaluation demonstrated that 5-FU markedly induced the cancer cell S phase arrest, while PPD increased arrest in G1 phase. Compared to the control, 5-FU and PPD increased apoptosis, and their co-administration significantly increased the number of apoptotic cells (p < 0.01). Using bioluminescence imaging, in vivo data revealed that 5-FU significantly reduced the tumor growth up to Day 20 (p < 0.05). PPD and 5-FU co-administration very significantly reduced the tumor size in a dose-related manner (p < 0.01 compared to the 5-FU alone). The quantification of the tumor size and weight changes for 43 days supported the in vivo imaging data. Our results demonstrated that the co-administration of PPD and 5-FU significantly inhibited the tumor growth, indicating that PPD significantly enhanced the anticancer action of 5-FU, a commonly used chemotherapeutic agent. PPD may have a clinical value in 5-FU’s cancer therapeutics. PMID:25625815

  11. In Vitro and In Vivo Antimalarial Activity Assays of Seeds from Balanites aegyptiaca: Compounds of the Extract Show Growth Inhibition and Activity against Plasmodial Aminopeptidase

    PubMed Central

    Kusch, Peter; Deininger, Susanne; Specht, Sabine; Maniako, Rudeka; Haubrich, Stefanie; Pommerening, Tanja; Lin, Paul Kong Thoo; Hoerauf, Achim; Kaiser, Annette

    2011-01-01

    Balanites aegyptiaca (Balanitaceae) is a widely grown desert plant with multiuse potential. In the present paper, a crude extract from B. aegyptiaca seeds equivalent to a ratio of 1 : 2000 seeds to the extract was screened for antiplasmodial activity. The determined IC50 value for the chloroquine-susceptible Plasmodium falciparum NF54 strain was 68.26 μg/μL ± 3.5. Analysis of the extract by gas chromatography-mass spectrometry detected 6-phenyl-2(H)-1,2,4-triazin-5-one oxime, an inhibitor of the parasitic M18 Aspartyl Aminopeptidase as one of the compounds which is responsible for the in vitro antiplasmodial activity. The crude plant extract had a Ki of 2.35 μg/μL and showed a dose-dependent response. After depletion of the compound, a significantly lower inhibition was determined with a Ki of 4.8 μg/μL. Moreover, two phenolic compounds, that is, 2,6-di-tert-butyl-phenol and 2,4-di-tert-butyl-phenol, with determined IC50 values of 50.29 μM ± 3 and 47.82 μM ± 2.5, respectively, were detected. These compounds may contribute to the in vitro antimalarial activity due to their antioxidative properties. In an in vivo experiment, treatment of BALB/c mice with the aqueous Balanite extract did not lead to eradication of the parasites, although a reduced parasitemia at day 12 p.i. was observed. PMID:21687598

  12. Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.

    PubMed

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

    The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils. PMID:25110971

  13. Activity/inactivity circadian rhythm shows high similarities between young obesity-induced rats and old rats.

    PubMed

    Bravo Santos, R; Delgado, J; Cubero, J; Franco, L; Ruiz-Moyano, S; Mesa, M; Rodríguez, A B; Uguz, C; Barriga, C

    2016-03-01

    The objective of the present study was to compare differences between elderly rats and young obesity-induced rats in their activity/inactivity circadian rhythm. The investigation was motivated by the differences reported previously for the circadian rhythms of both obese and elderly humans (and other animals), and those of healthy, young or mature individuals. Three groups of rats were formed: a young control group which was fed a standard chow for rodents; a young obesity-induced group which was fed a high-fat diet for four months; and an elderly control group with rats aged 2.5 years that was fed a standard chow for rodents. Activity/inactivity data were registered through actimetry using infrared actimeter systems in each cage to detect activity. Data were logged on a computer and chronobiological analysis were performed. The results showed diurnal activity (sleep time), nocturnal activity (awake time), amplitude, acrophase, and interdaily stability to be similar between the young obesity-induced group and the elderly control group, but different in the young control group. We have concluded that obesity leads to a chronodisruption status in the body similar to the circadian rhythm degradation observed in the elderly. PMID:27030628

  14. Rosmarinic acid from eelgrass shows nematicidal and antibacterial activities against pine wood nematode and its carrying bacteria.

    PubMed

    Wang, Jingyu; Pan, Xueru; Han, Yi; Guo, Daosen; Guo, Qunqun; Li, Ronggui

    2012-12-01

    Pine wilt disease (PWD), a destructive disease for pine trees, is caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus and additional bacteria. In this study, extracts of Zostera marina showed a high nematicidal activity against PWN and some of the bacteria that it carries. Light yellow crystals were obtained from extracts of Z. marina through solvent extraction, followed by chromatography on AB-8 resin and crystallization. The NMR and HPLC analysis showed that the isolated compound was rosmarinic acid (RosA). RosA showed effective nematicidal activity, of which the LC₅₀ (50% lethal concentration) to PWN at 24 h, 48 h and 72 h was 1.18 mg/g, 1.05 mg/g and 0.95 mg/g, respectively. To get a high yield rate of RosA from Z. marina, single factor experiments and an L₉ (3⁴) orthogonal experiment were performed. This extraction process involved 70% ethanol for 3 h at 40 °C. The extraction dosage was 1:50 (w/v). The highest yield of RosA from Zostera was 3.13 mg/g DW (dried weight). The crude extracts of Zostera marina (10 mg/mL) and RosA (1 mg/mL) also showed inhibitory effects to some bacterial strains carried by PWN: Klebsiella sp., Stenotrophomonas maltophilia, Streptomyces sp. and Pantoea agglomerans. The results of these studies provide clues for preparing pesticide to control PWD from Z. marina. PMID:23201594

  15. An Antimicrobial Metabolite from Bacillus sp.: Significant Activity Against Pathogenic Bacteria Including Multidrug-Resistant Clinical Strains

    PubMed Central

    Chalasani, Ajay G.; Dhanarajan, Gunaseelan; Nema, Sushma; Sen, Ramkrishna; Roy, Utpal

    2015-01-01

    In this study, the cell free modified tryptone soya broth (pH 7.4 ± 0.2) of Bacillus subtilis URID 12.1 showed significant antimicrobial activity against multidrug-resistant strains of Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes and Enterococcus faecalis. The partially purified antimicrobial molecule was found to be resistant to extremes of pH and temperatures and also to higher concentrations of trypsin and proteinase K. The antimicrobial molecule was purified by a three-step method that included reversed-phase high performance liquid chromatography (RP-HPLC). The minimum inhibitory concentration (MIC) values were determined for 14 species of bacteria using a microbroth dilution technique. The HPLC-purified fraction showed the MICs ranging from 0.5 to 16 μg/ml for methicillin and vancomycin-resistant Staphylococcus aureus (MVRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) strains. The molecular mass of the antimicrobial compound was determined to be 842.37 Da. The same antimicrobial fraction showed negligible haemolytic activity against human red blood cells even at a concentration as high as 100 μg/ml. Because of its significant antimicrobial activity at low MIC values coupled with its non-haemolytic property, it may prove to be a novel antimicrobial lead molecule. PMID:26696963

  16. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins.

    PubMed

    Fuhrmann, Gregor; Serio, Andrea; Mazo, Manuel; Nair, Rekha; Stevens, Molly M

    2015-05-10

    Extracellular vesicles (EVs) are phospholipid-based particles endogenously produced by cells. Their natural composition and selective cell interactions make them promising drug carriers. However, in order to harness their properties, efficient exogenous drug encapsulation methods need to be investigated. Here, EVs from various cellular origins (endothelial, cancer and stem cells) were produced and characterised for size and composition. Porphyrins of different hydrophobicities were employed as model drugs and encapsulated into EVs using various passive and active methods (electroporation, saponin, extrusion and dialysis). Hydrophobic compounds loaded very efficiently into EVs and at significantly higher amounts than into standard liposomes composed of phosphocholine and cholesterol using passive incubation. Moreover, loading into EVs significantly increased the cellular uptake by >60% and the photodynamic effect of hydrophobic porphyrins in vitro compared to free or liposome encapsulated drug. The active encapsulation techniques, with the saponin-assisted method in particular, allowed an up to 11 fold higher drug loading of hydrophilic porphyrins compared to passive methods. EVs loaded with hydrophilic porphyrins induced a stronger phototoxic effect than free drug in a cancer cell model. Our findings create a firm basis for the development of EVs as smart drug carriers based on straightforward and transferable methods. PMID:25483424

  17. Aspects of igneous activity significant to a repository at Yucca Mountain, Nevada

    SciTech Connect

    Krier, D. J.; Perry, F. V.

    2004-01-01

    Location, timing, volume, and eruptive style of post-Miocene volcanoes have defined the volcanic hazard significant to a proposed high-level radioactive waste (HLW) and spent nuclear fuel (SNF) repository at Yucca Mountain, Nevada, as a low-probability, high-consequence event. Examination of eruptive centers in the region that may be analogueues to possible future volcanic activity at Yucca Mountain have aided in defining and evaluating the consequence scenarios for intrusion into and eruption above a repository. The probability of a future event intersecting a repository at Yucca Mountain has a mean value of 1.7 x 10{sup -8} per year. This probability comes from the Probabilistic Volcanic Hazard Assessment (PVHA) completed in 1996 and updated to reflect change in repository layout. Since that time, magnetic anomalies representing potential buried volcanic centers have been identified fiom magnetic surveys; however these potential buried centers only slightly increase the probability of an event intersecting the repository. The proposed repository will be located in its central portion of Yucca Mountain at approximately 300m depth. The process for assessing performance of a repository at Yucca Mountain has identified two scenarios for igneous activity that, although having a very low probability of occurrence, could have a significant consequence should an igneous event occur. Either a dike swarm intersecting repository drifts containing waste packages, or a volcanic eruption through the repository could result in release of radioactive material to the accessible environment. Ongoing investigations are assessing the mechanisms and significance of the consequence scenarios. Lathrop Wells Cone ({approx}80,000 yrs), a key analogue for estimating potential future volcanic activity, is the youngest surface expression of apparent waning basaltic volcanism in the region. Cone internal structure, lavas, and ash-fall tephra have been examined to estimate eruptive volume

  18. Glycosynthase Mutants of Endoglycosidase S2 Show Potent Transglycosylation Activity and Remarkably Relaxed Substrate Specificity for Antibody Glycosylation Remodeling.

    PubMed

    Li, Tiezheng; Tong, Xin; Yang, Qiang; Giddens, John P; Wang, Lai-Xi

    2016-08-01

    Glycosylation can exert a profound impact on the structures and biological functions of antibodies. Glycosylation remodeling using the endoglycosidase-catalyzed deglycosylation and transglycosylation approach is emerging as a promising platform to produce homogeneous glycoforms of antibodies, but the broad application of this method will require the availability of highly efficient glycosynthase mutants. We describe in this paper a systematic site-directed mutagenesis of an endoglycosidase from Streptococcus pyogenes of serotype M49 (Endo-S2) and the evaluation of the resulting mutants for their hydrolysis and transglycosylation activities. We found that mutations at the Asp-184 residue gave mutants that demonstrated significantly different properties, some possessed potent transglycosylation activity with diminished hydrolysis activity but others did not, which would be otherwise difficult to predict without the comparative study. In contrast to the previously reported Endo-S mutants that are limited to action on complex type N-glycans, the Endo-S2 glycosynthases described here, including D184M and D184Q, were found to have remarkably relaxed substrate specificity and were capable of transferring three major types (complex, high-mannose, and hybrid type) of N-glycans for antibody glycosylation remodeling. In addition, the Endo-S2 glycosynthase mutants were found to be much more active in general than the Endo-S mutants for transglycosylation. The usefulness of these Endo-S2 glycosynthase mutants was exemplified by an efficient glycosylation remodeling of two therapeutic monoclonal antibodies, rituximab and trastuzumab (Herceptin). PMID:27288408

  19. T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy

    PubMed Central

    Raber, Patrick L.; Sierra, Rosa A.; Thevenot, Paul T.; Shuzhong, Zhang; Wyczechowska, Dorota D.; Kumai, Takumi; Celis, Esteban; Rodriguez, Paulo C.

    2016-01-01

    The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ Tcells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer. PMID:27007050

  20. Clinical significance of serum protease-activated receptor-1 levels in gastric cancer patients

    PubMed Central

    TAS, FARUK; KARABULUT, SENEM; TASTEKIN, DIDEM; DURANYILDIZ, DERYA

    2016-01-01

    Protease-activated receptor-1 (PAR-1) has a significant role in the pathogenesis of various malignancies and its expression mainly affects the survivals of cancer patients. The aim of the present study was to determine the clinical significance of the serum concentrations of PAR-1 in patients with gastric carcinoma. A total of 63 pathologically confirmed gastric cancer patients were enrolled in this study, with a median age of 62 years. Serum PAR-1 concentrations were determined by the enzyme-linked immunosorbent assay method and no significant difference in the baseline serum PAR-1 concentrations was found between patients and normal controls (P=0.5). The investigated clinical variables, including patient age, gender, localization of lesion, histology, grade of pathology, disease stage and serum tumor markers (lactate dehydrogenase, carcinoembryonic antigen and carbohydrate antigen 19-9) were not correlated with serum PAR-1 levels (P>0.05). Furthermore, no association was identified between the serum PAR-1 level and chemotherapy responsiveness (P=0.43). Serum PAR-1 level also had no prognostic role for survival (P=0.27). In conclusion, the serum PAR-1 concentration has no diagnostic, predictive and prognostic values in gastric cancer patients. PMID:27073639

  1. Discovery of LPMO activity on hemicelluloses shows the importance of oxidative processes in plant cell wall degradation.

    PubMed

    Agger, Jane W; Isaksen, Trine; Várnai, Anikó; Vidal-Melgosa, Silvia; Willats, William G T; Ludwig, Roland; Horn, Svein J; Eijsink, Vincent G H; Westereng, Bjørge

    2014-04-29

    The recently discovered lytic polysaccharide monooxygenases (LPMOs) are known to carry out oxidative cleavage of glycoside bonds in chitin and cellulose, thus boosting the activity of well-known hydrolytic depolymerizing enzymes. Because biomass-degrading microorganisms tend to produce a plethora of LPMOs, and considering the complexity and copolymeric nature of the plant cell wall, it has been speculated that some LPMOs may act on other substrates, in particular the hemicelluloses that tether to cellulose microfibrils. We demonstrate that an LPMO from Neurospora crassa, NcLPMO9C, indeed degrades various hemicelluloses, in particular xyloglucan. This activity was discovered using a glycan microarray-based screening method for detection of substrate specificities of carbohydrate-active enzymes, and further explored using defined oligomeric hemicelluloses, isolated polymeric hemicelluloses and cell walls. Products generated by NcLPMO9C were analyzed using high performance anion exchange chromatography and multidimensional mass spectrometry. We show that NcLPMO9C generates oxidized products from a variety of substrates and that its product profile differs from those of hydrolytic enzymes acting on the same substrates. The enzyme particularly acts on the glucose backbone of xyloglucan, accepting various substitutions (xylose, galactose) in almost all positions. Because the attachment of xyloglucan to cellulose hampers depolymerization of the latter, it is possible that the beneficial effect of the LPMOs that are present in current commercial cellulase mixtures in part is due to hitherto undetected LPMO activities on recalcitrant hemicellulose structures. PMID:24733907

  2. Discovery of LPMO activity on hemicelluloses shows the importance of oxidative processes in plant cell wall degradation

    PubMed Central

    Agger, Jane W.; Isaksen, Trine; Várnai, Anikó; Vidal-Melgosa, Silvia; Willats, William G. T.; Ludwig, Roland; Horn, Svein J.; Eijsink, Vincent G. H.; Westereng, Bjørge

    2014-01-01

    The recently discovered lytic polysaccharide monooxygenases (LPMOs) are known to carry out oxidative cleavage of glycoside bonds in chitin and cellulose, thus boosting the activity of well-known hydrolytic depolymerizing enzymes. Because biomass-degrading microorganisms tend to produce a plethora of LPMOs, and considering the complexity and copolymeric nature of the plant cell wall, it has been speculated that some LPMOs may act on other substrates, in particular the hemicelluloses that tether to cellulose microfibrils. We demonstrate that an LPMO from Neurospora crassa, NcLPMO9C, indeed degrades various hemicelluloses, in particular xyloglucan. This activity was discovered using a glycan microarray-based screening method for detection of substrate specificities of carbohydrate-active enzymes, and further explored using defined oligomeric hemicelluloses, isolated polymeric hemicelluloses and cell walls. Products generated by NcLPMO9C were analyzed using high performance anion exchange chromatography and multidimensional mass spectrometry. We show that NcLPMO9C generates oxidized products from a variety of substrates and that its product profile differs from those of hydrolytic enzymes acting on the same substrates. The enzyme particularly acts on the glucose backbone of xyloglucan, accepting various substitutions (xylose, galactose) in almost all positions. Because the attachment of xyloglucan to cellulose hampers depolymerization of the latter, it is possible that the beneficial effect of the LPMOs that are present in current commercial cellulase mixtures in part is due to hitherto undetected LPMO activities on recalcitrant hemicellulose structures. PMID:24733907

  3. High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute myeloid leukemia cells

    PubMed Central

    Pera, Benet; Calvo-Vidal, M. Nieves; Ambati, Srikanth; Jordi, Michel; Kahn, Alissa; Díaz, J. Fernando; Fang, Weishuo; Altmann, Karl-Heinz; Cerchietti, Leandro; Moore, Malcolm A.S.

    2016-01-01

    Treatment failure in acute myeloid leukemia (AML) is frequently due to the persistence of a cell population resistant to chemotherapy through different mechanisms, in which drug efflux via ATP-binding cassette (ABC) proteins, specifically P-glycoprotein, is one of the most recognized. However, disappointing results from clinical trials employing inhibitors for these transporters have demonstrated the need to adopt different strategies. We hypothesized that microtubule targeting compounds presenting high affinity or covalent binding could overcome the effect of ABC transporters. We therefore evaluated the activity of the high-affinity paclitaxel analog CTX-40 as well as the covalent binder zampanolide (ZMP) in AML cells. Both molecules were active in chemosensitive as well as in chemoresistant cell lines overexpressing P-glycoprotein. Moreover, ZMP or CTX-40 in combination with daunorubicin showed synergistic killing without increased in vitro hematopoietic toxicity. In a primary AML sample, we further demonstrated that ZMP and CTX-40 are active in progenitor and differentiated leukemia cell populations. In sum, our data indicate that high affinity and covalent-binding anti-microtubule agents are active in AML cells otherwise chemotherapy resistant. PMID:26277539

  4. Map showing recently active breaks along the San Andreas Fault between Pt. Delgada and Bolinas Bay, California

    USGS Publications Warehouse

    Brown, Robert D., Jr.; Wolfe, Edward W.

    1970-01-01

    This strip map is one of a series of maps showing recently active fault breaks along the San Andreas and other active faults in California. It is designed to inform persons who are concerned with land use near the fault of the location of those fault breaks that have moved recently. The lines on the map are lines of rupture and creep that can be identified by field evidence and that clearly affect the present surface of the land. Map users should keep in mind that these lines are intended primarily as guides to help locate the fault; the mapped lines are not necessarily shown with the precision demanded by some engineering or land utilization needs.

  5. Desmethylanhydroicaritin isolated from Sophora flavescens, shows antitumor activities in U87MG cells via inhibiting the proliferation, migration and invasion.

    PubMed

    Kang, Chang-Won; Kim, Nan-Hee; Jung, Huyn Ah; Choi, Hyung-Wook; Kang, Min-Jae; Choi, Jae-Sue; Kim, Gun-Do

    2016-04-01

    This study is the first report of the antitumor activities of desmethylanhydroicaritin (DMAI) isolated from Sophora flavescens on U87MG cells. Human glioblastoma is one of the most aggressive malignant type of brain tumors and highly diffuses to around normal brain tissues. DMAI showed anti-proliferation effects on U87MG cells at the concentration of 30μM, however did not affect to HEK-293 cells. DMAI induced anti-proliferation effects via ERK/MAPK, PI3K/Akt/mTOR signal pathway and G2/M phase cell cycle arrest. DMAI led to morphological change and inhibition of filapodia formation through regulation of Rac 1 and Cdc 42. In addition, migration and invasion of U87MG cells were inhibited by DMAI via down-regulation of matrix metalloproteinase (MMP) -2 and MMP -9 expressions and activities. Our results suggest that DMAI has a potential as a therapeutic agent against glioblastoma cells. PMID:26991848

  6. Proliferative activity is a significant prognostic factor in male breast carcinoma.

    PubMed Central

    Pich, A.; Margaria, E.; Chiusa, L.

    1994-01-01

    The proliferative activity of male breast carcinoma has been investigated using the staining of the argyrophilic nucleolar organizer regions (AgNORs), the monoclonal antibody against the proliferating cell nuclear antigen (PC10) and the monoclonal antibody MIB-1 in formalin-fixed, paraffin-embedded specimens from 27 primary male breast carcinomas at diagnosis. A significant correlation was found between survival and AgNOR counts (median of survival 77 months for cases with AgNOR/cell < or = 7.27 but 37 months only for cases with > 7.27 AgNOR/cell; P = 0.001), proliferating cell nuclear antigen scores (median of survival 73 months for cases with proliferating cell nuclear antigen < or = 18.25% versus 41 for cases with proliferating cell nuclear antigen > 18.25%; P = 0.013) and MIB-1 scores (median of survival 73 months for cases with MIB-1 scores < or = 23.5% versus 37 months for cases with MIB-1 scores > 23.5%; P = 0.01). Tumor histological grade was also correlated with prognosis (median of survival 72 months for grade 2 versus 33 months for grade 3 tumors; P = 0.01). Estrogen and progesterone receptors, immunohistochemically detected on paraffin-embedded sections, had no prognostic value. In the multivariate survival analysis, only AgNOR counts (P = 0.007) and tumor size (P = 0.003) had an independent prognostic significance. Our results indicate that methods for assessing the cell proliferation in routinely processed specimens offer significant prognostic information in male breast carcinoma. The finding, together with the lack of prognostic significance for estrogen receptors and progesterone receptors, suggests that male breast carcinoma is biologically different from female breast cancer. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7519830

  7. Significant Modules and Biological Processes between Active Components of Salvia miltiorrhiza Depside Salt and Aspirin

    PubMed Central

    Xie, Yanming; Wang, Lianxin; Zhang, Yingying; Gu, Hao; Chai, Yan

    2016-01-01

    The aim of this study is to examine and compare the similarities and differences between active components of S. miltiorrhiza depside salt and aspirin using perspective of pharmacological molecular networks. Active components of S. miltiorrhiza depside salt and aspirin's related genes were identified via the STITCH4.0 and GeneCards Database. A text search engine (Agilent Literature Search 2.71) and MCODE software were applied to construct network and divide modules, respectively. Finally, 32, 2, and 28 overlapping genes, modules, and pathways were identified between active components of S. miltiorrhiza depside salt and aspirin. A multidimensional framework of drug network showed that two networks reflected commonly in human aortic endothelial cells and atherosclerosis process. Aspirin plays a more important role in metabolism, such as the well-known AA metabolism pathway and other lipid or carbohydrate metabolism pathways. S. miltiorrhiza depside salt still plays a regulatory role in type II diabetes mellitus, insulin resistance, and adipocytokine signaling pathway. Therefore, this study suggests that aspirin combined with S. miltiorrhiza depside salt may be more efficient in treatment of CHD patients, especially those with diabetes mellitus or hyperlipidemia. Further clinical trials to confirm this hypothesis are still needed. PMID:27069488

  8. Significant Modules and Biological Processes between Active Components of Salvia miltiorrhiza Depside Salt and Aspirin.

    PubMed

    Li, Yuan; Xie, Yanming; Wang, Lianxin; Zhang, Yingying; Gu, Hao; Chai, Yan

    2016-01-01

    The aim of this study is to examine and compare the similarities and differences between active components of S. miltiorrhiza depside salt and aspirin using perspective of pharmacological molecular networks. Active components of S. miltiorrhiza depside salt and aspirin's related genes were identified via the STITCH4.0 and GeneCards Database. A text search engine (Agilent Literature Search 2.71) and MCODE software were applied to construct network and divide modules, respectively. Finally, 32, 2, and 28 overlapping genes, modules, and pathways were identified between active components of S. miltiorrhiza depside salt and aspirin. A multidimensional framework of drug network showed that two networks reflected commonly in human aortic endothelial cells and atherosclerosis process. Aspirin plays a more important role in metabolism, such as the well-known AA metabolism pathway and other lipid or carbohydrate metabolism pathways. S. miltiorrhiza depside salt still plays a regulatory role in type II diabetes mellitus, insulin resistance, and adipocytokine signaling pathway. Therefore, this study suggests that aspirin combined with S. miltiorrhiza depside salt may be more efficient in treatment of CHD patients, especially those with diabetes mellitus or hyperlipidemia. Further clinical trials to confirm this hypothesis are still needed. PMID:27069488

  9. Posterior parietal cortex activity reflects the significance of others' actions during natural viewing.

    PubMed

    Salmi, Juha; Glerean, Enrico; Jääskeläinen, Iiro P; Lahnakoski, Juha M; Kettunen, Juho; Lampinen, Jouko; Tikka, Pia; Sams, Mikko

    2014-09-01

    The posterior parietal cortex (PPC) has been associated with multiple stimulus-driven (e.g., processing stimulus movements, providing visual signals for the motor system), goal-directed (e.g., directing visual attention to a target, processing behavioral priority of intentions), and action-related functions in previous studies with non-naturalistic paradigms. Here, we examined how these functions reflect PPC activity during natural viewing. Fourteen healthy volunteers watched a re-edited movie during functional magnetic resonance imaging (fMRI). Participants separately annotated behavioral priority (accounting for percepts, thoughts, and emotions) they had experienced during movie episodes. Movements in the movie were quantified with computer vision and eye movements were recorded from a separate group of subjects. Our results show that while overlapping dorsomedial PPC areas respond to episodes with multiple types of stimulus content, ventrolateral PPC areas exhibit enhanced activity when viewing goal-directed human hand actions. Furthermore, PPC activity related to viewing goal-directed human hand actions was more accurately explained by behavioral priority than by movements of the stimulus or eye movements. Taken together, our results suggest that PPC participates in perception of goal-directed human hand actions, supporting the view that PPC has a special role in providing visual signals for the motor system ("how"), in addition to processing visual spatial movements ("where"). PMID:24706557

  10. HIV-1 Structural Proteins Serve as PAMPs for TLR2 Heterodimers Significantly Increasing Infection and Innate Immune Activation

    PubMed Central

    Henrick, Bethany M.; Yao, Xiao-Dan; Rosenthal, Kenneth Lee

    2015-01-01

    Immune activation is critical to HIV infection and pathogenesis; however, our understanding of HIV innate immune activation remains incomplete. Recently we demonstrated that soluble TLR2 (sTLR2) physically inhibited HIV-induced NFκB activation and inflammation, as well as HIV-1 infection. In light of these findings, we hypothesized that HIV-1 structural proteins may serve as pathogen-associated molecular patterns (PAMPs) for cellular TLR2 heterodimers. These studies made use of primary human T cells and TZMbl cells stably transformed to express TLR2 (TZMbl-2). Our results demonstrated that cells expressing TLR2 showed significantly increased proviral DNA compared to cells lacking TLR2, and mechanistically this may be due to a TLR2-mediated increased CCR5 expression. Importantly, we show that HIV-1 structural proteins, p17, p24, and gp41, act as viral PAMPs signaling through TLR2 and its heterodimers leading to significantly increased immune activation via the NFκB signaling pathway. Using co-immunoprecipitation and a dot blot method, we demonstrated direct protein interactions between these viral PAMPs and TLR2, while only p17 and gp41 bound to TLR1. Specifically, TLR2/1 heterodimer recognized p17 and gp41, while p24 lead to immune activation through TLR2/6. These results were confirmed using TLR2/1 siRNA knock down assays which ablated p17 and gp41-induced cellular activation and through studies of HEK293 cells expressing selected TLRs. Interestingly, our results show in the absence of TLR6, p24 bound to TLR2 and blocked p17 and gp41-induced activation, thus providing a novel mechanism by which HIV-1 can manipulate innate sensing. Taken together, our results identified, for the first time, novel HIV-1 PAMPs that play a role in TLR2-mediated cellular activation and increased proviral DNA. These findings have important implications for our fundamental understanding of HIV-1 immune activation and pathogenesis, as well as HIV-1 vaccine development. PMID:26347747

  11. Coadministration of doxorubicin and etoposide loaded in camel milk phospholipids liposomes showed increased antitumor activity in a murine model.

    PubMed

    Maswadeh, Hamzah M; Aljarbou, Ahmed N; Alorainy, Mohammed S; Rahmani, Arshad H; Khan, Masood A

    2015-01-01

    Small unilamellar vesicles from camel milk phospholipids (CML) mixture or from 1,2 dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) were prepared, and anticancer drugs doxorubicin (Dox) or etoposide (ETP) were loaded. Liposomal formulations were used against fibrosarcoma in a murine model. Results showed a very high percentage of Dox encapsulation (~98%) in liposomes (Lip) prepared from CML-Lip or DPPC-Lip, whereas the percentage of encapsulations of ETP was on the lower side, 22% of CML-Lip and 18% for DPPC-Lip. Differential scanning calorimetry curves show that Dox enhances the lamellar formation in CML-Lip, whereas ETP enhances the nonlamellar formation. Differential scanning calorimetry curves also showed that the presence of Dox and ETP together into DPPC-Lip produced the interdigitation effect. The in vivo anticancer activity of liposomal formulations of Dox or ETP or a combination of both was assessed against benzopyrene (BAP)-induced fibrosarcoma in a murine model. Tumor-bearing mice treated with a combination of Dox and ETP loaded into CML-Lip showed increased survival and reduced tumor growth compared to other groups, including the combination of Dox and ETP in DPPC-Lip. Fibrosarcoma-bearing mice treated with a combination of free (Dox + ETP) showed much higher tumor growth compared to those groups treated with CML-Lip-(Dox + ETP) or DPPC-Lip-(Dox + ETP). Immunohistochemical study was also performed to show the expression of tumor-suppressor PTEN, and it was found that the tumor tissues from the group of mice treated with a combination of free (Dox + ETP) showed greater loss of cytoplasmic PTEN than tumor tissues obtained from the groups of mice treated with CML-Lip-(Dox + ETP) or DPPC-Lip-(Dox + ETP). PMID:25926730

  12. Metal-based netropsin mimics showing AT-selective DNA binding and DNA cleavage activity at red light.

    PubMed

    Patra, Ashis K; Bhowmick, Tuhin; Ramakumar, Suryanarayanarao; Chakravarty, Akhil R

    2007-10-29

    Copper(II) bis-arginate [Cu(l-arg)2](NO3)2 (1) and [Cu(l-arg)(phen)Cl]Cl (2) as mimics of the minor-groove-binding natural antibiotic netropsin show preferential binding to the AT-rich region of double-stranded DNA. The complexes with a d-d band near 600 nm display oxidative DNA cleavage activity on photoirradiation at UV-A light of 365 nm and at red light of 647.1 nm (Ar-Kr laser) in a metal-assisted photoexcitation process forming singlet oxygen (1O2) species in a type-2 pathway. PMID:17880211

  13. Lack of significant promoting activity by benzene in the rat liver model of carcinogenesis

    SciTech Connect

    Taningher, M.; Perrotta, A.; Malacarne, D.

    1995-08-01

    The promoting activity of benzene on rat liver carcinogenesis was investigated. The chemical was tested for its ability to enhance the growth of preneoplastic foci, as detected by gamma-glutamyl transpeptidase (GGT) staining in diethylnitrosamine (DENA) initiated hepatocytes. Two weeks after receiving a single ip dose of 200 mg/kg DENA, F344 rats were given daily oral doses of 400 mg/kg benzene (5 d/wk) for 6 wk. At wk 3 after the experiment began, all animals underwent partial hepatectomy, and at wk 8 were sacrificed. Following benzene treatment, no variation in the liver/body weight ratio was observed. After scoring of foci in liver slides, no significant difference in foci number and area could be observed between rats treated with DENA plus benzene and rats treated with DENA alone. Practically no foci were observed in the liver of rats treated only with benzene. The lack of benzene promoting activity in the liver model is discussed. 28 refs., 1 fig., 1 tab.

  14. Single-trial fMRI Shows Contralesional Activity Linked to Overt Naming Errors in Chronic Aphasic Patients

    PubMed Central

    Postman-Caucheteux, Whitney Anne; Birn, Rasmus M.; Pursley, Randall H.; Butman, John A.; Solomon, Jeffrey M.; Picchioni, Dante; McArdle, Joe; Braun, Allen R.

    2016-01-01

    We used fMRI to investigate the roles played by perilesional and contralesional cortical regions during language production in stroke patients with chronic aphasia. We applied comprehensive psycholinguistic analyses based on well-established models of lexical access to overt picture-naming responses, which were evaluated using a single trial design that permitted distinction between correct and incorrect responses on a trial-by-trial basis. Although both correct and incorrect naming responses were associated with left-sided perilesional activation, incorrect responses were selectively associated with robust right-sided contralesional activity. Most notably, incorrect responses elicited overactivation in the right inferior frontal gyrus that was not observed in the contrasts for patients’ correct responses or for responses of age-matched control subjects. Errors were produced at slightly later onsets than accurate responses and comprised predominantly semantic paraphasias and omissions. Both types of errors were induced by pictures with greater numbers of alternative names, and omissions were also induced by pictures with late acquired names. These two factors, number of alternative names per picture and age of acquisition, were positively correlated with activation in left and right inferior frontal gyri in patients as well as control subjects. These results support the hypothesis that some right frontal activation may normally be associated with increasing naming difficulty, but in patients with aphasia, right frontal overactivation may reflect ineffective effort when left hemisphere perilesional resources are insufficient. They also suggest that contralesional areas continue to play a role—dysfunctional rather than compensatory—in chronic aphasic patients who have experienced a significant degree of recovery. PMID:19413476

  15. Polyphenol-rich strawberry extract (PRSE) shows in vitro and in vivo biological activity against invasive breast cancer cells.

    PubMed

    Amatori, Stefano; Mazzoni, Luca; Alvarez-Suarez, Josè Miguel; Giampieri, Francesca; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Yuliett; Afrin, Sadia; Errico Provenzano, Alfredo; Persico, Giuseppe; Mezzetti, Bruno; Amici, Augusto; Fanelli, Mirco; Battino, Maurizio

    2016-01-01

    We describe the biological effects of a polyphenol-rich strawberry extract (PRSE), obtained from the "Alba" variety, on the highly aggressive and invasive basal-like breast cancer cell line A17. Dose-response and time-course experiments showed that PRSE is able to decrease the cellular viability of A17 cells in a time- and dose-dependent manner. PRSE effect on cell survival was investigated in other tumor and normal cell lines of both mouse and human origin, demonstrating that PRSE is more active against breast cancer cells. Cytofluorimetric analysis of A17 cells demonstrated that sub-lethal doses of PRSE reduce the number of cells in S phase, inducing the accumulation of cells in G1 phase of cell cycle. In addition, the migration of A17 cells was studied monitoring the ability of PRSE to inhibit cellular mobility. Gene expression analysis revealed the modulation of 12 genes playing different roles in the cellular migration, adhesion and invasion processes. Finally, in vivo experiments showed the growth inhibition of A17 cells orthotopically transplanted into FVB syngeneic mice fed with PRSE. Overall, we demonstrated that PRSE exerts important biological activities against a highly invasive breast cancer cell line both in vitro and in vivo suggesting the strawberry extracts as preventive/curative food strategy. PMID:27498973

  16. Polyphenol-rich strawberry extract (PRSE) shows in vitro and in vivo biological activity against invasive breast cancer cells

    PubMed Central

    Amatori, Stefano; Mazzoni, Luca; Alvarez-Suarez, Josè Miguel; Giampieri, Francesca; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Yuliett; Afrin, Sadia; Errico Provenzano, Alfredo; Persico, Giuseppe; Mezzetti, Bruno; Amici, Augusto; Fanelli, Mirco; Battino, Maurizio

    2016-01-01

    We describe the biological effects of a polyphenol-rich strawberry extract (PRSE), obtained from the “Alba” variety, on the highly aggressive and invasive basal-like breast cancer cell line A17. Dose-response and time-course experiments showed that PRSE is able to decrease the cellular viability of A17 cells in a time- and dose-dependent manner. PRSE effect on cell survival was investigated in other tumor and normal cell lines of both mouse and human origin, demonstrating that PRSE is more active against breast cancer cells. Cytofluorimetric analysis of A17 cells demonstrated that sub-lethal doses of PRSE reduce the number of cells in S phase, inducing the accumulation of cells in G1 phase of cell cycle. In addition, the migration of A17 cells was studied monitoring the ability of PRSE to inhibit cellular mobility. Gene expression analysis revealed the modulation of 12 genes playing different roles in the cellular migration, adhesion and invasion processes. Finally, in vivo experiments showed the growth inhibition of A17 cells orthotopically transplanted into FVB syngeneic mice fed with PRSE. Overall, we demonstrated that PRSE exerts important biological activities against a highly invasive breast cancer cell line both in vitro and in vivo suggesting the strawberry extracts as preventive/curative food strategy. PMID:27498973

  17. The selective VEGFR1-3 inhibitor axitinib (AG-013736) shows antitumor activity in human neuroblastoma xenografts.

    PubMed

    Rössler, Jochen; Monnet, Yann; Farace, Francoise; Opolon, Paule; Daudigeos-Dubus, Estelle; Bourredjem, Abderrahmane; Vassal, Gilles; Geoerger, Birgit

    2011-06-01

    Tumor angiogenesis in childhood neuroblastoma is an important prognostic factor suggesting a potential role for antiangiogenic agents in the treatment of high-risk disease. Within the KidsCancerKinome project, we evaluated the new oral selective pan-VEGFR tyrosine kinase inhibitor axitinib (AG-013736) against neuroblastoma cell lines and the subcutaneous and orthotopic xenograft model IGR-N91 derived from a primary bone marrow metastasis. Axitinib reduced cell proliferation in a dose-dependent manner with IC(50) doses between 274 and >10,000 nmol/l. Oral treatment with 30 mg/kg BID for 2 weeks in advanced tumors yielded significant tumor growth delay, with a median time to reach five times initial tumor volume of 11.4 days compared to controls (p = 0.0006) and resulted in significant reduction in bioluminescence. Simultaneous inhibition of VEGFR downstream effector mTOR using rapamycin 20 mg/kg q2d×5 did not statistically enhance tumor growth delay compared to single agent activities. Axitinib downregulated VEGFR-2 phosphorylation resulting in significantly decreased microvessel density (MVD) and overall surface fraction of tumor vessels (OSFV) in all xenografts as measured by CD34 immunohistochemical staining (mean MVD ± SD and OSFV at 14 days 21.27 ± 10.03 in treated tumors vs. 48.79 ± 17.27 in controls and 0.56% vs. 1.29%; p = 0.0006, respectively). We further explored the effects of axitinib on circulating mature endothelial cells (CECs) and endothelial progenitor cells (CEPs) measured by flow cytometry. While only transient modification was observed for CECs, CEP counts were significantly reduced during and up to 14 days after end of treatment. Axitinib has potent antiangiogenic properties that may warrant further evaluation in neuroblastoma. PMID:20715103

  18. Trans Fatty Acid Derived Phospholipids Show Increased Membrane Cholesterol and Reduced Receptor Activation as Compared to Their Cis Analogs

    PubMed Central

    Niu, Shui-Lin; Mitchell, Drake C.; Litman, Burton J.

    2005-01-01

    The consumption of trans fatty acid (TFA) is linked to the elevation of LDL cholesterol and is considered to be a major health risk factor for coronary heart disease. Despite several decades of extensive research on this subject, the underlying mechanism of how TFA modulates serum cholesterol levels remains elusive. In this study, we examined the molecular interaction of TFA-derived phospholipid with cholesterol and the membrane receptor rhodopsin in model membranes. Rhodopsin is a prototypical member of the G-protein coupled receptor family. It has a well-characterized structure and function and serves as a model membrane receptor in this study. Phospholipid–cholesterol affinity was quantified by measuring cholesterol partition coefficients. Phospholipid–receptor interactions were probed by measuring the level of rhodopsin activation. Our study shows that phospholipid derived from TFA had a higher membrane cholesterol affinity than their cis analogues. TFA phospholipid membranes also exhibited a higher acyl chain packing order, which was indicated by the lower acyl chain packing free volume as determined by DPH fluorescence and the higher transition temperature for rhodopsin thermal denaturation. The level of rhodopsin activation was diminished in TFA phospholipids. Since membrane cholesterol level and membrane receptors are involved in the regulation of cholesterol homeostasis, the combination of higher cholesterol content and reduced receptor activation associated with the presence of TFA–phospholipid could be factors contributing to the elevation of LDL cholesterol. PMID:15766276

  19. Substrate uptake tests and quantitative FISH show differences in kinetic growth of bulking and non-bulking activated sludge.

    PubMed

    Lou, Inchio; de Los Reyes, Francis L

    2005-12-20

    The competition between filaments and floc formers in activated sludge has been historically described using kinetic selection. However, recent studies have suggested that bacterial storage may also be an important factor in microbial selection, since the dynamic nature of substrate flows into wastewater treatment plants elicit transient responses from microorganisms. Respirometry-based kinetic selection should thus be reevaluated by considering cell storage, and a more reliable method should be developed to include bacterial storage in the analysis of growth of filaments and floc formers in activated sludge. In this study, we applied substrate uptake tests combined with metabolic modeling to determine the growth rates, yields and maintenance coefficients of bulking and non-bulking activated sludge developed in lab scale reactors under feast and famine conditions. The results of quantitative fluorescence in situ hybridization (FISH) showed that the filaments Eikelboom Type 1851, Type 021N, and Thiothrix nivea were dominant in bulking sludge, comprising 42.0 % of mixed liquor volatile suspended solids (MLVSS), with 61.6% of the total filament length extending from flocs into bulk solution. Only low levels of Type 1851 filament length (4.9% of MLVSS) occurred in non-bulking sludge, 83.0% of which grew inside the flocs. The kinetic parameters determined from the substrate uptake tests were consistent with those from respirometry and showed that filamentous bulking sludge had lower growth rates and maintenance coefficients than non-bulking sludge. These results provide support for growth kinetic differences in explaining the competitive strategy of filamentous bacteria. PMID:16155949

  20. Preparation and characterization of quaternary ammonium chitosan hydrogel with significant antibacterial activity.

    PubMed

    Fan, Lihong; Yang, Jing; Wu, Huan; Hu, Zhihai; Yi, Jiayan; Tong, Jun; Zhu, Xiaoming

    2015-08-01

    Quaternary ammonium chitosan (HACC)/polyvinyl alcohol (PVA)/polyethylene oxide (PEO) hydrogels were prepared using gamma radiation. The chemical structure of the hydrogels was characterized using FT-IR. The results revealed that HACC, PVA and PEO were perfectly compatible and interacted via the hydrogen bonds. As revealed by SEM, scaffolds with a homogeneous interconnected pore structure were obtained after lyophilizing the hydrogels. The influence of different radiation doses and weight ratios on properties including gel content, swelling ability, water evaporation rate and mechanical properties were investigated. It indicated that the hydrogels had the good swelling ability, water evaporation rate and mechanical properties. In vitro antibacterial activity assessment, the hydrogels exhibited a pronounced inhibitory effect against two bacteria (Staphylococcus aureus and Escherichia coli). Therefore, the hydrogels showed a promising potential to be applied as wound dressing. PMID:25895959

  1. Dissociated functional significance of decision-related activity in the primate dorsal stream.

    PubMed

    Katz, Leor N; Yates, Jacob L; Pillow, Jonathan W; Huk, Alexander C

    2016-07-14

    During decision making, neurons in multiple brain regions exhibit responses that are correlated with decisions. However, it remains uncertain whether or not various forms of decision-related activity are causally related to decision making. Here we address this question by recording and reversibly inactivating the lateral intraparietal (LIP) and middle temporal (MT) areas of rhesus macaques performing a motion direction discrimination task. Neurons in area LIP exhibited firing rate patterns that directly resembled the evidence accumulation process posited to govern decision making, with strong correlations between their response fluctuations and the animal's choices. Neurons in area MT, in contrast, exhibited weak correlations between their response fluctuations and choices, and had firing rate patterns consistent with their sensory role in motion encoding. The behavioural impact of pharmacological inactivation of each area was inversely related to their degree of decision-related activity: while inactivation of neurons in MT profoundly impaired psychophysical performance, inactivation in LIP had no measurable impact on decision-making performance, despite having silenced the very clusters that exhibited strong decision-related activity. Although LIP inactivation did not impair psychophysical behaviour, it did influence spatial selection and oculomotor metrics in a free-choice control task. The absence of an effect on perceptual decision making was stable over trials and sessions and was robust to changes in stimulus type and task geometry, arguing against several forms of compensation. Thus, decision-related signals in LIP do not appear to be critical for computing perceptual decisions, and may instead reflect secondary processes. Our findings highlight a dissociation between decision correlation and causation, showing that strong neuron-decision correlations do not necessarily offer direct access to the neural computations underlying decisions. PMID:27376476

  2. UNESCO active learning approach in optics and photonics leads to significant change in Morocco

    NASA Astrophysics Data System (ADS)

    Berrada, K.; Channa, R.; Outzourhit, A.; Azizan, M.; Oueriagli, A.

    2014-07-01

    There are many difficulties in teaching science and technology in developing countries. Several different teaching strategies have to be applied in these cases. More specifically, for developing countries competencies in teaching science in the introductory classroom has attracted much attention. As a specific example we will consider the Moroccan system. In most developing countries everything is moving so slowly that the progress stays static for development. Also, any change needs time, effort and engagement. In our case we discovered that many teachers feel uncomfortable when introducing new teaching methods and evaluation in classes at introductory physics. However, the introduction of an Active Learning in our curricula showed difficulties that students have in understanding physics and especially concepts. Students were interested in having Active Learning courses much more than passive and traditional ones. Changing believes on physical phenomena and reality of the world students become more attractive and their way of thinking Science changed. The main philosophy of fostering modern hands-on learning techniques -adapted to local needs and availability of teaching resources- is elaborated. The Active Learning program provides the teachers with a conceptual evaluation instrument, drawn from relevant physics education research, giving teachers an important tool to measure student learning. We will try to describe the UNESCO Chair project in physics created in 2010 at Cadi Ayyad University since our first experience with UNESCO ALOP program. Many efforts have been done so far and the project helps now to develop more national and international collaborations between universities and Regional Academies of Education and Training. As a new result of these actions and according to our local needs, the translation of the ALOP program into Arabic is now available under the auspice of UNESCO and encouragement of international partners SPIE, ICTP, ICO and OSA.

  3. Significant activity of ecdysteroids on the resistance to doxorubicin in mammalian cancer cells expressing the human ABCB1 transporter.

    PubMed

    Martins, Ana; Tóth, Noémi; Ványolós, Attila; Béni, Zoltán; Zupkó, István; Molnár, József; Báthori, Mária; Hunyadi, Attila

    2012-06-14

    Multidrug resistance (MDR) is a major cause of failure of cancer chemotherapy. Fifty-eight ecdysteroids, herbal analogues of the insect molting hormone and their semisynthetic derivatives, were tested for their activity against L5178 mouse T-cell lymphoma cells (non-MDR) and their subcell line transfected with pHa MDR1/A retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line). The compounds showed very low antiproliferative activities but modulated the efflux of rhodamine 123 mediated by the ABCB1 transporter. Roughly depending on the polarity, mild to strong synergism or antagonism was observed by combining ecdysteroids with doxorubicin, and specific structure-activity relationships were also found. Our results show the effect of ecdysteroids on MDR cancer cells for the first time. Less polar derivatives may serve as valuable leads toward a potent and safe resistance modulator. Biological significance of the resistance-increasing activity of the most abundant phytoecdysteroids including 20-hydroxyecdysone is yet to be clarified. PMID:22578055

  4. Structural and functional characterization of "laboratory evolved" cytochrome P450cam mutants showing enhanced naphthalene oxygenation activity.

    PubMed

    Matsuura, Koji; Tosha, Takehiko; Yoshioka, Shiro; Takahashi, Satoshi; Ishimori, Koichiro; Morishima, Isao

    2004-10-29

    To elucidate molecular mechanisms for the enhanced oxygenation activity in the three mutants of cytochrome P450cam screened by 'laboratory evolution' [Nature 399 (1999) 670], we purified the mutants and characterized their functional and structural properties. The electronic absorption and resonance Raman spectra revealed that the structures of heme binding site of all purified mutants were quite similar to that of the wild-type enzyme, although the fraction of the inactivated form, called "P420," was increased. In the reaction with H(2)O(2), only trace amounts of the naphthalene hydroxylation product were detected by gas chromatography. We, therefore, conclude that the three mutants do not exhibit significant changes in the structural and functional properties from those of wild-type P450cam except for the stability of the axial ligand in the reduced form. The enhanced fluorescence in the whole-cell assay would reflect enhancement in the oxygenation activity below the detectable limit of the gas chromatography and/or contributions of other reactions catalyzed by the heme iron. PMID:15451425

  5. Immobilized MAS1 lipase showed high esterification activity in the production of triacylglycerols with n-3 polyunsaturated fatty acids.

    PubMed

    Wang, Xiumei; Li, Daoming; Qu, Man; Durrani, Rabia; Yang, Bo; Wang, Yonghua

    2017-02-01

    Immobilization of lipase MAS1 from marine Streptomyces sp. strain W007 and its application in catalyzing esterification of n-3 polyunsaturated fatty acids (PUFA) with glycerol were investigated. The resin XAD1180 was selected as a suitable support for the immobilization of lipase MAS1, and its absorption ability was 75mg/g (lipase/resin ratio) with initial buffer pH value of 8.0. The thermal stability of immobilized MAS1 was improved significantly compared with that of the free lipase. Immobilized MAS1 had no regiospecificity in the hydrolysis of triolein. The highest esterification degree (99.31%) and TAG content (92.26%) by immobilized MAS1-catalyzed esterification were achieved under the optimized conditions, which were significantly better than those (82.16% and 47.26%, respectively) by Novozym 435. More than 92% n-3 PUFA was incorporated into TAG that had similar fatty acids composition to the substrate (n-3 PUFA). The immobilized MAS1 exhibited 50% of its initial activity after being used for five cycles. PMID:27596418

  6. Evaluation of About Being Active, an online lesson about physical activity shows that perception of being physically active is higher in eating competent low-income women

    PubMed Central

    2013-01-01

    Background Eating competence (EC) has been associated with positive health outcomes such as reduced cardiovascular risk and higher diet quality. This study compared reported physical activity and EC in 512 low-income women participating in an online program that included a physical activity lesson and assessed response to this lesson. Methods Educational intervention and surveys were completed online. EC was assessed with the Satter Eating Competence Inventory for Low-Income (ecSI/LI). Results Participants were mostly white, <31 years, overweight/obese (60%), and food insecure (58%). EC was higher for those who self-reported being physically active (30.1 ± 8.3 vs. 24.9 ± 8.1; P<0.001) and were active for ≥ 30 minutes/day (29.9 ± 8.3 vs. 26.3 ± 8.6), even with age, weight satisfaction, and BMI controlled. EC of obese physically active persons was higher than normal weight, but physically inactive women. The physical activity module was well received with responses unrelated to time involved or physical activity level. Conclusions Low-income women were interested in learning about physical activity and responded positively to online delivery. Overall EC levels were low, but higher for physically active women, supporting efforts to enhance EC. Additional research is needed to determine if EC is associated with responses to physical activity education. PMID:23496893

  7. Genome-Wide Identification of Mitogen-Activated Protein Kinase Gene Family across Fungal Lineage Shows Presence of Novel and Diverse Activation Loop Motifs

    PubMed Central

    Mohanta, Tapan Kumar; Mohanta, Nibedita; Parida, Pratap; Panda, Sujogya Kumar; Ponpandian, Lakshmi Narayanan; Bae, Hanhong

    2016-01-01

    The mitogen-activated protein kinase (MAPK) is characterized by the presence of the T-E-Y, T-D-Y, and T-G-Y motifs in its activation loop region and plays a significant role in regulating diverse cellular responses in eukaryotic organisms. Availability of large-scale genome data in the fungal kingdom encouraged us to identify and analyse the fungal MAPK gene family consisting of 173 fungal species. The analysis of the MAPK gene family resulted in the discovery of several novel activation loop motifs (T-T-Y, T-I-Y, T-N-Y, T-H-Y, T-S-Y, K-G-Y, T-Q-Y, S-E-Y and S-D-Y) in fungal MAPKs. The phylogenetic analysis suggests that fungal MAPKs are non-polymorphic, had evolved from their common ancestors around 1500 million years ago, and are distantly related to plant MAPKs. We are the first to report the presence of nine novel activation loop motifs in fungal MAPKs. The specificity of the activation loop motif plays a significant role in controlling different growth and stress related pathways in fungi. Hence, the presences of these nine novel activation loop motifs in fungi are of special interest. PMID:26918378

  8. Renal adenylate cyclase assay for biologically active parathyroid hormone: clinical utility and physiological significance.

    PubMed

    Auf'mkolk, B; Hesch, R D

    1986-01-01

    The stimulation of cyclic AMP production by human renal cortical membranes in the presence of the GTP analogue 5'-guanylimidodiphosphate and a calcium chelator represents a homologous assay system for the evaluation of biologically active parathyroid hormone (bioPTH) in human serum. Bioactive PTH was raised above normal (normal range: undetectable to 4.6 pmol human PTH(1-34) per 1) in 13/17 (76%) patients with primary hyperparathyroidism, in 5/6 (83%) patients with surgically proven hyperparathyroidism secondary to chronic renal failure, in 4/5 (80%) patients with hyperparathyroidism secondary to hypocalcaemia, in all three patients with pseudohypoparathyroidism, in 5/17 (29%) patients with osteoporosis and in 1/9 (11%) patients with renal stones and/or hypercalciuria. Bioactive PTH correlated positively with immunoreactive PTH (iPTH) measured with a radioimmunoassay predominantly recognizing the middle- and carboxyl-terminal region of the PTH molecule (r = 0.503, P less than 0.001). A positive correlation (r = 0.572, P less than 0.05) was found between values of serum calcium and bioPTH in the group with primary hyperparathyroidism. Immunoreactive PTH did not correlate significantly with calcium in this group. In the other patients except those who had chronic renal failure, a negative correlation between serum calcium and both bioPTH and iPTH was observed (P less than 0.01). When alkaline phosphatase was compared with bioPTH in all patients, the correlation was positive (r = 0.390, P less than 0.01); no significant correlation existed between iPTH and alkaline phosphatase in the patients studied.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3944539

  9. The Nucleoside Analog BMS-986001 Shows Greater In Vitro Activity against HIV-2 than against HIV-1

    PubMed Central

    Raugi, Dana N.; Wu, Vincent H.; Leong, Sally S.; Parker, Kate M.; Oakes, Mariah K.; Sow, Papa Salif; Ba, Selly; Seydi, Moussa; Gottlieb, Geoffrey S.

    2015-01-01

    Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated the in vitro activity of the investigational nucleoside analog BMS-986001 (2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4′-ethynyl stavudine, or 4′-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC50s) ranging from 30 to 81 nM. In contrast, EC50s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC50 for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ± 18 nM versus 610 ± 200 nM, respectively; mean ± standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2ROD9 strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture. PMID:26392486

  10. The Nucleoside Analog BMS-986001 Shows Greater In Vitro Activity against HIV-2 than against HIV-1.

    PubMed

    Smith, Robert A; Raugi, Dana N; Wu, Vincent H; Leong, Sally S; Parker, Kate M; Oakes, Mariah K; Sow, Papa Salif; Ba, Selly; Seydi, Moussa; Gottlieb, Geoffrey S

    2015-12-01

    Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated the in vitro activity of the investigational nucleoside analog BMS-986001 (2',3'-didehydro-3'-deoxy-4'-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4'-ethynyl stavudine, or 4'-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC50s) ranging from 30 to 81 nM. In contrast, EC50s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC50 for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ± 18 nM versus 610 ± 200 nM, respectively; mean ± standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2ROD9 strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture. PMID:26392486

  11. "The Show"

    ERIC Educational Resources Information Center

    Gehring, John

    2004-01-01

    For the past 16 years, the blue-collar city of Huntington, West Virginia, has rolled out the red carpet to welcome young wrestlers and their families as old friends. They have come to town chasing the same dream for a spot in what many of them call "The Show". For three days, under the lights of an arena packed with 5,000 fans, the state's best…

  12. Unlike adults, children and adolescents show predominantly increased neural activation to social exclusion by members of the opposite gender.

    PubMed

    Bolling, Danielle Z; Pelphrey, Kevin A; Vander Wyk, Brent C

    2016-10-01

    The effects of group membership on brain responses to social exclusion have been investigated in adults, revealing greater anterior cingulate responses to exclusion by members of one's in-group (e.g., same-gender). However, social exclusion is a critical aspect of peer relations in youth and reaches heightened salience during adolescence, a time when social anxiety disorders are also emergent. While the behavioral and neural correlates of social exclusion in adolescence have been extensively explored, the effects of group membership on peer rejection are less clear. The current study used functional magnetic resonance imaging (fMRI) to investigate the differential neural correlates of being excluded by peers of one's same- versus opposite-gender during an online ball-toss game. Participants were a group of typically developing children and adolescents (7-17 years). As predicted, anterior cingulate cortex showed a main effect of social exclusion versus fair play. However, unlike a previous adult study, this region did not show increased activation to same-gender exclusion. Instead, several regions differentiating same- versus opposite-gender exclusion were exclusively more sensitive to exclusion by one's opposite gender. These results are discussed in the context of adolescent socio-emotional development. PMID:26592311

  13. Purification and characterization of patagonfibrase, a metalloproteinase showing alpha-fibrinogenolytic and hemorrhagic activities, from Philodryas patagoniensis snake venom.

    PubMed

    Peichoto, M E; Teibler, P; Mackessy, S P; Leiva, L; Acosta, O; Gonçalves, L R C; Tanaka-Azevedo, A M; Santoro, M L

    2007-05-01

    Venoms of Colubridae snakes are a rich source of novel compounds, which may have applications in medicine and biochemistry. In the present study, we describe the purification and characterization of a metalloproteinase (patagonfibrase), the first protein to be isolated from Philodryas patagoniensis (Colubridae) snake venom. Patagonfibrase is a single-chain protein, showing a molecular mass of 53,224 Da and an acidic isoelectric point (5.8). It hydrolyzed selectively the Aalpha-chain of fibrinogen and when incubated with fibrinogen or plasma, the thrombin clotting time was prolonged. Prominent hemorrhage developed in mouse skin after intradermal injection of patagonfibrase. When administered into mouse gastrocnemius muscle, it induced local hemorrhage and necrosis, and systemic bleeding in lungs. Patagonfibrase showed proteolytic activity toward azocasein, which was enhanced by Ca(2+) and inhibited by Zn(2+), cysteine, dithiothreitol and Na(2)EDTA. Patagonfibrase impaired platelet aggregation induced by collagen and ADP. Thus, patagonfibrase may play a key role in the pathogenesis of disturbances that occur in P. patagoniensis envenomation, and may be used as a biological tool to explore many facets of hemostasis. PMID:17306461

  14. The human interferon-regulated ISG95 protein interacts with RNA polymerase II and shows methyltransferase activity

    SciTech Connect

    Haline-Vaz, Thais; Lima Silva, Tereza Cristina; Zanchin, Nilson I.T.

    2008-08-08

    A major mechanism of cellular resistance to viral invasion involves genes from the interferon signaling pathway, called ISGs (interferon stimulated genes). Global transcriptional profiling studies have linked increased expression of ISG95 (KIAA0082) to response to interferon treatment and viral infection, suggesting that it may be part of the cellular defense against viral replication. In this work, we show that the ISG95 promoter can drive interferon-induced transcription of a reporter gene in Vero cells. Recombinant ISG95 shows RNA- and S-adenosyl-methionine binding and protein methyltransferase activity in vitro. ISG95 interacts with the C-terminal domain of RNA polymerase II, which is consistent with its nuclear localization and with the predicted function of the WW domain found in the C-terminal region of ISG95. The results presented in this work indicate that ISG95 is part of the interferon response pathway and functions in the pre-mRNA processing events mediated by the C-terminal domain of the RNA polymerase II.

  15. Crack users show high rates of antisocial personality disorder, engagement in illegal activities and other psychosocial problems.

    PubMed

    Paim Kessler, Felix Henrique; Barbosa Terra, Mauro; Faller, Sibele; Ravy Stolf, Anderson; Carolina Peuker, Ana; Benzano, Daniela; Pechansky, Flavio

    2012-01-01

    The aim of this study was to compare three groups of Brazilian psychoactive substance (PAS) abuse patients (crack cocaine users, cocaine snorters, and non-cocaine PAS users) in terms of psychiatric comorbidities and severity of psychosocial problems. A cross-sectional, multi-center study was conducted at five Brazilian research centers. A total of 738 current PAS abusers seeking specialized treatment (outpatient and inpatient clinics) were assessed using the sixth version of the Addiction Severity Index (ASI-6): 293 patients using crack cocaine were compared with 126 using powder cocaine and 319 using non-cocaine PAS (mostly alcohol and marijuana). Psychiatric comorbidities were assessed in a smaller sample (290 cases), originating from three of the centers, using the Mini International Neuropsychiatric Interview Plus (MINI-Plus). Crack and powder cocaine users were significantly younger than non-cocaine PAS users (31.1 ± 8.1 and 32.9 ± 8.8 vs. 42.4 ± 12, respectively; p < .001). Crack users presented a higher rate of antisocial personality disorder (25%) than powder cocaine (9%) and non-cocaine PAS users (9%), even when adjusted for confounding factors (Pr = 2.6; 95% CI 1.10-6.40). According to ASI-6 summary scores, crack users presented a significantly higher rate of occupational, family, and legal problems and reported more illegal and violent activities such as burglary and theft (23%) and threatening or assaulting (32%) than non-cocaine PAS users. Our findings, combined with the recent increase observed in the prevalence of crack use in Brazil, highlight the severity of psychiatric symptoms and psychosocial problems related to this powerful drug and corroborate the already suggested association between crack/cocaine, violence, and legal problems. Treatment programs for crack users should routinely consider the possibility of associated psychiatric comorbidities, such as antisocial personality disorder, which may affect treatment outcomes. PMID:22691017

  16. Ferrocenyl-L-amino acid copper(II) complexes showing remarkable photo-induced anticancer activity in visible light.

    PubMed

    Goswami, Tridib K; Gadadhar, Sudarshan; Balaji, Babu; Gole, Bappaditya; Karande, Anjali A; Chakravarty, Akhil R

    2014-08-21

    Ferrocene-conjugated copper(ii) complexes [Cu(Fc-aa)(aip)](ClO4) () and [Cu(Fc-aa)(pyip)](ClO4) () of l-amino acid reduced Schiff bases (Fc-aa), 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip) and 2-(1-pyrenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (pyip), where Fc-aa is ferrocenylmethyl-l-tyrosine (Fc-Tyr in , ), ferrocenylmethyl-l-tryptophan (Fc-Trp in , ) and ferrocenylmethyl-l-methionine (Fc-Met in , ), were prepared and characterized, and their photocytotoxicity was studied (Fc = ferrocenyl moiety). Phenyl analogues, viz. [Cu(Ph-Met)(aip)](ClO4) () and [Cu(Ph-Met)(pyip)](ClO4) (), were prepared and used as control compounds. The bis-imidazophenanthroline copper(ii) complexes, viz. [Cu(aip)2(NO3)](NO3) () and [Cu(pyip)2(NO3)](NO3) (), were also prepared and used as controls. Complexes having a redox inactive cooper(ii) center showed the Fc(+)-Fc redox couple at ∼0.5 V vs. SCE in DMF-0.1 mol [Bu(n)4N](ClO4). The copper(ii)-based d-d band was observed near 600 nm in DMF-Tris-HCl buffer (1 : 1 v/v). The ferrocenyl complexes showed low dark toxicity, but remarkably high photocytotoxicity in human cervical HeLa and human breast adenocarcinoma MCF-7 cancer cells giving an excellent photo-dynamic effect while their phenyl analogues were inactive. The photo-exposure caused significant morphological changes in the cancer cells when compared to the non-irradiated ones. The photophysical processes were rationalized from the theoretical studies. Fluorescence microscopic images showed and localizing predominantly in the endoplasmic reticulum (ER) of the cancer cells, thus minimizing any undesirable effects involving nuclear DNA. PMID:24971754

  17. Activation of Big Grain1 significantly improves grain size by regulating auxin transport in rice

    PubMed Central

    Liu, Linchuan; Tong, Hongning; Xiao, Yunhua; Che, Ronghui; Xu, Fan; Hu, Bin; Liang, Chengzhen; Chu, Jinfang; Li, Jiayang; Chu, Chengcai

    2015-01-01

    Grain size is one of the key factors determining grain yield. However, it remains largely unknown how grain size is regulated by developmental signals. Here, we report the identification and characterization of a dominant mutant big grain1 (Bg1-D) that shows an extra-large grain phenotype from our rice T-DNA insertion population. Overexpression of BG1 leads to significantly increased grain size, and the severe lines exhibit obviously perturbed gravitropism. In addition, the mutant has increased sensitivities to both auxin and N-1-naphthylphthalamic acid, an auxin transport inhibitor, whereas knockdown of BG1 results in decreased sensitivities and smaller grains. Moreover, BG1 is specifically induced by auxin treatment, preferentially expresses in the vascular tissue of culms and young panicles, and encodes a novel membrane-localized protein, strongly suggesting its role in regulating auxin transport. Consistent with this finding, the mutant has increased auxin basipetal transport and altered auxin distribution, whereas the knockdown plants have decreased auxin transport. Manipulation of BG1 in both rice and Arabidopsis can enhance plant biomass, seed weight, and yield. Taking these data together, we identify a novel positive regulator of auxin response and transport in a crop plant and demonstrate its role in regulating grain size, thus illuminating a new strategy to improve plant productivity. PMID:26283354

  18. Activation of Big Grain1 significantly improves grain size by regulating auxin transport in rice.

    PubMed

    Liu, Linchuan; Tong, Hongning; Xiao, Yunhua; Che, Ronghui; Xu, Fan; Hu, Bin; Liang, Chengzhen; Chu, Jinfang; Li, Jiayang; Chu, Chengcai

    2015-09-01

    Grain size is one of the key factors determining grain yield. However, it remains largely unknown how grain size is regulated by developmental signals. Here, we report the identification and characterization of a dominant mutant big grain1 (Bg1-D) that shows an extra-large grain phenotype from our rice T-DNA insertion population. Overexpression of BG1 leads to significantly increased grain size, and the severe lines exhibit obviously perturbed gravitropism. In addition, the mutant has increased sensitivities to both auxin and N-1-naphthylphthalamic acid, an auxin transport inhibitor, whereas knockdown of BG1 results in decreased sensitivities and smaller grains. Moreover, BG1 is specifically induced by auxin treatment, preferentially expresses in the vascular tissue of culms and young panicles, and encodes a novel membrane-localized protein, strongly suggesting its role in regulating auxin transport. Consistent with this finding, the mutant has increased auxin basipetal transport and altered auxin distribution, whereas the knockdown plants have decreased auxin transport. Manipulation of BG1 in both rice and Arabidopsis can enhance plant biomass, seed weight, and yield. Taking these data together, we identify a novel positive regulator of auxin response and transport in a crop plant and demonstrate its role in regulating grain size, thus illuminating a new strategy to improve plant productivity. PMID:26283354

  19. A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

    PubMed Central

    Ohnmacht, Stephan A; Marchetti, Chiara; Gunaratnam, Mekala; Besser, Rachael J; Haider, Shozeb M; Di Vita, Gloria; Lowe, Helen L; Mellinas-Gomez, Maria; Diocou, Seckou; Robson, Mathew; Šponer, Jiri; Islam, Barira; Barbara Pedley, R; Hartley, John A; Neidle, Stephen

    2015-01-01

    We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41. PMID:26077929

  20. A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer.

    PubMed

    Ohnmacht, Stephan A; Marchetti, Chiara; Gunaratnam, Mekala; Besser, Rachael J; Haider, Shozeb M; Di Vita, Gloria; Lowe, Helen L; Mellinas-Gomez, Maria; Diocou, Seckou; Robson, Mathew; Šponer, Jiri; Islam, Barira; Pedley, R Barbara; Hartley, John A; Neidle, Stephen

    2015-01-01

    We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41. PMID:26077929

  1. Clinical prognostic significance and pro-metastatic activity of RANK/RANKL via the AKT pathway in endometrial cancer.

    PubMed

    Wang, Jing; Liu, Yao; Wang, Lihua; Sun, Xiao; Wang, Yudong

    2016-02-01

    RANK/RANKL plays a key role in metastasis of certain malignant tumors, which makes it a promising target for developing novel therapeutic strategies for cancer. However, the prognostic value and pro-metastatic activity of RANK in endometrial cancer (EC) remain to be determined. Thus, the present study investigated the effect of RANK on the prognosis of EC patients, as well as the pro-metastatic activity of EC cells. The results indicated that those with high expression of RANK showed decreased overall survival and progression-free survival. Statistical analysis revealed the positive correlations between RANK/RANKL expression and metastasis-related factors. Additionally, RANK/RANKL significantly promoted cell migration/invasion via activating AKT/β-catenin/Snail pathway in vitro. However, RANK/RANKL-induced AKT activation could be suppressed after osteoprotegerin (OPG) treatment. Furthermore, the combination of medroxyprogesterone acetate (MPA) and RANKL could in turn attenuate the effect of RANKL alone. Similarly, MPA could partially inhibit the RANK-induced metastasis in an orthotopic mouse model via suppressing AKT/β-catenin/Snail pathway. Therefore, therapeutic inhibition of MPA in RANK/RANKL-induced metastasis was mediated by AKT/β-catenin/Snail pathway both in vitro and in vivo, suggesting a potential target of RANK for gene-based therapy for EC. PMID:26734994

  2. Clinical prognostic significance and pro-metastatic activity of RANK/RANKL via the AKT pathway in endometrial cancer

    PubMed Central

    Wang, Jing; Liu, Yao; Wang, Lihua; Sun, Xiao; Wang, Yudong

    2016-01-01

    RANK/RANKL plays a key role in metastasis of certain malignant tumors, which makes it a promising target for developing novel therapeutic strategies for cancer. However, the prognostic value and pro-metastatic activity of RANK in endometrial cancer (EC) remain to be determined. Thus, the present study investigated the effect of RANK on the prognosis of EC patients, as well as the pro-metastatic activity of EC cells. The results indicated that those with high expression of RANK showed decreased overall survival and progression-free survival. Statistical analysis revealed the positive correlations between RANK/RANKL expression and metastasis-related factors. Additionally, RANK/RANKL significantly promoted cell migration/invasion via activating AKT/β-catenin/Snail pathway in vitro. However, RANK/RANKL-induced AKT activation could be suppressed after osteoprotegerin (OPG) treatment. Furthermore, the combination of medroxyprogesterone acetate (MPA) and RANKL could in turn attenuate the effect of RANKL alone. Similarly, MPA could partially inhibit the RANK-induced metastasis in an orthotopic mouse model via suppressing AKT/β-catenin/Snail pathway. Therefore, therapeutic inhibition of MPA in RANK/RANKL-induced metastasis was mediated by AKT/β-catenin/Snail pathway both in vitro and in vivo, suggesting a potential target of RANK for gene-based therapy for EC. PMID:26734994

  3. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium.

    PubMed

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A S; Fernàndez-Busquets, Xavier

    2016-01-01

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses. PMID:27071342

  4. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium

    PubMed Central

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A. S.; Fernàndez-Busquets, Xavier

    2016-01-01

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses. PMID:27071342

  5. The significance of different health institutions and their respective contributions of active pharmaceutical ingredients to wastewater.

    PubMed

    Herrmann, Manuel; Olsson, Oliver; Fiehn, Rainer; Herrel, Markus; Kümmerer, Klaus

    2015-12-01

    Active pharmaceutical ingredients (APIs) have been frequently found in the environment. It is, however, still not quite clear who is mainly responsible for API emissions. Hospitals have been considered to be the main contributing point sources for wastewater (WW) discharge of APIs. However, recent studies have shown that the contribution of hospitals to the input of APIs into the aquatic environment is quite low. Due to demographic change and the increase of psychiatric diseases, health institutions (HIs) such as psychiatric hospitals and nursing homes are likely to be important sources as well, but no data is available in this respect. This study aims to assess the impact of HIs and to provide a methodology to measure their respective contributions. Drawing on pharmaceutical consumption data for the years 2010, 2011, and 2012, this study identified API usage patterns for a psychiatric hospital (146 beds), a nursing home (286 inhabitants), and a general hospital (741 beds), the latter of which comprises three separate locations. All the HIs are located in two sub-regions of a county district with about 400,000 citizens in southwestern Germany. A selection of neurological drugs was quantified in the sewer of these facilities to evaluate the correlation between consumption and emission. The API contribution of HIs was assessed by comparing the specific consumption in the facilities with the consumption in households, expressed as the emission potential (IEP). The study shows that the usage patterns of APIs in the psychiatric hospital and the nursing home were different from the general hospital. Neurological drugs such as anticonvulsants, psycholeptics, and psychoanaleptics were mainly consumed in the psychiatric hospital and the nursing home (74% and 65%, respectively). Predicted and average measured concentrations in the effluent of the investigated HIs differed mostly by less than one order of magnitude. Therefore, the consumption-based approach is a useful method

  6. Spaceflight and simulated microgravity cause a significant reduction of key gene expression in early T-cell activation.

    PubMed

    Martinez, Emily M; Yoshida, Miya C; Candelario, Tara Lynne T; Hughes-Fulford, Millie

    2015-03-15

    Healthy immune function depends on precise regulation of lymphocyte activation. During the National Aeronautics and Space Administration (NASA) Apollo and Shuttle eras, multiple spaceflight studies showed depressed lymphocyte activity under microgravity (μg) conditions. Scientists on the ground use two models of simulated μg (sμg): 1) the rotating wall vessel (RWV) and 2) the random positioning machine (RPM), to study the effects of altered gravity on cell function before advancing research to the true μg when spaceflight opportunities become available on the International Space Station (ISS). The objective of this study is to compare the effects of true μg and sμg on the expression of key early T-cell activation genes in mouse splenocytes from spaceflight and ground animals. For the first time, we compared all three conditions of microgravity spaceflight, RPM, and RWV during immune gene activation of Il2, Il2rα, Ifnγ, and Tagap; moreover, we confirm two new early T-cell activation genes, Iigp1 and Slamf1. Gene expression for all samples was analyzed using quantitative real-time PCR (qRT-PCR). Our results demonstrate significantly increased gene expression in activated ground samples with suppression of mouse immune function in spaceflight, RPM, and RWV samples. These findings indicate that sμg models provide an excellent test bed for scientists to develop baseline studies and augment true μg in spaceflight experiments. Ultimately, sμg and spaceflight studies in lymphocytes may provide insight into novel regulatory pathways, benefiting both future astronauts and those here on earth suffering from immune disorders. PMID:25568077

  7. Spaceflight and simulated microgravity cause a significant reduction of key gene expression in early T-cell activation

    PubMed Central

    Martinez, Emily M.; Yoshida, Miya C.; Candelario, Tara Lynne T.

    2015-01-01

    Healthy immune function depends on precise regulation of lymphocyte activation. During the National Aeronautics and Space Administration (NASA) Apollo and Shuttle eras, multiple spaceflight studies showed depressed lymphocyte activity under microgravity (μg) conditions. Scientists on the ground use two models of simulated μg (sμg): 1) the rotating wall vessel (RWV) and 2) the random positioning machine (RPM), to study the effects of altered gravity on cell function before advancing research to the true μg when spaceflight opportunities become available on the International Space Station (ISS). The objective of this study is to compare the effects of true μg and sμg on the expression of key early T-cell activation genes in mouse splenocytes from spaceflight and ground animals. For the first time, we compared all three conditions of microgravity spaceflight, RPM, and RWV during immune gene activation of Il2, Il2rα, Ifnγ, and Tagap; moreover, we confirm two new early T-cell activation genes, Iigp1 and Slamf1. Gene expression for all samples was analyzed using quantitative real-time PCR (qRT-PCR). Our results demonstrate significantly increased gene expression in activated ground samples with suppression of mouse immune function in spaceflight, RPM, and RWV samples. These findings indicate that sμg models provide an excellent test bed for scientists to develop baseline studies and augment true μg in spaceflight experiments. Ultimately, sμg and spaceflight studies in lymphocytes may provide insight into novel regulatory pathways, benefiting both future astronauts and those here on earth suffering from immune disorders. PMID:25568077

  8. Individuals at risk for Alzheimer’s disease show differential patterns of ERP brain activation during odor identification

    PubMed Central

    2012-01-01

    Background Studies suggest that older adults at risk of developing Alzheimer’s disease may show olfactory processing deficits before other signs of dementia appear. Methods We studied 60 healthy non-demented individuals, half of whom were positive for the genetic risk factor the Apolipoprotein E ɛ4 allele, in three different age groups. Event-related potentials to visual and olfactory identification tasks were recorded and analyzed for latency and amplitude differences, and plotted via topographical maps. Results Varying patterns of brain activation were observed over the post-stimulus epoch for ɛ4- versus ɛ4+ individuals on topographical maps. Individuals with the ɛ4 allele demonstrated different ERP peak latencies during identification of olfactory but not visual stimuli. High correct ApoE classification rates were obtained utilizing the olfactory ERP. Conclusions Olfactory ERPs demonstrate functional decline in individuals at risk for Alzheimer’s disease at much earlier ages than previously observed, suggesting the potential for pre-clinical detection of AD at very early stages. PMID:22849610

  9. Recombinant murine toxin from Yersinia pestis shows high toxicity and β-adrenergic blocking activity in mice.

    PubMed

    Fan, Yanxiao; Zhou, Yazhou; Feng, Na; Wang, Qiong; Tian, Guang; Wu, Xiaohong; Liu, Zizhong; Bi, Yujing; Yang, Ruifu; Wang, Xiaoyi

    2016-05-01

    Yersinia pestis murine toxin (Ymt) encoded on pMT1 is a 61-kDa protein, a member of the phospholipase D superfamily, which is found in all the domains of life. It is considered to be an intracellular protein required for the survival of Y. pestis in the midgut of the flea, but the exact role of Ymt in the pathogenesis of Y. pestis has not been clarified. Purified Ymt is highly toxic to mice and rats, but the exact mechanism of the animals' death is unclear. Here, we prepared a recombinant Ymt in Escherichia coli BL21 cells, and determined its toxicity and activity. We demonstrated that recombinant Ymt was as toxic to mice as the native protein when administered via the intraperitoneal or intravenous route, and inhibited the elevation of blood sugar caused by adrenaline. We also demonstrated that recombinant Ymt was highly toxic to mice when administered via the muscular or subcutaneous route. We also show that the multiple organ congestion or hemorrhage caused by Ymt poisoning may explain the death of the mice. PMID:26774329

  10. Relict landscapes in active mountain belts: their age, interpretation and geodynamic significance

    NASA Astrophysics Data System (ADS)

    van der Beek, Peter

    2010-05-01

    Planar topographic markers have been widely used to infer the topographic and erosional history of mountain belts. During the last two decades, attention has focused on high-elevation low-relief surfaces in orogenic belts, the interpretation of which has generated considerable controversy regarding their age, mechanism of formation and tectonic or climatic significance. I will review three case studies to illustrate these issues. In the Pyrenees, high-elevation, low-relief surfaces have been mapped throughout the mountain belt and were suggested to have developed at high elevations due to significant base-level rise as a result of backfilling of the southern foreland basin, which developed under endorheic conditions between Late Eocene and Late Miocene times. Isolation of these surface remnants has been suggested to result from a more erosive climate since the Pliocene. However, an alternative study suggests that such relict landscape elements are restricted to the Eastern Pyrenees, developed at low elevations during the Miocene and were subsequently tectonically uplifted. This second hypothesis appears to be comforted by a suite of thermochronological, stratigraphic and geophysical data from the Eastern Pyrenees. We have used a thermo-kinematic model integrating the existing thermochronometry data from the central Pyrenees to constrain the amount and timing of base-level change in that area and find that, while significant filling and re-excavation of the southern flank must have occurred, the timing of exhumation is Late Miocene rather than Pliocene-Quaternary and the relationship with hypothetical relict landscape elements in the high chain remains unclear. In the western European Alps, widespread high-elevation low-relief surfaces develop close to the interface between crystalline basement and sedimentary cover in the "external crystalline massifs" (e.g., Pelvoux-Ecrins, Belledonne, Aar). These surfaces clearly appear to be lithologically controlled and to have

  11. Significance of Plasma Dopamine β-Hydroxylase Activity as an Index of Sympathetic Neuronal Function

    PubMed Central

    Reid, John L.; Kopin, Irwin J.

    1974-01-01

    Plasma norepinephrine and dopamine β-hydroxylase (EC 1.14.17.1) activity were measured in rats. Adrenergic neuron blockade with bretylium for 4 hr and ganglion blockade with chlorisondamine for 72 hr lowered plasma norepinephrine. Neither treatment altered plasma dopamine β-hydroxylase activity. Phenoxybenzamine for up to 48 hr markedly raised plasma norepinephrine and transiently lowered plasma dopamine β-hydroxylase at 24 hr. Prolonged pharmacological modification of sympathetic nervous activity and plasma norepinephrine were not attended by parallel changes in circulating dopamine β-hydroxylase activity. Plasma dopamine β-hydroxylase activity does not appear to be a sensitive index of prolonged alterations in sympathetic neural activity. Norepinephrine in plasma, however, appears to reflect sensitively and accurately the rate of release of the neurotransmitter. PMID:4530990

  12. Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety.

    PubMed

    Skelton, Matthew R; Ponniah, Sathivel; Wang, Dennis Z-M; Doetschman, Thomas; Vorhees, Charles V; Pallen, Catherine J

    2003-09-12

    Receptor PTPalpha is a widely expressed transmembrane enzyme enriched in brain. PTPalpha knockout (PTPalpha(-/-)) mice are viable and display no gross abnormalities. Brain and embryo derived fibroblast src and fyn activity is reduced to <50% in PTPalpha(-/-) mice. These protein kinases are implicated in multiple aspects of neuronal development and function. However, the effect of the loss of function of the PTPalpha gene on behavior has yet to be investigated. PTPalpha(-/-) and WT mice were tested for anxiety, swimming ability, spatial learning, cued learning, locomotor activity, and novel object recognition (NOR). PTPalpha(-/-) mice were indistinguishable from WT in swimming ability, cued learning and novel object recognition. Knockout mice showed decreased anxiety without an increase in head dips and stretch-attend movements. During Morris water maze (MWM) learning, PTPalpha(-/-) mice had increased latencies to reach the goal compared to WT on acquisition, but no memory deficit on probe trials. On reversal learning, knockout mice showed no significant effects. PTPalpha(-/-) mice showed decreased exploratory locomotor activity, but responded normally to a challenge dose of D-methamphetamine. The data suggest that PTPalpha serves a regulatory function in learning and other forms of neuroplasticity. PMID:12932834

  13. Breadth and Intensity: Salient, Separable, and Developmentally Significant Dimensions of Structured Youth Activity Involvement

    ERIC Educational Resources Information Center

    Busseri, Michael A.; Rose-Krasnor, Linda

    2009-01-01

    In recent years, an impressive volume of evidence has accumulated demonstrating that youth involvement in structured, organized activities (e.g. school sports, community clubs) may facilitate positive youth development. We present a theory-based framework for studying structured activity involvement (SAI) as a context for positive youth…

  14. Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

    PubMed

    Beteck, Richard M; Coertzen, Dina; Smit, Frans J; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

    2016-07-01

    As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones. PMID:27210430

  15. A Gelatinases-targeting scFv-based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma.

    PubMed

    Gao, Ruijuan; Li, Liang; Shang, Boyang; Zhao, Chunyan; Sheng, Weijin; Li, Diandong

    2015-08-01

    Gelatinases play important roles in tumour invasion and metastasis and are thus considered promising targets for cancer therapy. In this study, a new single-chain variable fragment (scFv)-based fusion protein Fv-LDP, composed of the anti-gelatinases scFv and lidamycin apoprotein (LDP), was prepared, and its combination with angiogenesis inhibitor Endostar was then investigated. The fusion protein Fv-LDP specifically bound to various tumour cells, and its binding capability to human pulmonary giant cell carcinoma (PG) cells was higher than that of LDP. Fv-LDP inhibited the expression and secretion of gelatinases and could be internalized into tumour cells via endocytosis. Fv-LDP also suppressed the growth of human hepatoma cells and murine hepatoma 22 transplanted in Kunming mice in various degrees. In addition, Endostar could enhance the synergistic or additive inhibition of Fv-LDP on the growth, migration or invasion of human hepatoma cells shown by a colony formation assay and a transwell-based migration or invasion assay, respectively. In vivo, Fv-LDP/Endostar combination showed a significantly synergistic effect on the growth of a human hepatoma xenograft, with an inhibition rate of 80.8% compared with the Fv-LDP (44.1%) or Endostar (8.9%)-treated group. The above-mentioned results indicate that the fusion protein Fv-LDP is effective against transplantable hepatoma in mice and human hepatoma xenografts in athymic mice. Moreover, Endostar can potentiate the inhibition effect of Fv-LDP on the growth of human hepatoma cells and xenografts. These data will provide a new combined strategy for improving the therapeutic efficacy of treatments for hepatoma or other gelatinase-overexpressing tumours. PMID:25615234

  16. An Echinococcus multilocularis Antigen B3 Proteoform That Shows Specific Antibody Responses to Active-Stage Alveolar Echinococcosis.

    PubMed

    Ahn, Chun-Seob; Cai, Huixia; Kim, Jeong-Geun; Han, Xiumin; Ma, Xiao; Bae, Young-An; Yang, Hyun-Jong; Kang, Insug; Wang, Hu; Kong, Yoon

    2015-10-01

    Alveolar echinococcosis (AE), caused by the Echinococcus multilocularis metacestode, represents one of the most frequently fatal zoonoses. Early diagnosis significantly reduces morbidity and mortality associated with AE. Diagnosis of AE largely depends on a combination of imaging and serological tests due to its minimal clinical manifestations. Several antigens derived from the whole worm and protoscolex have been targeted for AE serodiagnosis, while the antigenic properties of E. multilocularis hydatid fluid (EmHF) are unclear. We observed two AE-specific 6- and 8-kDa antigen proteoforms through an immunoproteome array of the EmHF. We identified these proteins as representing an E. multilocularis antigen B3 (EmAgB3) isoform, and the proteins were shown to be encoded by the same gene. We cloned the gene and expressed the recombinant EmAgB3 protein (rEmAgB3) in Escherichia coli. rEmAgB3 exhibited sensitivity of 90.9% (80/88 cases) and specificity of 98.5% (597/606 samples) by immunoblotting. The positive and negative predictive values were 89.9% and 98.6%, respectively. The protein did not show antibody responses to 33 AE sera collected during posttreatment follow-up monitoring. Mouse sera experimentally infected with AE protoscoleces began to demonstrate specific antibody responses to native and recombinant EmAgB3 6 months after infection. At that stage, fully mature metacestode vesicles that harbored the brood capsule, primary cell, and protoscolex were observed within an AE mass(es). The response declined along with worm degeneration. Our results demonstrate that the immune responses to this EmAgB3 isoform were highly correlated with worm viability accompanied with AE progression. rEmAgB3 is a promising biomarker for serological assessment of AE patients. PMID:26269620

  17. An Echinococcus multilocularis Antigen B3 Proteoform That Shows Specific Antibody Responses to Active-Stage Alveolar Echinococcosis

    PubMed Central

    Ahn, Chun-Seob; Cai, Huixia; Kim, Jeong-Geun; Han, Xiumin; Ma, Xiao; Bae, Young-An; Yang, Hyun-Jong; Kang, Insug; Wang, Hu

    2015-01-01

    Alveolar echinococcosis (AE), caused by the Echinococcus multilocularis metacestode, represents one of the most frequently fatal zoonoses. Early diagnosis significantly reduces morbidity and mortality associated with AE. Diagnosis of AE largely depends on a combination of imaging and serological tests due to its minimal clinical manifestations. Several antigens derived from the whole worm and protoscolex have been targeted for AE serodiagnosis, while the antigenic properties of E. multilocularis hydatid fluid (EmHF) are unclear. We observed two AE-specific 6- and 8-kDa antigen proteoforms through an immunoproteome array of the EmHF. We identified these proteins as representing an E. multilocularis antigen B3 (EmAgB3) isoform, and the proteins were shown to be encoded by the same gene. We cloned the gene and expressed the recombinant EmAgB3 protein (rEmAgB3) in Escherichia coli. rEmAgB3 exhibited sensitivity of 90.9% (80/88 cases) and specificity of 98.5% (597/606 samples) by immunoblotting. The positive and negative predictive values were 89.9% and 98.6%, respectively. The protein did not show antibody responses to 33 AE sera collected during posttreatment follow-up monitoring. Mouse sera experimentally infected with AE protoscoleces began to demonstrate specific antibody responses to native and recombinant EmAgB3 6 months after infection. At that stage, fully mature metacestode vesicles that harbored the brood capsule, primary cell, and protoscolex were observed within an AE mass(es). The response declined along with worm degeneration. Our results demonstrate that the immune responses to this EmAgB3 isoform were highly correlated with worm viability accompanied with AE progression. rEmAgB3 is a promising biomarker for serological assessment of AE patients. PMID:26269620

  18. The Significance of Turning Passive Into Active in Control Mastery Theory

    PubMed Central

    FOREMAN, STEVEN A.

    1996-01-01

    Turning passive into active was first described by Freud but was later given expanded importance by Weiss. This new conceptualization of turning passive into active as an interpersonal communication and test has made a major contribution to the clinical treatment of difficult patients. This article reviews "control mastery" theory and puts its notion of passive-into-active testing into perspective with regard to Freud’s original conception as well as other conceptions, such as identification with the aggressor and projective identification. Formulation and the treatment of patients are illustrated with clinical examples. PMID:22700271

  19. Cystic fibrosis transmembrane conductance regulator Cl- channels with R domain deletions and translocations show phosphorylation-dependent and -independent activity.

    PubMed

    Baldursson, O; Ostedgaard, L S; Rokhlina, T; Cotten, J F; Welsh, M J

    2001-01-19

    Phosphorylation of the R domain regulates cystic fibrosis transmembrane conductance regulator Cl- channel activity. Earlier studies suggested that the R domain controls activity via more than one mechanism; a phosphorylated R domain may stimulate activity, and an unphosphorylated R domain may prevent constitutive activity, i.e. opening with ATP alone. However, the mechanisms responsible for these two regulatory properties are not understood. In this study we asked whether the two effects are dependent on its position in the protein and whether smaller regions from the R domain mediate the effects. We found that several portions of the R domain conferred phosphorylation-stimulated activity. This was true whether the R domain sequences were present in their normal location or were translocated to the C terminus. We also found that some parts of the R domain could be deleted without inducing constitutive activity. However, when residues 760-783 were deleted, channels opened without phosphorylation. Translocation of the R domain to the C terminus did not prevent constitutive activity. These results suggest that different parts of the phosphorylated R domain can stimulate activity and that their location within the protein is not critical. In contrast, prevention of constitutive activity required a short specific sequence that could not be moved to the C terminus. These results are consistent with a recent model of an R domain composed primarily of random coil in which more than one phosphorylation site is capable of stimulating channel activity, and net activity reflects interactions between multiple sites in the R domain and the rest of the channel. PMID:11038358

  20. Biological Significance of Local TGF-β Activation in Liver Diseases

    PubMed Central

    Hayashi, Hiromitsu; Sakai, Takao

    2012-01-01

    The cytokine transforming growth factor-β (TGF-β) plays a pivotal role in a diverse range of cellular responses, including cell proliferation, apoptosis, differentiation, migration, adhesion, angiogenesis, stimulation of extracellular matrix (ECM) synthesis, and downregulation of ECM degradation. TGF-β and its receptors are ubiquitously expressed by most cell types and tissues in vivo. In intact adult tissues and organs, TGF-β is secreted in a biologically inactive (latent) form associated in a non-covalent complex with the ECM. In response to injury, local latent TGF-β complexes are converted into active TGF-β according to a tissue- and injury type-specific activation mechanism. Such a well and tightly orchestrated regulation in TGF-β activity enables an immediate, highly localized response to type-specific tissue injury. In the pathological process of liver fibrosis, TGF-β plays as a master profibrogenic cytokine in promoting activation and myofibroblastic differentiation of hepatic stellate cells, a central event in liver fibrogenesis. Continuous and/or persistent TGF-β signaling induces sustained production of ECM components and of tissue inhibitor of metalloproteinase synthesis. Therefore, the regulation of locally activated TGF-β levels is increasingly recognized as a therapeutic target for liver fibrogenesis. This review summarizes our present knowledge of the activation mechanisms and bioavailability of latent TGF-β in biological and pathological processes in the liver. PMID:22363291

  1. Lung Adenocarcinomas and Lung Cancer Cell Lines Show Association of MMP-1 Expression With STAT3 Activation1

    PubMed Central

    Schütz, Alexander; Röser, Katrin; Klitzsch, Jana; Lieder, Franziska; Aberger, Fritz; Gruber, Wolfgang; Mueller, Kristina M.; Pupyshev, Alexander; Moriggl, Richard; Friedrich, Karlheinz

    2015-01-01

    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non–small cell lung carcinoma (NSCLC) cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1) was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549) were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6). In A549 cells, STAT3 activity enhanced the level of MMP-1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6–stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs. PMID:25926075

  2. Physical Activity in the Life of a Woman with Severe Cerebral Palsy: Showing Competence and Being Socially Connected

    ERIC Educational Resources Information Center

    Gaskin, Cadeyrn J.; Andersen, Mark B.; Morris, Tony

    2009-01-01

    We used a life-history approach to investigate the meanings and experiences of physical activity in the life of a 25-year-old woman with severe cerebral palsy (Amy). Amy and her mother were interviewed about Amy's life and her involvement in physical activity. The conversation was audio-recorded and transcribed verbatim. We interpreted Amy's story…

  3. Active Learning Facilitated by Using a Game-Show Format or Who Doesn't Want to Be a Millionaire?

    ERIC Educational Resources Information Center

    Sarason, Yolanda; Banbury, Catherine

    2004-01-01

    University faculty are increasingly called on to be less of a sage on the stage and more a guide on the side. This discussion introduces the underlying philosophy and assumptions of active learning theory. With this shift in pedagogical philosophy, there has been an increasing call for tools that actively engage students in the learning process. A…

  4. Nonexercise Activity Thermogenesis is Significantly Lower in Type 2 Diabetic Patients With Mental Disorders Than in Those Without Mental Disorders

    PubMed Central

    Hamasaki, Hidetaka; Ezaki, Osamu; Yanai, Hidekatsu

    2016-01-01

    Abstract Physical activity improves health in patients with mental disorders. Nonexercise activity thermogenesis (NEAT) represents energy expenditure due to daily physical activities other than volitional exercise. We aimed to evaluate NEAT in type 2 diabetic patients with and without accompanying mental disorders. Between September 2010 and September 2014, we studied 150 patients with type 2 diabetes, 50 of whom also had a diagnosis of mental disorder, such as schizophrenia or mood disorder. We evaluated their NEAT in structured interviews using a validated questionnaire, and investigated differences in NEAT score and metabolic parameters between patients with and without mental disorders. The NEAT score was significantly lower in patients with mental disorders than in those without (56.3 ± 9.9 vs 61.9 ± 12.1; P = 0.005). Patients with mental disorders had significantly higher triglyceride (184.5 ± 116.3 vs 146.4 ± 78.4 mg/dL; P = 0.02) and insulin levels (18.7 ± 20.1 vs 11.2 ± 8.5 μU/mL; P = 0.006), and significantly lower B-type natriuretic peptide (12.1 ± 13.3 vs 26.3 ± 24.8 pg/mL; P < 0.001) and brachial-ankle pulse wave velocity levels (1501 ± 371 vs 1699 ± 367 cm/s; P = 0.003) than patients without mental disorders. In patients with schizophrenia, specifically, NEAT showed a negative correlation with hemoglobin A1c levels (β = −0.493, P = 0.031), and a positive correlation with high-density lipoprotein cholesterol (β = 0.519, P = 0.023) and B-type natriuretic peptide levels (β = 0.583, P = 0.02). Our results suggest that NEAT may be beneficial for the management of obesity, insulin sensitivity, and lipid profiles in patients with mental disorders. Incorporating NEAT into interventions for type 2 diabetes in patients with mental disorders, especially schizophrenia, shows promise and warrants further investigation. PMID:26765475

  5. [Plasminogen activator system and its clinical significance in patients with a malignant disease].

    PubMed

    Halámková, J; Kiss, I; Tomásek, J; Pavlovský, Z; Cech, Z; Tutek, S; Hanáková, L; Moulis, M; Penka, M

    2011-01-01

    Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, a serine protease participating in the activation of matrixmetaloproteinases, latent elastases, growth factors and cytokines involved in the degradation of extracellular matrix elements. Together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI-1, PAI-2, PAI-3 and protease nexin), it forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. Plasminogen activator inhibitor 1 inhibits uPA-dependent invasiveness of some cancer cell lines. The vitronectin-PAI-1 complex inhibits migration of smooth muscle cells by binding alpha(v)beta3 integrin to vitronectin. PAI-1 or its deficiency interferes with signalling pathways such as PI3K/Akt and JAK/STAT and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death. PAI-1 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways. The individual components of PAS undoubtedly play an important role in angiogenesis and metastasising of malignant tumours. In the near future, results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and, at the same time, could serve as the goal for targeted therapies. PMID:22257230

  6. Significant role of climatic trends on hydrothermal activity Coso Hot Springs, California

    SciTech Connect

    Lofgren, B.E. )

    1990-05-01

    The hydrothermal features of Coso Hot Springs have attracted visitors for 130 yr and scientific investigators for two decades. In 1978, anticipating effects of major geothermal developments nearby, the Naval Weapons Center (NWC) initiated a comprehensive monitoring program at a dozen hydrothermal sites in the Coso Hot Springs area. Nine years of monitoring preceded power production in the nearby Coso geothermal field in July 1987. During this period, steam was rising from numerous vents and gently boiling mud pots. Local rainfall caused increased boiling activity in several mud pots, with some overflowing during wet periods. Then in August 1988, a year after geothermal power production began major changes in hot spring activity commenced. Small mud pots and steamers started to grow and coalesce. In March 1989, mud-pot activity became more violent. Many buried wells failed causing surface activity in other areas to diminish. During ensuing months, large mud cones developed and much of the steam and boiling water occurred in a few major pots. Because the abrupt changes in hydrothermal activity followed so closely after nearby geothermal production began, the obvious cause has been attributed to geothermal developments. Studies of NWC baseline monitoring data indicate, however, that no effects of geothermal developments have been felt in the hot springs area. Rainfall and barometric effects account for most of the fluctuations in records of the past decade. Early accounts and field evidence suggest similar changes have occurred in the past.

  7. The Gamma-Glutamyl-Transpeptidase to Platelet Ratio Does not Show Advantages than APRI and Fib-4 in Diagnosing Significant Fibrosis and Cirrhosis in Patients With Chronic Hepatitis B

    PubMed Central

    Li, Qiang; Song, Jie; Huang, Yuxian; Li, Xinyan; Zhuo, Qibin; Li, Weixia; Chen, Chong; Lu, Chuan; Qi, Xun; Chen, Liang

    2016-01-01

    Abstract The gamma-glutamyl-transpeptidase to platelet ratio (GPR) is a new liver fibrosis model, which is reported to be more accurate than aspartate transaminase (AST) to platelet ratio index (APRI) and fibrosis index based on the four factors (Fib-4) for diagnosing significant fibrosis and cirrhosis in patients with chronic hepatitis B (CHB) in West Africa. The aim of this study is to assess the diagnostic accuracy of GPR for significant fibrosis and cirrhosis in Chinese CHB patients, and explore whether GPR deserves to be popularized in China. A total of 372 CHB patients who underwent liver biopsies and routine laboratory tests were retrospectively studied. The Scheuer scoring system was adopted as the pathological standard of liver fibrosis. Using liver histology as a gold standard, the diagnostic accuracies of GPR, APRI, and Fib-4 for significant fibrosis and cirrhosis are evaluated and compared by the receiver operating characteristic (ROC) curves and the area under the ROC curves (AUROCs). Of these 372 patients, 176 (47.3%), 129 (34.7%), and 72 (19.4%) were classified as having significant fibrosis (≥ S2), severe fibrosis (≥ S3), and cirrhosis (S4), respectively. The AUROCs of GPR for significant fibrosis (0.72 vs. 0.78; P = 0.01), severe fibrosis (0.75 vs. 0.80; P = 0.04), and cirrhosis (0.78 vs. 0.83; P = 0.02) were lower than those of APRI. The AUROCs of GPR and Fib-4 for diagnosing significant fibrosis (0.72 vs. 0.70; P = 0.29), severe fibrosis (0.75 vs. 0.73; P = 0.33), and cirrhosis (0.78 vs. 0.75; P = 0.38) were comparable. GPR is a new serum diagnostic model for liver fibrosis and cirrhosis, but does not show advantages than APRI and Fib-4 in identifying significant fibrosis, severe fibrosis, and cirrhosis in CHB patients in China. PMID:27100421

  8. Factor analysis shows that female rat behaviour is characterized primarily by activity, male rats are driven by sex and anxiety.

    PubMed

    Fernandes, C; González, M I; Wilson, C A; File, S E

    1999-12-01

    This experiment explored sex differences in behaviour using factor analysis to describe the relationship between different behavioral variables. A principal component solution with an orthogonal rotation of the factor matrix was used, ensuring that the extracted factors are independent of one another, and thus reflect separate processes. In the elevated plus-maze test of anxiety, in male rats factor 1 accounted for 75% of the variance and reflected anxiety, factor 2 represented activity, and accounted for 24% of the variance. This contrasted with the finding in female rats in which factor 1 was activity, accounting for 57% of the variance, with the anxiety factor accounting for only 34% of the variance. When behaviour in both the plus-maze and holeboard were analysed, a similar sex difference was found with anxiety emerging as factor 1 in males and holeboard activity as factor 1 in females. Locomotor activity in the inner portion of the holeboard loaded on the anxiety factor for males, but on activity for females. When behaviours in the plus-maze and sexual orientation tests were analysed, anxiety emerged as factor 1 in males, sexual preferences factor 2, and activity factor 3. In females, activity was factor 1, sexual preference factor 2, anxiety factor 3, and social interest factor 4. These results suggest caution should be exercised in interpreting the results from female rats in tests validated on males because the primary controlling factor may be different. PMID:10593196

  9. The evolution of magnetic activity on V711 Tauri and evidence for a significant facular contribution

    NASA Technical Reports Server (NTRS)

    Dorren, J. D.; Guinan, E. F.

    1990-01-01

    The nature of the long-term evolution of magnetic activity in the RS CVn binary V711 Tauri is investigated using the complete set of available archival IUE SWP low-dispersion spectra of V711 Tau for the period covering August 1978 - December 1984. An analysis of the spectra confirmed the pattern of a long-term smooth variation of chromospheric and transition region emission found previosly by Dorren et al. (1986). An explanation of the relationship between the different facets of the magnetic activity on V711 Tau is presented.

  10. Residual disease detected by multidimensional flow cytometry shows prognostic significance in childhood acute myeloid leukemia with intermediate cytogenetics and negative FLT3-ITD: a report from the Tokyo Children's Cancer Study Group.

    PubMed

    Keino, Dai; Kinoshita, Akitoshi; Tomizawa, Daisuke; Takahashi, Hiroyuki; Ida, Kohmei; Kurosawa, Hidemitsu; Koike, Kazutoshi; Ota, Setsuo; Iwasaki, Noriyuki; Fujimura, Junya; Yuza, Yuki; Kiyotani, Chikako; Yamamoto, Shohei; Osumi, Tomoo; Ueda, Takahiro; Mochizuki, Shinji; Isoyama, Keiichi; Hanada, Ryoji; Tawa, Akio; Manabe, Atsushi; Toguchi, Yoichi; Ohara, Akira

    2016-04-01

    Residual disease (RD) after induction chemotherapy may predict clinical outcome in acute myeloid leukemia (AML). In the present study, we investigated the prognostic significance of RD detected by multidimensional flow cytometry (MDF) among 34 children treated for AML in a clinical trial (JPLSG AML-05) in Japan. Bone marrow samples were analyzed at the points of the end of the first induction course (BMA-1) and second induction course (BMA-2) by MDF. RD was evaluated by detecting the immature cells showing abnormal antigen expression pattern; CD34(+), CD15(+), CD7(+). Thirteen (39.4 %) of 34 patients at BMA-1 and 8 (27.6 %) of 34 at BMA-2 had RD levels ≥0.1 %. There was no significant difference in 3y-EFS and 3y-OS between patients with RD levels ≥0.1 % and those with RD levels <0.1 % (53.8 versus 70.0 %, P = 0.30 and 50.0 versus 66.7 %, P = 0.27, respectively). However, IR cytogenetics and negative FLT3-ITD patients with RD levels ≥0.1 % exhibited significantly lower 3y-EFS and 3y-OS than those with RD levels <0.1 % (33.3 versus 83.3 %, P = 0.02 and 20.0 versus 76.9 %, P = 0.005, respectively). Our study suggests that RD shows prognostic relevance in pediatric patients with IR cytogenetics and negative FLT3-ITD AML. PMID:26781613

  11. B-Ring-Aryl Substituted Luotonin A Analogues with a New Binding Mode to the Topoisomerase 1-DNA Complex Show Enhanced Cytotoxic Activity

    PubMed Central

    González-Ruiz, Víctor; Pascua, Irene; Fernández-Marcelo, Tamara; Ribelles, Pascual; Bianchini, Giulia; Sridharan, Vellaisamy; Iniesta, Pilar; Ramos, M. Teresa; Olives, Ana I.; Martín, M. Antonia; Menéndez, J. Carlos

    2014-01-01

    Topoisomerase 1 inhibition is an important strategy in targeted cancer chemotherapy. The drugs currently in use acting on this enzyme belong to the family of the camptothecins, and suffer severe limitations because of their low stability, which is associated with the hydrolysis of the δ-lactone moiety in their E ring. Luotonin A is a natural camptothecin analogue that lacks this functional group and therefore shows a much-improved stability, but at the cost of a lower activity. Therefore, the development of luotonin A analogues with an increased potency is important for progress in this area. In the present paper, a small library of luotonin A analogues modified at their A and B rings was generated by cerium(IV) ammonium nitrate-catalyzed Friedländer reactions. All analogues showed an activity similar or higher than the natural luotonin A in terms of topoisomerase 1 inhibition and some compounds had an activity comparable to that of camptothecin. Furthermore, most compounds showed a better activity than luotonin A in cell cytotoxicity assays. In order to rationalize these results, the first docking studies of luotonin-topoisomerase 1-DNA ternary complexes were undertaken. Most compounds bound in a manner similar to luotonin A and to standard topoisomerase poisons such as topotecan but, interestingly, the two most promising analogues, bearing a 3,5-dimethylphenyl substituent at ring B, docked in a different orientation. This binding mode allows the hydrophobic moiety to be shielded from the aqueous environment by being buried between the deoxyribose belonging to the G(+1) guanine and Arg364 in the scissile strand and the surface of the protein and a hydrogen bond between the D-ring carbonyl and the basic amino acid. The discovery of this new binding mode and its associated higher inhibitory potency is a significant advance in the design of new topoisomerase 1 inhibitors. PMID:24830682

  12. The Social and Economic Significance of Recreation Activities in the Marine Environment.

    ERIC Educational Resources Information Center

    Ditton, Robert B.

    Although the data obtained by an Outdoor Recreation Resources Review Commission in 1960 indicated that 44 percent of participants in outdoor recreation prefer water-based activities, the potential demand for recreation within the coastal zone is much greater than that study indicates, because the unfulfilled recreational demands of the urban…

  13. The Measurement of Brain Electrical Activity and Its Significance to the Educator.

    ERIC Educational Resources Information Center

    Torello, Michael W.

    The article discusses the measurement of brain electrical activity and, in particular, the examination of electroencephalographic (EEG) data, as providing useful information in the diagnosis of dyslexia and other learning disabilities. Topographic imaging of EEG (TIE) is described as a procedure which provides functional data at comparatively low…

  14. Significant Centers of Tectonic Activity as Identified by Wrinkle Ridges for the Western Hemisphere of Mars

    NASA Technical Reports Server (NTRS)

    Anderson, R.C.; Haldemann, A. F. C.; Golombek, M. P.; Franklin, B. J.; Dohm, J. M.; Lias, J.

    2000-01-01

    The western hemisphere region of Mars has been the site of numerous scientific investigations regarding its tectonic evolution. For this region of Mars, the dominant tectonic region is the Tharsis province. Tharsis is characterized by an enormous system of radiating grabens and a circumferential system of wrinkle ridges. Past investigations of grabens associated with Tharsis have identified specific centers of tectonic activity. A recent structural analysis of the western hemisphere region of Mars which includes the Tharsis region, utilized 25,000 structures to determine the history of local and regional centers of tectonic activity based primarily on the spatial and temporal relationships of extensional features. This investigation revealed that Tharsis is more structurally complex (heterogeneous) than has been previously identified: it consists of numerous regional and local centers of tectonic activity (some are more dominant and/or more long lived than others). Here we use the same approach as Anderson et al. to determine whether the centers of tectonic activity that formed the extensional features also contributed to wrinkle ridge (compressional) formation.

  15. Using the Significant Learning Taxonomy and Active Learning to Improve Accounting Education

    ERIC Educational Resources Information Center

    Killian, Larita J.; Brandon, Christopher D.

    2009-01-01

    Like other members of the academy, accounting professors are challenged to improve student learning. We must help students move beyond the "bean counter" role and develop higher-level skills such as analysis, synthesis, and problem-solving. The Significant Learning Taxonomy was used as a template to improve learning in an introductory accounting…

  16. Novel 2-aryl-naphtho[1,2-d]oxazole derivatives as potential PTP-1B inhibitors showing antihyperglycemic activities.

    PubMed

    Kumar, Atul; Ahmad, Pervez; Maurya, Ram Awatar; Singh, A B; Srivastava, Arvind K

    2009-01-01

    A series of 2-aryl-naphtho[1,2-d]oxazole derivatives have been synthesized and evaluated for PTP-1B inhibitory activity. The compounds have been screened in vivo for antidiabetic activity under sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) and db/db mice model. Compounds 8 and 12 have shown promising PTP-1B inhibitory activity, significant antidiabetic activity, moderate lipid and triglyceride lowering activity. PMID:18436346

  17. Nogo-A-deficient Transgenic Rats Show Deficits in Higher Cognitive Functions, Decreased Anxiety, and Altered Circadian Activity Patterns

    PubMed Central

    Petrasek, Tomas; Prokopova, Iva; Sladek, Martin; Weissova, Kamila; Vojtechova, Iveta; Bahnik, Stepan; Zemanova, Anna; Schönig, Kai; Berger, Stefan; Tews, Björn; Bartsch, Dusan; Schwab, Martin E.; Sumova, Alena; Stuchlik, Ales

    2014-01-01

    Decreased levels of Nogo-A-dependent signaling have been shown to affect behavior and cognitive functions. In Nogo-A knockout and knockdown laboratory rodents, behavioral alterations were observed, possibly corresponding with human neuropsychiatric diseases of neurodevelopmental origin, particularly schizophrenia. This study offers further insight into behavioral manifestations of Nogo-A knockdown in laboratory rats, focusing on spatial and non-spatial cognition, anxiety levels, circadian rhythmicity, and activity patterns. Demonstrated is an impairment of cognitive functions and behavioral flexibility in a spatial active avoidance task, while non-spatial memory in a step-through avoidance task was spared. No signs of anhedonia, typical for schizophrenic patients, were observed in the animals. Some measures indicated lower anxiety levels in the Nogo-A-deficient group. Circadian rhythmicity in locomotor activity was preserved in the Nogo-A knockout rats and their circadian period (tau) did not differ from controls. However, daily activity patterns were slightly altered in the knockdown animals. We conclude that a reduction of Nogo-A levels induces changes in CNS development, manifested as subtle alterations in cognitive functions, emotionality, and activity patterns. PMID:24672453

  18. Significantly enhancing supercapacitive performance of nitrogen-doped graphene nanosheet electrodes by phosphoric acid activation.

    PubMed

    Wang, Ping; He, Haili; Xu, Xiaolong; Jin, Yongdong

    2014-02-12

    In this work, we present a new method to synthesize the phosphorus, nitrogen contained graphene nanosheets, which uses dicyandiamide to prevent the aggregation of graphene oxide and act as the nitrogen precursor, and phosphoric acid (H3PO4) as the activation reagent. We have found that through the H3PO4 activation, the samples exhibit the remarkably enhanced supercapacitive performance, and depending on the amount of H3PO4 introduced, the specific capacitance of the samples is gradually increased from 7.6 to 244.6 F g(-1). Meanwhile, the samples also exhibit the good rate capability and excellent stability (up to 10 000 cycles). Through the transmission electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy and Brunauer-Emmett-Teller analyses, H3PO4 treatment induced large pore volume and phosphorus related function groups in the product are assumed to response for the enhancement. PMID:24456232

  19. Shortened cecropin A-melittin hybrids. Significant size reduction retains potent antibiotic activity.

    PubMed

    Andreu, D; Ubach, J; Boman, A; Wåhlin, B; Wade, D; Merrifield, R B; Boman, H G

    1992-01-20

    We have earlier reported two 26-residue antibacterial peptides made up from different segments of cecropin A (CA) and melittin (M). We now report a substantial reduction in size at the C-terminal section of the highly active hybrid CA(1-8)M(1-18), leading to a series of 20-, 18- and 15-residue analogs with antibiotic properties similar to the larger molecule. In particular, the 15-residue hybrids CA(1-7)M(2-9), CA(1-7)M(4-11) and CA(1-7)M(5-12) are the shortest cecropin-based peptide antibiotics described so far, with antibacterial activity and spectra similar or better than cecropin A and a 60% reduction in size. Their reduced size and highly alpha-helical structure require an alternative mechanism for their interaction with bacterial membranes. PMID:1733777

  20. Primary School Children's Health-Enhancing Physical Activity Patterns: The School as a Significant Environment?

    ERIC Educational Resources Information Center

    Fairclough, S. J.; Butcher, Z. H.; Stratton, G.

    2008-01-01

    The moderate-to-vigorous physical activity (MVPA) of 70 children (age 8.6 years; 40 boys) was measured and gender and age differences were compared. Boys spent 28 minutes per day more than girls in MVPA (p=0.02, d=0.54), and younger children accumulated 24 minutes more MVPA than older peers (p=0.0001, d=0.91). Similar gender and age-related trends…

  1. Molecular and functional significance of Ca2+-activated Cl− channels in pulmonary arterial smooth muscle

    PubMed Central

    Forrest, Abigail S.; Ayon, Ramon J.; Wiwchar, Michael; Angermann, Jeff E.; Pritchard, Harry A. T.; Singer, Cherie A.; Valencik, Maria L.; Britton, Fiona; Greenwood, Iain A.

    2015-01-01

    Abstract Increased peripheral resistance of small distal pulmonary arteries is a hallmark signature of pulmonary hypertension (PH) and is believed to be the consequence of enhanced vasoconstriction to agonists, thickening of the arterial wall due to remodeling, and increased thrombosis. The elevation in arterial tone in PH is attributable, at least in part, to smooth muscle cells of PH patients being more depolarized and displaying higher intracellular Ca2+ levels than cells from normal subjects. It is now clear that downregulation of voltage-dependent K+ channels (e.g., Kv1.5) and increased expression and activity of voltage-dependent (Cav1.2) and voltage-independent (e.g., canonical and vanilloid transient receptor potential [TRPC and TRPV]) Ca2+ channels play an important role in the functional remodeling of pulmonary arteries in PH. This review focuses on an anion-permeable channel that is now considered a novel excitatory mechanism in the systemic and pulmonary circulations. It is permeable to Cl− and is activated by a rise in intracellular Ca2+ concentration (Ca2+-activated Cl− channel, or CaCC). The first section outlines the biophysical and pharmacological properties of the channel and ends with a description of the molecular candidate genes postulated to encode for CaCCs, with particular emphasis on the bestrophin and the newly discovered TMEM16 and anoctamin families of genes. The second section provides a review of the various sources of Ca2+ activating CaCCs, which include stimulation by mobilization from intracellular Ca2+ stores and Ca2+ entry through voltage-dependent and voltage-independent Ca2+ channels. The third and final section summarizes recent findings that suggest a potentially important role for CaCCs and the gene TMEM16A in PH. PMID:26064450

  2. Therapeutic significance and pharmacological activities of antidiarrheal medicinal plants mention in Ayurveda: A review.

    PubMed

    Mishra, Ashish; Seth, Ankit; Maurya, Santosh Kumar

    2016-01-01

    Diarrhea is a serious problem affecting 3-5 billion people per year around the world, especially children of below 5 years. 70% of the world population uses traditional and indigenous medicine for their primary health care. The facts of these indigenous remedies are passed verbally and sometimes as documents. Since ancient time, Ayurveda is the main system of healing in South East Asian countries. Indian literature from ayurvedic texts and other books claim the potency of several plants in the treatment of diarrhea. As the global prospective of ayurvedic medicine is increasing, interest regarding the scientific basis of their action is parallely increasing. Researchers are doing experiments to establish the relation between the claimed action and observed pharmacological activities. In the present article, an attempt was made to compile the scientific basis of medicinal plants used to cure diarrhea in Ayurveda. Literature was collected via electronic search (PubMed, ScienceDirect, Medline, and Google Scholar) from published articles that reports antidiarrheal activity of plants that were mentioned in Ayurveda classics. A total of 109 plant species belonging to 58 families were reported for their antidiarrheal activity. Several Indian medicinal plants have demonstrated promising antidiarrheal effects, but the studies on the antidiarrheal potentials of these plants are not taken beyond proof of concept stage. It is hoped that the article would stimulate future clinical studies because of the paucity of knowledge in this area. PMID:27366356

  3. Therapeutic significance and pharmacological activities of antidiarrheal medicinal plants mention in Ayurveda: A review

    PubMed Central

    Mishra, Ashish; Seth, Ankit; Maurya, Santosh Kumar

    2016-01-01

    Diarrhea is a serious problem affecting 3-5 billion people per year around the world, especially children of below 5 years. 70% of the world population uses traditional and indigenous medicine for their primary health care. The facts of these indigenous remedies are passed verbally and sometimes as documents. Since ancient time, Ayurveda is the main system of healing in South East Asian countries. Indian literature from ayurvedic texts and other books claim the potency of several plants in the treatment of diarrhea. As the global prospective of ayurvedic medicine is increasing, interest regarding the scientific basis of their action is parallely increasing. Researchers are doing experiments to establish the relation between the claimed action and observed pharmacological activities. In the present article, an attempt was made to compile the scientific basis of medicinal plants used to cure diarrhea in Ayurveda. Literature was collected via electronic search (PubMed, ScienceDirect, Medline, and Google Scholar) from published articles that reports antidiarrheal activity of plants that were mentioned in Ayurveda classics. A total of 109 plant species belonging to 58 families were reported for their antidiarrheal activity. Several Indian medicinal plants have demonstrated promising antidiarrheal effects, but the studies on the antidiarrheal potentials of these plants are not taken beyond proof of concept stage. It is hoped that the article would stimulate future clinical studies because of the paucity of knowledge in this area. PMID:27366356

  4. Saraca indica Bark Extract Shows In Vitro Antioxidant, Antibreast Cancer Activity and Does Not Exhibit Toxicological Effects

    PubMed Central

    Yadav, Navneet Kumar; Saini, Karan Singh; Hossain, Zakir; Omer, Ankur; Sharma, Chetan; Gayen, Jiaur R.; Singh, Poonam; Arya, K. R.; Singh, R. K.

    2015-01-01

    Medicinal plants are used as a complementary and alternative medicine in treatment of various diseases including cancer worldwide, because of their ease of accessibility and cost effectiveness. Multicomposed mixture of compounds present in a plant extract has synergistic activity, increases the therapeutic potential many folds, compensates toxicity, and increases bioavailability. Saraca indica (family Caesalpiniaceae) is one of the most ancient sacred plants with medicinal properties, exhibiting a number of pharmacological effects. Antioxidant, antibreast cancer activity and toxicological evaluation of Saraca indica bark extract (SIE) were carried out in the present study. The results of the study indicated that this herbal preparation has antioxidant and antibreast cancer activity. Toxicological studies suggest that SIE is safer to use and may have a potential to be used as complementary and alternative medicine for breast cancer therapy. PMID:25861411

  5. Sulfur Use Efficiency Is a Significant Determinant of Drought Stress Tolerance in Relation to Photosynthetic Activity in Brassica napus Cultivars.

    PubMed

    Lee, Bok-Rye; Zaman, Rashed; Avice, Jean-Christophe; Ourry, Alain; Kim, Tae-Hwan

    2016-01-01

    To investigate the varietal difference in sulfur use efficiency (SUE) and drought stress tolerance, Brassica napus 'Mosa' and 'Saturnin' were exposed to polyethylene glycol (PEG)-induced drought stress for 72 h. Direct quantification of S uptake, de novo synthesis of amino acids and proteins was performed by tracing (34)S. The responses of photosynthetic activity in relation to SUE were also examined. The total amount of newly absorbed S decreased with drought stress in both cultivars but the decrease rate was significantly higher in Mosa (-64%) than in Saturnin (-41%). Drought stress also decreased the amount of S assimilated into amino acids ((34)S-amino acids) and proteins ((34)S-proteins). The total amount of S incorporated into amino acids and proteins was generally higher in Saturnin (663.7 μg S per plant) than in Mosa (337.3 μg S per plant). The estimation of SUE based on S uptake (SUpE) and S assimilation (SUaE) showed that SUE was much higher in Saturnin than in Mosa. The inhibition of photosynthetic activity including Rubisco protein degradation caused by drought stress was much lower in the cultivar with higher SUE (Saturnin). The present study clearly indicates that the genotype with higher SUE is more tolerant to PEG-induced drought stress. PMID:27092167

  6. Sulfur Use Efficiency Is a Significant Determinant of Drought Stress Tolerance in Relation to Photosynthetic Activity in Brassica napus Cultivars

    PubMed Central

    Lee, Bok-Rye; Zaman, Rashed; Avice, Jean-Christophe; Ourry, Alain; Kim, Tae-Hwan

    2016-01-01

    To investigate the varietal difference in sulfur use efficiency (SUE) and drought stress tolerance, Brassica napus ‘Mosa’ and ‘Saturnin’ were exposed to polyethylene glycol (PEG)-induced drought stress for 72 h. Direct quantification of S uptake, de novo synthesis of amino acids and proteins was performed by tracing 34S. The responses of photosynthetic activity in relation to SUE were also examined. The total amount of newly absorbed S decreased with drought stress in both cultivars but the decrease rate was significantly higher in Mosa (-64%) than in Saturnin (-41%). Drought stress also decreased the amount of S assimilated into amino acids (34S-amino acids) and proteins (34S-proteins). The total amount of S incorporated into amino acids and proteins was generally higher in Saturnin (663.7 μg S per plant) than in Mosa (337.3 μg S per plant). The estimation of SUE based on S uptake (SUpE) and S assimilation (SUaE) showed that SUE was much higher in Saturnin than in Mosa. The inhibition of photosynthetic activity including Rubisco protein degradation caused by drought stress was much lower in the cultivar with higher SUE (Saturnin). The present study clearly indicates that the genotype with higher SUE is more tolerant to PEG-induced drought stress. PMID:27092167

  7. Life satisfaction in young adults 10 or more years after hematopoietic stem cell transplantation for childhood malignant and nonmalignant diseases does not show significant impairment compared with healthy controls: a case-matched study.

    PubMed

    Uderzo, Cornelio; Corti, Paola; Pappalettera, Marco; Baldini, Valentina; Lucchini, Giovanna; Meani, Dario; Rovelli, Attilio

    2012-11-01

    Patients undergoing hematopoietic stem cell transplantation (HSCT) may experience physical and psychological deterioration that impairs their life satisfaction (LS). This study focused on LS in long-term survivors at 10 or more years after HSCT. Fifty-five patients (39 males, median age 25 years) undergoing allogeneic HSCT for childhood malignant (n = 52) or nonmalignant diseases (n = 3) were enrolled. A control group of 98 young adults (59 males, median age 24 years) was considered. A questionnaire with a modified Satisfaction Life Domain Scale was administered. We assessed such domains as education, employment, leisure time, social relationships, and perception of physical status with a 30-item questionnaire. To investigate the association between the domains and the probability of diminished LS, we performed a logistical procedure using the maximum likelihood method. Predictive factors of LS were adjusted for sociodemographic variables. In the multivariate analysis, the participant's level of LS was not significantly correlated with sociodemographic factors or with HSCT status. The same analysis showed a slight trend in favor of the control group (P = .06) for body perception. Our data suggest that the patients who undergo HSCT in childhood have no significant difference in long-term LS compared with healthy controls. PMID:22766222

  8. Functional activity maps based on significance measures and Independent Component Analysis.

    PubMed

    Martínez-Murcia, F J; Górriz, J M; Ramírez, J; Puntonet, C G; Illán, I A

    2013-07-01

    The use of functional imaging has been proven very helpful for the process of diagnosis of neurodegenerative diseases, such as Alzheimer's Disease (AD). In many cases, the analysis of these images is performed by manual reorientation and visual interpretation. Therefore, new statistical techniques to perform a more quantitative analysis are needed. In this work, a new statistical approximation to the analysis of functional images, based on significance measures and Independent Component Analysis (ICA) is presented. After the images preprocessing, voxels that allow better separation of the two classes are extracted, using significance measures such as the Mann-Whitney-Wilcoxon U-Test (MWW) and Relative Entropy (RE). After this feature selection step, the voxels vector is modelled by means of ICA, extracting a few independent components which will be used as an input to the classifier. Naive Bayes and Support Vector Machine (SVM) classifiers are used in this work. The proposed system has been applied to two different databases. A 96-subjects Single Photon Emission Computed Tomography (SPECT) database from the "Virgen de las Nieves" Hospital in Granada, Spain, and a 196-subjects Positron Emission Tomography (PET) database from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Values of accuracy up to 96.9% and 91.3% for SPECT and PET databases are achieved by the proposed system, which has yielded many benefits over methods proposed on recent works. PMID:23660005

  9. A novel rat model of heart failure induced by high methionine diet showing evidence of association between hyperhomocysteinemia and activation of NF-kappaB

    PubMed Central

    Liu, Bin; Ma, Shengting; Wang, Tao; Zhao, Chengjun; Li, Yi; Yin, Jie; Liu, Cuixia; Gao, Chengzhi; Sun, Ling; Yue, Wenwei; Yu, Huapeng; Jia, Ruyi

    2016-01-01

    Heart failure is one of the most serious diseases worldwide, and can be caused by many factors, among them hyperhomocysteinemia can increase the risk for development of heart failure. In this study, we treated rats with high methionine diet (HMD), which can be conversed to homocysteine in human body, to induce a novel model of heart failure. We proved the successful establishment of this model by echocardiography and pathological evaluation at the termination of treatment. Ejection fraction and fractional shortening were significantly deceased after HMD treatment, while left ventricular volume in systole was increased. HMD treatment caused hypertrophy of cardiomyocytes, disarrangement of myofibers, and infiltration of inflammatory cells, as well as abundant apoptotic cells appeared after HMD treatment. Plasmatic homocysteine level was elevated after HMD treatment. Furthermore, through electrophoretic mobility shift assay and chromatin immunoprecipitation, the activity of NF-κB in nuclear extract was also significantly elevated, showing evidence of positive relationship between hyperhomocysteinemia and activation of NF-κB in HMD-induced heart failure. The successful development and validation of this model have made it a new tool for translational medical research of metabolic disorders-related cardiovascular disease. PMID:27069545

  10. 11-Oxoaerothionin isolated from the marine sponge Aplysina fistularis shows anti-inflammatory activity in LPS-stimulated macrophages.

    PubMed

    de Medeiros, Alexandra Ivo; Gandolfi, Renata C; Secatto, Adriana; Falcucci, Romulo M; Faccioli, Lucia H; Hajdu, Eduardo; Peixinho, Solange; Berlinck, Roberto G S

    2012-12-01

    Marine sponges of the order Verongida are a rich source of biologically active bromotyrosine-derived secondary metabolites. However, none of these compounds are known to display anti-inflammatory activity. In the present investigation, we report the anti-inflammatory effects of 11-oxoaerothionin isolated from the Verongida sponge Aplysina fistularis. When RAW264.7 cells and primary macrophages were preincubated with 11-oxoaerothionin and stimulated with LPS (lipopolysaccharide), a concentration-dependent inhibition of iNOS(inducible nitric oxide synthase) protein and NO(2)(-) (Nitrite) production were observed. The same effect was observed when proinflammatory cytokines and PGE(2) (Prostaglandin E2) production was evaluated. In summary, we demonstrated that in the presence of LPS, 11-oxoaerothionin suppresses NO(2) and iNOS expression as well as inflammatory cytokines and PGE(2). PMID:22537094

  11. Modest Activity of Pomalidomide in Patients with Myelofibrosis and Significant Anemia

    PubMed Central

    Daver, Naval; Shastri, Aditi; Kadia, Tapan; Quintas-Cardama, Alfonso; Jabbour, Elias; Konopleva, Marina; O’Brien, Susan; Pierce, Sherry; Zhou, Lingsha; Cortes, Jorge; Kantarjian, Hagop; Verstovsek, Srdan

    2014-01-01

    We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis. PMID:23890523

  12. Antimicrobial Peptides Expressed in Medicinal Maggots of the Blow Fly Lucilia sericata Show Combinatorial Activity against Bacteria

    PubMed Central

    Pöppel, Anne-Kathrin; Vogel, Heiko; Wiesner, Jochen

    2015-01-01

    The larvae of the common green bottle fly (Lucilia sericata) produce antibacterial secretions that have a therapeutic effect on chronic and nonhealing wounds. Recent developments in insect biotechnology have made it possible to use these larvae as a source of novel anti-infectives. Here, we report the application of next-generation RNA sequencing (RNA-Seq) to characterize the transcriptomes of the larval glands, crop, and gut, which contribute to the synthesis of antimicrobial peptides (AMPs) and proteins secreted into wounds. Our data confirm that L. sericata larvae have adapted in order to colonize microbially contaminated habitats, such as carrion and necrotic wounds, and are protected against infection by a diverse spectrum of AMPs. L. sericata AMPs include not only lucifensin and lucimycin but also novel attacins, cecropins, diptericins, proline-rich peptides, and sarcotoxins. We identified 47 genes encoding putative AMPs and produced 23 as synthetic analogs, among which some displayed activities against a broad spectrum of microbial pathogens, including Pseudomonas aeruginosa, Proteus vulgaris, and Enterococcus faecalis. Against Escherichia coli (Gram negative) and Micrococcus luteus (Gram positive), we found mostly additive effects but also synergistic activity when selected AMPs were tested in combination. The AMPs that are easy to synthesize are currently being produced in bulk to allow their evaluation as novel anti-infectives that can be formulated in hydrogels to produce therapeutic wound dressings and adhesive bandages. PMID:25666157

  13. Antimicrobial peptides expressed in medicinal maggots of the blow fly Lucilia sericata show combinatorial activity against bacteria.

    PubMed

    Pöppel, Anne-Kathrin; Vogel, Heiko; Wiesner, Jochen; Vilcinskas, Andreas

    2015-05-01

    The larvae of the common green bottle fly (Lucilia sericata) produce antibacterial secretions that have a therapeutic effect on chronic and nonhealing wounds. Recent developments in insect biotechnology have made it possible to use these larvae as a source of novel anti-infectives. Here, we report the application of next-generation RNA sequencing (RNA-Seq) to characterize the transcriptomes of the larval glands, crop, and gut, which contribute to the synthesis of antimicrobial peptides (AMPs) and proteins secreted into wounds. Our data confirm that L. sericata larvae have adapted in order to colonize microbially contaminated habitats, such as carrion and necrotic wounds, and are protected against infection by a diverse spectrum of AMPs. L. sericata AMPs include not only lucifensin and lucimycin but also novel attacins, cecropins, diptericins, proline-rich peptides, and sarcotoxins. We identified 47 genes encoding putative AMPs and produced 23 as synthetic analogs, among which some displayed activities against a broad spectrum of microbial pathogens, including Pseudomonas aeruginosa, Proteus vulgaris, and Enterococcus faecalis. Against Escherichia coli (Gram negative) and Micrococcus luteus (Gram positive), we found mostly additive effects but also synergistic activity when selected AMPs were tested in combination. The AMPs that are easy to synthesize are currently being produced in bulk to allow their evaluation as novel anti-infectives that can be formulated in hydrogels to produce therapeutic wound dressings and adhesive bandages. PMID:25666157

  14. [The significance of free radicals and antioxidants due to the load induced by sport activity].

    PubMed

    Holecek, V; Liska, J; Racek, J; Rokyta, R

    2004-01-01

    Sport performance is followed by a high production of free radicals. The main reasons are reperfusion after the previous imbalance between the increased need of the organism and the ability of blood supply by oxygen, increased production of ATP, decomposition of the cells particularly white blood cells, oxidation of the purin basis from DNA, stress, output of epinephrine release of free iron, increased temperature in the muscle and its inflammation, and the reception of free radicals from external environment. Peroxidation of lipids, proteins, DNA and other compounds follows the previous biochemical steps. Antioxidants are consumed by free radicals, antioxidative enzymes are released into blood plasma, intracellular calcium is increased, the production of nitric oxide rises, the levels of hydrogen peroxide and hypochlorous acid increase. These penetrate through the membranes and oxidatively damage the tissues. Training improves the ability of the organism to balance the increased load of free radicals. The damage can be lowered by the application of a mixture of antioxidants, the most important are vitamin C, A, E, glutathione, selenium, carnosine, eventually bioflavonoids and ginkgo biloba. The lack of antioxidants can significantly diminish the sport performance and therefore the supplementation with antioxidants is for top sportsmen but also for aged people advisable. PMID:15709642

  15. Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain

    PubMed Central

    Webster, J Christopher; Francis, Michael M; Porter, Julia K; Robinson, Gillian; Stokes, Clare; Horenstein, Ben; Papke, Roger L

    1999-01-01

    We show that a portion of the TM2 domain regulates the sensitivity of beta subunit-containing rat neuronal nicotinic AChR to the ganglionic blocker mecamylamine, such that the substitution of 4 amino acids of the muscle beta subunit sequence into the neuronal beta4 sequence decreases the potency of mecamylamine by a factor of 200 and eliminates any long-term effects of this drug on receptor function.The same exchange of sequence that decreases inhibition by mecamylamine produces a comparable potentiation of long-term inhibition by nicotine.Inhibition by mecamylamine is voltage-dependent, suggesting a direct interaction of mecamylamine with sequence elements within the membrane field. We have previously shown that sensitivity to TMP (tetramethylpiperidine) inhibitors is controlled by the same sequence elements that determine mecamylamine sensitivity. However, inhibition by bis-TMP compounds is independent of voltage.Our experiments did not show any influence of voltage on the inhibition of chimeric receptors by nicotine, suggesting that the inhibitory effects of nicotine are mediated by binding to a site outside the membrane's electric field.An analysis of point mutations indicates that the residues at the 6′ position within the beta subunit TM2 domain may be important for determining the effects of both mecamylamine and nicotine in a reciprocal manner. Single mutations at the 10′ position are not sufficient to produce effects, but 6′ 10′ double mutants show more effect than do the 6′ single mutants. PMID:10455283

  16. Significance of redox-active cysteines in human FAD synthase isoform 2.

    PubMed

    Miccolis, Angelica; Galluccio, Michele; Nitride, Chiara; Giancaspero, Teresa Anna; Ferranti, Pasquale; Iametti, Stefania; Indiveri, Cesare; Bonomi, Francesco; Barile, Maria

    2014-12-01

    FAD synthase (FMN:ATP adenylyl transferase, FMNAT or FADS, EC 2.7.7.2) is the last enzyme in the pathway converting riboflavin into FAD. In humans, FADS is localized in different subcellular compartments and exists in different isoforms. Isoform 2 (490-amino acids) is organized in two domains: the 3'-phosphoadenosine-5'-phosphosulfate (PAPS) reductase domain, that is the FAD-forming catalytic domain, and one resembling a molybdopterin-binding (MPTb) domain, with a hypothetical regulatory role. hFADS2 contains ten Cys residues, seven of which located in the PAPS reductase domain, with a possible involvement either in FAD synthesis or in FAD delivery to cognate apo-flavoproteins. A homology model of the PAPS reductase domain of hFADS2 revealed a co-ordinated network among the Cys residues in this domain. In this model, C312 and C303 are very close to the flavin substrate, consistent with a significantly lowered FAD synthesis rate in C303A and C312A mutants. FAD synthesis is also inhibited by thiol-blocking reagents, suggesting the involvement of free cysteines in the hFADS2 catalytic cycle. Mass spectrometry measurements and titration with thiol reagents on wt hFADS2 and on several individual cysteine/alanine mutants allowed us to detect two stably reduced cysteines (C139 and C241, one for each protein domain), two stable disulfide bridges (C399-C402, C303-C312, both in the PAPS domain), and two unstable disulfides (C39-C50; C440-C464). Whereas the C39-C50 unstable disulfide is located in the MPTb domain and appears to have no catalytic relevance, a cysteine-based redox switch may involve formation and breakdown of a disulfide between C440 and C464 in the PAPS domain. PMID:25135855

  17. The Lipid Portion of Activated Platelet-Rich Plasma Significantly Contributes to Its Wound Healing Properties

    PubMed Central

    Hoeferlin, Lauren Alexis; Huynh, Quoc K.; Mietla, Jennifer A.; Sell, Scott A.; Tucker, Jason; Chalfant, Charles Edward; Wijesinghe, Dayanjan Shanaka

    2015-01-01

    Objective: Platelet-rich plasma (PRP) is a popular choice for the treatment of chronic wounds. Current dogma attributes these healing properties to the peptide growth factors of PRP. However, PRP is also rich in bioactive lipids whose contribution to healing has not been characterized and warrants investigation due to the protease-rich environment of chronic wounds. Approach: The lipid fraction of PRP was tested with respect to proliferation and migration of primary adult human dermal fibroblasts (HDFa)±exposure to chronic wound fluid (CWF). This fraction was also characterized via LC-MS/MS for bioactive lipids. A synthetic formulation of the bioactive lipid composition was developed and tested for the ability to overcome proliferative growth arrest induced by CWF. Results: The data demonstrate the ability of the lipid fraction of PRP to significantly enhance the migration and proliferation of HDFa, and to overcome the proliferative growth arrest induced by CWF. Furthermore, the synthetic lipid formulation generated following characterization of the PRP lipidome demonstrated a similar ability to overcome proliferative arrest of HDFa in the presence of CWF. Innovation: For the first time, we demonstrate the relevance of the lipid fraction of PRP toward the biology of wound healing. These studies open the possibility of altering the lipid profile of PRP via diet or exogenous pathway manipulation to obtain a better healing outcome. Conclusion: The lipid fraction of PRP is under investigated and yet relevant component in wound healing. The current study demonstrates the relevance of this fraction in wound healing by PRP. PMID:25713752

  18. Drug and food-deprivation modulation of activity in rats given chronic dietary lead: significance of type of activity measure.

    PubMed

    Yamamoto, B K; Kutscher, C L

    1981-09-01

    In Experiment 1, rats were given a 1% lead acetate diet from Day 100 of life to the termination of the experiment. After 82 days of lead feeding behavioral tests were started. Lead exposure increased wheel-turning hyperactivity produced by food deprivation and phenylethylamine injection. Lead produced no activity change in the unchallenged condition. In the open field, lead-exposure rats were less responsive to the stimulating action of PEA and amphetamine and to the sedating action of pentobarbital. In Experiment 2, the interaction of lead with food deprivation of PEA on wheel-turning was replicated in naive animals given only a 32-day exposure. Chemical analysis was made of tissues. Ingested lead entered the brain. Regional steady-state levels of brain norepinephrine, dopamine and serotonin were not altered by lead treatment when measured following four days of starvation at a time when lead-induced behavioral change was distinct. It was concluded that pharmacological challenges on activity may be sensitive indicators of lead exposure, but the type of activity measure is critical. PMID:7291253

  19. Significance of an Active Volcanic Front in the Far Western Aleutian Arc

    NASA Astrophysics Data System (ADS)

    Yogodzinski, G. M.; Kelemen, P. B.; Hoernle, K.

    2015-12-01

    Discovery of a volcanic front west of Buldir Volcano, the western-most emergent Aleutian volcano, demonstrates that the surface expression of Aleutian volcanism falls below sea level just west of 175.9° E longitude, but is otherwise continuous from mainland Alaska to Kamchatka. The newly discovered sites of western Aleutian seafloor volcanism are the Ingenstrem Depression, a 60 km-long structural depression just west of Buldir, and an unnamed area 300 km further west, referred to as the Western Cones. These locations fall along a volcanic front that stretches from Buldir to Piip Seamount near the Komandorsky Islands. Western Aleutian seafloor volcanic rocks include large quantities of high-silica andesite and dacite, which define a highly calc-alkaline igneous series and carry trace element signatures that are unmistakably subduction-related. This indicates that subducting oceanic lithosphere is present beneath the westernmost Aleutian arc. The rarity of earthquakes below depths of 200 km indicates that the subducting plate is unusually hot. Some seafloor volcanoes are 6-8 km wide at the base, and so are as large as many emergent Aleutian volcanoes. The seafloor volcanoes are submerged in water depths >3000 m because they sit on oceanic lithosphere of the Bering Sea. The volcanic front is thus displaced to the north of the ridge of arc crust that underlies the western Aleutian Islands. This displacement, which developed since approximately 6 Ma when volcanism was last active on the islands, must be a consequence of oblique convergence in a system where the subducting plate and large blocks of arc crust are both moving primarily in an arc-parallel sense. The result is a hot-slab system where low subduction rates probably limit advection of hot mantle to the subarc, and produce a relatively cool and perhaps stagnant mantle wedge. The oceanic setting and highly oblique subduction geometry also severely limit rates of sediment subduction, so the volcanic rocks, which

  20. Ecotoxicological assessment of solar cell leachates: Copper indium gallium selenide (CIGS) cells show higher activity than organic photovoltaic (OPV) cells.

    PubMed

    Brun, Nadja Rebecca; Wehrli, Bernhard; Fent, Karl

    2016-02-01

    Despite the increasing use of photovoltaics their potential environmental risks are poorly understood. Here, we compared ecotoxicological effects of two thin-film photovoltaics: established copper indium gallium selenide (CIGS) and organic photovoltaic (OPV) cells. Leachates were produced by exposing photovoltaics to UV light, physical damage, and exposure to environmentally relevant model waters, representing mesotrophic lake water, acidic rain, and seawater. CIGS cell leachates contained 583 μg L(-1) molybdenum at lake water, whereas at acidic rain and seawater conditions, iron, copper, zinc, molybdenum, cadmium, silver, and tin were present up to 7219 μg L(-1). From OPV, copper (14 μg L(-1)), zinc (87 μg L(-1)) and silver (78 μg L(-1)) leached. Zebrafish embryos were exposed until 120 h post-fertilization to these extracts. CIGS leachates produced under acidic rain, as well as CIGS and OPV leachates produced under seawater conditions resulted in a marked hatching delay and increase in heart edema. Depending on model water and solar cell, transcriptional alterations occurred in genes involved in oxidative stress (cat), hormonal activity (vtg1, ar), metallothionein (mt2), ER stress (bip, chop), and apoptosis (casp9). The effects were dependent on the concentrations of cationic metals in leachates. Addition of ethylenediaminetetraacetic acid protected zebrafish embryos from morphological and molecular effects. Our study suggests that metals leaching from damaged CIGS cells, may pose a potential environmental risk. PMID:26615488

  1. A new peptide (Ruviprase) purified from the venom of Daboia russelii russelii shows potent anticoagulant activity via non-enzymatic inhibition of thrombin and factor Xa.

    PubMed

    Thakur, Rupamoni; Kumar, Ashok; Bose, Biplab; Panda, Dulal; Saikia, Debashree; Chattopadhyay, Pronobesh; Mukherjee, Ashis K

    2014-10-01

    Compounds showing dual inhibition of thrombin and factor Xa (FXa) are the subject of great interest owing to their broader specificity for effective anticoagulation therapy against cardiovascular disorders. This is the first report on the functional characterization and assessment of therapeutic potential of a 4423.6 Da inhibitory peptide (Ruviprase) purified from Daboia russelii russelii venom. The secondary structure of Ruviprase is composed of α-helices (61.9%) and random coils (38.1%). The partial N-terminal sequence (E(1)-V(2)-X(3)-W(4)-W(5)-W(6)-A(7)-Q(8)-L(9)-S(10)) of Ruviprase demonstrated significant similarity (80.0%) with an internal sequence of apoptosis-stimulating protein reported from the venom of Ophiophagus hannah and Python bivittatus; albeit Ruviprase did not show sequence similarity with existing thrombin/FXa inhibitors, suggesting its uniqueness. Ruviprase demonstrated a potent in vitro anticoagulant property and inhibited both thrombin and FXa following slow binding kinetics. Ruviprase inhibited thrombin by binding to its active site via an uncompetitive mechanism with a Ki value and dissociation constant (KD) of 0.42 μM and 0.46 μM, respectively. Conversely, Ruviprase demonstrated mixed inhibition (Ki = 0.16 μM) of FXa towards its physiological substrate prothrombin. Furthermore, the biological properties of Ruviprase could not be neutralized by commercial polyvalent or monovalent antivenom. Ruviprase at a dose of 2.0 mg/kg was non-toxic and showed potent in vivo anticoagulant activity after 6 h of intraperitoneal treatment in mice. Because of the potent anticoagulant property as well as non-toxic nature of Ruviprase, the possible application of the peptide as an antithrombotic agent for combating thrombosis-associated ailments appears promising. PMID:25038567

  2. The Aminosteroid Derivative RM-133 Shows In Vitro and In Vivo Antitumor Activity in Human Ovarian and Pancreatic Cancers

    PubMed Central

    Kenmogne, Lucie Carolle; Ayan, Diana; Roy, Jenny; Maltais, René; Poirier, Donald

    2015-01-01

    Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new drugs acting via a different mechanism of action represents a clear priority. Herein, we are reporting for the first time that the aminosteroid derivative RM-133, developed in our laboratory, displays promising activity on two models of aggressive cancers, namely ovarian (OVCAR-3) and pancreatic (PANC-1) cancers. The IC50 value of RM-133 was 0.8 μM and 0.3 μM for OVCAR-3 and PANC-1 cell lines in culture, respectively. Based on pharmacokinetic studies on RM-133 using 11 different vehicles, we selected two main vehicles: aqueous 0.4% methylcellulose:ethanol (92:8) and sunflower oil:ethanol (92:8) for in vivo studies. Using subcutaneous injection of RM-133 with the methylcellulose-based vehicle, growth of PANC-1 tumors xenografted to nude mice was inhibited by 63%. Quite interestingly, RM-133 injected subcutaneously with the methylcellulose-based or sunflower-based vehicles reduced OVCAR-3 xenograft growth by 122% and 100%, respectively. After the end of RM-133 treatment using the methylcellulose-based vehicle, OVCAR-3 tumor growth inhibition was maintained for ≥ 1 week. RM-133 was also well tolerated in the whole animal, no apparent sign of toxicity having been detected in the xenograft studies. PMID:26660672

  3. Zero Valent Iron Significantly Enhances Methane Production from Waste Activated Sludge by Improving Biochemical Methane Potential Rather Than Hydrolysis Rate

    PubMed Central

    Liu, Yiwen; Wang, Qilin; Zhang, Yaobin; Ni, Bing-Jie

    2015-01-01

    Anaerobic digestion has been widely applied for waste activated sludge (WAS) treatment. However, methane production from anaerobic digestion of WAS is usually limited by the slow hydrolysis rate and/or poor biochemical methane potential of WAS. This work systematically studied the effects of three different types of zero valent iron (i.e., iron powder, clean scrap and rusty scrap) on methane production from WAS in anaerobic digestion, by using both experimental and mathematical approaches. The results demonstrated that both the clean and the rusty iron scrap were more effective than the iron powder for improving methane production from WAS. Model-based analysis showed that ZVI addition significantly enhanced methane production from WAS through improving the biochemical methane potential of WAS rather than its hydrolysis rate. Economic analysis indicated that the ZVI-based technology for enhancing methane production from WAS is economically attractive, particularly considering that iron scrap can be freely acquired from industrial waste. Based on these results, the ZVI-based anaerobic digestion process of this work could be easily integrated with the conventional chemical phosphorus removal process in wastewater treatment plant to form a cost-effective and environment-friendly approach, enabling maximum resource recovery/reuse while achieving enhanced methane production in wastewater treatment system. PMID:25652244

  4. Zero Valent Iron Significantly Enhances Methane Production from Waste Activated Sludge by Improving Biochemical Methane Potential Rather Than Hydrolysis Rate

    NASA Astrophysics Data System (ADS)

    Liu, Yiwen; Wang, Qilin; Zhang, Yaobin; Ni, Bing-Jie

    2015-02-01

    Anaerobic digestion has been widely applied for waste activated sludge (WAS) treatment. However, methane production from anaerobic digestion of WAS is usually limited by the slow hydrolysis rate and/or poor biochemical methane potential of WAS. This work systematically studied the effects of three different types of zero valent iron (i.e., iron powder, clean scrap and rusty scrap) on methane production from WAS in anaerobic digestion, by using both experimental and mathematical approaches. The results demonstrated that both the clean and the rusty iron scrap were more effective than the iron powder for improving methane production from WAS. Model-based analysis showed that ZVI addition significantly enhanced methane production from WAS through improving the biochemical methane potential of WAS rather than its hydrolysis rate. Economic analysis indicated that the ZVI-based technology for enhancing methane production from WAS is economically attractive, particularly considering that iron scrap can be freely acquired from industrial waste. Based on these results, the ZVI-based anaerobic digestion process of this work could be easily integrated with the conventional chemical phosphorus removal process in wastewater treatment plant to form a cost-effective and environment-friendly approach, enabling maximum resource recovery/reuse while achieving enhanced methane production in wastewater treatment system.

  5. Hedgehog Signaling Pathway Is Active in GBM with GLI1 mRNA Expression Showing a Single Continuous Distribution Rather than Discrete High/Low Clusters

    PubMed Central

    Biswas, Nidhan K.; Rote, Sarang; Chatterjee, Uttara; Ghosh, Samarendra N.; Deb, Sumit; Saha, Suniti K.; Chowdhury, Anup K.; Ghosh, Subhashish; Rudin, Charles M.; Mukherjee, Ankur; Basu, Analabha; Dhara, Surajit

    2015-01-01

    Hedgehog (Hh) signaling pathway is a valid therapeutic target in a wide range of malignancies. We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we show here a strong correlation (r = 0.7) between GLI1 and PTCH1 mRNA expression—as a hallmark of the canonical Hh-pathway activity in this malignancy. GLI1 mRNA expression varied in 3 orders of magnitude among the GBM patients of the same cohort showing a single continuous distribution—unlike the discrete high/low-GLI1 mRNA expressing clusters of medulloblastoma (MB). When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the “high-Hh” cluster of MB but 5.6 fold higher than that of the “low-Hh” cluster of MB. Next, we demonstrated statistically significant up- and down-regulation of GLI1 mRNA expressions in GBM patient-derived low-passage neurospheres in vitro by sonic hedgehog ligand-enriched conditioned media (shh-CM) and by Hh-inhibitor drug vismodegib respectively. We also showed clinically achievable dose (50 μM) of vismodegib alone to be sufficient to induce apoptosis and cell cycle arrest in these low-passage GBM neurospheres in vitro. Vismodegib showed an effect on the neurospheres, both by down-regulating GLI1 mRNA expression and by inducing apoptosis/cell cycle arrest, irrespective of their relative endogenous levels of GLI1 mRNA expression. We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity. That is suggestive of therapies with Hh-pathway inhibitor drugs in this malignancy without a need for further stratification of patients on the basis of relative levels of Hh-pathway activity among them. PMID:25775002

  6. Endophytic Bacteria Isolated from Common Bean (Phaseolus vulgaris) Exhibiting High Variability Showed Antimicrobial Activity and Quorum Sensing Inhibition.

    PubMed

    Lopes, Ralf Bruno Moura; Costa, Leonardo Emanuel de Oliveira; Vanetti, Maria Cristina Dantas; de Araújo, Elza Fernandes; de Queiroz, Marisa Vieira

    2015-10-01

    Endophytic bacteria play a key role in the biocontrol of phytopathogenic microorganisms. In this study, genotypic diversity was analyzed via repetitive element PCR (rep-PCR) of endophytic isolates of the phylum Actinobacteria that were previously collected from leaves of cultivars of common bean (Phaseolus vulgaris). Considerable variability was observed, which has not been reported previously for this phylum of endophytic bacteria of the common bean. Furthermore, the ethanol extracts from cultures of various isolates inhibited the growth of pathogenic bacteria in vitro, especially Gram-positive pathogens. Extracts from cultures of Microbacterium testaceum BAC1065 and BAC1093, which were both isolated from the 'Talismã' cultivar, strongly inhibited most of the pathogenic bacteria tested. Bean endophytic bacteria were also demonstrated to have the potential to inhibit the quorum sensing of Gram-negative bacteria. This mechanism may regulate the production of virulence factors in pathogens. The ability to inhibit quorum sensing has also not been reported previously for endophytic microorganisms of P. vulgaris. Furthermore, M. testaceum with capacity to inhibit quorum sensing appears to be widespread in common bean. The genomic profiles of M. testaceum were also analyzed via pulsed-field gel electrophoresis, and greater differentiation was observed using this method than rep-PCR; in general, no groups were formed based on the cultivar of origin. This study showed for the first time that endophytic bacteria from common bean plants exhibit high variability and may be useful for the development of strategies for the biological control of diseases in this important legume plant. PMID:26202846

  7. Effects of nanomaterials on luciferase with significant protection and increased enzyme activity observed for zinc oxide nanomaterials.

    PubMed

    Barber, S; Abdelhakiem, M; Ghosh, K; Mitchell, L; Spidle, R; Jacobs, B; Washington, L; Li, J; Wanekaya, A; Glaspell, G; DeLong, R K

    2011-12-01

    This principle goal of this research was to examine the effects of various nanomaterials on the activity and behavior of the firefly enzyme luciferase. Nanomaterials have been found to stabilize, and in some instances, shown to increase the activity of enzymes. In this study gold, manganese oxide (MnO), and zinc oxide (ZnO) nanomaterials were utilized in order to test their effects on enzyme activity. Luciferase was used because its activity is easy to analyze, as it typically produces a large amount of bioluminescence easily detected by a Microtiter plate reader. Following incubation with the various nanomaterials, luciferase was subjected to degradation by several protein denaturing agents, such as heat, SDS, urea, ethanol, protease, hydrogen peroxide, and pH changes. Results indicated that luciferase activity is indeed affected when combined with nanomaterials, accompanied by both increases and decreases in enzyme activity depending on the type of nanomaterial and denaturing agent used. In most of the experiments, when incubated with ZnO nanomaterials, luciferase depicted significant increases in activity and bioluminescence. Additional experiments, in which human A375 cells were treated with luciferase-nanomaterial mixtures, also depicted increased enzyme activity and bioluminescence for luciferase incubated with ZnO nanomaterials. Ultimately, our findings indicated that when luciferase was subjected to multiple types of denaturation, zinc oxide nanomaterials dramatically preserved and increased enzyme activity and bioluminescence. PMID:22408903

  8. Efficacious gene silencing in serum and significant apoptotic activity induction by survivin downregulation mediated by new cationic gemini tocopheryl lipids.

    PubMed

    Kumar, Krishan; Maiti, Bappa; Kondaiah, Paturu; Bhattacharya, Santanu

    2015-02-01

    Nonviral gene delivery offers cationic liposomes as promising instruments for the delivery of double-stranded RNA (ds RNA) molecules for successful sequence-specific gene silencing (RNA interference). The efficient delivery of siRNA (small interfering RNA) to cells while avoiding unexpected side effects is an important prerequisite for the exploitation of the power of this excellent tool. We present here six new tocopherol based cationic gemini lipids, which induce substantial gene knockdown without any obvious cytotoxicity. All the efficient coliposomal formulations derived from each of these geminis and a helper lipid, dioleoylphosphatidylethanolamine (DOPE), were well characterized using physical methods such as atomic force microscopy (AFM) and dynamic light scattering (DLS). Zeta potential measurements were conducted to estimate the surface charge of these formulations. Flow cytometric analysis showed that the optimized coliposomal formulations could transfect anti-GFP siRNA efficiently in three different GFP expressing cell lines, viz., HEK 293T, HeLa, and Caco-2, significantly better than a potent commercial standard Lipofectamine 2000 (L2K) both in the absence and in the presence of serum (FBS). Notably, the knockdown activity of coliposomes of gemini lipids was not affected even in the presence of serum (10% and 50% FBS) while it dropped down for L2K significantly. Observations under a fluorescence microscope, RT-PCR, and Western blot analysis substantiated the flow cytometry results. The efficient cellular entry of labeled siRNA in GFP expressing cells as evidenced from confocal microscopy put forward these gemini lipids among the potent lipidic carriers for siRNA. The efficient transfection capabilities were also profiled in a more relevant fashion while performing siRNA transfections against survivin (an anti-apoptotic protein) which induced substantial apoptosis. Furthermore, the survivin downregulation improved the therapeutic efficacy levels of an

  9. Peroxidases identified in a subtractive cDNA library approach show tissue-specific transcript abundance and enzyme activity during seed germination of Lepidium sativum

    PubMed Central

    Linkies, Ada; Schuster-Sherpa, Uta; Tintelnot, Stefanie; Leubner-Metzger, Gerhard; Müller, Kerstin

    2010-01-01

    The micropylar endosperm is a major regulator of seed germination in endospermic species, to which the close Brassicaceae relatives Arabidopsis thaliana and Lepidium sativum (cress) belong. Cress seeds are about 20 times larger than the seeds of Arabidopsis. This advantage was used to construct a tissue-specific subtractive cDNA library of transcripts that are up-regulated late in the germination process specifically in the micropylar endosperm of cress seeds. The library showed that a number of transcripts known to be up-regulated late during germination are up-regulated in the micropylar endosperm cap. Detailed germination kinetics of SALK lines carrying insertions in genes present in our library showed that the identified transcripts do indeed play roles during germination. Three peroxidases were present in the library. These peroxidases were identified as orthologues of Arabidopsis AtAPX01, AtPrx16, and AtPrxIIE. The corresponding SALK lines displayed significant germination phenotypes. Their transcripts were quantified in specific cress seed tissues during germination in the presence and absence of ABA and they were found to be regulated in a tissue-specific manner. Peroxidase activity, and particularly its regulation by ABA, also differed between radicles and micropylar endosperm caps. Possible implications of this tissue-specificity are discussed. PMID:19884228

  10. Phosphatase activity of the voltage-sensing phosphatase, VSP, shows graded dependence on the extent of activation of the voltage sensor.

    PubMed

    Sakata, Souhei; Okamura, Yasushi

    2014-03-01

    The voltage-sensing phosphatase (VSP) consists of a voltage sensor and a cytoplasmic phosphatase region, and the movement of the voltage sensor is coupled to the phosphatase activity. However, its coupling mechanisms still remain unclear. One possible scenario is that the phosphatase is activated only when the voltage sensor is in a fully activated state. Alternatively, the enzymatic activity of single VSP proteins could be graded in distinct activated states of the voltage sensor, and partial activation of the voltage sensor could lead to partial activation of the phosphatase. To distinguish between these two possibilities, we studied a voltage sensor mutant of zebrafish VSP, where the voltage sensor moves in two steps as evidenced by analyses of charge movements of the voltage sensor and voltage clamp fluorometry. Measurements of the phosphatase activity toward phosphatidylinositol 4,5-bisphosphate revealed that both steps of voltage sensor activation are coupled to the tuning of phosphatase activities, consistent with the idea that the phosphatase activity is graded by the magnitude of the movement of the voltage sensor. PMID:24277865

  11. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6

    PubMed Central

    Saini, Chaman; Siddiqui, Anisuddin; Ramesh, Venkatesh; Nath, Indira

    2016-01-01

    Background 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions. Methodology and Principle Findings Quantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients. Conclusions Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation. PMID:27035913

  12. Synthesis and in vitro Evaluation of 3H-Pyrrolo[3,2-f]-quinolin-9-one Derivatives That Show Potent and Selective Anti-leukemic Activity

    PubMed Central

    Bortolozzi, Roberta; Brun, Paola; Castagliuolo, Ignazio; Hamel, Ernest; Basso, Giuseppe; Viola, Giampietro

    2010-01-01

    A series of new substituted 7-phenyl-3H-pyrrolo[3,2-f]quinolin-9-ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI50 values in the nanomolar range. The active compounds strongly blocked tubulin assembly and colchicine binding to tubulin. Their activities were equal to or greater than that of the reference compound combretastatin A-4. Flow cytometry studies showed that the two most active compounds arrested Jurkat cells in the G2/M cell-cycle phase in a concentration-dependent manner. This effect was associated with apoptosis, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and cleavage of the enzyme poly(ADP-ribose) polymerase. PMID:20629070

  13. Show What You Know

    ERIC Educational Resources Information Center

    Eccleston, Jeff

    2007-01-01

    Big things come in small packages. This saying came to the mind of the author after he created a simple math review activity for his fourth grade students. Though simple, it has proven to be extremely advantageous in reinforcing math concepts. He uses this activity, which he calls "Show What You Know," often. This activity provides the perfect…

  14. Modeling prograde TiO2 activity and its significance for Ti-in-quartz thermobarometry of pelitic metamorphic rocks

    NASA Astrophysics Data System (ADS)

    Ashley, Kyle T.; Law, Richard D.

    2015-02-01

    Since its calibration, the Ti-in-quartz thermobarometer has been applied to a wide variety of geologic scenarios. The abundance of quartz in the continental crust and the involvement of silica in metamorphic reactions, deformation, and fluid flux processes make it a particularly powerful tool for constraining the pressure and temperature evolution of rocks, which is essential for developing tectonic models. Being able to quantitatively determine the solubility of Ti in quartz, however, is dependent upon being able to determine the activity of TiO2 in the rock during quartz growth or re-equilibration. Here we calculate TiO2 chemical potentials of the system relative to that of rutile (as a standard state), projected in P- T space for an average sub-aluminous pelite composition. Titania activities are calculated from these dependent potentials, with resultant activities used to correct for Ti isopleth projection in the Thomas et al. (2010) solubility equation. The modeling results are in good agreement with previous studies that suggest ilmenite-bearing assemblages buffer high TiO2 activities and titanite-bearing assemblages have much lower activities (≥0.5). At elevated temperatures, however, significant deviation from an assumed average pelite activity of 1.0 occurs, where the projected Ti concentration in quartz is up to 400 % different when assuming a dynamic system activity. This is due, in part, to the sequestering of Ti in biotite during heating and the destabilization of Ti-oxides at higher temperatures. With quartz-producing reactions, deformation-driven solution-transfer processes and other Si-mobilization events occur during the prograde and retrograde history of metapelites, and assuming TiO2 activities associated with the peak metamorphic paragenesis may be misleading and result in significant errors in P- T calculations.

  15. AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity

    PubMed Central

    Fuchs, Sebastian P.; Martinez-Navio, José M.; Lifson, Jeffrey D.; Gao, Guangping; Desrosiers, Ronald C.

    2015-01-01

    Long-term delivery of potent broadly-neutralizing antibodies is a promising approach for the prevention of HIV-1 infection. We used AAV vector intramuscularly to deliver anti-SIV monoclonal antibodies (mAbs) in IgG1 form to rhesus monkeys. Persisting levels of delivered mAb as high as 270 μg/ml were achieved. However, host antibody responses to the delivered antibody were observed in 9 of the 12 monkeys and these appeared to limit the concentration of delivered antibody that could be achieved. This is reflected in the wide range of delivered mAb concentrations that were achieved: 1–270 μg/ml. Following repeated, marginal dose, intravenous challenge with the difficult-to-neutralize SIVmac239, the six monkeys in the AAV-5L7 IgG1 mAb group showed clear protective effects despite the absence of detectable neutralizing activity against the challenge virus. The protective effects included: lowering of viral load at peak height; lowering of viral load at set point; delay in the time to peak viral load from the time of the infectious virus exposure. All of these effects were statistically significant. In addition, the monkey with the highest level of delivered 5L7 mAb completely resisted six successive SIVmac239 i.v. challenges, including a final challenge with a dose of 10 i.v. infectious units. Our results demonstrate the continued promise of this approach for the prevention of HIV-1 infection in people. However, the problem of anti-antibody responses will need to be understood and overcome for the promise of this approach to be effectively realized. PMID:26248318

  16. Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves

    PubMed Central

    Bhadoo, Divya; Bajpai, M.; Abid, Ali; Sukanya, Gayan; Agarwala, Sandeep; Srinivas, M.; Deka, Deepika; Agarwal, Nutan; Agarwal, Ramesh; Kumar, Rakesh

    2015-01-01

    Aims: Study on prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. Materials and Methods: Antenatally diagnosed hydronephrosis patients were included. Postnatally, they were divided into two groups, posterior urethral valve (PUV) and non-PUV. The studied parameters were: Gestational age at detection, surgical intervention, ultrasound findings, cord blood and follow up plasma renin activity (PRA) values, vesico-ureteric reflux (VUR), renal scars, and glomerular filtration rate (GFR). Results: A total of 25 patients were included, 10 PUV and 15 non-PUV. All infants with PUV underwent primary valve incision. GFR was less than 60 ml/min/1.73 m2 body surface area in 4 patients at last follow-up. Keyhole sign, oligoamnios, absent bladder cycling, and cortical cysts were not consistent findings on antenatal ultrasound in PUV. Cord blood PRA was significantly higher (P < 0.0001) in PUV compared to non-PUV patients. Gestational age at detection of hydronephrosis, cortical cysts, bladder wall thickness, and amniotic fluid index were not significantly correlated with GFR while PRA could differentiate between poor and better prognosis cases with PUV. Conclusions: Ultrasound was neither uniformly useful in diagnosing PUV antenatally, nor differentiating it from cases with non-PUV hydronephrosis. In congenital hydronephrosis, cord blood PRA was significantly higher in cases with PUV compared to non-PUV cases and fell significantly after valve ablation. Cord blood PRA could distinguish between poor and better prognosis cases with PUV. PMID:25829668

  17. Sesquiterpene lactone containing extracts from two cultivars of forage chicory (Cichorium intybus) show distinctive chemical profiles and in vitro activity against Ostertagia ostertagi

    PubMed Central

    Peña-Espinoza, Miguel; Boas, Ulrik; Williams, Andrew R.; Thamsborg, Stig M.; Simonsen, Henrik T.; Enemark, Heidi L.

    2015-01-01

    The study investigated direct anthelmintic effects of sesquiterpene lactones (SL)-containing extracts from forage chicory against free-living and parasitic stages of Ostertagia ostertagi. Freeze-dried leaves from chicory cultivars ‘Spadona’ and ‘Puna II’ were extracted using methanol/water. Total SL were further fractionated by solid-phase extraction and resulting extracts were characterised by high-performance liquid chromatography (HPLC). O. ostertagi eggs from faeces of mono-infected calves were hatched and L1 were used in a larval feeding inhibition assay (LFIA), while cultured L3 were used in a larval exsheathment inhibition assay (LEIA). Adult worms were immediately recovered after slaughter and used for motility inhibition assays (AMIA). Electron microscopy (EM) was performed on adult O. ostertagi exposed to 1000 μg extract mL−1 of both chicory cultivars. In all assays, decreasing concentrations of SL-containing extracts in PBS (1% DMSO) were tested in replicates with 1% DMSO in PBS as negative controls. HPLC demonstrated similar concentrations of most SL in both extracts. However, Spadona-extract contained significantly higher concentrations of 11, 13-dihydro-8-deoxylactucin (P = 0.01), while Puna II-extract had increased levels of 11, 13-dihydrolactucin (P < 0.0001). In the LFIA, both extracts reduced larval feeding at increasing concentrations, but Spadona-extract showed higher potency confirmed by significantly lower EC50 (P < 0.0001). In the LEIA, neither of the two extracts interfered with the exsheathment of L3 (P > 0.05). In the AMIA, both SL-containing extracts induced a dose-dependent effect but Spadona-extract showed greater activity and exerted faster worm paralysis than Puna II-extract with significantly lower EC50 (P < 0.0001). No cuticular damage was observed by EM in worms exposed to any of the extracts. We have demonstrated that SL-containing extracts from forage chicory can inhibit feeding of free-living larvae and

  18. Sesquiterpene lactone containing extracts from two cultivars of forage chicory (Cichorium intybus) show distinctive chemical profiles and in vitro activity against Ostertagia ostertagi.

    PubMed

    Peña-Espinoza, Miguel; Boas, Ulrik; Williams, Andrew R; Thamsborg, Stig M; Simonsen, Henrik T; Enemark, Heidi L

    2015-12-01

    The study investigated direct anthelmintic effects of sesquiterpene lactones (SL)-containing extracts from forage chicory against free-living and parasitic stages of Ostertagia ostertagi. Freeze-dried leaves from chicory cultivars 'Spadona' and 'Puna II' were extracted using methanol/water. Total SL were further fractionated by solid-phase extraction and resulting extracts were characterised by high-performance liquid chromatography (HPLC). O. ostertagi eggs from faeces of mono-infected calves were hatched and L1 were used in a larval feeding inhibition assay (LFIA), while cultured L3 were used in a larval exsheathment inhibition assay (LEIA). Adult worms were immediately recovered after slaughter and used for motility inhibition assays (AMIA). Electron microscopy (EM) was performed on adult O. ostertagi exposed to 1000 μg extract mL(-1) of both chicory cultivars. In all assays, decreasing concentrations of SL-containing extracts in PBS (1% DMSO) were tested in replicates with 1% DMSO in PBS as negative controls. HPLC demonstrated similar concentrations of most SL in both extracts. However, Spadona-extract contained significantly higher concentrations of 11, 13-dihydro-8-deoxylactucin (P = 0.01), while Puna II-extract had increased levels of 11, 13-dihydrolactucin (P < 0.0001). In the LFIA, both extracts reduced larval feeding at increasing concentrations, but Spadona-extract showed higher potency confirmed by significantly lower EC50 (P < 0.0001). In the LEIA, neither of the two extracts interfered with the exsheathment of L3 (P > 0.05). In the AMIA, both SL-containing extracts induced a dose-dependent effect but Spadona-extract showed greater activity and exerted faster worm paralysis than Puna II-extract with significantly lower EC50 (P < 0.0001). No cuticular damage was observed by EM in worms exposed to any of the extracts. We have demonstrated that SL-containing extracts from forage chicory can inhibit feeding of free-living larvae and exert

  19. A rapid quantitative activity assay shows that the Vibrio cholerae colonization factor GbpA is an active lytic polysaccharide monooxygenase.

    PubMed

    Loose, Jennifer S M; Forsberg, Zarah; Fraaije, Marco W; Eijsink, Vincent G H; Vaaje-Kolstad, Gustav

    2014-09-17

    The discovery of the copper-dependent lytic polysaccharide monooxygenases (LPMOs) has revealed new territory for chemical and biochemical analysis. These unique mononuclear copper enzymes are abundant, suggesting functional diversity beyond their established roles in the depolymerization of biomass polysaccharides. At the same time basic biochemical methods for characterizing LPMOs, such as activity assays are not well developed. Here we describe a method for quantification of C1-oxidized chitooligosaccharides (aldonic acids), and hence LPMO activity. The method was used to quantify the activity of a four-domain LPMO from Vibriocholerae, GbpA, which is a virulence factor with no obvious role in biomass processing. PMID:25109775

  20. Risk of significant cytopenias after treatment with tocilizumab in systemic juvenile arthritis patients with a history of macrophage activation syndrome

    PubMed Central

    2012-01-01

    Tocilizumab (TCZ) is the first FDA- approved treatment for systemic juvenile idiopathic arthritis (sJIA). We report 3 cases of cytopenias in children with sJIA treated with TCZ. Two of the children who developed significant cytopenias shortly after initiation of TCZ had a history of macrophage activation syndrome. We raise the possibility that patients with a tendency towards MAS have an increased risk of developing cytopenias when treated with tocilizumab. PMID:22931129

  1. Identification of a new mutagenic polychlorinated biphenyl derivative in the Waka River, Wakayama, Japan, showing activation of an aryl hydrocarbon receptor-dependent transcription.

    PubMed

    Takamura-Enya, Takeji; Watanabe, Tetsushi; Tada, Atsuko; Hirayama, Teruhisa; Nukaya, Haruo; Sugimura, Takashi; Wakabayashi, Keiji

    2002-03-01

    Water samples from the Waka River, which runs through an area housing many chemical industry facilities in Wakayama, Japan, have been found to show significant mutagenicity, especially without a mammalian metabolic activation system (S9 mix) in the Salmonella typhimurium YG1024 strain. Mutagens in the river water were adsorbed to 3 kg of blue cotton, extracted with methanol/ammonia, and separated by several low- and high-pressure liquid chromatography steps with reversed-phase columns. One mutagen (0.6 mg), accounting for 50% of the total mutagenicity of the adsorbed materials, was isolated. On the basis of the mass, high-resolution mass, (1)H NMR and (13)C NMR spectra, the chemical was determined to have a polychlorinated biphenyl skeleton with nitro and amino substitution groups. Well-designed chemical synthesis of the putative mutagen revealed it to be 4-amino-3,3'-dichloro-5,4'-dinitrobiphenyl. This novel compound exerted strong mutagenicity without the S9 mix, inducing 66,000 and 140,000 revertants/nmol in S. typhimurium TA98 and YG1024, respectively. Moreover, this polychlorinated biphenyl derivative was proven to activate the human aryl hydrocarbon receptor-mediated transcription in a lac Z reporter gene assay with an efficiency almost the same as that of beta-naphthoflavone, well-known to be a synthetic aryl hydrocarbon receptor agonist. It is possible that the mutagen is formed unintentionally via postemission modification of drainage water containing parent chemicals, such as 3,3'-dichlorobenzidine or 3,3'-dichloro-4,4'-dinitrobiphenyl, which are known to be raw materials in the manufacture of polymers and dye intermediates in chemical plants. PMID:11896690

  2. Partially resistant Cucurbita pepo showed late onset of the Zucchini yellow mosaic virus infection due to rapid activation of defense mechanisms as compared to susceptible cultivar

    PubMed Central

    Nováková, Slavomíra; Flores-Ramírez, Gabriela; Glasa, Miroslav; Danchenko, Maksym; Fiala, Roderik; Skultety, Ludovit

    2015-01-01

    Zucchini yellow mosaic virus (ZYMV) is an emerging viral pathogen in cucurbit-growing areas wordwide. Infection causes significant yield losses in several species of the family Cucurbitaceae. To identify proteins potentially involved with resistance toward infection by the severe ZYMV-H isolate, two Cucurbita pepo cultivars (Zelena susceptible and Jaguar partially resistant) were analyzed using a two-dimensional gel electrophoresis-based proteomic approach. Initial symptoms on leaves (clearing veins) developed 6–7 days post-inoculation (dpi) in the susceptible C. pepo cv. Zelena. In contrast, similar symptoms appeared on the leaves of partially resistant C. pepo cv. Jaguar only after 15 dpi. This finding was confirmed by immune-blot analysis which showed higher levels of viral proteins at 6 dpi in the susceptible cultivar. Leaf proteome analyses revealed 28 and 31 spots differentially abundant between cultivars at 6 and 15 dpi, respectively. The variance early in infection can be attributed to a rapid activation of proteins involved with redox homeostasis in the partially resistant cultivar. Changes in the proteome of the susceptible cultivar are related to the cytoskeleton and photosynthesis. PMID:25972878

  3. Partially resistant Cucurbita pepo showed late onset of the Zucchini yellow mosaic virus infection due to rapid activation of defense mechanisms as compared to susceptible cultivar.

    PubMed

    Nováková, Slavomíra; Flores-Ramírez, Gabriela; Glasa, Miroslav; Danchenko, Maksym; Fiala, Roderik; Skultety, Ludovit

    2015-01-01

    Zucchini yellow mosaic virus (ZYMV) is an emerging viral pathogen in cucurbit-growing areas wordwide. Infection causes significant yield losses in several species of the family Cucurbitaceae. To identify proteins potentially involved with resistance toward infection by the severe ZYMV-H isolate, two Cucurbita pepo cultivars (Zelena susceptible and Jaguar partially resistant) were analyzed using a two-dimensional gel electrophoresis-based proteomic approach. Initial symptoms on leaves (clearing veins) developed 6-7 days post-inoculation (dpi) in the susceptible C. pepo cv. Zelena. In contrast, similar symptoms appeared on the leaves of partially resistant C. pepo cv. Jaguar only after 15 dpi. This finding was confirmed by immune-blot analysis which showed higher levels of viral proteins at 6 dpi in the susceptible cultivar. Leaf proteome analyses revealed 28 and 31 spots differentially abundant between cultivars at 6 and 15 dpi, respectively. The variance early in infection can be attributed to a rapid activation of proteins involved with redox homeostasis in the partially resistant cultivar. Changes in the proteome of the susceptible cultivar are related to the cytoskeleton and photosynthesis. PMID:25972878

  4. Statistical evaluation of the significance of the influence of abrupt changes in solar activity on the dynamics of the epidemic process

    NASA Technical Reports Server (NTRS)

    Druzhinin, I. P.; Khamyanova, N. V.; Yagodinskiy, V. N.

    1974-01-01

    Statistical evaluations of the significance of the relationship of abrupt changes in solar activity and discontinuities in the multi-year pattern of an epidemic process are reported. They reliably (with probability of more than 99.9%) show the real nature of this relationship and its great specific weight (about half) in the formation of discontinuities in the multi-year pattern of the processes in question.

  5. Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus

    PubMed Central

    Dostalek, Miroslav; Court, Michael H; Yan, Bingfang; Akhlaghi, Fatemeh

    2011-01-01

    BACKGROUND AND PURPOSE Patients with diabetes mellitus require pharmacotherapy with numerous medications. However, the effect of diabetes on drug biotransformation is not well understood. Our goal was to investigate the effect of diabetes on liver cytochrome P450 3As, the most abundant phase I drug-metabolizing enzymes in humans. EXPERIMENTAL APPROACH Human liver microsomal fractions (HLMs) were prepared from diabetic (n = 12) and demographically matched nondiabetic (n = 12) donors, genotyped for CYP3A4*1B and CYP3A5*3 polymorphisms. Cytochrome P450 3A4, 3A5 and 2E1 mRNA expression, protein level and enzymatic activity were compared between the two groups. KEY RESULTS Midazolam 1′- or 4-hydroxylation and testosterone 6β-hydroxylation, catalyzed by P450 3A, were markedly reduced in diabetic HLMs, irrespective of genotype. Significantly lower P450 3A4 protein and comparable mRNA levels were observed in diabetic HLMs. In contrast, neither P450 3A5 protein level nor mRNA expression differed significantly between the two groups. Concurrently, we have observed increased P450 2E1 protein level and higher chlorzoxazone 6-hydroxylation activity in diabetic HLMs. CONCLUSIONS AND IMPLICATIONS These studies indicate that diabetes is associated with a significant decrease in hepatic P450 3A4 enzymatic activity and protein level. This finding could be clinically relevant for diabetic patients who have additional comorbidities and are receiving multiple medications. To further characterize the effect of diabetes on P450 3A4 activity, a well-controlled clinical study in diabetic patients is warranted. PMID:21323901

  6. Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway.

    PubMed

    Xu, Xin-Rong; Yu, Hai-Tao; Yang, Yan; Hang, Li; Yang, Xue-Wen; Ding, Shu-Hua

    2016-01-01

    Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a crucial role in the pathogenesis of dry AMD. Quercetin has potent anti-oxidative activities, but poor bioavailability limits its therapeutic application. Herein, we prepared the phospholipid complex of quercetin (quercetin-PC), characterized its structure by differential scanning calorimetry, infrared spectrum and x-ray diffraction. Quercetin-PC had equilibrium solubility of 38.36 and 1351.27μg/ml in water and chloroform, respectively, which was remarkably higher than those of quercetin alone. Then we established hydrogen peroxide (H2O2)-induced oxidative injury model in human ARPE-19 cells to examine the effects of quercetin-PC. Quercetin-PC, stronger than quercetin, promoted cell proliferation, and the proliferation rate was increased to be 78.89% when treated with Quercetin-PC at 400μM. Moreover, quercetin-PC effectively prevented ARPE-19 cells from apoptosis, and the apoptotic rate was reduced to be 3.1% when treated with Quercetin-PC at 200μM. In addition, quercetin-PC at 200μM significantly increased the activities of SOD, CAT and GSH-PX, and reduced the levels of reactive oxygen species and MDA in H2O2-treated ARPE-19 cells, but quercetin at 200μM failed to do so. Molecular examinations revealed that quercetin-PC at 200μM significantly activated Nrf2 nuclear translocation and significantly enhanced the expression of target genes HO-1, NQO-1 and GCL by different folds at both mRNA and protein levels. Our current data collectively indicated that quercetin-PC had stronger protective effects against oxidative-induced damages in ARPE-19 cells, which was associated with activation of Nrf2 pathway and its target genes implicated in antioxidant defense. PMID:26643168

  7. Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations.

    PubMed

    Felipo, Vicente; Piedrafita, Blanca; Barios, Juan A; Agustí, Ana; Ahabrach, Hanan; Romero-Vives, María; Barrio, Luis C; Rey, Beatriz; Gaztelu, Jose M; Llansola, Marta

    2015-01-01

    Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light. PMID:26203935

  8. Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma

    PubMed Central

    Costa, Bruno M.; Smith, Justin S.; Chen, Ying; Chen, Justin; Phillips, Heidi S.; Aldape, Kenneth D.; Zardo, Giuseppe; Nigro, Janice; James, C. David; Fridlyand, Jane; Reis, Rui M.; Costello, Joseph F.

    2010-01-01

    HOXA genes encode critical transcriptional regulators of embryonic development that have been implicated in cancer. In this study, we documented functional relevance and mechanism of activation of HOXA9 in glioblastoma (GBM), the most common malignant brain tumor. Expression of HOXA genes was investigated using RT-PCR in primary gliomas and glioblastoma cell lines and was validated in two sets of expression array data. In a subset of GBM, HOXA genes are aberrantly activated within confined chromosomal domains. Transcriptional activation of the HOXA cluster was reversible by a PI3K inhibitor through an epigenetic mechanism involving histone H3K27 trimethylation. Functional studies of HOXA9 showed its capacity to decrease apoptosis and increase cellular proliferation along with TRAIL resistance. Notably, aberrant expression of HOXA9 was independently predictive of shorter overall and progression-free survival in two GBM patient sets, and improved survival prediction by MGMT promoter methylation. Thus, HOXA9 activation is a novel, independent and negative prognostic marker in GBM that is reversible through a PI3K-associated epigenetic mechanism. Our findings suggest a transcriptional pathway through which PI3K activates oncogenic HOXA expression with implications for mTOR or PI3K targeted therapies. PMID:20068170

  9. Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma.

    PubMed

    Costa, Bruno M; Smith, Justin S; Chen, Ying; Chen, Justin; Phillips, Heidi S; Aldape, Kenneth D; Zardo, Giuseppe; Nigro, Janice; James, C David; Fridlyand, Jane; Reis, Rui M; Costello, Joseph F

    2010-01-15

    HOXA genes encode critical transcriptional regulators of embryonic development that have been implicated in cancer. In this study, we documented functional relevance and mechanism of activation of HOXA9 in glioblastoma (GBM), the most common malignant brain tumor. Expression of HOXA genes was investigated using reverse transcription-PCR in primary gliomas and glioblastoma cell lines and was validated in two sets of expression array data. In a subset of GBM, HOXA genes are aberrently activated within confined chromosomal domains. Transcriptional activation of the HOXA cluster was reversible by a phosphoinostide 3-kinase (PI3K) inhibitor through an epigenetic mechanism involving histone H3K27 trimethylation. Functional studies of HOXA9 showed its capacity to decrease apoptosis and increase cellular proliferation along with tumor necrosis factor-related apoptosis-including ligand resistance. Notably, aberrant expression of HOXA9 was independently predictive of shorter overall and progression-free survival in two GBM patient sets and improved survival prediction by MGMT promoter methylation. Thus, HOXA9 activation is a novel, independent, and negative prognostic marker in GBM that is reversible through a PI3K-associated epigenetic mechanism. Our findings suggest a transcriptional pathway through which PI3K activates oncogenic HOXA expression with implications for mTOR or PI3K targeted therapies. PMID:20068170

  10. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: a post-mortem autoradiographic study.

    PubMed

    Gulyás, Balázs; Brockschnieder, Damian; Nag, Sangram; Pavlova, Elena; Kása, Péter; Beliczai, Zsuzsa; Légrádi, Adám; Gulya, Károly; Thiele, Andrea; Dyrks, Thomas; Halldin, Christer

    2010-01-01

    Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[(18)F]FMeNER-D(2). (S,S)-[(18)F]FMeNER-D(2) appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[(18)F]FMeNER-D(2) in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[(18)F]FMeNER-D(2) as a molecular imaging biomarker in AD. PMID:20211213

  11. A case report of motor neuron disease in a patient showing significant level of DDTs, HCHs and organophosphate metabolites in hair as well as levels of hexane and toluene in blood.

    PubMed

    Kanavouras, Konstantinos; Tzatzarakis, Manolis N; Mastorodemos, Vasileios; Plaitakis, Andreas; Tsatsakis, Aristidis M

    2011-11-01

    Motor neuron disease is a devastating neurodegenerative condition, with the majority of sporadic, non-familial cases being of unknown etiology. Several epidemiological studies have suggested that occupational exposure to chemicals may be associated with disease pathogenesis. We report the case of a patient developing progressive motor neuron disease, who was chronically exposed to pesticides and organic solvents. The patient presented with leg spasticity and developed gradually clinical signs suggestive of amyotrophic lateral sclerosis, which was supported by the neurophysiologic and radiological findings. Our report is an evidence based case of combined exposure to organochlorine (DDTs), organophosphate pesticides (OPs) and organic solvents as confirmed by laboratory analysis in samples of blood and hair confirming systematic exposure. The concentration of non-specific dialkylphosphates metabolites (DAPs) of OPs in hair (dimethyphopshate (DMP) 1289.4 pg/mg and diethylphosphate (DEP) 709.4 pg/mg) and of DDTs (opDDE 484.0 pg/mg, ppDDE 526.6 pg/mg, opDDD 448.4 pg/mg, ppDDD+opDDT 259.9 pg/mg and ppDDT 573.7 pg/mg) were considerably significant. Toluene and n-hexane were also detected in blood on admission at hospital and quantified (1.23 and 0.87 μg/l, respectively), while 3 months after hospitalization blood testing was found negative for toluene and n-hexane and hair analysis was provided decrease levels of HCHs, DDTs and DAPs. PMID:21851830

  12. Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients.

    PubMed

    Halamkova, J; Kiss, I; Pavlovsky, Z; Tomasek, J; Jarkovsky, J; Cech, Z; Tucek, S; Hanakova, L; Moulis, M; Zavrelova, J; Man, M; Benda, P; Robek, O; Kala, Z; Penka, M

    2011-01-01

    Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, and together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. In our project we examined the expression of uPA, uPAR, PAI 1 and PAI 2 in tumor tissue and we also studied the plasma levels of PAI 1 before and after the initiation of therapy in patients with colorectal carcinoma in relationship to grade of tumor and the treatment response. In our prospective evaluation we included 80 patients treated for adenocarcinoma of the colon and rectum. Analysis of collected data revealed statistically significant evidence of a relationship between the level of PAI 1 in plasma before treatment and grade of the tumor, which increases with tumor grade (p=0.025). We demonstrated that there exists a statistically significant relationship between the expression of PAI 2 (p<0.001) and uPAR (p=0.031) and grade of tumor. We also confirmed a statistically significant relationship between soluble levels of PAI 1 before treatment and therapeutic response (p=0.021). In our group of patients the expression of uPA, uPAR, PAI 1 and 2 in tumor tissue in relation to response to treatment was also assessed. Our results suggest that the greater expression of these parameters in tumor tissue is linked to a worse response to therapy. In conclusion, PAS factors help as a prognostic indicators and could also act as a predictive factor in colorectal carcinoma. PMID:21744990

  13. Fusion peptide P15-CSP shows antibiofilm activity and pro-osteogenic activity when deposited as a coating on hydrophilic but not hydrophobic surfaces.

    PubMed

    Li, Xian; Contreras-Garcia, Angel; LoVetri, Karen; Yakandawala, Nandadeva; Wertheimer, Michael R; De Crescenzo, Gregory; Hoemann, Caroline D

    2015-12-01

    In the context of porous bone void filler for oral bone reconstruction, peptides that suppress microbial growth and promote osteoblast function could be used to enhance the performance of a porous bone void filler. We tested the hypothesis that P15-CSP, a novel fusion peptide containing collagen-mimetic osteogenic peptide P15, and competence-stimulating peptide (CSP), a cationic antimicrobial peptide, has emerging properties not shared by P15 or CSP alone. Peptide-coated surfaces were tested for antimicrobial activity toward Streptoccocus mutans, and their ability to promote human mesenchymal stem cell (MSC) attachment, spreading, metabolism, and osteogenesis. In the osteogenesis assay, peptides were coated on tissue culture plastic and on thin films generated by plasma-enhanced chemical vapor deposition to have hydrophilic or hydrophobic character (water contact angles 63°, 42°, and 92°, respectively). S. mutans planktonic growth was specifically inhibited by CSP, whereas biofilm formation was inhibited by P15-CSP. MSC adhesion and actin stress fiber formation was strongly enhanced by CSP, P15-CSP, and fibronectin coatings and modestly enhanced by P15 versus uncoated surfaces. Metabolic assays revealed that CSP was slightly cytotoxic to MSCs. MSCs developed alkaline phosphatase activity on all surfaces, with or without peptide coatings, and consistently deposited the most biomineralized matrix on hydrophilic surfaces coated with P15-CSP. Hydrophobic thin films completely suppressed MSC biomineralization, consistent with previous findings of suppressed osteogenesis on hydrophobic bioplastics. Collective data in this study provide new evidence that P15-CSP has unique dual capacity to suppress biofilm formation, and to enhance osteogenic activity as a coating on hydrophilic surfaces. PMID:26097095

  14. A Model for Aryl Hydrocarbon Receptor-Activated Gene Expression Shows Potency and Efficacy Changes and Predicts Squelching Due to Competition for Transcription Co-Activators

    PubMed Central

    Simon, Ted W.; Budinsky, Robert A.; Rowlands, J. Craig

    2015-01-01

    A stochastic model of nuclear receptor-mediated transcription was developed based on activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and subsequent binding the activated AHR to xenobiotic response elements (XREs) on DNA. The model was based on effects observed in cells lines commonly used as in vitro experimental systems. Following ligand binding, the AHR moves into the cell nucleus and forms a heterodimer with the aryl hydrocarbon nuclear translocator (ARNT). In the model, a requirement for binding to DNA is that a generic coregulatory protein is subsequently bound to the AHR-ARNT dimer. Varying the amount of coregulator available within the nucleus altered both the potency and efficacy of TCDD for inducing for transcription of CYP1A1 mRNA, a commonly used marker for activation of the AHR. Lowering the amount of available cofactor slightly increased the EC50 for the transcriptional response without changing the efficacy or maximal response. Further reduction in the amount of cofactor reduced the efficacy and produced non-monotonic dose-response curves (NMDRCs) at higher ligand concentrations. The shapes of these NMDRCs were reminiscent of the phenomenon of squelching. Resource limitations for transcriptional machinery are becoming apparent in eukaryotic cells. Within single cells, nuclear receptor-mediated gene expression appears to be a stochastic process; however, intercellular communication and other aspects of tissue coordination may represent a compensatory process to maintain an organism’s ability to respond on a phenotypic level to various stimuli within an inconstant environment. PMID:26039703

  15. The antiviral activity, mechanism of action, clinical significance and resistance of abacavir in the treatment of pediatric AIDS.

    PubMed

    Melroy, Joel; Nair, Vasu

    2005-01-01

    The novel carbocyclic nucleoside, abacavir, is metabolized in cells to carbovir triphosphate which is a potent inhibitor of HIV reverse transcriptase (K(i) 0.021 microM with calf thymus DNA template primer). Abacavir exhibits potent in vitro antiviral activity against wild-type HIV-1 (IC(50) 4.0 microM, MT-4 cells) but this activity is lower than the activity of AZT (IC(50) 0.040 microM, MT-4 cells). However, there is no significant difference between the levels of activity of abacavir (IC(50) 0.26 microM) and AZT (IC(50) 0.23 microM) against clinical isolates of HIV-1. The in vitro toxicity data (CC(50)) of abacavir were: 160 microM (CEM cells); 140 microM (CD4+ CEM cells) and 110 microM (normal bone progenitor cells, BFU-E). Abacavir has been approved in the United States for the treatment of pediatric and adult HIV infection and current recommendations consist of combination therapy in children with HIV infection. Resistance to abacavir develops relatively slowly, with most of the mutations conferring minimal resistance. The M184V mutation appears to be the cornerstone of higher level resistance in regimens containing abacavir, imparting a 2-4 fold reduction in the susceptibility of HIV to abacavir. PMID:16305515

  16. The Crystal Structure of the Streptococcal Collagen-like Protein 2 Globular Domain from Invasive M3-type Group A Streptococcus Shows Significant Similarity to Immunomodulatory HIV Protein gp41*

    PubMed Central

    Squeglia, Flavia; Bachert, Beth; De Simone, Alfonso; Lukomski, Slawomir; Berisio, Rita

    2014-01-01

    The arsenal of virulence factors deployed by streptococci includes streptococcal collagen-like (Scl) proteins. These proteins, which are characterized by a globular domain and a collagen-like domain, play key roles in host adhesion, host immune defense evasion, and biofilm formation. In this work, we demonstrate that the Scl2.3 protein is expressed on the surface of invasive M3-type strain MGAS315 of Streptococcus pyogenes. We report the crystal structure of Scl2.3 globular domain, the first of any Scl. This structure shows a novel fold among collagen trimerization domains of either bacterial or human origin. Despite there being low sequence identity, we observed that Scl2.3 globular domain structurally resembles the gp41 subunit of the envelope glycoprotein from human immunodeficiency virus type 1, an essential subunit for viral fusion to human T cells. We combined crystallographic data with modeling and molecular dynamics techniques to gather information on the entire lollipop-like Scl2.3 structure. Molecular dynamics data evidence a high flexibility of Scl2.3 with remarkable interdomain motions that are likely instrumental to the protein biological function in mediating adhesive or immune-modulatory functions in host-pathogen interactions. Altogether, our results provide molecular tools for the understanding of Scl-mediated streptococcal pathogenesis and important structural insights for the future design of small molecular inhibitors of streptococcal invasion. PMID:24356966

  17. In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3-dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas- Tragedy survivors.

    PubMed

    Khan, Inbesat; Senthilkumar, Chinnu Sugavanam; Upadhyay, Nisha; Singh, Hemant; Sachdeva, Meenu; Jatawa, Suresh Kumar; Tiwari, Archana

    2015-01-01

    DNA methyltransferase 1 (DNMT1) is a relatively large protein family responsible for maintenance of normal methylation, cell growth and survival in mammals. Toxic industrial chemical exposure associated methylation misregulation has been shown to have epigenetic influence. Such misregulation could effectively contribute to cancer development and progression. Methyl isocyanate (MIC) is a noxious industrial chemical used extensively in the production of carbamate pesticides. We here applied an in silico molecular docking approach to study the interaction of MIC with diverse domains of DNMT1, to predict cancer risk in the Bhopal population exposed to MIC during 1984. For the first time, we investigated the interaction of MIC and its hydrolytic product (1,3-dimethylurea) with DNMT1 interacting (such as DMAP1, RFTS, and CXXC) and catalytic (SAM, SAH, and Sinefungin) domains using computer simulations. The results of the present study showed a potential interaction of MIC and 1,3-dimethylurea with these domains. Obviously, strong binding of MIC with DNMT1 interrupting normal methylation will lead to epigenetic alterations in the exposed humans. We suggest therefore that the MIC- exposed individuals surviving after 1984 disaster have excess risk of cancer, which can be attributed to alterations in their epigenome. Our findings will help in better understanding the underlying epigenetic mechanisms in humans exposed to MIC. PMID:26625778

  18. Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance.

    PubMed

    Crowley, Maeve P; Kevane, Barry; O'Shea, Susan I; Quinn, Shane; Egan, Karl; Gilligan, Oonagh M; Ní Áinle, Fionnuala

    2016-09-01

    The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies. PMID:26759370

  19. A case report of motor neuron disease in a patient showing significant level of DDTs, HCHs and organophosphate metabolites in hair as well as levels of hexane and toluene in blood

    SciTech Connect

    Kanavouras, Konstantinos; Tzatzarakis, Manolis N.; Mastorodemos, Vasileios; Plaitakis, Andreas; Tsatsakis, Aristidis M.

    2011-11-15

    Motor neuron disease is a devastating neurodegenerative condition, with the majority of sporadic, non-familial cases being of unknown etiology. Several epidemiological studies have suggested that occupational exposure to chemicals may be associated with disease pathogenesis. We report the case of a patient developing progressive motor neuron disease, who was chronically exposed to pesticides and organic solvents. The patient presented with leg spasticity and developed gradually clinical signs suggestive of amyotrophic lateral sclerosis, which was supported by the neurophysiologic and radiological findings. Our report is an evidence based case of combined exposure to organochlorine (DDTs), organophosphate pesticides (OPs) and organic solvents as confirmed by laboratory analysis in samples of blood and hair confirming systematic exposure. The concentration of non-specific dialkylphosphates metabolites (DAPs) of OPs in hair (dimethyphopshate (DMP) 1289.4 pg/mg and diethylphosphate (DEP) 709.4 pg/mg) and of DDTs (opDDE 484.0 pg/mg, ppDDE 526.6 pg/mg, opDDD 448.4 pg/mg, ppDDD + opDDT 259.9 pg/mg and ppDDT 573.7 pg/mg) were considerably significant. Toluene and n-hexane were also detected in blood on admission at hospital and quantified (1.23 and 0.87 {mu}g/l, respectively), while 3 months after hospitalization blood testing was found negative for toluene and n-hexane and hair analysis was provided decrease levels of HCHs, DDTs and DAPs. -- Highlights: Black-Right-Pointing-Pointer Exposure to pesticides and organic solvents might be a risk factor for sporadic MND. Black-Right-Pointing-Pointer We report a patient who developed progressive upper and lower motor neuron disease. Black-Right-Pointing-Pointer The patient had a history of occupational exposure to pesticides and solvents. Black-Right-Pointing-Pointer High DDTs' levels and increased levels of DMP and DEP were measured in his hair. Black-Right-Pointing-Pointer The patients' exposure to chemicals might have played

  20. Hyperthermostable Thermotoga maritima xylanase XYN10B shows high activity at high temperatures in the presence of biomass-dissolving hydrophilic ionic liquids.

    PubMed

    Yu, Tianyi; Anbarasan, Sasikala; Wang, Yawei; Telli, Kübra; Aslan, Aşkın Sevinç; Su, Zhengding; Zhou, Yin; Zhang, Li; Iivonen, Piia; Havukainen, Sami; Mentunen, Tero; Hummel, Michael; Sixta, Herbert; Binay, Baris; Turunen, Ossi; Xiong, Hairong

    2016-07-01

    The gene of Thermotoga maritima GH10 xylanase (TmXYN10B) was synthesised to study the extreme limits of this hyperthermostable enzyme at high temperatures in the presence of biomass-dissolving hydrophilic ionic liquids (ILs). TmXYN10B expressed from Pichia pastoris showed maximal activity at 100 °C and retained 92 % of maximal activity at 105 °C in a 30-min assay. Although the temperature optimum of activity was lowered by 1-ethyl-3-methylimidazolium acetate ([EMIM]OAc), TmXYN10B retained partial activity in 15-35 % hydrophilic ILs, even at 75-90 °C. TmXYN10B retained over 80 % of its activity at 90 °C in 15 % [EMIM]OAc and 15-25 % 1-ethyl-3-methylimidazolium dimethylphosphate ([EMIM]DMP) during 22-h reactions. [EMIM]OAc may rigidify the enzyme and lower V max. However, only minor changes in kinetic parameter K m showed that competitive inhibition by [EMIM]OAc of TmXYN10B is minimal. In conclusion, when extended enzymatic reactions under extreme conditions are required, TmXYN10B shows extraordinary potential. PMID:27240671

  1. Physiological Sleep Propensity Might Be Unaffected by Significant Variations in Self-Reported Well-Being, Activity, and Mood.

    PubMed

    Putilov, Arcady A

    2015-01-01

    Background and Objective. Depressive state is often associated with such physical symptoms as general weakness, fatigue, tiredness, slowness, reduced activity, low energy, and sleepiness. The involvement of the sleep-wake regulating mechanisms has been proposed as one of the plausible explanations of this association. Both physical depressive symptoms and increased physiological sleep propensity can result from disordered and insufficient sleep. In order to avoid the influence of disordered and insufficient sleep, daytime and nighttime sleepiness were tested in winter depression characterized by normal night sleep duration and architecture. Materials and Methods. A total sample consisted of 6 healthy controls and 9 patients suffered from depression in the previous winter season. Sleep latency was determined across 5 daytime and 4 nighttime 20-min attempts to nap in summer as well as in winter before and after a week of 2-hour evening treatment with bright light. Results and Conclusions. Patients self-reported abnormally lowered well-being, activity, and mood only in winter before the treatment. Physiological sleep propensity was neither abnormal nor linked to significant changes in well-being, activity, and mood following the treatment and change in season. It seems unlikely that the mechanisms regulating the sleep-wake cycle contributed to the development of the physical depressive symptoms. PMID:26294978

  2. Physiological Sleep Propensity Might Be Unaffected by Significant Variations in Self-Reported Well-Being, Activity, and Mood

    PubMed Central

    Putilov, Arcady A.

    2015-01-01

    Background and Objective. Depressive state is often associated with such physical symptoms as general weakness, fatigue, tiredness, slowness, reduced activity, low energy, and sleepiness. The involvement of the sleep-wake regulating mechanisms has been proposed as one of the plausible explanations of this association. Both physical depressive symptoms and increased physiological sleep propensity can result from disordered and insufficient sleep. In order to avoid the influence of disordered and insufficient sleep, daytime and nighttime sleepiness were tested in winter depression characterized by normal night sleep duration and architecture. Materials and Methods. A total sample consisted of 6 healthy controls and 9 patients suffered from depression in the previous winter season. Sleep latency was determined across 5 daytime and 4 nighttime 20-min attempts to nap in summer as well as in winter before and after a week of 2-hour evening treatment with bright light. Results and Conclusions. Patients self-reported abnormally lowered well-being, activity, and mood only in winter before the treatment. Physiological sleep propensity was neither abnormal nor linked to significant changes in well-being, activity, and mood following the treatment and change in season. It seems unlikely that the mechanisms regulating the sleep-wake cycle contributed to the development of the physical depressive symptoms. PMID:26294978

  3. Ranking of stimuli that evoked memories in significant others after exposure to circumcerebral magnetic fields: correlations with ambient geomagnetic activity.

    PubMed

    Booth, J N; Charette, J C; Persinger, M A

    2002-10-01

    To identify means to enhance the laboratory production of alleged paranormal phenomena, 15 pairs of men and women involved emotionally were tested by male and female experimenters who were not familiar with the hypothesis that ambient (geomagnetic) activity could modulate this production. While the female of the pair was exposed to six different patterns of complex magnetic fields designed to affect states of consciousness, the male wrote his reminiscences about shared experiences evoked by a postcard randomly selected from a collection of five. Increased global geomagnetic activity (k values between 0 and 5) at the time of the experiments was significantly and moderately correlated with the more accurate ranking of the stimulus cards. These results were similar to those of a previous study. We suggest that alleged paranormal phenomena involve processes that might be produced by experimentally altering the electroencephalographic correlates of consciousness with circumcerebral applications of counterclockwise weak magnetic fields. However, these processes may be enhanced if global geomagnetic activity is increasing during the periods of exposure. PMID:12434850

  4. An alpha2,6-sialyltransferase cloned from Photobacterium leiognathi strain JT-SHIZ-119 shows both sialyltransferase and neuraminidase activity.

    PubMed

    Mine, Toshiki; Katayama, Sakurako; Kajiwara, Hitomi; Tsunashima, Masako; Tsukamoto, Hiroshi; Takakura, Yoshimitsu; Yamamoto, Takeshi

    2010-02-01

    We cloned, expressed, and characterized a novel beta-galactoside alpha2,6-sialyltransferase from Photobacterium leiognathi strain JT-SHIZ-119. The protein showed 56-96% identity to the marine bacterial alpha2,6-sialyltransferases classified into glycosyltransferase family 80. The sialyltransferase activity of the N-terminal truncated form of the recombinant enzyme was 1477 U/L of Escherichia coli culture. The truncated recombinant enzyme was purified as a single band by sodium dodecyl sulfate polyacrylamide gel electrophoresis through 3 column chromatography steps. The enzyme had distinct activity compared with known marine bacterial alpha2,6-sialyltransferases. Although alpha2,6-sialyltransferases cloned from marine bacteria, such as Photobacterium damselae strain JT0160, P. leiognathi strain JT-SHIZ-145, and Photobacterium sp. strain JT-ISH-224, show only alpha2,6-sialyltransferase activity, the recombinant enzyme cloned from P. leiognathi strain JT-SHIZ-119 showed both alpha2,6-sialyltransferase and alpha2,6-linkage-specific neuraminidase activity. Our results provide important information toward a comprehensive understanding of the bacterial sialyltransferases belonging to the group 80 glycosyltransferase family in the CAZy database. PMID:19797322

  5. Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax

    PubMed Central

    Hockings, C; Anwari, K; Ninnis, R L; Brouwer, J; O'Hely, M; Evangelista, M; Hinds, M G; Czabotar, P E; Lee, E F; Fairlie, W D; Dewson, G; Kluck, R M

    2015-01-01

    The mitochondrial pathway of apoptosis is initiated by Bcl-2 homology region 3 (BH3)-only members of the Bcl-2 protein family. On upregulation or activation, certain BH3-only proteins can directly bind and activate Bak and Bax to induce conformation change, oligomerization and pore formation in mitochondria. BH3-only proteins, with the exception of Bid, are intrinsically disordered and therefore, functional studies often utilize peptides based on just their BH3 domains. However, these reagents do not possess the hydrophobic membrane targeting domains found on the native BH3-only molecule. To generate each BH3-only protein as a recombinant protein that could efficiently target mitochondria, we developed recombinant Bid chimeras in which the BH3 domain was replaced with that of other BH3-only proteins (Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk). The chimeras were stable following purification, and each immunoprecipitated with full-length Bcl-xL according to the specificity reported for the related BH3 peptide. When tested for activation of Bak and Bax in mitochondrial permeabilization assays, Bid chimeras were ~1000-fold more effective than the related BH3 peptides. BH3 sequences from Bid and Bim were the strongest activators, followed by Puma, Hrk, Bmf and Bik, while Bad and Noxa were not activators. Notably, chimeras and peptides showed no apparent preference for activating Bak or Bax. In addition, within the BH3 domain, the h0 position recently found to be important for Bax activation, was important also for Bak activation. Together, our data with full-length proteins indicate that most BH3-only proteins can directly activate both Bak and Bax. PMID:25906158

  6. The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia

    PubMed Central

    Eriksson, A; Hermanson, M; Wickström, M; Lindhagen, E; Ekholm, C; Jenmalm Jensen, A; Löthgren, A; Lehmann, F; Larsson, R; Parrow, V; Höglund, M

    2012-01-01

    Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nℳ), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μℳ). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing). PMID:22864397

  7. Increase of electrodermal activity of heart meridian during physical exercise: the significance of electrical values in acupuncture and diagnostic importance.

    PubMed

    Pontarollo, Francesco; Rapacioli, Giuliana; Bellavite, Paolo

    2010-08-01

    Electric field measurements of skin potential and electrical currents are physiological indicators of electrodermal activity (EDA) and have been associated with a variety of sensory, cognitive and emotional stimuli. The aim of this study was to investigate the EDA at some hand acupoints before, during and after a physical exercise. EDA of eight points located at the corner of fingernails of hands was measured in 10 healthy young volunteers before, during and after a 14-min acute exercise in a bicycle ergometer. In pre-exercise resting state the parameters were stable and similar between the 8 different tested points, while during exercise a significant increase of current (from 1000-2000 to 4000-8000 nA) was observed, with the maximal values related to the point located on the ulnar side of the little finger, at the base of the nail, corresponding to the Shao chong (HT9) of heart meridian. PMID:20621275

  8. Establishment by adriamycin exposure of multidrug-resistant rat ascites hepatoma AH130 cells showing low DT-diaphorase activity and high cross resistance to mitomycins.

    PubMed

    Wakusawa, S; Nakamura, S; Miyamoto, K

    1997-01-01

    A resistant subline (AH130/5A) selected from rat hepatoma AH130 cells after exposure to adriamycin (ADM) showed remarkable resistance to multiple antitumor drugs, including mitomycin C (MMC) and porfiromycin (PFM). PFM, vinblastine (VLB), and ADM accumulated in AH130/5A far less than in the parent AH130 (AH130/P) cells. AH130/5A cells showed overexpression of P-glycoprotein (PGP), an increase in glutathione S-transferase activity, and a decrease in DT-diaphorase and glutathione peroxidase activity. The resistance to MMC and VLB of AH130/5A cells was partly reversed by H-87, an inhibitor of PGP. Buthionine sulfoximine, an inhibitor of glutathione synthase, did not affect the action of MMC. tert-Butylhydroquinone induced DT-diaphorase activity, increased PFM uptake, and enhanced the growth-inhibitory action of MMC in AH130/5A cells. Dicumarol, an inhibitor of DT-diaphorase, decreased PFM uptake and reduced the growth-inhibitory action of MMC in AH130/P cells. These results indicated that the adriamycin treatment of hepatoma cells caused multifactorial multidrug resistance involving a decrease in DT-diaphorase activity. PMID:9045901

  9. Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury

    PubMed Central

    Faridi, Mohd Hafeez; Altintas, Mehmet M.; Gomez, Camilo; Duque, Juan Camilo; Vazquez-Padron, Roberto I.; Gupta, Vineet

    2013-01-01

    BACKGROUND CD11b/CD18 is a key adhesion receptor that mediates leukocyte adhesion, migration and immune functions. We recently identified novel compounds, leukadherins, that allosterically enhance CD11b/CD18-dependent cell adhesion and reduce inflammation in vivo, suggesting integrin activation to be a novel mechanism of action for the development of anti-inflammatory therapeutics. Since a number of well-characterized anti-CD11b/CD18 activating antibodies are currently available, we wondered if such biological agonists could also become therapeutic leads following this mechanism of action. METHODS We compared the two types of agonists using in vitro cell adhesion and wound-healing assays and using animal model systems. We also studied effects of the two types of agonists on outside-in signaling in treated cells. RESULTS Both types of agonists similarly enhanced integrin-mediated cell adhesion and decreased cell migration. However, unlike leukadherins, the activating antibodies produced significant CD11b/CD18 macro clustering and induced phosphorylation of key proteins involved in outside-in signaling. Studies using conformation reporter antibodies showed that leukadherins did not induce global conformational changes in CD11b/CD18 explaining the reason behind their lack of ligand-mimetic outside-in signaling. In vivo, leukadherins reduced vascular injury in a dose-dependent fashion, but, surprisingly, the anti-CD11b activating antibody ED7 was ineffective. CONCLUSIONS Our results suggest that small molecule allosteric agonists of CD11b/CD18 have clear advantages over the biologic activating antibodies and provide a mechanistic basis for the difference. GENERAL SIGNIFICANCE CD11b/CD18 activation represents a novel strategy for reducing inflammatory injury. Our study establishes small molecule leukadherins as preferred agonists over activating antibodies for future development as novel anti-inflammatory therapeutics. PMID:23454649

  10. Candida tropicalis from veterinary and human sources shows similar in vitro hemolytic activity, antifungal biofilm susceptibility and pathogenesis against Caenorhabditis elegans.

    PubMed

    Brilhante, Raimunda Sâmia Nogueira; Oliveira, Jonathas Sales de; Evangelista, Antônio José de Jesus; Serpa, Rosana; Silva, Aline Lobão da; Aguiar, Felipe Rodrigues Magalhães de; Pereira, Vandbergue Santos; Castelo-Branco, Débora de Souza Collares Maia; Pereira-Neto, Waldemiro Aquino; Cordeiro, Rossana de Aguiar; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha

    2016-08-30

    The aim of this study was to evaluate the in vitro hemolytic activity and biofilm antifungal susceptibility of veterinary and human Candida tropicalis strains, as well as their pathogenesis against Caenorhabditis elegans. Twenty veterinary isolates and 20 human clinical isolates of C. tropicalis were used. The strains were evaluated for their hemolytic activity and biofilm production. Biofilm susceptibility to itraconazole, fluconazole, voriconazole, amphotericin B and caspofungin was assessed using broth microdilution assay. The in vivo evaluation of strain pathogenicity was investigated using the nematode C. elegans. Hemolytic factor was observed in 95% of the strains and 97.5% of the isolates showed ability to form biofilm. Caspofungin and amphotericin B showed better results than azole antifungals against mature biofilms. Paradoxical effect on mature biofilm metabolic activity was observed at elevated concentrations of caspofungin (8-64μg/mL). Azole antifungals were not able to inhibit mature C. tropicalis biofilms, even at the higher tested concentrations. High mortality rates of C. elegans were observed when the worms were exposed to with C. tropicalis strains, reaching up to 96%, 96h after exposure of the worms to C. tropicalis strains. These results reinforce the high pathogenicity of C. tropicalis from veterinary and human sources and show the effectiveness of caspofungin and amphotericin B against mature biofilms of this species. PMID:27527785

  11. The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity

    PubMed Central

    Tortajada, Agustín; Montes, Tamara; Martinez-Barricarte, Ruben; Morgan, B. Paul; Harris, Claire L.; de Córdoba, Santiago Rodríguez

    2011-01-01

    Summary Mutations and polymorphisms in the gene encoding factor H (CFH) have been associated with atypical haemolytic uraemic syndrome, dense deposit disease and age-related macular degeneration. The disease-predisposing CFH variants show a differential association with pathology that has been very useful to unravel critical events in the pathogenesis of one or other disease. In contrast, the fH-Ile62 polymorphism confers strong protection to all three diseases. Using ELISA-based methods and surface plasmon resonance analyses we show here that the protective fH-Ile62 variant binds more efficiently to C3b than fH-Val62 and competes better with factor B in proconvertase formation. Functional analyses demonstrate an increased cofactor activity for fH-Ile62 in the factor I-mediated cleavage of fluid phase and surface-bound C3b; however, the two fH variants show no differences in decay accelerating activity. From these data we conclude that the protective effect of the fH-Ile62 variant is due to its better capacity to bind C3b, inhibit proconvertase formation and catalyse inactivation of fluid-phase and surface-bound C3b. This demonstration of the functional consequences of the fH-Ile62 polymorphism provides relevant insights into the complement regulatory activities of fH that will be useful in disease prediction and future development of effective therapeutics for disorders caused by complement dysregulation. PMID:19549636

  12. Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection.

    PubMed

    Stec, Jozef; Onajole, Oluseye K; Lun, Shichun; Guo, Haidan; Merenbloom, Benjamin; Vistoli, Giulio; Bishai, William R; Kozikowski, Alan P

    2016-07-14

    Our team had previously identified certain indolecarboxamides that represented a new chemical scaffold that showed promising anti-TB activity at both an in vitro and in vivo level. Based on mutational analysis using bacteria found resistant to one of these indolecarboxamides, we identified the trehalose monomycolate transporter MmpL3 as the likely target of these compounds. In the present work, we now further elaborate on the SAR of these compounds, which has led in turn to the identification of a new analog, 4,6-difluoro-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-indole-2-carboxamide (26), that shows excellent activity against drug-sensitive (MIC = 0.012 μM; SI ≥ 16000), multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains, has superior ADMET properties, and shows excellent activity in the TB aerosol lung infection model. Compound 26 is also shown to work in synergy with rifampin. Because of these properties, we believe that indolecarboxamide 26 is a possible candidate for advancement to human clinical trials. PMID:27275668

  13. The Ozone Show.

    ERIC Educational Resources Information Center

    Mathieu, Aaron

    2000-01-01

    Uses a talk show activity for a final assessment tool for students to debate about the ozone hole. Students are assessed on five areas: (1) cooperative learning; (2) the written component; (3) content; (4) self-evaluation; and (5) peer evaluation. (SAH)

  14. Showing What They Know

    ERIC Educational Resources Information Center

    Cech, Scott J.

    2008-01-01

    Having students show their skills in three dimensions, known as performance-based assessment, dates back at least to Socrates. Individual schools such as Barrington High School--located just outside of Providence--have been requiring students to actively demonstrate their knowledge for years. The Rhode Island's high school graduating class became…

  15. Synergistic activity of rifampicin and ethambutol against slow-growing nontuberculous mycobacteria is currently of questionable clinical significance.

    PubMed

    van Ingen, Jakko; Hoefsloot, Wouter; Mouton, Johan W; Boeree, Martin J; van Soolingen, Dick

    2013-07-01

    A key issue in the treatment of disease caused by slow-growing nontuberculous mycobacteria is the limited association between in vitro minimum inhibitory concentrations (MICs) of rifampicin and ethambutol alone and the in vivo outcome of treatment with these drugs. Combined susceptibility testing to rifampicin and ethambutol could provide a more realistic view of the efficacy of these drugs. In this study, Mycobacterium avium (n = 5), Mycobacterium chimaera (n = 6), Mycobacterium intracellulare (n = 4), Mycobacterium xenopi (n = 4), Mycobacterium malmoense (n = 3) and Mycobacterium simiae (n = 2) clinical isolates were selected and the MICs of rifampicin and ethambutol alone and in combination were measured using the Middlebrook 7H10 agar dilution method. Synergy was defined as a fractional inhibitory concentration index ≤ 0.5. Rifampicin and ethambutol showed synergistic activity against the majority of M. avium (4/5), M. chimaera (5/6) and M. intracellulare (3/4) isolates and 1 of 2 eligible M. malmoense isolates. No synergistic activity was measured against M. xenopi and M. simiae. Synergy was neither universal for all species nor for all isolates of one species; it thus needs to be tested for rather than assumed. Even if this synergy exists in vivo, it is questionable whether the MICs to the combined drugs can be overcome by the drug exposure attained by current regimens at the recommended dosages. New dosing strategies for rifampicin and ethambutol should be studied to increase the exposure to these drugs and thus maximise their impact. PMID:23664674

  16. Significant antibacterial activity and synergistic effects of camel lactoferrin with antibiotics against methicillin-resistant Staphylococcus aureus (MRSA).

    PubMed

    Redwan, Elrashdy M; El-Baky, Nawal Abd; Al-Hejin, Ahmed M; Baeshen, Mohammed N; Almehdar, Hussein A; Elsaway, Abdulrahman; Gomaa, Abu-Bakr M; Al-Masaudi, Saad Berki; Al-Fassi, Fahad A; AbuZeid, Isam Eldin; Uversky, Vladimir N

    2016-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) causes major healthcare problems in many countries, as it is present as several hospital- and community-associated strains. Hospital-associated MRSA is one of the most prevalent nosocomial pathogens throughout the world and infections caused by community-acquired MRSA are rising. This emphasizes the need for new and efficient anti-MRSA agents. We evaluated the antibacterial effects of camel lactoferrin (cLf) and human lactoferrin (hLf) alone and in combination with several antibiotics against MRSA. Antimicrobials were tested against MRSA and an S. aureus control strain by the agar disc diffusion method. The minimum inhibitory concentration (MIC) was determined for antimicrobials by the broth microdilution method. Synergy between cLf or hLf and antibiotics was examined by checkerboard and time-kill assays. The agar disc diffusion assay showed that MRSA growth was inhibited by cLf at 0.25-3 mg/ml and hLf at 1-3 mg/ml. cLf demonstrated 3 times higher inhibitory activity against MRSA than hLf in terms of MIC values (250 vs. 750 μg/ml, respectively). Biotinylated cLf was recognized by two membrane proteins of MRSA, 66-67 KDa. Combinations of cLf or hLf and oxacillin or vancomycin at sub-MIC levels enhanced in vitro antibacterial activity against MRSA compared with each agent alone. PMID:27130281

  17. Drug-Metabolizing Activity, Protein and Gene Expression of UDP-Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients

    PubMed Central

    Lu, Linlin; Zhou, Juan; Shi, Jian; Peng, Xiao-juan; Qi, Xiao-xiao; Wang, Ying; Li, Fang-yuan; Zhou, Fu-Yuan; Liu, Liang; Liu, Zhong-Qiu

    2015-01-01

    UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV-positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either Vmax (maximum reaction rate, Rmax for UGT1A1) or the clearance rates (Vmax/Km, Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV-positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which would

  18. Drug-Metabolizing Activity, Protein and Gene Expression of UDP-Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients.

    PubMed

    Lu, Linlin; Zhou, Juan; Shi, Jian; Peng, Xiao-juan; Qi, Xiao-xiao; Wang, Ying; Li, Fang-Yuan; Zhou, Fu-Yuan; Liu, Liang; Liu, Zhong-Qiu

    2015-01-01

    UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV-positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either V(max) (maximum reaction rate, R(max) for UGT1A1) or the clearance rates (V(max)/K(m), Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV-positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which

  19. Turkish Scorzonera Species Extracts Attenuate Cytokine Secretion via Inhibition of NF-κB Activation, Showing Anti-Inflammatory Effect in Vitro.

    PubMed

    Bahadır Acikara, Özlem; Hošek, Jan; Babula, Petr; Cvačka, Josef; Budešínský, Miloš; Dračinský, Martin; Saltan İşcan, Gülçin; Kadlecová, Daniela; Ballová, Ludmila; Šmejkal, Karel

    2015-01-01

    Scorzonera species are used in different folk medicines to combat many diseases, including the illnesses connected with inflammation. Previous experiments showed anti-inflammatory activity of Scorzonera extracts in vivo. S. latifolia, S. cana var. jacquiniana, S. tomentosa, S. mollis ssp. szowitsii, S. eriophora, S. incisa, S. cinerea, and S. parviflora extracts were, therefore, evaluated for their inhibitory activities of TNF-α and IL-1β production, and NF-κB nuclear translocation in THP-1 macrophages. The HPLC analysis was carried out to elucidate and to compare the composition of these extracts. Major compounds of the tested extracts have been isolated using different chromatographic techniques and further tested for their inhibitory activities on TNF-α and IL-1β production. Several extracts showed promising anti-inflammatory activity in these in vitro tests. Results of HPLC analysis revealed chlorogenic acid as a compound present in all tested extracts. Hyperoside, quercetin-3-O-β-d-glucoside and rutin were also present in varying amount in some Scorzonera species analyzed. Furthermore, eight phenolics which were identified as quercetin-3-O-β-d-glucoside (1), hyperoside (2), hydrangenol-8-O-glucoside (3), swertisin (4), 7-methylisoorientin (5), 4,5-O-dicaffeoyl-quinic acid (6), 3,5-di-O-caffeoyl-quinic acid (7), and chlorogenic acid (8) have been isolated as major phenolic compounds of the tested extracts and, together with eight terpenoids (9-16) previously obtained from different Scorzonera species, have been tested for the inhibition of TNF-α production, unfortunately with no activity comparable with standard. PMID:26729082

  20. CD10-Equipped Melanoma Cells Acquire Highly Potent Tumorigenic Activity: A Plausible Explanation of Their Significance for a Poor Prognosis

    PubMed Central

    Hashimoto-Hachiya, Akiko; Liu, Min; Abe, Takeru; Hagihara, Akihito; Yokomizo, Takehiko; Furue, Masutaka

    2016-01-01

    CD10 has been widely used in cancer diagnosis. We previously demonstrated that its expression in melanoma increased with tumor progression and predicted poor patient survival. However, the mechanism by which CD10 promotes melanoma progression remains unclear. In order to elucidate the role of CD10 in melanoma, we established CD10-overexpressing A375 melanoma cells and performed DNA microarray and qRT–PCR analyses to identify changes in the gene expression profile. The microarray analysis revealed that up-regulated genes in CD10-A375 were mostly involved in cell proliferation, angiogenesis, and resistance to apoptosis; down-regulated genes mostly belonged to the categories associated with cell adhesion and migration. Accordingly, in functional experiments, CD10-A375 showed significantly greater cell proliferation in vitro and higher tumorigenicity in vivo; CD10 enzymatic inhibitors, thiorphan and phosphoramidon, significantly blocked the tumor growth of CD10-A375 in mice. In migration and invasion assays, CD10-A375 displayed lower migratory and invasive capacity than mock-A375. CD10 augmented melanoma cell resistance to apoptosis mediated by etoposide and gemcitabine. These findings indicate that CD10 may promote tumor progression by regulating the expression profiles of genes related to cell proliferation, angiogenesis, and resistance to apoptosis. PMID:26881775

  1. A family of Fe(3+) based double-stranded helicates showing a magnetocaloric effect, and Rhodamine B dye and DNA binding activities.

    PubMed

    Adhikary, Amit; Jena, Himanshu Sekhar; Konar, Sanjit

    2015-09-21

    Herein, the synthesis, structural characterization, magnetic properties and guest binding activities of four Fe(3+) based double-stranded helicates namely; [Fe2(L)2](ClO4)(Cl)·4(CH3OH)·2(H2O) (), [Fe2(L)2](BF4)2·2(H2O) (), [Fe2(L)2](NO3)2·3(CH3OH)·2(H2O) (), and [Fe2(L)2](Cl)2·2(CH3OH)·4(H2O) () are reported. Complexes have been synthesized using the hydrazide-based ligand H2L (H2L = N'1,N'4-bis(2-hydroxybenzylidene)succinohydrazide) and the corresponding Fe(2+) salts. Each of the independent cationic complexes [Fe2(L)2](2+) shows double-stranded helicates from the self-assembly of the ligand and metal ions in a 2 : 2 ratio, where the individual Fe(3+) centre is lying on a C2-axis and the ligand strands wrap around it. In , ligand L adopts "pseudo-C" conformations and forms a double-stranded dinuclear helicate with a small cage in between them. Moreover, in , each of the independent cationic complexes [Fe2L2](2+) is inherently chiral and possesses P for right-hand and M for left-hand helicity and as a consequence is a racemic solid. Detailed magnetic studies of all the complexes reveal that the Fe(3+) centres are magnetically isolated and isotropic in nature. Estimation of the Magnetocaloric Effect (MCE) from magnetization data unveils a moderate MCE at a temperature of 3 K with magnetic entropy changes (-ΔSm) of 22.9, 27.7, 24.1, 26.5 J kg(-1) K(-1) at a magnetic field of 7 T for complexes , respectively. Also, the variation of the -ΔSm values was justified by considering the parameter of magnetization per unit mass. Stability of all the complexes in solution phase was confirmed by ESI-mass spectrometric analysis and liquid phase FT-IR spectroscopy. Further, the interaction of the complexes with Rhodamine B dye was examined by UV-vis and fluorescence spectroscopic study. The observed blue-shift in the fluorescence study and hyperchromicity and hypochromicity with the appearance of two isosbestic points in the UV-vis study ascertain the interactions of

  2. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

    PubMed

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-01-01

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities. PMID:26304458

  3. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon

    PubMed Central

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-01-01

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities. PMID:26304458

  4. 5-epi-Torrubiellutin C shows antiproliferative activity on DU145 prostate cancer cells through inactivation of the AKT/mTOR pathway.

    PubMed

    Singh, Ashita; Mahipal, Bodugam; Chandrasekhar, Srivari; Ummanni, Ramesh

    2014-04-01

    Cell-based assays for evaluation of the anticancer potential of a focused small molecule library have identified a few potential hit molecules. Among the hits identified, Torrubiellutins (3a) showed good anticancer potential across the cells used in screening assays. Torrubiellutins are isolated from fungal insects Torrubiella luteorostrata and diverse pharmacological effects for these have been reported. However, it is not known as to how Torrubiellutins act through signaling pathways inhibiting the growth of eukaryotic cells. The current study aimed to determine the anticancer potential of Torrubiellutins by defining the molecular mechanism of cytotoxicity using DU145 cells. The results showed that the inhibition of prostate cancer cell growth by 3a was associated with inhibition of anchorage-independent growth, cell migration, and, to a small extent, apoptosis-mediated cell death by caspase activation. The growth-inhibitory effects of 3a are supported by inactivation of prosurvival pathways. Immunoblot analysis showed that the treatment of DU145 cells with 3a resulted in specific downregulation of AKT/mammalian target of rapamycin (mTOR) and its downstream effector proteins p70S6K, GSK3β, and STAT3. On the basis of these findings, we propose that the changes observed in the AKT/mTOR signaling axis are new targets of 3a that are involved in its inhibitory activity on the proliferation of prostate cancer cells, suggesting its potential for further investigation as a promising anticancer agent. PMID:24445589

  5. An Amphipathic Undecapeptide with All d-Amino Acids Shows Promising Activity against Colistin-Resistant Strains of Acinetobacter baumannii and a Dual Mode of Action.

    PubMed

    Oddo, Alberto; Thomsen, Thomas T; Kjelstrup, Susanne; Gorey, Ciara; Franzyk, Henrik; Frimodt-Møller, Niels; Løbner-Olesen, Anders; Hansen, Paul R

    2016-01-01

    Multiple strains of Acinetobacter baumannii have developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-α-melittin hybrid BP100 (KKLFKKILKYL-NH2) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated the in vitro antibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDR A. baumannii strain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains of A. baumannii that acquired resistance to colistin due to mutations of the lpxC, lpxD, pmrA, and pmrB genes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 μM and a hemolytic 50% effective concentration (EC50) of >150 μM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 when pmrAB and lpxC mutants were challenged. PMID:26574005

  6. PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects

    PubMed Central

    Zazo, Sandra; Arpí, Oriol; Menéndez, Silvia; Manso, Rebeca; Lluch, Ana; Eroles, Pilar; Rovira, Ana; Albanell, Joan; García-Foncillas, Jesús; Madoz-Gúrpide, Juan; Rojo, Federico

    2015-01-01

    The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease. PMID:25726524

  7. Acylated oleanane-type triterpene saponins from the flowers of Bellis perennis show anti-proliferative activities against human digestive tract carcinoma cell lines.

    PubMed

    Ninomiya, Kiyofumi; Motai, Chiaki; Nishida, Eriko; Kitagawa, Niichiro; Yoshihara, Kazuya; Hayakawa, Takao; Muraoka, Osamu; Li, Xuezheng; Nakamura, Seikou; Yoshikawa, Masayuki; Matsuda, Hisashi; Morikawa, Toshio

    2016-07-01

    Seven oleanane-type triterpene saponin bisdesmosides, perennisaponins N-T (1-7), were newly isolated from a methanol extract of daisy, the flowers of Bellis perennis L. (Asteraceae). The structures were determined based on chemical and physicochemical data and confirmed using previously isolated related compounds as references. The isolates, including 13 previously reported perennisaponins A-M (8-20), exhibited anti-proliferative activities against human digestive tract carcinoma HSC-2, HSC-4, and MKN-45 cells. Among them, perennisaponin O (2, IC50 = 11.2, 14.3, and 6.9 μM, respectively) showed relatively strong activities. The mechanism of action of 2 against HSC-2 was found to involve apoptotic cell death. PMID:27178360

  8. Comparative genomic and transcriptional analyses of the carbohydrate-active enzymes and secretomes of phytopathogenic fungi reveal their significant roles during infection and development.

    PubMed

    Lyu, Xueliang; Shen, Cuicui; Fu, Yanping; Xie, Jiatao; Jiang, Daohong; Li, Guoqing; Cheng, Jiasen

    2015-01-01

    Our comparative genomic analysis showed that the numbers of plant cell wall (PCW)- and fungal cell wall (FCW)-degradation-associated carbohydrate-active enzymes (CAZymes) in necrotrophic and hemibiotrophic fungi are significantly larger than that in most biotrophic fungi. However, our transcriptional analyses of CAZyme-encoding genes in Melampsora larici-populina, Puccinia graminis and Sclerotinia sclerotiorum showed that many genes encoding PCW- and FCW-degradation-associated CAZymes were significantly up-regulated during the infection of both necrotrophic fungi and biotrophic fungi, indicating an existence of a universal mechanism underlying PCW degradation and FCW reorganization or modification, which are both intimately involved in necrotrophic and biotrophic fungal infection. Furthermore, our results showed that the FCW reorganization or modification was also related to the fungal development. Additionally, our transcriptional analysis of the secretome of S. sclerotiorum showed that many secreted protein-encoding genes were dramatically induced during infection. Among them, a small, cysteine-rich protein SsCVNH was experimentally confirmed to be essential for the virulence and sclerotial development, indicating that the small secreted proteins might also play crucial roles as potential effectors in host-non-specific necrotrophic fungi. PMID:26531059

  9. Comparative genomic and transcriptional analyses of the carbohydrate-active enzymes and secretomes of phytopathogenic fungi reveal their significant roles during infection and development

    PubMed Central

    Lyu, Xueliang; Shen, Cuicui; Fu, Yanping; Xie, Jiatao; Jiang, Daohong; Li, Guoqing; Cheng, Jiasen

    2015-01-01

    Our comparative genomic analysis showed that the numbers of plant cell wall (PCW)- and fungal cell wall (FCW)-degradation-associated carbohydrate-active enzymes (CAZymes) in necrotrophic and hemibiotrophic fungi are significantly larger than that in most biotrophic fungi. However, our transcriptional analyses of CAZyme-encoding genes in Melampsora larici-populina, Puccinia graminis and Sclerotinia sclerotiorum showed that many genes encoding PCW- and FCW-degradation-associated CAZymes were significantly up-regulated during the infection of both necrotrophic fungi and biotrophic fungi, indicating an existence of a universal mechanism underlying PCW degradation and FCW reorganization or modification, which are both intimately involved in necrotrophic and biotrophic fungal infection. Furthermore, our results showed that the FCW reorganization or modification was also related to the fungal development. Additionally, our transcriptional analysis of the secretome of S. sclerotiorum showed that many secreted protein-encoding genes were dramatically induced during infection. Among them, a small, cysteine-rich protein SsCVNH was experimentally confirmed to be essential for the virulence and sclerotial development, indicating that the small secreted proteins might also play crucial roles as potential effectors in host-non-specific necrotrophic fungi. PMID:26531059

  10. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose

    SciTech Connect

    Penza, M.; Jeremic, M.; Marrazzo, E.; Maggi, A.; Ciana, P.; Rando, G.; Grigolato, P.G.; Di Lorenzo, D.

    2011-08-15

    Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5 {mu}g/kg). At higher doses (50-500 {mu}g/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE-dependent reporter plus or minus ER{alpha} or ER{beta}, TBT (in a dose range of 1-100 nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ER{alpha} in undifferentiated preadipocytic cells and by ER{beta} in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. - Research Highlights: > The environmental organotin tributyltin chloride shows dose-dependent estrogenic and adipogenic activities in mice. > The duration and extent of these effects depend on the sex and the dose of the compound. > The estrogenic and adipogenic effects of TBT occur at doses closed to

  11. Appropriate Fe (II) Addition Significantly Enhances Anaerobic Ammonium Oxidation (Anammox) Activity through Improving the Bacterial Growth Rate

    PubMed Central

    Liu, Yiwen; Ni, Bing-Jie

    2015-01-01

    The application of anaerobic ammonium oxidation (Anammox) process is often limited by the slow growth rate of Anammox bacteria. As the essential substrate element that required for culturing Anammox sludge, Fe (II) is expected to affect Anammox bacterial growth. This work systematically studied the effects of Fe (II) addition on Anammox activity based on the kinetic analysis of specific growth rate using data from batch tests with an enriched Anammox sludge at different dosing levels. Results clearly demonstrated that appropriate Fe (II) dosing (i.e., 0.09 mM) significantly enhanced the specific Anammox growth rate up to 0.172 d−1 compared to 0.118 d−1 at regular Fe (II) level (0.03 mM). The relationship between Fe (II) concentration and specific Anammox growth rate was found to be well described by typical substrate inhibition kinetics, which was integrated into currently well-established Anammox model to describe the enhanced Anammox growth with Fe (II) addition. The validity of the integrated Anammox model was verified using long-term experimental data from three independent Anammox reactors with different Fe (II) dosing levels. This Fe (II)-based approach could be potentially implemented to enhance the process rate for possible mainstream application of Anammox technology, in order for an energy autarchic wastewater treatment. PMID:25644239

  12. Appropriate Fe (II) Addition Significantly Enhances Anaerobic Ammonium Oxidation (Anammox) Activity through Improving the Bacterial Growth Rate

    NASA Astrophysics Data System (ADS)

    Liu, Yiwen; Ni, Bing-Jie

    2015-02-01

    The application of anaerobic ammonium oxidation (Anammox) process is often limited by the slow growth rate of Anammox bacteria. As the essential substrate element that required for culturing Anammox sludge, Fe (II) is expected to affect Anammox bacterial growth. This work systematically studied the effects of Fe (II) addition on Anammox activity based on the kinetic analysis of specific growth rate using data from batch tests with an enriched Anammox sludge at different dosing levels. Results clearly demonstrated that appropriate Fe (II) dosing (i.e., 0.09 mM) significantly enhanced the specific Anammox growth rate up to 0.172 d-1 compared to 0.118 d-1 at regular Fe (II) level (0.03 mM). The relationship between Fe (II) concentration and specific Anammox growth rate was found to be well described by typical substrate inhibition kinetics, which was integrated into currently well-established Anammox model to describe the enhanced Anammox growth with Fe (II) addition. The validity of the integrated Anammox model was verified using long-term experimental data from three independent Anammox reactors with different Fe (II) dosing levels. This Fe (II)-based approach could be potentially implemented to enhance the process rate for possible mainstream application of Anammox technology, in order for an energy autarchic wastewater treatment.

  13. Acute ethanol intoxication shows no effect on Ca sup 2+ -uptake of Ca sup 2+ -dependent ATPase activity in myocardial sarcoplasmic reticulum vesicles

    SciTech Connect

    McAllister, K.P.; Horton, J.W.; Kaufman, T.M.; White, D.J. )

    1989-02-09

    We have previously shown that acute ethanolism impairs left ventricular (LV) function. We hypothesized that cardiac dysfunction may be related to altered Ca{sup 2+} pump function by the sarcoplasmic reticulum (SR). In this study, LV function (in isolated perfused hearts) was compared to Ca{sup 2+} transport in SR vesicles isolated from nonperfused hearts in control (C) and acutely intoxicated (ETOH, 2.5 ml/kg IV) guinea pigs. Compared to control hearts, ETOH hearts had significantly lower LV systolic pressure maximal rate of LV pressure rise and fall. Ca{sup 2+}-ATPase activity was not significantly different in either group of animals. Although maximum Ca{sup 2+} uptake tended to be slightly lower in ETOH compared to control hearts coupling ratios (mol Ca{sup 2+} transported/mol ATP hydrolyzed) were not significantly different. We conclude that changes in SR Ca{sup 2+} pump function are not responsible for the depressed LV function seen in acute ethanolism.

  14. Cry1Ac Transgenic Sugarcane Does Not Affect the Diversity of Microbial Communities and Has No Significant Effect on Enzyme Activities in Rhizosphere Soil within One Crop Season

    PubMed Central

    Zhou, Dinggang; Xu, Liping; Gao, Shiwu; Guo, Jinlong; Luo, Jun; You, Qian; Que, Youxiong

    2016-01-01

    Cry1Ac transgenic sugarcane provides a promising way to control stem-borer pests. Biosafety assessment of soil ecosystem for cry1Ac transgenic sugarcane is urgently needed because of the important role of soil microorganisms in nutrient transformations and element cycling, however little is known. This study aimed to explore the potential impact of cry1Ac transgenic sugarcane on rhizosphere soil enzyme activities and microbial community diversity, and also to investigate whether the gene flow occurs through horizontal gene transfer. We found no horizontal gene flow from cry1Ac sugarcane to soil. No significant difference in the population of culturable microorganisms between the non-GM and cry1Ac transgenic sugarcane was observed, and there were no significant interactions between the sugarcane lines and the growth stages. A relatively consistent trend at community-level, represented by the functional diversity index, was found between the cry1Ac sugarcane and the non-transgenic lines. Most soil samples showed no significant difference in the activities of four soil enzymes: urease, protease, sucrose, and acid phosphate monoester between the non-transgenic and cry1Ac sugarcane lines. We conclude, based on one crop season, that the cry1Ac sugarcane lines may not affect the microbial community structure and functional diversity of the rhizosphere soil and have few negative effects on soil enzymes. PMID:27014291

  15. Integrating the public in mosquito management: active education by community peers can lead to significant reduction in peridomestic container mosquito habitats.

    PubMed

    Healy, Kristen; Hamilton, George; Crepeau, Taryn; Healy, Sean; Unlu, Isik; Farajollahi, Ary; Fonseca, Dina M

    2014-01-01

    Mosquito species that utilize peridomestic containers for immature development are commonly aggressive human biters, and because they often reach high abundance, create significant nuisance. One of these species, the Asian tiger mosquito Aedes albopictus, is an important vector of emerging infectious diseases, such as dengue, chikungunya, and Zika fevers. Integrated mosquito management (IMM) of Ae. albopictus is particularly difficult because it requires access to private yards in urban and suburban residences. It has become apparent that in the event of a public health concern due to this species, homeowners will have to be active participants in the control process by reducing mosquito habitats in their properties, an activity known as source reduction. However, limited attempts at quantifying the effect of source reduction by homeowners have had mixed results. Of note, many mosquito control programs in the US have some form of education outreach, however the primary approach is often passive focusing on the distribution of education materials as flyers. In 2010, we evaluated the use of active community peer education in a source reduction program, using AmeriCorps volunteers. The volunteers were mobilized over a 4-week period, in two areas with approximately 1,000 residences each in urban Mercer and suburban Monmouth counties in New Jersey, USA. The volunteers were first provided training on peridomestic mosquitoes and on basic approaches to reducing the number of container habitats for mosquito larvae in backyards. Within the two treatment areas the volunteers successfully engaged 758 separate homes. Repeated measures analysis of variance showed a significant reduction in container habitats in the sites where the volunteers actively engaged the community compared to untreated control areas in both counties. Our results suggest that active education using community peer educators can be an effective means of source reduction, and a critical tool in the arsenal

  16. Integrating the Public in Mosquito Management: Active Education by Community Peers Can Lead to Significant Reduction in Peridomestic Container Mosquito Habitats

    PubMed Central

    Healy, Kristen; Hamilton, George; Crepeau, Taryn; Healy, Sean; Unlu, Isik; Farajollahi, Ary; Fonseca, Dina M.

    2014-01-01

    Mosquito species that utilize peridomestic containers for immature development are commonly aggressive human biters, and because they often reach high abundance, create significant nuisance. One of these species, the Asian tiger mosquito Aedes albopictus, is an important vector of emerging infectious diseases, such as dengue, chikungunya, and Zika fevers. Integrated mosquito management (IMM) of Ae. albopictus is particularly difficult because it requires access to private yards in urban and suburban residences. It has become apparent that in the event of a public health concern due to this species, homeowners will have to be active participants in the control process by reducing mosquito habitats in their properties, an activity known as source reduction. However, limited attempts at quantifying the effect of source reduction by homeowners have had mixed results. Of note, many mosquito control programs in the US have some form of education outreach, however the primary approach is often passive focusing on the distribution of education materials as flyers. In 2010, we evaluated the use of active community peer education in a source reduction program, using AmeriCorps volunteers. The volunteers were mobilized over a 4-week period, in two areas with approximately 1,000 residences each in urban Mercer and suburban Monmouth counties in New Jersey, USA. The volunteers were first provided training on peridomestic mosquitoes and on basic approaches to reducing the number of container habitats for mosquito larvae in backyards. Within the two treatment areas the volunteers successfully engaged 758 separate homes. Repeated measures analysis of variance showed a significant reduction in container habitats in the sites where the volunteers actively engaged the community compared to untreated control areas in both counties. Our results suggest that active education using community peer educators can be an effective means of source reduction, and a critical tool in the arsenal

  17. Total body calcium by neutron activation analysis in normals and osteoporotic populations: a discriminator of significant bone mass loss

    SciTech Connect

    Ott, S.M.; Murano, R.; Lewellen, T.K.; Nelp, W.B.; Chesnut, C.M.

    1983-10-01

    Measurements of total body calcium by neutron activation (TBC) in 94 normal individuals and 86 osteoporotic patients are reported. The ability of TBC to discriminate normal from osteoporotic females was evaluated with decision analysis. Bone mineral content (BMC) by single-photon absorptiometry was also measured. TBC was higher in males (range 826 to 1363 gm vs 537 to 1054 in females) and correlated with height in all normals. In females over age 55 there was a negative correlation with age. Thus, for normals an algorithm was derived to allow comparison between measured TBC and that predicted by sex, age, and height (TBCp). In the 28 normal females over age 55, the TBC was 764 +/- 115 gm vs. 616 +/- 90 in the osteoporotics. In 63 of the osteoporotic females an estimated height, from tibial length, was used to predict TBC. In normals the TBC/TBCp ratio was 1.00 +/- 0.12, whereas in osteoporotic females it was 0.80 +/- 0.12. A receiver operating characteristic curve showed better discrimination of osteoporosis with TBC/TBCp than with wrist BMC. By using Bayes' theorem, with a 25% prevalence of osteoporosis (estimate for postmenopausal women), the posttest probability of disease was 90% when the TBC/TBCp ratio was less than 0.84. The authors conclude that a low TBC/TBCp ratio is very helpful in determining osteoporosis.

  18. Structures, chemotaxonomic significance, cytotoxic and Na(+),K(+)-ATPase inhibitory activities of new cardenolides from Asclepias curassavica.

    PubMed

    Zhang, Rong-Rong; Tian, Hai-Yan; Tan, Ya-Fang; Chung, Tse-Yu; Sun, Xiao-Hui; Xia, Xue; Ye, Wen-Cai; Middleton, David A; Fedosova, Natalya; Esmann, Mikael; Tzen, Jason T C; Jiang, Ren-Wang

    2014-11-28

    Five new cardenolide lactates (1–5) and one new dioxane double linked cardenolide glycoside (17) along with 15 known compounds (6–16 and 18–21) were isolated from the ornamental milkweed Asclepias curassavica. Their structures were elucidated by extensive spectroscopic methods (IR, UV, MS, 1D- and 2D-NMR). The molecular structures and absolute configurations of 1–3 and 17 were further confirmed by single-crystal X-ray diffraction analysis. Simultaneous isolation of dioxane double linked cardenolide glycosides (17–21) and cardenolide lactates (1–5) provided unique chemotaxonomic markers for this genus. Compounds 1–21 were evaluated for the inhibitory activities against DU145 prostate cancer cells. The dioxane double linked cardenolide glycosides showed the most potent cytotoxic effect followed by normal cardenolides and cardenolide lactates, while the C21 steroids were non-cytotoxic. Enzymatic assay established a correlation between the cytotoxic effects in DU145 cancer cells and the Ki for the inhibition of Na(+),K(+)-ATPase. Molecular docking analysis revealed relatively strong H-bond interactions between the bottom of the binding cavity and compounds 18 or 20, and explained why the dioxane double linked cardenolide glycosides possessed higher inhibitory potency on Na(+),K(+)-ATPase than the cardenolide lactate. PMID:25270760

  19. Modified high-density lipoproteins by artificial sweetener, aspartame, and saccharin, showed loss of anti-atherosclerotic activity and toxicity in zebrafish.

    PubMed

    Kim, Jae-Yong; Park, Ki-Hoon; Kim, Jihoe; Choi, Inho; Cho, Kyung-Hyun

    2015-01-01

    Safety concerns have been raised regarding the association of chronic consumption of artificial sweeteners (ASs) with metabolic disorders, especially in the heart and brain. There has been no information on the in vivo physiological effects of AS consumption in lipoprotein metabolism. High-dosage treatment (final 25, 50, and 100 mM) with AS (aspartame, acesulfame K, and saccharin) to human high-density lipoprotein (HDL) induced loss of antioxidant ability along with elevated atherogenic effects. Aspartame-treated HDL3 (final 100 mM) almost all disappeared due to putative proteolytic degradation. Aspartame- and saccharin-treated HDL3 showed more enhanced cholesteryl ester transfer activity, while their antioxidant ability was disappeared. Microinjection of the modified HDL3 exacerbated the inflammatory death in zebrafish embryos in the presence of oxLDL. These results show that AS treatment impaired the beneficial functions of HDL, resulting in loss of antioxidant and anti-atherogenic activities. These results suggest that aspartame and saccharin could be toxic to the human circulation system as well as embryonic development via impairment of lipoprotein function. PMID:25142179

  20. Sag-ponding and its Significance in determining Paleo-seismic events along the active strike- slip fault

    NASA Astrophysics Data System (ADS)

    Li, C.; Zhang, P.; Yuan, D.

    2007-12-01

    During the development of one active fault, we really want to know how it behaves and what it will do next. This mostly depends on the record and preservation of the information showing the action of the fault. Sparse young sediments or sediments with coarse grain along most of big strike-slip faults make it hard record and preserve the vestige of the paleo-seismic events. This extremely restricts the development of the Paleo-seismic research. Sag-ponding as well as the deposits in ponds, which are formed by the movement of the fault, can help settling the difficulty. Periodic sag-ponding is a feature to which should be paid more attention along the strike-slip fault, it can develop a pond to capture plenty fine sediments which well record the action of the faults. Sag-ponding can easily be found on the main active strike-slip faults in northern and eastern Tibet. By disclosing the sag-ponding depositions with 3-D excavations, sediment distribution and characters of relevant sag-ponds, and the relation between the sag-ponding and faulting were discussed. 1. Mechanism of the formation of the sag-pond When the valleys and ridges intersecting with the fault are displaced, the fault scarps will block the flow of the streams cut by the fault, or make the gullies develop ancon-like bend. This would form a space for water-storage, and thus a sag-pond comes into being. If the fault behaves like this many times, multi-sag-ponding will occur. 2. Rhythmic sag-ponding deposition features and stratigraphic sequence (1) Vertical characteristics. Observed from the stratigraphic profiles disclosed by the excavation, stratigraphic sequence shows good rhythms. There are several rhythms in each pond, and one rhythm is composed of the lower coarse layers and the upper fine layers. That is, the grains are coarser below and finer upward. (2) Transverse variation. In the direction parallel to the fault, the deposition center of each sag-pond appears regular movement, or migration

  1. A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models.

    PubMed

    Ye, Xiang S; Fan, Li; Van Horn, Robert D; Nakai, Ryuichiro; Ohta, Yoshihisa; Akinaga, Shiro; Murakata, Chikara; Yamashita, Yoshinori; Yin, Tinggui; Credille, Kelly M; Donoho, Gregory P; Merzoug, Farhana F; Li, Heng; Aggarwal, Amit; Blanchard, Kerry; Westin, Eric H

    2015-11-01

    Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355. PMID:26304237

  2. Identification of a new cyathane diterpene that induces mitochondrial and autophagy-dependent apoptosis and shows a potent in vivo anti-colorectal cancer activity.

    PubMed

    He, Luwei; Han, Junjie; Li, Baowei; Huang, Li; Ma, Ke; Chen, Quan; Liu, Xinzhong; Bao, Li; Liu, Hongwei

    2016-03-23

    Diterpenes has been reported to possess multiple bioactivities consisting of anti-microbial and anti-inflammatory properties. This study reveals a new cyathane-type diterpene (cyathin Q) from the culture of the fungus Cyathus africanus by bioactivity-guided separation. The structure of cyathin Q was determined based on spectroscopic measurements (NMR and MS). The bioactivity evaluation shows that cyathin Q has a strong anticancer activity against HCT116 cells and Bax-deficient HCT116 in vitro and in vivo. This compound induced hallmarks of apoptotic events in HCT116 cells, including caspase activation, cytochrome c release, poly (ADP-ribose) polymerase (PARP) cleavage, and depolarization of the mitochondrial inner transmembrane potential. This process is accompanied with the increased mitochondrial ROS, down-regulation of Bcl-2 protein, and up-regulation of Bim protein. We also observed the cleavage of autophagy-related protein ATG5 in cyathin Q-induced apoptosis. Taken together, our study identified a new fungal diterpene that exhibited anticancer activity via induction of mitochondria and autophagy-dependent apoptosis in HCT116 cells. PMID:26871659

  3. Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

    PubMed Central

    Blancafort, Adriana; Giró-Perafita, Ariadna; Oliveras, Glòria; Palomeras, Sònia; Turrado, Carlos; Campuzano, Òscar; Carrión-Salip, Dolors; Massaguer, Anna; Brugada, Ramon; Palafox, Marta; Gómez-Miragaya, Jorge; González-Suárez, Eva; Puig, Teresa

    2015-01-01

    Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies. PMID:26107737

  4. One Decade of Active Avian Influenza Wild Bird Surveillance in Belgium Showed a Higher Viroprevalence in Hunter-Harvested Than in Live-Ringed Birds.

    PubMed

    Steensels, M; Vangeluwe, D; Linden, A; Houdart, Ph; van den Berg, Thierry P; Lambrecht, B

    2016-05-01

    Active monitoring of avian influenza (AI) viruses in wild birds was initiated in Belgium in 2005 in response to the first highly pathogenic avian influenza (HPAI) H5N1 outbreaks occurring in Europe. In Belgium, active wild bird surveillance that targeted live-ringed and hunter-harvested wild birds was developed and maintained from 2005 onward. After one decade, this program assimilated, analyzed, and reported on over 35,000 swabs. The 2009-2014 datasets were used for the current analysis because detailed information was available for this period. The overall prevalence of avian influenza (AI) in samples from live-ringed birds during this period was 0.48% whereas it was 6.12% in hunter-harvested samples. While the ringing sampling targeted a large number of bird species and was realized over the years, the hunting sampling was mainly concentrated on mallard (Anas platyrhynchos) during the hunting season, from mid-August to late January. Even when using just AI prevalence for live-ringed A. platyrhynchos during the hunting season, the value remained significantly lower (2.10%) compared to that detected for hunter-harvested mallards. One explanation for this significant difference in viroprevalence in hunter-harvested mallards was the game restocking practice, which released captive-bred birds in the wild before the hunting period. Indeed, the released game restocking birds, having an AI-naïve immune status, could act as local amplifiers of AI viruses already circulating in the wild, and this could affect AI epidemiology. Also, the release into the wild of noncontrolled restocking birds might lead to the introduction of new strains in the natural environment, leading to increased AI presence in the environment. Consequently, the release of naïve or infected restocking birds may affect AI dynamics. PMID:27309083

  5. Selective imaging of presynaptic activity in the mouse olfactory bulb shows concentration and structure dependence of odor responses in identified glomeruli

    PubMed Central

    Fried, Hans U.; Fuss, Stefan H.; Korsching, Sigrun I.

    2002-01-01

    More chemicals can be smelled than there are olfactory receptors for them, necessitating a combinatorial representation by somewhat broadly tuned receptors. To understand the perception of odor quality and concentration, it is essential to establish the nature of the receptor repertoires that are activated by particular odorants at particular concentrations. We have taken advantage of the one-to-one correspondence of glomeruli and olfactory receptor molecules in the mouse olfactory bulb to analyze the tuning properties of a major receptor population by high resolution calcium imaging of odor responses selectively in the presynaptic compartment of glomeruli. We show that eighty different olfactory receptors projecting to the dorsal olfactory bulb respond to high concentrations of aldehydes with limited specificity. Varying ensembles of about 10 to 20 receptors encode any particular aldehyde at low stimulus concentrations with high specificity. Even normalized odor response patterns are markedly concentration dependent, caused by pronounced differences in affinity within the aldehyde receptor repertoire. PMID:11854464

  6. Highly efficient solution-processed host-free organic light-emitting diodes showing an external quantum efficiency of nearly 18% with a thermally activated delayed fluorescence emitter

    NASA Astrophysics Data System (ADS)

    Wada, Yoshimasa; Shizu, Katsuyuki; Kubo, Shosei; Fukushima, Tatsuya; Miwa, Takuya; Tanaka, Hiroyuki; Adachi, Chihaya; Kaji, Hironori

    2016-03-01

    We demonstrate solution-processed host-free organic light-emitting diodes (OLEDs) using a thermally activated delayed fluorescence emitter 10-[4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl]-9,9-dimethylacridan (DMAC-TRZ). A spin-coated neat DMAC-TRZ film shows weak concentration quenching, leading to a high photoluminescence quantum yield (PLQY) of 84%. OLEDs containing a neat film of DMAC-TRZ display a maximum external quantum efficiency (EQE) of 17.6%. Both the PLQY and EQE are the highest reported for solution-processed host-free films and OLEDs, respectively. In addition, the OLEDs exhibit an EQE of 16.8% at high luminance (over 400 cd m-2).

  7. The Great Cometary Show

    NASA Astrophysics Data System (ADS)

    2007-01-01

    The ESO Very Large Telescope Interferometer, which allows astronomers to scrutinise objects with a precision equivalent to that of a 130-m telescope, is proving itself an unequalled success every day. One of the latest instruments installed, AMBER, has led to a flurry of scientific results, an anthology of which is being published this week as special features in the research journal Astronomy & Astrophysics. ESO PR Photo 06a/07 ESO PR Photo 06a/07 The AMBER Instrument "With its unique capabilities, the VLT Interferometer (VLTI) has created itself a niche in which it provide answers to many astronomical questions, from the shape of stars, to discs around stars, to the surroundings of the supermassive black holes in active galaxies," says Jorge Melnick (ESO), the VLT Project Scientist. The VLTI has led to 55 scientific papers already and is in fact producing more than half of the interferometric results worldwide. "With the capability of AMBER to combine up to three of the 8.2-m VLT Unit Telescopes, we can really achieve what nobody else can do," added Fabien Malbet, from the LAOG (France) and the AMBER Project Scientist. Eleven articles will appear this week in Astronomy & Astrophysics' special AMBER section. Three of them describe the unique instrument, while the other eight reveal completely new results about the early and late stages in the life of stars. ESO PR Photo 06b/07 ESO PR Photo 06b/07 The Inner Winds of Eta Carinae The first results presented in this issue cover various fields of stellar and circumstellar physics. Two papers deal with very young solar-like stars, offering new information about the geometry of the surrounding discs and associated outflowing winds. Other articles are devoted to the study of hot active stars of particular interest: Alpha Arae, Kappa Canis Majoris, and CPD -57o2874. They provide new, precise information about their rotating gas envelopes. An important new result concerns the enigmatic object Eta Carinae. Using AMBER with

  8. Healthy co-twins of patients with affective disorders show reduced risk-related activation of the insula during a monetary gambling task

    PubMed Central

    Macoveanu, Julian; Miskowiak, Kamilla; Kessing, Lars Vedel; Vinberg, Maj; Siebner, Hartwig Roman

    2016-01-01

    Background Healthy first-degree relatives of patients with affective disorders are at increased risk for affective disorders and express discrete structural and functional abnormalities in the brain reward system. However, value-based decision making is not well understood in these at-risk individuals. Methods We investigated healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorders (high-risk and low-risk groups, respectively) using functional MRI during a gambling task. We assessed group differences in activity related to gambling risk over the entire brain. Results We included 30 monozygotic and 37 dizygotic twins in our analysis. Neural activity in the anterior insula and ventral striatum increased linearly with the amount of gambling risk in the entire cohort. Individual neuroticism scores were positively correlated with the neural response in the ventral striatum to increasing gambling risk and negatively correlated with individual risk-taking behaviour. Compared with low-risk twins, the high-risk twins showed a bilateral reduction of risk-related activity in the middle insula extending into the temporal cortex with increasing gambling risk. Post hoc analyses revealed that this effect was strongest in dizygotic twins. Limitations The relatively old average age of the mono- and dizygotic twin cohort (49.2 yr) may indicate an increased resilience to affective disorders. The size of the monozygotic high-risk group was relatively small (n = 13). Conclusion The reduced processing of risk magnitude in the middle insula may indicate a deficient integration of exteroceptive information related to risk-related cues with interoceptive states in individuals at familial risk for affective disorders. Impaired risk processing might contribute to increased vulnerability to affective disorders. PMID:26395812

  9. Background Synaptic Activity in Rat Entorhinal Cortex Shows a Progressively Greater Dominance of Inhibition over Excitation from Deep to Superficial Layers

    PubMed Central

    Greenhill, Stuart David; Chamberlain, Sophie Elizabeth Lyn; Lench, Alex; Massey, Peter Vernon; Yuill, Kathryn Heather; Woodhall, Gavin Lawrence; Jones, Roland Spencer Gwynne

    2014-01-01

    The entorhinal cortex (EC) controls hippocampal input and output, playing major roles in memory and spatial navigation. Different layers of the EC subserve different functions and a number of studies have compared properties of neurones across layers. We have studied synaptic inhibition and excitation in EC neurones, and we have previously compared spontaneous synaptic release of glutamate and GABA using patch clamp recordings of synaptic currents in principal neurones of layers II (L2) and V (L5). Here, we add comparative studies in layer III (L3). Such studies essentially look at neuronal activity from a presynaptic viewpoint. To correlate this with the postsynaptic consequences of spontaneous transmitter release, we have determined global postsynaptic conductances mediated by the two transmitters, using a method to estimate conductances from membrane potential fluctuations. We have previously presented some of this data for L3 and now extend to L2 and L5. Inhibition dominates excitation in all layers but the ratio follows a clear rank order (highest to lowest) of L2>L3>L5. The variance of the background conductances was markedly higher for excitation and inhibition in L2 compared to L3 or L5. We also show that induction of synchronized network epileptiform activity by blockade of GABA inhibition reveals a relative reluctance of L2 to participate in such activity. This was associated with maintenance of a dominant background inhibition in L2, whereas in L3 and L5 the absolute level of inhibition fell below that of excitation, coincident with the appearance of synchronized discharges. Further experiments identified potential roles for competition for bicuculline by ambient GABA at the GABAA receptor, and strychnine-sensitive glycine receptors in residual inhibition in L2. We discuss our results in terms of control of excitability in neuronal subpopulations of EC neurones and what these may suggest for their functional roles. PMID:24454801

  10. Tentacles of in vitro-grown round-leaf sundew (Drosera rotundifolia L.) show induction of chitinase activity upon mimicking the presence of prey.

    PubMed

    Matusíková, Ildikó; Salaj, Ján; Moravcíková, Jana; Mlynárová, Ludmila; Nap, Jan-Peter; Libantová, Jana

    2005-12-01

    Induction of plant-derived chitinases in the leaves of a carnivorous plant was demonstrated using aseptically grown round-leaf sundew (Drosera rotundifolia L.). The presence of insect prey was mimicked by placing the chemical inducers gelatine, salicylic acid and crustacean chitin on leaves. In addition, mechanical stirring of tentacles was performed. Chitinase activity was markedly increased in leaf exudates upon application of notably chitin. Application of gelatine increased the proteolytic activity of leaf exudates, indicating that the reaction of sundew leaves depends on the molecular nature of the inducer applied. In situ hybridization of sundew leaves with a Drosera chitinase probe showed chitinase gene expression in different cell types of non-treated leaves, but not in the secretory cells of the glandular heads. Upon induction, chitinase mRNA was also present in the secretory cells of the sundew leaf. The combined results indicate that chitinase is likely to be involved in the decomposition of insect prey by carnivorous plants. This adds a novel role to the already broad function of chitinases in the plant kingdom and may contribute to our understanding of the molecular mechanisms behind the ecological success of carnivorous plants in nutritionally poor environments. PMID:16049675

  11. Inactivated E. coli transformed with plasmids that produce dsRNA against infectious salmon anemia virus hemagglutinin show antiviral activity when added to infected ASK cells

    PubMed Central

    García, Katherine; Ramírez-Araya, Sebastián; Díaz, Álvaro; Reyes-Cerpa, Sebastián; Espejo, Romilio T.; Higuera, Gastón; Romero, Jaime

    2015-01-01

    Infectious salmon anemia virus (ISAV) has caused great losses to the Chilean salmon industry, and the success of prevention and treatment strategies is uncertain. The use of RNA interference (RNAi) is a promising approach because during the replication cycle, the ISAV genome must be transcribed to mRNA in the cytoplasm. We explored the capacity of E. coli transformed with plasmids that produce double-stranded RNA (dsRNA) to induce antiviral activity when added to infected ASK cells. We transformed the non-pathogenic Escherichia coli HT115 (DE3) with plasmids that expressed highly conserved regions of the ISAV genes encoding the nucleoprotein (NP), fusion (F), hemagglutinin (HE), and matrix (M) proteins as dsRNA, which is the precursor of the RNAi mechanism. The inactivated transformed bacteria carrying dsRNA were tested for their capacity to silence the target ISAV genes, and the dsRNA that were able to inhibit gene expression were subsequently tested for their ability to attenuate the cytopathic effect (CPE) and reduce the viral load. Of the four target genes tested, inactivated E. coli transformed with plasmids producing dsRNA targeting HE showed antiviral activity when added to infected ASK cells. PMID:25932022

  12. Factors that Influence Physical Activity in Long-Term Care: Perspectives of Residents, Staff, and Significant Others

    ERIC Educational Resources Information Center

    Benjamin, Kathleen; Edwards, Nancy; Guitard, Paulette; Murray, Mary Ann; Caswell, Wenda; Perrier, Marie Josee

    2011-01-01

    Physical activity has been linked to positive health outcomes for frail seniors. However, our understanding of factors that influence the physical activity of residents in the long-term care (LTC) setting is limited. This article describes our work with focus groups, one component of a multi-component study that examined factors influencing the…

  13. New sub-family of lysozyme-like proteins shows no catalytic activity: crystallographic and biochemical study of STM3605 protein from Salmonella Typhimurium

    SciTech Connect

    Michalska, Karolina; Brown, Roslyn N.; Li, Hui; Jedrzejczak, Robert; Niemann, George; Heffron, Fred; Cort, John R.; Adkins, Joshua N.; Babnigg, Gyorgy; Joachimiak, Andrzej

    2013-03-01

    Phage viruses that infect prokaryotes integrate their genome into the host chromosome; thus, microbial genomes typically contain genetic remnants of both recent and ancient phage infections. Often phage genes occur in clusters of atypical G+C content that reflect integration of the foreign DNA. However, some phage genes occur in isolation without other phage gene neighbors, probably resulting from horizontal gene transfer. In these cases, the phage gene product is unlikely to function as a component of a mature phage particle, and instead may have been co-opted by the host for its own benefit. The product of one such gene from Salmonella enterica serovar Typhimurium, STM3605, encodes a protein with modest sequence similarity to phage-like lysozyme (N-acetylmuramidase) but appears to lack essential catalytic residues that are strictly conserved in all lysozymes. Close homologs in other bacteria share this characteristic. The structure of the STM3605 protein was characterized by X-ray crystallography, and functional assays showed that it is a stable, folded protein whose structure closely resembles lysozyme. However, this protein is unlikely to hydrolyze peptidoglycan. Instead, STM3605 is presumed to have evolved an alternative function because it shows some lytic activity and partitions to micelles.

  14. Regulatory Implications of Non-Trivial Splicing: Isoform 3 of Rab1A Shows Enhanced Basal Activity and Is Not Controlled by Accessory Proteins.

    PubMed

    Schöppner, Patricia; Csaba, Gergely; Braun, Tatjana; Daake, Marina; Richter, Bettina; Lange, Oliver F; Zacharias, Martin; Zimmer, Ralf; Haslbeck, Martin

    2016-04-24

    Alternative splicing often affects structured and highly conserved regions of proteins, generating so called non-trivial splicing variants of unknown structure and cellular function. The human small G-protein Rab1A is involved in the regulation of the vesicle transfer from the ER to Golgi. A conserved non-trivial splice variant lacks nearly 40% of the sequence of the native Rab1A, including most of the regulatory interaction sites. We show that this variant of Rab1A represents a stable and folded protein, which is still able to bind nucleotides and co-localizes with membranes. Nevertheless, it should be mentioned that compared to other wild-typeRabGTPases, the measured nucleotide binding affinities are dramatically reduced in the variant studied. Furthermore, the Rab1A variant forms hetero-dimers with wild-type Rab1A and its presence in the cell enhances the efficiency of alkaline phosphatase secretion. However, this variant shows no specificity for GXP nucleotides, a constantly enhanced GTP hydrolysis activity and is no longer controlled by GEF or GAP proteins, indicating a new regulatory mechanism for the Rab1A cycle via alternative non-trivial splicing. PMID:26953259

  15. Pseudoephedrine/ephedrine shows potent anti-inflammatory activity against TNF-α-mediated acute liver failure induced by lipopolysaccharide/D-galactosamine.

    PubMed

    Wu, Zhongping; Kong, Xiangliang; Zhang, Tong; Ye, Jin; Fang, Zhaoqin; Yang, Xuejun

    2014-02-01

    The anti-inflammatory effects of pseudoephedrine/ephedrine were investigated using the experimental model of lipopolysaccharide (LPS)-induced acute liver failure in D-galactosamine (D-GalN)-sensitised male rats in order to elucidate effects other than sympathomimetic effects. Rats were intraperitoneally injected with D-GalN (400 mg/kg) and LPS (40 μg/kg) to induce acute liver failure. The treatment groups were then intraperitoneally administered pseudoephedrine/ephedrine at 0 h and 4 h after induction and the activation induced by treatment with pseudoephedrine and/or LPS on the primary Kupffer cells (KCs) was monitored. Compared with controls induced by GalN/LPS alone, pseudoephedrine dramatically reduced the infiltration of inflammatory cells and bile ductular hyperplasia and hepatic necrosis observed in liver sections. It inhibited both hepatocellular apoptosis and the expression of monocyte chemotactic protein-1. It lowered the production of tumour necrosis factor-α (TNF-α) in the beginning of acute liver failure induced by D-GalN/LPS. Correspondingly, levels of alanine aminotransferase (ALT), total bilirubin (TBIL) and malondialdehyde were attenuated. Ephedrine demonstrated all these identical protective effects as well. In addition, pseudoephedrine significantly suppressed the production of p-IκB-α, reducing the degradation of sequestered nuclear factor kappa B (NF-κB) in the cytoplasm, and inhibited the translocation of NF-κB/p65 to the nucleus, the transcription of TNF-α mRNA and the production of TNF-α in primary KCs. These results suggest that pseudoephedrine and ephedrine have a potent anti-inflammatory activity against D-GalN/LPS-induced acute liver failure in rats, and this comprehensive anti-inflammatory effect may result from the inhibition of TNF-α production. PMID:24365491

  16. Trichoderma harzianum IOC-4038: A promising strain for the production of a cellulolytic complex with significant β-glucosidase activity from sugarcane bagasse cellulignin.

    PubMed

    de Castro, Aline Machado; Pedro, Kelly Cristina Nascimento Rodrigues; da Cruz, Juliana Cunha; Ferreira, Marcela Costa; Leite, Selma Gomes Ferreira; Pereira, Nei

    2010-11-01

    Sugarcane bagasse is an agroindustrial residue generated in large amounts in Brazil. This biomass can be used for the production of cellulases, aiming at their use in second-generation processes for bioethanol production. Therefore, this work reports the ability of a fungal strain, Trichoderma harzianum IOC-4038, to produce cellulases on a novel material, xylan free and cellulose rich, generated from sugarcane bagasse, named partially delignified cellulignin. The extract produced by T. harzianum under submerged conditions reached 745, 97, and 559 U L(-1) of β-glucosidase, FPase, and endoglucanase activities, respectively. The partial characterization of this enzyme complex indicated, using a dual analysis, that the optimal pH values for the biocatalysis ranged from 4.9 to 5.2 and optimal temperatures were between 47 and 54 °C, depending on the activity studied. Thermal stability analyses revealed no significant decrease in activity at 37 °C during 23 h of incubation. When compared to model strains, Aspergillus niger ATCC-16404 and Trichoderma reesei RutC30, T. harzianum fermentation was faster and its extract showed a better balanced enzyme complex, with adequate characteristics for its application in simultaneous saccharification and fermentation processes. PMID:20455032

  17. Targeting the annulus fibrosus of the intervertebral disc: Col1a2-Cre(ER)T mice show specific activity of Cre recombinase in the outer annulus fibrosus.

    PubMed

    Bedore, Jake; Quesnel, Katherine; Quinonez, Diana; Séguin, Cheryle A; Leask, Andrew

    2016-06-01

    Degeneration of the intervertebral disc (IVD) is a major underlying contributor to back pain-the single leading cause of disability worldwide. However, we possess a limited understanding of the etiology underlying IVD degeneration. To date, there are a limited number of mouse models that have been used to target proteins in specific compartments of the IVD to explore their functions in disc development, homeostasis and disease. Furthermore, the majority of reports exploring the composition and function of the outer encapsulating annulus fibrosus (AF) of the IVD have considered it as one tissue, without considering the numerous structural and functional differences existing between the inner and outer AF. In addition, no mouse models have yet been reported that enable specific targeting of genes within the outer AF. In the current report, we discuss these issues and demonstrate the localized activity of Cre recombinase in the IVD of Col1a2-Cre(ER)T;ROSA26mTmG mice possessing a tamoxifen-dependent Cre recombinase driven by a Cola2 promoter and distal enhancer and the mTmG fluorescent reporter. Following tamoxifen injection of 3-week-old Col1a2-Cre(ER)T;ROSA26mTmG mice, we show Cre activity specifically in the outer AF of the IVD, as indicated by expression of the GFP reporter. Thus, Col1a2-Cre(ER)T;ROSA26mTmG mice may prove to be a valuable tool in delineating the function of proteins in this unique compartment of the IVD, and in further exploring the compositional differences between the inner and outer AF in disc homeostasis, aging and disease. PMID:27173473

  18. Nonexercise Activity Thermogenesis is Significantly Lower in Type 2 Diabetic Patients With Mental Disorders Than in Those Without Mental Disorders: A Cross-sectional Study.

    PubMed

    Hamasaki, Hidetaka; Ezaki, Osamu; Yanai, Hidekatsu

    2016-01-01

    Physical activity improves health in patients with mental disorders. Nonexercise activity thermogenesis (NEAT) represents energy expenditure due to daily physical activities other than volitional exercise. We aimed to evaluate NEAT in type 2 diabetic patients with and without accompanying mental disorders.Between September 2010 and September 2014, we studied 150 patients with type 2 diabetes, 50 of whom also had a diagnosis of mental disorder, such as schizophrenia or mood disorder. We evaluated their NEAT in structured interviews using a validated questionnaire, and investigated differences in NEAT score and metabolic parameters between patients with and without mental disorders.The NEAT score was significantly lower in patients with mental disorders than in those without (56.3 ± 9.9 vs 61.9 ± 12.1; P = 0.005). Patients with mental disorders had significantly higher triglyceride (184.5 ± 116.3 vs 146.4 ± 78.4 mg/dL; P = 0.02) and insulin levels (18.7 ± 20.1 vs 11.2 ± 8.5 μU/mL; P = 0.006), and significantly lower B-type natriuretic peptide (12.1 ± 13.3 vs 26.3 ± 24.8 pg/mL; P < 0.001) and brachial-ankle pulse wave velocity levels (1501 ± 371 vs 1699 ± 367 cm/s; P = 0.003) than patients without mental disorders. In patients with schizophrenia, specifically, NEAT showed a negative correlation with hemoglobin A1c levels (β = -0.493, P = 0.031), and a positive correlation with high-density lipoprotein cholesterol (β = 0.519, P = 0.023) and B-type natriuretic peptide levels (β = 0.583, P = 0.02).Our results suggest that NEAT may be beneficial for the management of obesity, insulin sensitivity, and lipid profiles in patients with mental disorders. Incorporating NEAT into interventions for type 2 diabetes in patients with mental disorders, especially schizophrenia, shows promise and warrants further investigation. PMID:26765475

  19. A socio-ecological approach promoting physical activity and limiting sedentary behavior in adolescence showed weight benefits maintained 2.5 years after intervention cessation

    PubMed Central

    Simon, C; Kellou, N; Dugas, J; Platat, C; Copin, N; Schweitzer, B; Hausser, F; Bergouignan, A; Lefai, E; Blanc, S

    2014-01-01

    Background: Obesity in youth remains a major public health issue. Yet no effective long-term preventive strategy exists. We previously showed that a school-based socio-ecological approach targeting behavior and social/environmental influences on physical activity (PA) prevented 4-year excessive weight gain in 12-year olds. In this study, we investigated if this efficacy persists 30 months after intervention cessation. Methods and Findings: The program targeted students, family, school and the living environment to promote/support PA and prevent sedentary behavior (SB). A total of 732 students from eight randomized middle schools completed the 4-year trial. At the 30-month post-trial follow-up, body mass index (BMI), fat mass index (FMI), leisure PA (LPA), home/school/workplace active commuting, TV/video time (TVT), and attitudes toward PA were measured in 531 adolescents. The beneficial effects of the intervention on the excess BMI increase (+0.01 vs +0.34 kg m−2 in the intervention and control groups, respectively) and on the overweight incidence in initially non-overweight students (4.3% vs 8.6% odds ratio=0.48 (95% confidence interval: 0.23–1.01)) were maintained at the post-trial follow-up. LPA was not maintained at the level achieved during the trial. However, we still observed a prevention of the age-related decrease of the adolescents' percentage reporting regular LPA (−14.4% vs −26.5%) and a higher intention to exercise in the intervention group. The intervention promoted lower TVT (−14.0 vs +13.6 min per day) and higher active commuting changes (+11.7% vs −4.8%). Trends in higher BMI reduction in students with high initial TVT and in the least wealthy group were noted. TVT changes throughout the follow-up predicted excess BMI and FMI changes. Conclusions: Long-term multilevel approach targeting PA and SB prevents excessive weight gain up to 30 months after intervention cessation. The efficacy may be higher in the most sedentary and least

  20. Carbonization of self-assembled nanoporous hemin with a significantly enhanced activity for the oxygen reduction reaction.

    PubMed

    Xie, Yan; Tang, Chizhou; Hao, Zhiqiang; Lv, Yang; Yang, Ruixia; Wei, Xuming; Deng, Weiqiao; Wang, Anjie; Yi, Baolian; Song, Yujiang

    2014-01-01

    The scarcity and high cost of Pt-based electrocatalysts for the oxygen reduction reaction (ORR) hinder the practical application of proton exchange membrane fuel cells (PEMFCs). It is critical to replace platinum with non-noble metal electrocatalysts (NNMEs). Carbonized metalloporphyrins represent an important class of NNMEs, but most metalloporphyrins are costly and the corresponding NNMEs do not possess a high ORR activity. Herein, we report that the self-assembly of inexpensive hemin leads to porous nanomaterials in water under ambient conditions and subsequent heat-treatment of the unprecedented nanoporous hemin results in a magnetic NNME with a much enhanced ORR activity compared with directly carbonized hemin without self-assembly. The improvement of the ORR activity likely originates from the exposure of more ORR active sites, caused by the surface area increase of the nanoporous hemin after carbonization over that of micro-scale pristine hemin crystals. Moreover, the ORR activity of heat-treated nanoporous hemin is actually comparable to that of commercial Pt/C in alkaline solution. Additionally, the carbonized nanoporous hemin is much better than commercial Pt/C in terms of durability and tolerance to methanol. This study opens up a new avenue to the production of inexpensive metalloporphyrin-based NNMEs with a high ORR performance by using a self-assembly method in combination with traditional pyrolysis. PMID:25406677

  1. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action.

    PubMed

    Currie, Richard A; Peffer, Richard C; Goetz, Amber K; Omiecinski, Curtis J; Goodman, Jay I

    2014-07-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA. PMID:24675475

  2. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    PubMed Central

    Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

    2014-01-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA. PMID:24675475

  3. Elucidation of procoagulant mechanism and pathophysiological significance of a new prothrombin activating metalloprotease purified from Daboia russelii russelii venom.

    PubMed

    Thakur, Rupamoni; Chattopadhyay, Pronobesh; Ghosh, Siddharth S; Mukherjee, Ashis K

    2015-06-15

    The procoagulant proteases present in Russell's Viper venom (RVV) are responsible for promoting consumption coagulopathy in victims. In this study, a procoagulant metalloprotease (Rusviprotease) possessing prothrombin activating and α-fibrinogenase properties has been purified and characterized from RVV. Rusviprotease is a 26.8 kDa glycoprotein which also exists in other multimeric forms. The peptide mass fingerprinting and secondary structure analyses of Rusviprotease revealed its similarity with snake venom prothrombin activators and metalloproteases. Similar to group A prothrombin activators, Rusviprotease cleaved prothrombin independent of any co-factor requirement generating meizothrombin which is further cleaved to form thrombin. The Km and Vmax values of Rusviprotease towards prothrombin were determined to be 1.73 μM, and 153.5 nM thrombin generated/min/μmoles of Rusviprotease, respectively. The Km and Vmax values of Rusviprotease towards fibrinogen were calculated to be 3.14 μM and 78.7 nmol/min, respectively. Spectrofluorometric study provided the evidence of interaction between Rusviprotease and factor Xa with a Kd value of 6.64 nM. This interaction augmented the prothrombin activating property of the factor Xa-prothrombinase-Rusviprotease complex by 2.5 fold. Intravenous injection of Rusviprotease to BALB/c mice (0.1 mg/kg) resulted in in vivo defibrinogenation rendering the blood incoagulable. In conclusion, Rusviprotease is the first example of a prothrombin activator with fibrinogenolytic property purified from Daboia russelii russelii venom. PMID:25817001

  4. Cloud condensation nucleus activity comparison of dry- and wet-generated mineral dust aerosol: the significance of soluble material

    NASA Astrophysics Data System (ADS)

    Garimella, S.; Huang, Y.-w.; Seewald, J. S.; Cziczo, D. J.

    2013-11-01

    This study examines the interaction of clay mineral particles and water vapor to determine the conditions required for cloud droplet formation. Droplet formation conditions are investigated for three clay minerals: illite, sodium-rich montmorillonite, and Arizona Test Dust. Using wet and dry particle generation coupled to a differential mobility analyzer (DMA) and cloud condensation nuclei counter, the critical activation of the clay mineral particles as cloud condensation nuclei is characterized. Electron microscopy (EM) is used to determine non-sphericity in particle shape. EM is also used to determine particle surface area and account for transmission of multiply charged particles by the DMA. Single particle mass spectrometry and ion chromatography are used to investigate soluble material in wet-generated samples and demonstrate that wet and dry generation yield compositionally different particles. Activation results are analyzed in the context of both κ-Köhler theory and Frenkel, Halsey, and Hill (FHH) adsorption activation theory. This study has two main results: (1) κ-Köhler is a suitable framework, less complex than FHH theory, to describe clay mineral nucleation activity despite apparent differences in κ with respect to size. For dry-generated particles the size dependence is likely an artifact of the shape of the size distribution: there is a sharp drop-off in particle concentration at ~300 nm, and a large fraction of particles classified with a mobility diameter less than ~300 nm are actually multiply charged, resulting in a much lower critical supersaturation for droplet activation than expected. For wet-generated particles, deviation from κ-Köhler theory is likely a result of the dissolution and redistribution of soluble material. (2) Wet-generation is found to be unsuitable for simulating the lofting of fresh dry dust because it changes the size-dependent critical supersaturations by fractionating and re-partitioning soluble material.

  5. Histone Deacetylase 6-Controlled Hsp90 Acetylation Significantly Alters Mineralocorticoid Receptor Subcellular Dynamics But Not its Transcriptional Activity.

    PubMed

    Jiménez-Canino, Rubén; Lorenzo-Díaz, Fabián; Jaisser, Frederic; Farman, Nicolette; Giraldez, Teresa; Alvarez de la Rosa, Diego

    2016-06-01

    The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis, and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein (Hsp) 90), Hsp70, and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and -independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or nonacetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast with the down-regulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell. PMID:27100623

  6. Electrogastrography in Adults and Children: The Strength, Pitfalls, and Clinical Significance of the Cutaneous Recording of the Gastric Electrical Activity

    PubMed Central

    Indrio, Flavia

    2013-01-01

    Cutaneous electrogastrography (EGG) is a non-invasive technique to record gastric myoelectrical activity from the abdominal surface. Although the recent rapid increase in the development of electrocardiography, EGG still suffers from several limitations. Currently, computer analysis of EGG provides few reliable parameters, such as frequency and the percentage of normal and altered slow wave activity (bradygastria and tachygastria). New EGG hardware and software, along with an appropriate arrangement of abdominal electrodes, could detect the coupling of the gastric slow wave from the EGG. At present, EGG does not diagnose a specific disease, but it puts in evidence stomach motor dysfunctions in different pathological conditions as gastroparesis and functional dyspepsia. Despite the current pitfalls of EGG, a multitasking diagnostic protocol could involve the EGG and the 13C-breath testing for the evaluation of the gastric emptying time—along with validated gastrointestinal questionnaires and biochemical evaluations of the main gastrointestinal peptides—to identify dyspeptic subgroups. The present review tries to report the state of the art about the pathophysiological background of the gastric electrical activity, the recording and processing methodology of the EGG with particular attention to multichannel recording, and the possible clinical application of the EGG in adult and children. PMID:23762836

  7. Significant Treasures.

    ERIC Educational Resources Information Center

    Andrews, Ian A.

    1999-01-01

    Provides a crossword puzzle with an answer key corresponding to the book entitled "Significant Treasures/Tresors Parlants" that is filled with color and black-and-white prints of paintings and artifacts from 131 museums and art galleries as a sampling of the 2,200 such Canadian institutions. (CMK)

  8. Final Environmental Assessment and Finding of No Significant Impact: Waste Disposition Activities at the Paducah Site Paducah, Kentucky

    SciTech Connect

    N /A

    2002-11-05

    The U.S. Department of Energy (DOE) has completed an environmental assessment (DOE/EA-1339), which is incorporated herein by reference, for proposed disposition of polychlorinated biphenyl (PCB) wastes, low-level radioactive waste (LLW), mixed low-level radioactive waste (MLLW), and transuranic (TRU) waste from the Paducah Gaseous Diffusion Plant Site (Paducah Site) in Paducah, Kentucky. All of the wastes would be transported for disposal at various locations in the United States. Based on the results of the impact analysis reported in the EA, DOE has determined that the proposed action is not a major federal action that would significantly affect the quality of the human environment with in the context of the National Environmental Policy Act of 1969 (NEPA). Therefore, preparation of an environmental impact statement is not necessary, and DOE is issuing this Finding of No Significant Impact (FONSI).

  9. Cloud condensation nucleus activity comparison of dry- and wet-generated mineral dust aerosol: the significance of soluble material

    NASA Astrophysics Data System (ADS)

    Garimella, S.; Huang, Y.-W.; Seewald, J. S.; Cziczo, D. J.

    2014-06-01

    This study examines the interaction of clay mineral particles and water vapor for determining the conditions required for cloud droplet formation. Droplet formation conditions are investigated for two common clay minerals, illite and sodium-rich montmorillonite, and an industrially derived sample, Arizona Test Dust. Using wet and dry particle generation coupled to a differential mobility analyzer (DMA) and cloud condensation nuclei counter, the critical activation of the clay mineral particles as cloud condensation nuclei is characterized. Electron microscopy (EM) is used in order to determine non-sphericity in particle shape. It is also used in order to determine particle surface area and account for transmission of multiply charged particles by the DMA. Single particle mass spectrometry and ion chromatography are used to investigate soluble material in wet-generated samples and demonstrate that wet and dry generation yield compositionally different particles. Activation results are analyzed in the context of both κ-Köhler theory (κ-KT) and Frenkel-Halsey-Hill (FHH) adsorption activation theory. This study has two main results: (1) κ-KT is the suitable framework to describe clay mineral nucleation activity. Apparent differences in κ with respect to size arise from an artifact introduced by improper size-selection methodology. For dust particles with mobility sizes larger than ~300 nm, i.e., ones that are within an atmospherically relevant size range, both κ-KT and FHH theory yield similar critical supersaturations. However, the former requires a single hygroscopicity parameter instead of the two adjustable parameters required by the latter. For dry-generated particles, the size dependence of κ is likely an artifact of the shape of the size distribution: there is a sharp drop-off in particle concentration at ~300 nm, and a large fraction of particles classified with a mobility diameter less than ~300 nm are actually multiply charged, resulting in a much

  10. Very low amount of TiO2 on N-doped carbon nanotubes significantly improves oxygen reduction activity and stability of supported Pt nanoparticles.

    PubMed

    Zhao, Anqi; Masa, Justus; Xia, Wei

    2015-04-28

    Electrochemical corrosion is a major problem for carbon materials used in electrocatalysis. Highly dispersed TiO2 was deposited on O-functionalized and N-doped carbon nanotubes by chemical vapour deposition to tackle the carbon corrosion problem. Very low Ti loadings of about 1 wt% were applied to minimize the negative influence of TiO2 as a semiconductor on the high conductivity of carbon materials. Both N doping and TiO2 coating facilitate strong metal-support interactions and favour the formation of small Pt particles. N doping improved the intrinsic catalytic activity of the carbon support and enhanced the conductivity due to the removal of surface oxygen groups, while the negative effect of TiO2 on conductivity is counterbalanced by its promoting effect on metal-support interactions leading to enhanced overall catalytic performance. Pt/TiO2/NCNTs showed the highest ORR activity, and significantly outperformed Pt/NCNTs in electrochemical stability tests. PMID:25811122

  11. Chemically synthesized dicarba H2 relaxin analogues retain strong RXFP1 receptor activity but show an unexpected loss of in vitro serum stability.

    PubMed

    Hossain, Mohammed Akhter; Haugaard-Kedström, Linda M; Rosengren, K Johan; Bathgate, Ross A D; Wade, John D

    2015-11-28

    Peptides and proteins are now acknowledged as viable alternatives to small molecules as potential therapeutic agents. A primary limitation to their more widespread acceptance is their generally short in vivo half-lives due to serum enzyme susceptibility and rapid renal clearance. Numerous chemical approaches to address this concern have been undertaken in recent years. The replacement of disulfide bonds with non-reducible elements has been demonstrated to be one effective means by eliminating the deleterious effect of serum reductases. In particular, substitution with dicarba bonds via ring closure metathesis has been increasingly applied to many bioactive cystine-rich peptides. We used this approach for the replacement of the A-chain intramolecular disulfide bond of human relaxin 2 (H2 relaxin), an insulin-like peptide that has important regulatory roles in cardiovascular and connective tissue homeostasis that has led to successful Phase IIIa clinical trials for the treatment of acute heart failure. Use of efficient solid phase synthesis of the two peptide chains was followed by on-resin ring closure metathesis and formation of the dicarba bond within the A-chain and then by off-resin combination with the B-chain via sequential directed inter-chain disulfide bond formation. After purification and comprehensive chemical characterization, the two isomeric synthetic H2 relaxin analogues were shown to retain near-equipotent RXFP1 receptor binding and activation propensity. Unexpectedly, the in vitro serum stability of the analogues was greatly reduced compared with the native peptide. Circular dichroism spectroscopy studies showed subtle differences in the secondary structures between dicarba analogues and H2 relaxin suggesting that, although the overall fold is retained, it may be destabilized which could account for rapid degradation of dicarba analogues in serum. Caution is therefore recommended when using ring closure metathesis as a general approach to enhance

  12. Post-hoc analysis showing better clinical response with the loading dose of certolizumab pegol in Japanese patients with active rheumatoid arthritis

    PubMed Central

    Takeuchi, Tsutomu; Yamamoto, Kazuhiko; Yamanaka, Hisashi; Ishiguro, Naoki; Tanaka, Yoshiya; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Kobayashi, Mariko; Shoji, Toshiharu; Togo, Osamu; Miyasaka, Nobuyuki; Koike, Takao

    2016-01-01

    Abstract Objectives: To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Methods: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. Results: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Conclusions: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile. PMID:26472043

  13. Protonation state of a single histidine residue contributes significantly to the kinetics of the reaction of plasminogen activator inhibitor-1 with tissue-type plasminogen activator.

    PubMed

    Komissarov, Andrey A; Declerck, Paul J; Shore, Joseph D

    2004-05-28

    Stopped-flow fluorometry was used to study the kinetics of the reactive center loop insertion occurring during the reaction of N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-3-diazole (NBD) P9 plasminogen activator inhibitor-1 (PAI-1) with tissue-(tPA) and urokinase (uPA)-type plasminogen activators and human pancreatic elastase at pH 5.5-8.5. The limiting rate constants of reactive center loop insertion (k(lim)) and concentrations of proteinase at half-saturation (K(0.5)) for tPA and uPA and the specificity constants (k(lim)/K(0.5)) for elastase were determined. The pH dependences of k(lim)/K(0.5) reflected inactivation of each enzyme due to protonation of His57 of the catalytic triad. However, the specificity of the inhibitory reaction with tPA and uPA was notably higher than that for the substrate reaction catalyzed by elastase. pH dependences of k(lim) and K(0.5) obtained for tPA revealed an additional ionizable group (pKa, 6.0-6.2) affecting the reaction. Protonation of this group resulted in a significant increase in both k(lim) and K(0.5) and a 4.6-fold decrease in the specificity of the reaction of tPA with NBD P9 PAI-1. Binding of monoclonal antibody MA-55F4C12 to PAI-1 induced a decrease in k(lim) and K(0.5) at any pH but did not affect either the pKa of the group or an observed decrease in k(lim)/K(0.5) due to protonation of the group. In contrast to tPA, the k(lim) and K(0.5) for the reactions of uPA with NBD P9 PAI-1 or its complex with the monoclonal antibody were independent of pH in the 6.5-8.5 range. Since slightly acidic pH is a feature of a number of malignant tumors, alterations in PAI-1/tPA kinetics could play a role in the cancerogenesis. Changes in the protonation state of His(188), which is placed closely to the S1 site and is unique for tPA, has been proposed to contribute to the observed pH dependences of k(lim) and K(0.5). PMID:15033993

  14. The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer.

    PubMed

    Şakalar, Çağrı; İzgi, Kenan; İskender, Banu; Sezen, Sedat; Aksu, Huriye; Çakır, Mustafa; Kurt, Büşra; Turan, Ali; Canatan, Halit

    2016-04-01

    Thymoquinone (TQ) is the active ingredient of Nigella sativa which has a therapeutic potential in cancer therapy and prevention. In this study, TQ has been shown to induce specific cytotoxicity and apoptosis and to inhibit wound healing in triple-negative breast cancer cell line. TQ also inhibited cancer growth in a mouse tumor model. Moreover, TQ and paclitaxel (Pac) combination inhibited cancer growth in cell culture and in mice. Genes involved in TQ and TQ-Pac-mediated cytotoxicity were studied using focused real-time PCR arrays. After bioinformatic analysis, genes in apoptosis, cytokine, and p53 signaling categories were found to be modulated with a high significance in TQ-treated cells (p < 10(-28), p < 10(-8), and p < 10(-6), respectively). Important to note, TQ has been found to regulate the genes involved in the induction of apoptosis through death receptors (p = 5.5 × 10(-5)). Additionally, tumor suppressor genes such as p21, Brca1, and Hic1 were highly upregulated by TQ and TQ-Pac combination. Interestingly, when cells were treated with high dose TQ, several growth factors such as Vegf and Egf were upregulated and several pro-apoptotic factors such as caspases were downregulated possibly pointing out key pathways manipulated by cancer cells to resist against TQ. In cells treated with the combination of TQ and Pac, genes in apoptosis cascade (p < 10(-12)), p53 signaling (p = 10(-5)), and JAK-STAT signaling (p < 10(-3)) were differentially expressed. TQ has also been shown to induce protein levels of cleaved Caspase-3, Caspase-7, and Caspase-12 and PARP and to reduce phosphorylated p65 and Akt1. The in vivo therapeutic potential of TQ-Pac combination and the genetic network involved in this synergy have been shown for the first time to the best of our knowledge. PMID:26500095

  15. Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

    PubMed Central

    Salomé, Christophe; Salomé-Grosjean, Elise; Stables, James P.; Kohn, Harold

    2010-01-01

    Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3″-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases. PMID:20394379

  16. Biochemical characterization of a novel thermophilic α-galactosidase from Talaromyces leycettanus JCM12802 with significant transglycosylation activity.

    PubMed

    Wang, Caihong; Wang, Huimin; Ma, Rui; Shi, Pengjun; Niu, Canfang; Luo, Huiying; Yang, Peilong; Yao, Bin

    2016-01-01

    Thermophilic α-galactosidases have great potentials in biotechnological and medicinal applications due to their high-temperature activity and specific stability. In this study, a novel α-galactosidase gene of glycoside hydrolase family 27 (aga27A) was cloned from Talaromyces leycettanus JCM12802 and successfully expressed in Pichia pastoris GS115. Purified recombinant Aga27A (rAga27A) was thermophilic and thermotolerant, exhibiting the maximum activity at 70°C and retaining stability at 65°C. Like most fungal α-galactosidases, rAga27A had an acidic pH optimum (pH 4.0) but retained stability over a boarder pH range (pH 3.0-11.0) at 70°C. Moreover, the enzyme exhibited strong resistance to most metal ions and chemicals tested (except for Ag(+) and SDS) and great tolerance to galactose (19 mM). The preferable transglycosylation capacity of rAga27A with various substrates further widens its application spectrum. Thus rAga27A with excellent enzymatic properties will be ideal for applications in various industries, especially for the synthesis of galactooligosaccharides. PMID:26087712

  17. Valued Life Activity Disability Played a Significant Role in Self-Rated Health among Adults with Chronic Health Conditions

    PubMed Central

    Katz, Patricia; Morris, Anne; Gregorich, Steve; Yazdany, Jinoos; Eisner, Mark; Yelin, Edward; Blanc, Paul

    2009-01-01

    Objective Because self-rated health (SRH) is strongly associated with health outcomes, it is important to identify factors that individuals take into account when they assess their health. We examined the role of valued life activities (VLAs), the wide range of activities deemed to be important to individuals, in SRH assessments. Study Design and Setting Data were from 3 cohort studies of individuals with different chronic conditions – rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and chronic obstructive pulmonary disease (COPD). Each cohort’s data were collected through structured telephone interviews. Logistic regression analyses identified factors associated with ratings of fair/poor SRH. All analyses included sociodemographic characteristics, general and disease-specific health-related factors, and general measures of physical functioning. Results Substantial portions of each group rated their health as fair/poor (RA 37%, SLE 47%, COPD 40%). In each group, VLA disability was strongly associated with fair/poor health (RA: OR=4.44 [1.86,10.62]; SLE: OR=3.60 [2.10,6.16]; COPD: OR=2.76 [1.30,5.85], even after accounting for covariates. Conclusion VLA disability appears to play a substantial role in individual perceptions of health, over and above other measures of health status, disease symptoms, and general physical functioning. PMID:18722089

  18. Stress Sensitive Healthy Females Show Less Left Amygdala Activation in Response to Withdrawal-Related Visual Stimuli under Passive Viewing Conditions

    ERIC Educational Resources Information Center

    Baeken, Chris; Van Schuerbeek, Peter; De Raedt, Rudi; Vanderhasselt, Marie-Anne; De Mey, Johan; Bossuyt, Axel; Luypaert, Robert

    2012-01-01

    The amygdalae are key players in the processing of a variety of emotional stimuli. Especially aversive visual stimuli have been reported to attract attention and activate the amygdalae. However, as it has been argued that passively viewing withdrawal-related images could attenuate instead of activate amygdalae neuronal responses, its role under…

  19. A 'Propagating' Active Across-Arc Normal Fault Shows Rupture Process of the Basement: the Case of the Southwestern Ryukyu Arc

    NASA Astrophysics Data System (ADS)

    Matsumoto, T.; Shinjo, R.; Nakamura, M.; Kubo, A.; Doi, A.; Tamanaha, S.

    2011-12-01

    Ryukyu Arc is located on the southwestern extension of Japanese Island-arc towards the east of Taiwan Island along the margin of the Asian continent off China. The island-arc forms an arcuate trench-arc-backarc system. A NW-ward subduction of the Philippine Sea Plate (PSP)at a rate of 6-8 cm/y relative to the Eurasian Plate (EP) causes frequent earthquakes. The PSP is subducting almost normally in the north-central area and more obliquely around the southwestern area. Behind the arc-trench system, the Okinawa Trough (OT) was formed by back-arc rifting, where active hydrothermal vent systems have been discovered. Several across-arc submarine faults are located in the central and southern Ryukyu Arc. The East Ishigaki Fault (EIF) is one of the across-arc normal faults located in the southwestern Ryukyu Arc, ranging by 44km and extending from SE to NW. This fault was surveyed by SEABAT8160 multibeam echo sounder and by ROV Hyper-Dolphin in 2005 and 2008. The result shows that the main fault consists of five fault segments. A branched segment from the main fault was also observed. The southernmost segment is most mature (oldest but still active) and the northernmost one is most nascent. This suggests the north-westward propagation of the fault rupture corresponding to the rifting of the southwestern OT and the southward retreat of the arc-trench system. Considering that the fault is segmented and in some part branched, propagation might take place episodically rather than continuously from SE to NW. The ROV survey also revealed the rupture process of the limestone basement along this fault from the nascent stage to the mature stage. Most of the rock samples collected from the basement outcrop were limestone blocks (or calcareous sedimentary rocks). Limestone basement was observed to the west on the hanging wall far away from the main fault scarp. Then fine-grained sand with ripple marks was observed towards the main scarp. Limestone basement was observed on the main

  20. Phylogenetic and experimental characterization of an acyl-ACP thioesterase family reveals significant diversity in enzymatic specificity and activity

    PubMed Central

    2011-01-01

    Background Acyl-acyl carrier protein thioesterases (acyl-ACP TEs) catalyze the hydrolysis of the thioester bond that links the acyl chain to the sulfhydryl group of the phosphopantetheine prosthetic group of ACP. This reaction terminates acyl chain elongation of fatty acid biosynthesis, and in plant seeds it is the biochemical determinant of the fatty acid compositions of storage lipids. Results To explore acyl-ACP TE diversity and to identify novel acyl ACP-TEs, 31 acyl-ACP TEs from wide-ranging phylogenetic sources were characterized to ascertain their in vivo activities and substrate specificities. These acyl-ACP TEs were chosen by two different approaches: 1) 24 TEs were selected from public databases on the basis of phylogenetic analysis and fatty acid profile knowledge of their source organisms; and 2) seven TEs were molecularly cloned from oil palm (Elaeis guineensis), coconut (Cocos nucifera) and Cuphea viscosissima, organisms that produce medium-chain and short-chain fatty acids in their seeds. The in vivo substrate specificities of the acyl-ACP TEs were determined in E. coli. Based on their specificities, these enzymes were clustered into three classes: 1) Class I acyl-ACP TEs act primarily on 14- and 16-carbon acyl-ACP substrates; 2) Class II acyl-ACP TEs have broad substrate specificities, with major activities toward 8- and 14-carbon acyl-ACP substrates; and 3) Class III acyl-ACP TEs act predominantly on 8-carbon acyl-ACPs. Several novel acyl-ACP TEs act on short-chain and unsaturated acyl-ACP or 3-ketoacyl-ACP substrates, indicating the diversity of enzymatic specificity in this enzyme family. Conclusion These acyl-ACP TEs can potentially be used to diversify the fatty acid biosynthesis pathway to produce novel fatty acids. PMID:21831316

  1. Pyruvate dehydrogenase complex of ascites tumour. Activation by AMP and other properties of potential significance in metabolic regulation.

    PubMed Central

    Lazo, P A; Sols, A

    1980-01-01

    1. AMP is an activator of the pyruvate dehydrogenase complex of the Ehrlich--Lettré ascites tumour, increasing its V up to 2-fold, with Ka of 40 microM at pH 7.4. This activation appears to be an allosteric effect on the decarboxylase subunit of the complex. 2. The pyruvate dehydrogenase complex has a Km for pyruvate within the range 17--36 microM depending on the pH, the optimum pH being approx. 7.4, with a V of approx. 0.1 unit/g of cells. The rate-limiting step is dependent on the transformation of the enzyme--substrate complex. The Km for CoA is 15 microM. The Km for NAD+ is 0.7 mM for both the complex and the lipoamide dehydrogenase. The complex is inhibited by acetyl-CoA competitively with CoA; the Ki is 60 microM. The lipoamide dehydrogenase is inhibited by NADH and NADPH competitively with NAD+, with Ki values of 80 and 90 microM respectively. In the reverse reaction the Km values for NADH and NADPH are essentially equal to their Ki values for the forward reaction, the V for the latter being 0.09 of that of the former. Hence the reaction rate of the complex in vivo is likely to be markedly affected by feedback isosteric inhibition by reduced nicotinamide nucleotides and possibly acetyl-CoA. PMID:7193456

  2. 55P0110, a Novel Synthetic Compound Developed from a Plant Derived Backbone Structure, Shows Promising Anti-Hyperglycaemic Activity in Mice.

    PubMed

    Brunmair, Barbara; Lehner, Zsuzsanna; Stadlbauer, Karin; Adorjan, Immanuel; Frobel, Klaus; Scherer, Thomas; Luger, Anton; Bauer, Leonhardt; Fürnsinn, Clemens

    2015-01-01

    Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0 ± 1.2 vs. 10.1 ± 1.1; diabetic mice with 180 mg/kg 55P0110, 23.1 ± 0.9 vs. 11.1 ± 1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49 ± 0.27; 55P0110, 2.99 ± 0.35; gliclazide, 8.97 ± 0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53 ± 0.41; 55P0110, 3.80 ± 0.46; gliclazide, 3.99 ± 0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of

  3. 55P0110, a Novel Synthetic Compound Developed from a Plant Derived Backbone Structure, Shows Promising Anti-Hyperglycaemic Activity in Mice

    PubMed Central

    Brunmair, Barbara; Lehner, Zsuzsanna; Stadlbauer, Karin; Adorjan, Immanuel; Frobel, Klaus; Scherer, Thomas; Luger, Anton; Bauer, Leonhardt; Fürnsinn, Clemens

    2015-01-01

    Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0±1.2 vs. 10.1±1.1; diabetic mice with 180 mg/kg 55P0110, 23.1±0.9 vs. 11.1±1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49±0.27; 55P0110, 2.99±0.35; gliclazide, 8.97±0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53±0.41; 55P0110, 3.80±0.46; gliclazide, 3.99±0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic

  4. Powerful Complex Immunoadjuvant Based on Synergistic Effect of Combined TLR4 and NOD2 Activation Significantly Enhances Magnitude of Humoral and Cellular Adaptive Immune Responses

    PubMed Central

    Dzharullaeva, Alina S.; Tukhvatulina, Natalia M.; Shcheblyakov, Dmitry V.; Shmarov, Maxim M.; Dolzhikova, Inna V.; Stanhope-Baker, Patricia; Naroditsky, Boris S.; Gudkov, Andrei V.; Logunov, Denis Y.; Gintsburg, Alexander L.

    2016-01-01

    Binding of pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs) activates innate immune responses and contributes to development of adaptive immunity. Simultaneous stimulation of different types of PRRs can have synergistic immunostimulatory effects resulting in enhanced production of molecules that mediate innate immunity such as inflammatory cytokines, antimicrobial peptides, etc. Here, we evaluated the impact of combined stimulation of PRRs from different families on adaptive immunity by generating alum-based vaccine formulations with ovalbumin as a model antigen and the Toll-like receptor 4 (TLR4) agonist MPLA and the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist MDP adsorbed individually or together on the alum-ovalbumin particles. Multiple in vitro and in vivo readouts of immune system activation all showed that while individual PRR agonists increased the immunogenicity of vaccines compared to alum alone, the combination of both PRR agonists was significantly more effective. Combined stimulation of TLR4 and NOD2 results in a stronger and broader transcriptional response in THP-1 cells compared to individual PRR stimulation. Immunostimulatory composition containing both PRR agonists (MPLA and MDP) in the context of the alum-based ovalbumin vaccine also enhanced uptake of vaccine particles by bone marrow derived dendritic cells (BMDCs) and promoted maturation (up-regulation of expression of CD80, CD86, MHCII) and activation (production of cytokines) of BMDCs. Finally, immunization of mice with vaccine particles containing both PRR agonists resulted in enhanced cellular immunity as indicated by increased proliferation and activation (IFN-γ production) of splenic CD4+ and CD8+ T cells following in vitro restimulation with ovalbumin and enhanced humoral immunity as indicated by higher titers of ovalbumin-specific IgG antibodies. These results indicate that combined stimulation of TLR4 and NOD2

  5. Further observations of the lambda 10830 He line in stars and their significance as a measure of stellar activity

    NASA Technical Reports Server (NTRS)

    Zirin, H.

    1975-01-01

    Measurements of the lambda 1030 He line in 198 stars are given along with data on other features in that spectral range. Nearly 80% of all G and K stars show some lambda 10830; of these, half are variable and 1/4 show emission. It was confirmed that lambda 10830 is not found in M stars, is weak in F stars, and is particularly strong in close binaries. The line is found in emission in extremely late M and S stars, along with P gamma, but P gamma is not in emission in G and K stars with lambda 10830 emissions. Variable He emission and Ti I emission are found in the RV Tauri variables R Scuti and U Mon. In R Aqr the Fe XIII coronal line lambda 10747 and a line at lambda 11012 which may be singlet He or La II are found, as well as lambda 10830 and P gamma. The nature of coronas or hot chromospheres in the various stars is discussed. It was concluded that the lambda 10830 intensity must be more or less proportional to the energy deposited in the chromosphere corona by non-thermal processes.

  6. Systems biology defines the biological significance of redox-active proteins during cellulose degradation in an aerobic bacterium.

    PubMed

    Gardner, Jeffrey G; Crouch, Lucy; Labourel, Aurore; Forsberg, Zarah; Bukhman, Yury V; Vaaje-Kolstad, Gustav; Gilbert, Harry J; Keating, David H

    2014-10-01

    Microbial depolymerization of plant cell walls contributes to global carbon balance and is a critical component of renewable energy. The genomes of lignocellulose degrading microorganisms encode diverse classes of carbohydrate modifying enzymes, although currently there is a paucity of knowledge on the role of these proteins in vivo. We report the comprehensive analysis of the cellulose degradation system in the saprophytic bacterium Cellvibrio japonicus. Gene expression profiling of C. japonicus demonstrated that three of the 12 predicted β-1,4 endoglucanases (cel5A, cel5B, and cel45A) and the sole predicted cellobiohydrolase (cel6A) showed elevated expression during growth on cellulose. Targeted gene disruptions of all 13 predicted cellulase genes showed that only cel5B and cel6A were required for optimal growth on cellulose. Our analysis also identified three additional genes required for cellulose degradation: lpmo10B encodes a lytic polysaccharide monooxygenase (LPMO), while cbp2D and cbp2E encode proteins containing carbohydrate binding modules and predicted cytochrome domains for electron transfer. CjLPMO10B oxidized cellulose and Cbp2D demonstrated spectral properties consistent with redox function. Collectively, this report provides insight into the biological role of LPMOs and redox proteins in cellulose utilization and suggests that C. japonicus utilizes a combination of hydrolytic and oxidative cleavage mechanisms to degrade cellulose. PMID:25294408

  7. Lipid droplets in activated mast cells - a significant source of triglyceride-derived arachidonic acid for eicosanoid production.

    PubMed

    Dichlberger, Andrea; Schlager, Stefanie; Kovanen, Petri T; Schneider, Wolfgang J

    2016-08-15

    Mast cells are potent effectors of immune reactions and key players in various inflammatory diseases such as atherosclerosis, asthma, and rheumatoid arthritis. The cellular defense response of mast cells represents a unique and powerful system, where external signals can trigger cell activation resulting in a stimulus-specific and highly coordinated release of a plethora of bioactive mediators. The arsenal of mediators encompasses preformed molecules stored in cytoplasmic secretory granules, as well as newly synthesized proteinaceous and lipid mediators. The release of mediators occurs in strict chronological order and requires proper coordination between the endomembrane system and various enzymatic machineries. For the generation of lipid mediators, cytoplasmic lipid droplets have been shown to function as a major intracellular pool of arachidonic acid, the precursor for eicosanoid biosynthesis. Recent studies have revealed that not only phospholipids in mast cell membranes, but also triglycerides in mast cell lipid droplets are a substrate source for eicosanoid formation. The present review summarizes current knowledge about mast cell lipid droplet biology, and discusses expansions and challenges of traditional mechanistic models for eicosanoid production. PMID:26164793

  8. 4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity

    PubMed Central

    Opsenica, Igor M.; Tot, Mikloš; Gomba, Laura; Nuss, Jonathan E.; Sciotti, Richard J.; Bavari, Sina; Burnett, James C.; Šolaja, Bogdan A.

    2013-01-01

    Structurally simplified analogs of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and non-toxic. Twelve, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45-12.11 nM against five Plasmodium falciparum (P.f.) strains: W2, D6, C235, C2A, C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. Twelve, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules. PMID:23815186

  9. Positive Control Mutations in the MyoD Basic Region Fail to Show Cooperative DNA Binding and Transcriptional Activation in vitro

    NASA Astrophysics Data System (ADS)

    Bengal, Eyal; Flores, Osvaldo; Rangarajan, Pundi N.; Chen, Amy; Weintraub, Harold; Verma, Inder M.

    1994-06-01

    An in vitro transcription system from HeLa cells has been established in which MyoD and E47 proteins activate transcription both as homodimers and heterodimers. However, heterodimers activate transcription more efficiently than homodimers, and function synergistically from multiple binding sites. Positive control mutants in the basic region of MyoD that have previously been shown to be defective in initiating the myogenic program, can bind DNA but have lost their ability to function as transcriptional activators in vitro. Additionally, positive control mutants, unlike wild-type MyoD, fail to bind cooperatively to DNA. We propose that binding of MyoD complexes to high affinity MyoD binding sites induces conformational changes that facilitate cooperative binding to multiple sites and promote transcriptional activation.

  10. Ethanolic extracts of Tinospora cordifolia and Alstonia scholaris show antimicrobial activity towards clinical isolates of methicillin-resistant and carbapenemase-producing bacteria.

    PubMed

    Bonvicini, Francesca; Mandrone, Manuela; Antognoni, Fabiana; Poli, Ferruccio; Gentilomi, Giovanna Angela

    2014-01-01

    The aim of this study was to determine the in vitro antimicrobial activity of crude extracts of three plants from Ayurveda tradition (Tinospora cordifolia, Alstonia scholaris, Crataeva nurvala) against reference microbial strains and clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenemase-producing Klebsiella pneumoniae. IC50 values were obtained by micro-dilution methods meeting the requirements of the NCCLS standard. The cytotoxicity of the extracts was also investigated on a mammalian cell line. Extracts displayed a variable degree of antimicrobial activity and did not interfere with mammalian cell proliferation. T. cordifolia and A. scholaris exhibited a higher inhibitory activity against clinical isolates of MRSA and carbapenemase-producing K. pneumoniae compared with reference strains, while C. nurvala exhibited a different behaviour. An antifungal activity towards Candida albicans was observed for A. scholaris extract. Results indicate that constituents from T. cordifolia and A. scholaris may be a potential source of new therapeutic strategies for infectious diseases. PMID:24749692

  11. [Carbon dioxide inhibits the generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in biology and medicine].

    PubMed

    Boljevic, S; Kogan, A H; Gracev, S V; Jelisejeva, S V; Daniljak, I G

    1996-01-01

    Carbon dioxide (CO2) influence in generation of active oxygen forms (AOF) in human mononuclear cells (blood phagocytes and alveolar macrophages) and animal cells (tissue phagocytes, parenchymal and interstitial cells of liver, kidney, lung, brain and stomach) was investigated. The AOF generation was examined by the methods of chemiluminiscence (CL) using luminol, lucigenin and NBT (nitro blue tetrazolium) reaction. It was established that CO2 in concentrations similar to those in blood (5.1%, pCO2 37.5 mmHg) and at high concentrations (8.2%, pCO2 60 mmHg; 20%, pCO2 146 mmHg) showed pronounced inhibitory effect on the AOF generation in all the studied cells (usually reducing it 2 to 4 times). Those results were obtained not only after the direct contact of isolated cells with CO2, but also after the whole body exposure to CO2. Besides, it was established that venous blood gas mixture (CO2 - 45 mmHg, +O2 - 39 mmHg, + N2 - 646 mmHg) inhibited the AOF generation in cited cells more than the arterial blood gas mixture (CO2 - 40 mmHg, + O2 - 95 mmHg, + N2 - 595 mmHg). Carbon dioxide action mechanism was developed partially through the inhibition of the OAF generation in mitochondria and through deceleration of NADPH oxidative activity. Finally, it was established that CO2 led to the better coordination of oxidation and phosphorylation and increased the phosphorylation velocity in liver mitochondria. The results clearly confirmed the general property of CO2 to inhibit significantly the AOF generation in all the cell types. This favors the new explanation of the well-known evolutionary paradox: the Earth life and organisms preservation when the oxygen, that shows toxic effects on the cells through the AOF, occurs in the atmosphere. The results can also be used to explain in a new way the vasodilating effect of CO2 and the favorable hypercapnotherapy influence on the course of some bronchial asthma forms. The results are probably significant for the analysis of important

  12. Parents' dietary patterns are significantly correlated: findings from the Melbourne Infant Feeding Activity and Nutrition Trial Program.

    PubMed

    Lioret, Sandrine; McNaughton, Sarah A; Crawford, David; Spence, Alison C; Hesketh, Kylie; Campbell, Karen J

    2012-08-01

    The objectives of the present study were to identify dietary patterns independently in first-time mothers and fathers, and to examine whether these patterns were correlated within families. Dietary intakes were collected at baseline in the Melbourne Infant Feeding Activity and Nutrition Trial Program using a validated FFQ in 454 pairs of first-time mothers and fathers. Education level was reported in associated questionnaires. Principal components analyses included frequencies of fifty-five food groups and were performed independently in mothers and fathers. Spearman's correlation coefficients were used to assess associations between dietary pattern scores. A total of four dietary patterns were identified in mothers and fathers. Of these, three dietary patterns had similar characteristics between these two populations, namely 'Fruits and vegetables', 'High-energy snack and processed foods', 'High-fat foods' in mothers; and 'Fruits', 'High-energy snack and processed foods', 'High-fat foods' in fathers. The following two additional patterns were identified: 'Cereals and sweet foods' in mothers and 'Potatoes and vegetables' in fathers. Patterns incorporating healthier food items were found to be positively associated with parent education. An inverse association with education was found for the 'High-fat foods' and 'High-energy snack and processed foods' dietary patterns. Qualitatively similar patterns between corresponding mothers and fathers were the most strongly correlated (ρ = 0·34-0·45, P < 0·001). There were some differences in dietary patterns between mothers and fathers, suggesting that it is worth deriving patterns separately when considering couples, and more generally between men and women. Exploring how these various patterns correlate within households provides important insights to guide the development and implementation of family-based interventions. PMID:22040598

  13. Evaluation of Techniques to Detect Significant Network Performance Problems using End-to-End Active Network Measurements

    SciTech Connect

    Cottrell, R.Les; Logg, Connie; Chhaparia, Mahesh; Grigoriev, Maxim; Haro, Felipe; Nazir, Fawad; Sandford, Mark

    2006-01-25

    End-to-End fault and performance problems detection in wide area production networks is becoming increasingly hard as the complexity of the paths, the diversity of the performance, and dependency on the network increase. Several monitoring infrastructures are built to monitor different network metrics and collect monitoring information from thousands of hosts around the globe. Typically there are hundreds to thousands of time-series plots of network metrics which need to be looked at to identify network performance problems or anomalous variations in the traffic. Furthermore, most commercial products rely on a comparison with user configured static thresholds and often require access to SNMP-MIB information, to which a typical end-user does not usually have access. In our paper we propose new techniques to detect network performance problems proactively in close to realtime and we do not rely on static thresholds and SNMP-MIB information. We describe and compare the use of several different algorithms that we have implemented to detect persistent network problems using anomalous variations analysis in real end-to-end Internet performance measurements. We also provide methods and/or guidance for how to set the user settable parameters. The measurements are based on active probes running on 40 production network paths with bottlenecks varying from 0.5Mbits/s to 1000Mbit/s. For well behaved data (no missed measurements and no very large outliers) with small seasonal changes most algorithms identify similar events. We compare the algorithms' robustness with respect to false positives and missed events especially when there are large seasonal effects in the data. Our proposed techniques cover a wide variety of network paths and traffic patterns. We also discuss the applicability of the algorithms in terms of their intuitiveness, their speed of execution as implemented, and areas of applicability. Our encouraging results compare and evaluate the accuracy of our detection

  14. Allosteric mutants show that PrfA activation is dispensable for vacuole escape but required for efficient spread and Listeria survival in vivo

    PubMed Central

    Deshayes, Caroline; Bielecka, Magdalena K; Cain, Robert J; Scortti, Mariela; de las Heras, Aitor; Pietras, Zbigniew; Luisi, Ben F; Núñez Miguel, Ricardo; Vázquez-Boland, José A

    2012-01-01

    The transcriptional regulator PrfA controls key virulence determinants of the facultative intracellular pathogen Listeria monocytogenes. PrfA-dependent gene expression is strongly induced within host cells. While the basis of this activation is unknown, the structural homology of PrfA with the cAMP receptor protein (Crp) and the finding of constitutively activated PrfA* mutants suggests it may involve ligand-induced allostery. Here, we report the identification of a solvent-accessible cavity within the PrfA N-terminal domain that may accommodate an activating ligand. The pocket occupies a similar position to the cAMP binding site in Crp but lacks the cyclic nucleotide-anchoring motif and has its entrance on the opposite side of the β-barrel. Site-directed mutations in this pocket impaired intracellular PrfA-dependent gene activation without causing extensive structural/functional alterations to PrfA. Two substitutions, L48F and Y63W, almost completely abolished intracellular virulence gene induction and thus displayed the expected phenotype for allosteric activation-deficient PrfA mutations. Neither PrfAallo substitution affected vacuole escape and initial intracellular growth of L. monocytogenes in epithelial cells and macrophages but caused defective cell-to-cell spread and strong attenuation in mice. Our data support the hypothesis that PrfA is allosterically activated during intracellular infection and identify the probable binding site for the effector ligand. They also indicate that PrfA allosteric activation is not required for early intracellular survival but is essential for full Listeria virulence and colonization of host tissues. PMID:22646689

  15. Addition of an N-terminal epitope tag significantly increases the activity of plant fatty acid desaturases expressed in yeast cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Saccharomyces cerevisiae shows great potential for development of bioreactor systems geared towards the production of high-value lipids such as polyunsaturated omega-3 fatty acids, the yields of which are largely dependent on the activity of ectopically-expressed enzymes. Here we show that the addit...

  16. Supplementation with Sodium Selenite and Selenium-Enriched Microalgae Biomass Show Varying Effects on Blood Enzymes Activities, Antioxidant Response, and Accumulation in Common Barbel (Barbus barbus)

    PubMed Central

    Kouba, Antonín; Velíšek, Josef; Stará, Alžběta; Masojídek, Jiří; Kozák, Pavel

    2014-01-01

    Yearling common barbel (Barbus barbus L.) were fed four purified casein-based diets for 6 weeks in outdoor cages. Besides control diet, these were supplemented with 0.3 mg kg−1 dw selenium (Se) from sodium selenite, or 0.3 and 1.0 mg kg−1 from Se-enriched microalgae biomass (Chlorella), a previously untested Se source for fish. Fish mortality, growth, Se accumulation in muscle and liver, and activity of selected enzymes in blood plasma, muscle, liver, and intestine were evaluated. There was no mortality, and no differences in fish growth, among groups. Se concentrations in muscle and liver, activity of alanine aminotransferase and creatine kinase in blood plasma, glutathione reductase (GR) in muscle, and GR and catalase in muscle and liver suggested that selenium from Se-enriched Chlorella is more readily accumulated and biologically active while being less toxic than sodium selenite. PMID:24772422

  17. Supplementation with sodium selenite and selenium-enriched microalgae biomass show varying effects on blood enzymes activities, antioxidant response, and accumulation in common barbel (Barbus barbus).

    PubMed

    Kouba, Antonín; Velíšek, Josef; Stará, Alžběta; Masojídek, Jiří; Kozák, Pavel

    2014-01-01

    Yearling common barbel (Barbus barbus L.) were fed four purified casein-based diets for 6 weeks in outdoor cages. Besides control diet, these were supplemented with 0.3 mg kg(-1) dw selenium (Se) from sodium selenite, or 0.3 and 1.0 mg kg(-1) from Se-enriched microalgae biomass (Chlorella), a previously untested Se source for fish. Fish mortality, growth, Se accumulation in muscle and liver, and activity of selected enzymes in blood plasma, muscle, liver, and intestine were evaluated. There was no mortality, and no differences in fish growth, among groups. Se concentrations in muscle and liver, activity of alanine aminotransferase and creatine kinase in blood plasma, glutathione reductase (GR) in muscle, and GR and catalase in muscle and liver suggested that selenium from Se-enriched Chlorella is more readily accumulated and biologically active while being less toxic than sodium selenite. PMID:24772422

  18. Maps showing mines, quarries, oil and gas activity, and sample localities in and near the Sipsey Wilderness and additions, Lawrence and Winston counties, Alabama

    USGS Publications Warehouse

    Mory, Peter C.; Behum, Paul T.; Ross, Robert B., Jr.

    1982-01-01

    No mining activities are being conducted in the study area at present.  Previous mining has been limited to small-scale production of limestone and coal.  Two oil and gas test holes have been drilled inside the study area.

  19. Nanocomposites of tantalum-based pyrochlore and indium hydroxide showing high and stable photocatalytic activities for overall water splitting and carbon dioxide reduction.

    PubMed

    Hsieh, Meng-Chun; Wu, Guan-Chang; Liu, Wei-Guang; Goddard, William A; Yang, Chia-Min

    2014-12-15

    Nanocomposites of tantalum-based pyrochlore nanoparticles and indium hydroxide were prepared by a hydrothermal process for UV-driven photocatalytic reactions including overall water splitting, hydrogen production from photoreforming of methanol, and CO2 reduction with water to produce CO. The best catalyst was more than 20 times more active than sodium tantalate in overall water splitting and 3 times more active than Degussa P25 TiO2 in CO2 reduction. Moreover, the catalyst was very stable while generating stoichiometric products of H2 (or CO) and O2 throughout long-term photocatalytic reactions. After the removal of In(OH)3, the pyrochlore nanoparticles remained highly active for H2 production from pure water and aqueous methanol solution. Both experimental studies and density functional theory calculations suggest that the pyrochlore nanoparticles catalyzed the water reduction to produce H2, whereas In(OH)3 was the major active component for water oxidation to produce O2. PMID:25384922

  20. Fibrous Papule of the Face, Similar to Tuberous Sclerosis Complex-Associated Angiofibroma, Shows Activation of the Mammalian Target of Rapamycin Pathway: Evidence for a Novel Therapeutic Strategy?

    PubMed Central

    Chan, Jung-Yi Lisa; Wang, Kuo-Hsien; Fang, Chia-Lang; Chen, Wei-Yu

    2014-01-01

    Fibrous papules of the face are hamartomas characterized by stellate-shaped stromal cells, multinucleated giant cells, and proliferative blood vessels in the dermis. The pathogenesis of fibrous papules remains unclear. There is a striking microscopic resemblance between fibrous papules and tuberous sclerosis complex (TSC)-associated angiofibromas. A germline mutation of the TSC1 or TSC2 gene, leading to activation of the mammalian target of rapamycin (mTOR) pathway, accounts for the pathogenesis of TSC-associated angiofibromas. Activated mTOR subsequently activates p70 ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (S6) by phosphorylation. Rapamycin, a mTOR inhibitor, is effective in treating TSC-associated angiofibromas. The aim of this study was to understand whether the mTOR pathway is activated in fibrous papules. We studied immunoexpressions of phosphorylated (p-) mTOR effectors in fibrous papules, TSC-associated angiofibromas, and normal skin controls. P-mTOR, p-p70S6K and p-S6 were highly expressed in dermal stromal cells and epidermal keratinocytes in fibrous papules and TSC-associated angiofibromas but not in fibroblasts and epidermal keratinocytes of normal skin controls (p<0.001). The results suggest topical rapamycin may be a novel treatment option for fibrous papules. PMID:24558502

  1. Maps showing mines, quarries, oil and gas activity, and sample localities in and near the Sipsey Wilderness and additions, Lawrence and Winston Counties, Alabama

    SciTech Connect

    Mory, P.C.; Behum, P.T.; Ross, R.B. Jr.

    1982-01-01

    This report presents the results of a mineral survey of the Sipsey Wilderness and additions, William B. Bankhead National Forest, Lawrence and Winston Counties, Alabama. The survey includes: limestone quarrying, coal mining, and oil and gas activity. 7 references, 5 figures, 2 tables.

  2. Lycorine, the Main Phenanthridine Amaryllidaceae Alkaloid, Exhibits Significant Anti-Tumor Activity in Cancer Cells that Display Resistance to Proapoptotic Stimuli: an Investigation of Structure-Activity Relationship and Mechanistic Insight

    PubMed Central

    Lamoral-Theys, Delphine; Andolfi, Anna; Van Goietsenoven, Gwendoline; Cimmino, Alessio; Le Calvé, Benjamin; Wauthoz, Nathalie; Mégalizzi, Véronique; Gras, Thierry; Bruyère, Céline; Dubois, Jacques; Mathieu, Véronique; Kornienko, Alexander; Kiss, Robert; Evidente, Antonio

    2011-01-01

    Twenty-two lycorine-related compounds were investigated for in vitro anti-tumor activity using four cancer cell lines displaying different levels of resistance to pro-apoptotic stimuli and two cancer cell lines sensitive to pro-apoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro anti-tumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at non-toxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to pro-apoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, metastatic cancers, among others. PMID:19788245

  3. Significant 99mTc-MDP but Unimpressive 18F-NaF Gastric Activity in a Patient With Multiple Myeloma.

    PubMed

    Zhang, Shumao; Chen, Yue; Huang, Zhanwen; Cai, Liang; Zhang, Yin

    2016-09-01

    A 69-year-old man with a history of low back pain for more than 4 months underwent Tc-MDP bone scan to determine the cause of the symptoms. In addition to the osseous lesions, significant activity in the stomach wall was noted. However, a subsequent F-NaF PET/CT only revealed bone lesion without increased activity in the stomach wall. The cause of the back pain was eventually confirmed due to multiple myeloma. PMID:27504809