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Sample records for factor iiib generates

  1. Transcription factor IIIB generates extended DNA interactions in RNA polymerase III transcription complexes on tRNA genes.

    PubMed Central

    Kassavetis, G A; Riggs, D L; Negri, R; Nguyen, L H; Geiduschek, E P

    1989-01-01

    Transcription complexes that assemble on tRNA genes in a crude Saccharomyces cerevisiae cell extract extend over the entire transcription unit and approximately 40 base pairs of contiguous 5'-flanking DNA. We show here that the interaction with 5'-flanking DNA is due to a protein that copurifies with transcription factor TFIIIB through several steps of purification and shares characteristic properties that are normally ascribed to TFIIIB: dependence on prior binding of TFIIIC and great stability once the TFIIIC-TFIIIB-DNA complex is formed. SUP4 gene (tRNATyr) DNA that was cut within the 5'-flanking sequence (either 31 or 28 base pairs upstream of the transcriptional start site) was no longer able to stably incorporate TFIIIB into a transcription complex. The TFIIIB-dependent 5'-flanking DNA protein interaction was predominantly not sequence specific. The extension of the transcription complex into this DNA segment does suggest two possible explanations for highly diverse effects of flanking-sequence substitutions on tRNA gene transcription: either (i) proteins that are capable of binding to these upstream DNA segments are also potentially capable of stimulating or interfering with the incorporation of TFIIIB into transcription complexes or (ii) 5'-flanking sequence influences the rate of assembly of TFIIIB into stable transcription complexes. Images PMID:2668737

  2. Crystal structure of a transcription factor IIIB core interface ternary complex.

    PubMed

    Juo, Z Sean; Kassavetis, George A; Wang, Jimin; Geiduschek, E Peter; Sigler, Paul B

    2003-04-01

    Transcription factor IIIB (TFIIIB), consisting of the TATA-binding protein (TBP), TFIIB-related factor (Brf1) and Bdp1, is a central component in basal and regulated transcription by RNA polymerase III. TFIIIB recruits its polymerase to the promoter and subsequently has an essential role in the formation of the open initiation complex. The amino-terminal half of Brf1 shares a high degree of sequence similarity with the polymerase II general transcription factor TFIIB, but it is the carboxy-terminal half of Brf1 that contributes most of its binding affinity with TBP. The principal anchoring region is located between residues 435 and 545 of yeast Brf1, comprising its homology domain II. The same region also provides the primary interface for assembling Bdp1 into the TFIIIB complex. We report here a 2.95 A resolution crystal structure of the ternary complex containing Brf1 homology domain II, the conserved region of TBP and 19 base pairs of U6 promoter DNA. The structure reveals the core interface for assembly of TFIIIB and demonstrates how the loosely packed Brf1 domain achieves remarkable binding specificity with the convex and lateral surfaces of TBP. PMID:12660736

  3. The expression of keratinocyte growth factor receptor (FGFR2-IIIb) correlates with the high proliferative rate of HaCaT keratinocytes.

    PubMed

    Nagy, Nikoletta; Bata-Csörgo, Zsuzsanna; Kopasz, Norbert; Szeg, Csilla; Pivarcsi, Andor; Koreck, Andrea; Dobozy, Attila; Kemény, Lajos; Széll, Márta

    2006-08-01

    Keratinocyte growth factor receptor (KGFR = FGFR2-IIIb) is a tyrosine kinase receptor expressed by keratinocytes, which mediates the effects of fibroblast growth factors (FGF). There are contradictory data in the literature regarding the role of FGFR2-IIIb during the proliferation/differentiation programme of keratinocytes. In this study, we aimed to investigate whether overexpression of FGFR2-IIIb may have a role in the regulation of keratinocyte proliferation. We analysed the expression of FGFR2-IIIb in an in vitro HaCaT model system representing different stages of proliferation and differentiation of keratinocytes. Real-time RT-PCR and Western blot analyses demonstrated a correlation between FGFR2-IIIb mRNA and protein expression and the proportion of cells in S/G2/M phase in synchronized HaCaT keratinocytes and thus with proliferation activity (r = 0.96). After treatment with the antipsoriatic drug, dithranol, FGFR2-IIIb is downregulated dose dependently both at mRNA and protein levels. Moreover, when the rate of proliferation is decreased by the lack of cell attachment to the culturing surface, FGFR2-IIIb mRNA (P = 0.0315) and protein expressions were also reduced (P = 0.0242), while a differentiation marker, keratin 10, mRNA (P = 0.0003) and protein levels (P = 0.001) were increased (r = -0.92). Based on our results we conclude that FGFR2-IIIb expression in HaCaT keratinocytes corresponds with the proliferative activation of the cells and is not related to the differentiation programme. PMID:16842598

  4. The role of transcription initiation factor IIIB subunits in promoter opening probed by photochemical cross-linking.

    PubMed

    Kassavetis, George A; Han, Shulin; Naji, Souad; Geiduschek, E Peter

    2003-05-16

    The core transcription initiation factor (TF) IIIB recruits its conjugate RNA polymerase (pol) III to the promoter and also plays an essential role in promoter opening. TFIIIB assembled with certain deletion mutants of its Brf1 and Bdp1 subunits is competent in pol III recruitment, but the resulting preinitiation complex does not open the promoter. Whether Brf1 and Bdp1 participate in opening the promoter by direct DNA interaction (as sigma subunits of bacterial RNA polymerases do) or indirectly by their action on pol III has been approached by site-specific photochemical protein-DNA cross-linking of TFIIIB-pol III-U6 RNA gene promoter complexes. Brf1, Bdp1, and several pol III subunits can be cross-linked to the nontranscribed strand of the U6 promoter at base pair -9/-8 and +2/+3 (relative to the transcriptional start as +1), respectively the upstream and downstream ends of the DNA segment that opens up into the transcription bubble. Cross-linking of Bdp1 and Brf1 is detected at 0 degrees C in closed preinitiation complexes and at 30 degrees C in complexes that are partly open, but also it is detected in mutant TFIIIB-pol III-DNA complexes that are unable to open the promoter. In contrast, promoter opening-defective TFIIIB mutants generate significant changes of cross-linking of polymerase subunits. The weight of this evidence argues in favor of an indirect mode of action of TFIIIB in promoter opening. PMID:12637540

  5. Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts

    PubMed Central

    Kan, Shih-hsin; Troitskaya, Larisa A.; Sinow, Carolyn S.; Haitz, Karyn; Todd, Amanda K.; Di Stefano, Ariana; Le, Steven Q.; Dickson, Patricia I.; Tippin, Brigette L.

    2014-01-01

    Enzyme replacement therapy for mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo B syndrome) has been hindered by inadequate mannose 6-phosphorylation and cellular uptake of recombinantly produced human α-N-acetyl-glucosamindase (rhNAGLU). We expressed and characterized a modified, recombinant human NAGLU fused to the receptor binding motif of insulin-like growth factor-II (rhNAGLU-IGF-II) to enhance its ability to enter cells using the cation-independent mannose 6-phosphate receptor, which is also the receptor for IGF-II (at a different binding site). RhNAGLU-IGF-II was stably expressed in Chinese hamster ovary cells, secreted and purified to apparent homogeneity. The Km and pH optimum of the fusion enzyme was similar to those reported for rhNAGLU. Both intracellular uptake and confocal microscopy suggested MPS IIIB fibroblasts readily take up the fusion enzyme via receptor-mediated endocytosis that was significantly inhibited (p<0.001) by monomeric IGF-II peptide. Glycosaminoglycan storage was reduced by 60% (p<0.001) to near background levels in MPS IIIB cells after treatment with rhNAGLU-IGF-II, with half-maximal correction at concentrations of 3–12 pM. Similar cellular uptake mechanism via the IGF-II receptor was also demonstrated in two different brain tumor-derived cell lines. Fusion of NAGLU to IGF-II enhanced its cellular uptake while maintaining enzymatic activity, supporting its potential as a therapeutic candidate for MPS IIIB. PMID:24266751

  6. Cervical Cancer Stage IIIB

    MedlinePlus

    ... Cancer Stage IIIB Description: Stage IIIB cervical cancer; drawing shows cancer in the cervix, the vagina, and ... that connect the kidneys to the bladder). The drawing shows the ureter on the right blocked by ...

  7. Mutational analysis of the transcription factor IIIB-DNA target of Ty3 retroelement integration.

    PubMed

    Yieh, Lynn; Hatzis, Heather; Kassavetis, George; Sandmeyer, Suzanne B

    2002-07-19

    The Ty3 retrovirus-like element inserts preferentially at the transcription initiation sites of genes transcribed by RNA polymerase III. The requirements for transcription factor (TF) IIIC and TFIIIB in Ty3 integration into the two initiation sites of the U6 gene carried on pU6LboxB were previously examined. Ty3 integrates at low but detectable frequencies in the presence of TFIIIB subunits Brf1 and TATA-binding protein. Integration increases in the presence of the third subunit, Bdp1. TFIIIC is not essential, but the presence of TFIIIC specifies an orientation of TFIIIB for transcriptional initiation and directs integration to the U6 gene-proximal initiation site. In the current study, recombinant wild type TATA-binding protein, wild type and mutant Brf1, and Bdp1 proteins and highly purified TFIIIC were used to investigate the roles of specific protein domains in Ty3 integration. The amino-terminal half of Brf1, which contains a TFIIB-like repeat, contributed more strongly than the carboxyl-terminal half of Brf1 to Ty3 targeting. Each half of Bdp1 split at amino acid 352 enhanced integration. In the presence of TFIIIB and TFIIIC, the pattern of integration extended downstream by several base pairs compared with the pattern observed in vitro in the absence of TFIIIC and in vivo, suggesting that TFIIIC may not be present on genes targeted by Ty3 in vivo. Mutations in Bdp1 that affect its interaction with TFIIIC resulted in TFIIIC-independent patterns of Ty3 integration. Brf1 zinc ribbon and Bdp1 internal deletion mutants that are competent for polymerase III recruitment but defective in promoter opening were competent for Ty3 integration irrespective of the state of DNA supercoiling. These results extend the similarities between the TFIIIB domains required for transcription and Ty3 integration and also reveal requirements that are specific to transcription. PMID:11994300

  8. Reconfiguring the connectivity of a multiprotein complex: fusions of yeast TATA-binding protein with Brf1, and the function of transcription factor IIIB.

    PubMed

    Kassavetis, George A; Soragni, Elisabetta; Driscoll, Robert; Geiduschek, E Peter

    2005-10-25

    Transcription factor (TF) IIIB, the central transcription initiation factor of RNA polymerase III (pol III), is composed of three subunits, Bdp1, Brf1 and TATA-binding protein (TBP), all essential for normal function in vivo and in vitro. Brf1 is a modular protein: Its N-proximal half is related to TFIIB and binds similarly to the C-terminal stirrup of TBP; its C-proximal one-third provides most of the affinity for TBP by binding along the entire length of the convex surface and N-terminal lateral face of TBP. A structure-informed triple fusion protein, with TBP core placed between the N- and C-proximal domains of Brf1, has been constructed. The Brf1-TBP triple fusion protein effectively replaces both Brf1 and TBP in TFIIIC-dependent and -independent transcription in vitro, and forms extremely stable TFIIIB-DNA complexes that are indistinguishable from wild-type TFIIIB-DNA complexes by chemical nuclease footprinting. Unlike Brf1 and TBP, the triple fusion protein is able to recruit pol III for TATA box-directed transcription of linear and supercoiled DNA in the absence of Bdp1. The Brf1-TBP triple fusion protein also effectively replaces Brf1 function in vivo as the intact protein, creating a TBP paralogue in yeast that is privatized for pol III transcription. PMID:16227432

  9. IIIB or not IIIB: a previously unanswered question.

    PubMed

    Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Mammen, Pradeep P A; Markham, David W; Drazner, Mark H

    2012-05-01

    The term New York Heart Association (NYHA) class IIIB has been used increasingly in clinical medicine, including as an inclusion criteria for many clinical trials assessing left ventricular assist devices (LVADs). Indeed, NYHA class IIIB is incorporated in the Food and Drug Administration's approved indication for the Heartmate II. However, on review of the medical literature, we found that there is no consensus definition of NYHA class IIIB. Until the ambiguity is resolved, we suggest that this designation not be used in clinical practice or by investigators leading clinical trials assessing therapies which convey substantial risk to patients and therefore require clarity in describing the enrolled patient population. With ongoing improvements in LVADs, this therapy will increasingly be considered in patients less sick than those who require inotropic support, providing urgency to establish a consensus system of classifying such patients who nevertheless fall within the spectrum of advanced heart failure. Herein we propose a modification of the standard NYHA classification system which can be used to fill this void. PMID:22555265

  10. Mucopolysaccharidosis type IIIB (MPS IIIB) masquerading as a behavioural disorder

    PubMed Central

    Brady, Jacqueline; Trehan, Aditi; Landis, Dennis; Toro, Camilo

    2013-01-01

    Inborn errors of metabolism (IEMs) that manifest primarily as psychiatric and behavioural symptoms in childhood are often mistaken for idiopathic primary psychiatric disorders. The pathophysiological basis of these symptoms may be overlooked until later in the disease course when neurological deficits become dominant; this results in a significant delay in establishing a proper diagnosis. To illustrate this, we describe two siblings who presented with behavioural issues and mild learning disabilities in childhood, and were consequently given multiple psychiatric diagnoses. In early adulthood, however, they manifested a rapid cognitive decline. Subsequent cranial MRI imaging revealed progressive brain iron accumulation in deep brain nuclei. Whole exome sequencing and biochemical investigation confirmed the diagnosis of mucopolysaccharidosis type IIIB. Their long diagnostic odyssey illustrates the importance of considering IEMs when assessing individuals with behavioural abnormalities and cognitive impairment. PMID:23661660

  11. Mucopolysaccharidosis type IIIB (MPS IIIB) masquerading as a behavioural disorder.

    PubMed

    Brady, Jacqueline; Trehan, Aditi; Landis, Dennis; Toro, Camilo

    2013-01-01

    Inborn errors of metabolism (IEMs) that manifest primarily as psychiatric and behavioural symptoms in childhood are often mistaken for idiopathic primary psychiatric disorders. The pathophysiological basis of these symptoms may be overlooked until later in the disease course when neurological deficits become dominant; this results in a significant delay in establishing a proper diagnosis. To illustrate this, we describe two siblings who presented with behavioural issues and mild learning disabilities in childhood, and were consequently given multiple psychiatric diagnoses. In early adulthood, however, they manifested a rapid cognitive decline. Subsequent cranial MRI imaging revealed progressive brain iron accumulation in deep brain nuclei. Whole exome sequencing and biochemical investigation confirmed the diagnosis of mucopolysaccharidosis type IIIB. Their long diagnostic odyssey illustrates the importance of considering IEMs when assessing individuals with behavioural abnormalities and cognitive impairment. PMID:23661660

  12. Classification of Epidermal Growth Factor Receptor Gene Mutation Status Using Serum Proteomic Profiling Predicts Tumor Response in Patients with Stage IIIB or IV Non-Small-Cell Lung Cancer

    PubMed Central

    Yang, Lin; Tang, Chuanhao; Xu, Bin; Wang, Weixia; Li, Jianjie; Li, Xiaoyan; Qin, Haifeng; Gao, Hongjun; He, Kun; Song, Santai; Liu, Xiaoqing

    2015-01-01

    Objectives Epidermal growth factor receptor (EGFR) gene mutations in tumors predict tumor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). However, obtaining tumor tissue for mutation analysis is challenging. Here, we aimed to detect serum peptides/proteins associated with EGFR gene mutation status, and test whether a classification algorithm based on serum proteomic profiling could be developed to analyze EGFR gene mutation status to aid therapeutic decision-making. Patients and Methods Serum collected from 223 stage IIIB or IV NSCLC patients with known EGFR gene mutation status in their tumors prior to therapy was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Differences in serum peptides/proteins between patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes were detected in a training group of 100 patients; based on this analysis, a serum proteomic classification algorithm was developed to classify EGFR gene mutation status and tested in an independent validation group of 123 patients. The correlation between EGFR gene mutation status, as identified with the serum proteomic classifier and response to EGFR-TKIs was analyzed. Results Nine peptide/protein peaks were significantly different between NSCLC patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes in the training group. A genetic algorithm model consisting of five peptides/proteins (m/z 4092.4, 4585.05, 1365.1, 4643.49 and 4438.43) was developed from the training group to separate patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes. The classifier exhibited a sensitivity of 84.6% and a specificity of 77.5% in the validation group. In the 81 patients from the validation group treated with EGFR-TKIs, 28 (59.6%) of 47 patients whose matched samples were labeled as “mutant” by the classifier and 3 (8.8%) of 34 patients

  13. Chemical vapor deposition of group IIIB metals

    DOEpatents

    Erbil, A.

    1989-11-21

    Coatings of Group IIIB metals and compounds thereof are formed by chemical vapor deposition, in which a heat decomposable organometallic compound of the formula given in the patent where M is a Group IIIB metal, such as lanthanum or yttrium and R is a lower alkyl or alkenyl radical containing from 2 to about 6 carbon atoms, with a heated substrate which is above the decomposition temperature of the organometallic compound. The pure metal is obtained when the compound of the formula 1 is the sole heat decomposable compound present and deposition is carried out under nonoxidizing conditions. Intermetallic compounds such as lanthanum telluride can be deposited from a lanthanum compound of formula 1 and a heat decomposable tellurium compound under nonoxidizing conditions.

  14. Chemical vapor deposition of group IIIB metals

    DOEpatents

    Erbil, Ahmet

    1989-01-01

    Coatings of Group IIIB metals and compounds thereof are formed by chemical vapor deposition, in which a heat decomposable organometallic compound of the formula (I) ##STR1## where M is a Group IIIB metal, such as lanthanum or yttrium and R is a lower alkyl or alkenyl radical containing from 2 to about 6 carbon atoms, with a heated substrate which is above the decomposition temperature of the organometallic compound. The pure metal is obtained when the compound of the formula I is the sole heat decomposable compound present and deposition is carried out under nonoxidizing conditions. Intermetallic compounds such as lanthanum telluride can be deposited from a lanthanum compound of formula I and a heat decomposable tellurium compound under nonoxidizing conditions.

  15. GCP II inhibition rescues neurons from gp120IIIB-induced neurotoxicity.

    PubMed

    Thomas, Ajit G; Bodner, Amos; Ghadge, Ghanashyam; Roos, Raymond P; Slusher, Barbara S

    2009-09-01

    Excessive glutamate neurotransmission has been implicated in neuronal injury in many disorders of the central nervous system (CNS), including human immunodeficiency virus (HIV)-associated dementia. Gp120IIIB is a strain of a HIV glycoprotein with specificity for the CXCR4 receptor that induces neuronal apoptosis in in vitro models of acquired immunodeficiency syndrome (AIDS)-induced neurodegeneration. Since the catabolism of the neuropeptide N-acetylaspartylglutamate (NAAG) by glutamate carboxypeptidase (GCP) II increases cellular glutamate, an event associated with excitotoxicity, we hypothesized that inhibition of GCP II may prevent gp120IIIB-induced cell death. Furthermore, through GCP II inhibition, increased NAAG may be neuroprotective via its agonist effects at the mGlu(3) receptor. To ascertain the therapeutic potential of GCP II inhibitors, embryonic day 17 hippocampal cultures were exposed to gp120IIIB in the presence of a potent and highly selective GCP II inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). 2-PMPA was found to abrogate gp120IIIB-induced toxicity in a dose-dependent manner. Additionally, 2-PMPA was neuroprotective when applied up to 2 h after the application of gp120IIIB. The abrogation of apoptosis by 2-PMPA was reversed with administration of mGlu(3) receptor antagonists and with antibodies to transforming growth factor (TGF)-beta. Further, consistent with the localization of GCP II, 2-PMPA failed to provide neuroprotection in the absence of glia. GCP II activity and its inhibition by 2-PMPA were confirmed in the hippocampal cultures using radiolabeled NAAG and high-performance liquid chromatography (HPLC) analysis. Taken together, these data suggest that GCP II is involved in mediating gp120-induced apoptosis in hippocampal neurons and GCP II inhibitors may have potential in the treatment of neuronal injury related to AIDS. PMID:19995130

  16. Dental Findings and Management in a Mucopolysaccharidosis Type IIIB Patient.

    PubMed

    Mellara, Talitha de Siqueira; Azevedo, Danielle Torres; Faria, Gisele; Nelson Filho, Paulo; Queiroz, Alexandra Mussolino de; Brentegani, Luiz Guilherme

    2012-01-01

    Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme a-N-acetylglucosaminidase. Affected subjects present developmental delay, attention deficit disorder, uncontrollable hyperactivity, and aggressive behavior, followed by progressive dementia and death in late adolescence. The purpose of this paper is to report the dental findings and treatment in a child with MPS IIIB. His primary molars and permanent mandibular incisors presented obliterated pulp chambers and root canals, which may be a clinical manifestation of this disorder. PMID:23433622

  17. The neurobehavioral phenotype in mucopolysaccharidosis Type IIIB: An exploratory study

    PubMed Central

    Shapiro, E.; King, K.; Ahmed, A.; Rudser, K.; Rumsey, R.; Yund, B.; Delaney, K.; Nestrasil, I.; Whitley, C.; Potegal, M.

    2016-01-01

    Objectives Our goal was to describe the neurobehavioral phenotype in mucopolysaccharidosis Type IIIB (MPS IIIB). Parents report that behavioral abnormalities are a major problem in MPS III posing serious challenges to parenting and quality-of-life for both patient and parent. Our previous research on MPS IIIA identified autistic symptoms, and a Klüver-Bucy-type syndrome as indicated by reduced startle and loss of fear associated with amygdala atrophy. We hypothesized that MPS IIIB would manifest similar attributes when assessed with the same neurobehavioral protocol. Methods Ten patients with MPS IIIB were compared with 9 MPS IIIA patients, all older than 6. 8 younger children with Hurler syndrome (1H) were chosen as a comparison group for the Risk Room procedure; MPS IH does not directly affect social/emotional function and these younger children were closer to the developmental level of the MPS IIIB group. To examine disease severity, cognitive ability was assessed. Four evaluations were used: the Risk Room procedure (to measure social-emotional characteristics, especially fear and startle responses), the Autism Diagnostic Observation Schedule (ADOS), the Sanfilippo Behavior Rating Scale (SBRS), and amygdala brain volumes calculated from manually-traced MRI images. Results The two groups are equivalent in severity and show severe cognitive impairment. On the ADOS, the MPS IIIB patients exhibited the same autistic features as IIIA. The IIIB means differed from MPS IH means on most measures. However, the IIIB group did not approach the Risk Room stranger, like the MPS IH group who kept their distance, but unlike the IIIA group who showed no fear of the stranger. On the SBRS, the MPS IIIB patients were described as more inattentive and more fearful, especially of new people than the MPS IIIA. Onsets of some disease characteristics appeared more closely spaced and slightly earlier in MPS IIIB than IIIA. Conclusions On most behavioral measures, MPS IIIB patients did

  18. Persistence Factors of First-Generation Learners

    ERIC Educational Resources Information Center

    Braswell, Tawanda M.

    2010-01-01

    This dissertation utilized a qualitative narrative case study method to explore the unknown factors and elements of perseverance in spite of adversity and crisis. The study documented the lives of five African American women in order to describe, understand, and explain the central research question of how and why some first-generation learners…

  19. Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB

    PubMed Central

    Kan, Shih-hsin; Aoyagi-Scharber, Mika; Le, Steven Q.; Vincelette, Jon; Ohmi, Kazuhiro; Bullens, Sherry; Wendt, Daniel J.; Christianson, Terri M.; Tiger, Pascale M. N.; Brown, Jillian R.; Lawrence, Roger; Yip, Bryan K.; Holtzinger, John; Bagri, Anil; Crippen-Harmon, Danielle; Vondrak, Kristen N.; Chen, Zhi; Hague, Chuck M.; Woloszynek, Josh C.; Cheung, Diana S.; Webster, Katherine A.; Adintori, Evan G.; Lo, Melanie J.; Wong, Wesley; Fitzpatrick, Paul A.; LeBowitz, Jonathan H.; Crawford, Brett E.; Bunting, Stuart; Dickson, Patricia I.; Neufeld, Elizabeth F.

    2014-01-01

    Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α–N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood–brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood–brain barrier, the fusion protein (“enzyme”) in artificial cerebrospinal fluid (“vehicle”) was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1–28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB. PMID:25267636

  20. Novel mutation detection of fibroblast growth factor receptor 1 (FGFR1) gene, FGFR2IIIa, FGFR2IIIb, FGFR2IIIc, FGFR3, FGFR4 gene for craniosynostosis: A prospective study in Asian Indian patient

    PubMed Central

    Barik, Mayadhar; Bajpai, Minu; Malhotra, Arun; Samantaray, Jyotish Chandra; Dwivedi, Sadananda; Das, Sambhunath

    2015-01-01

    Background: Craniosynostosis (CS) syndrome is an autosomal dominant condition classically combining craniosynostosis and non-syndromic craniosynostosis with digital anomalies of the hands and feet. The majority of cases are caused by heterozygous mutations in the third immunoglobulin-like domain (IgIII) of FGFR2, whilst a larger number of cases can be attributed to mutations outside this region of the protein. Aims: To find out the FGFR1, FGFR2, FGFR3 and FGFR4 gene in craniosynostosis syndrome. Settings and Design: A hospital based prospective study. Materials and Methods: Prospective analysis of clinical records of patients registered in CS clinic from December 2007 to January 2015 was done in patients between 4 months to 13 years of age. We have performed genetic findings in a three generation Indian family with Craniosynostosis syndrome. Results: We report for the first time the clinical and genetic findings in a three generation Indian family with Craniosynostosis syndrome caused by a heterozygous missense mutation, Thr 392 Thr and ser 311 try, located in the IgII domain of FGFR2. FGFR 3 and 4 gene basis syndrome was eponymously named. Genetic analysis demonstrated that 51/56 families to be unrelated. In FGFR3 gene 10/TM location of 1172 the nucleotide changes C>A, Ala 391 Glu 19/56 and Exon-19, 5q35.2 at conserved linker region the changes occurred pro 246 Arg in 25/56 families. Conclusions: Independent genetic origins, but phenotypic similarities in the 51 families add to the evidence supporting the theory of selfish spermatogonial selective advantage for this rare gain-of-function FGFR2 mutation. PMID:26557159

  1. Genetic relationships among Italian and Mexican maize-rhizosphere Burkholderia cepacia complex (BCC) populations belonging to Burkholderia cenocepacia IIIB and BCC6 group

    PubMed Central

    2011-01-01

    Background A close association between maize roots and Burkholderia cepacia complex (BCC) bacteria has been observed in different locations globally. In this study we investigated by MultiLocus Restriction Typing (MLRT) the genetic diversity and relationships among Burkholderia cenocepacia IIIB and BCC6 populations associated with roots of maize plants cultivated in geographically distant countries (Italy and Mexico), in order to provide new insights into their population structure, evolution and ecology. Results The 31 B. cenocepacia IIIB and 65 BCC6 isolates gave rise to 29 and 39 different restriction types (RTs), respectively. Two pairs of isolates of B. cenocepacia IIIB and BCC6, recovered from both Italian and Mexican maize rhizospheres, were found to share the same RT. The eBURST (Based Upon Related Sequence Types) analysis of MLRT data grouped all the B. cenocepacia IIIB isolates into four clonal complexes, with the RT-4-complex including the 42% of them, while the majority of the BCC6 isolates (94%) were grouped into the RT-104-complex. These two main clonal complexes included RTs shared by both Italian and Mexican maize rhizospheres and a clear relationship between grouping and maize variety was also found. Grouping established by eBURST correlated well with the assessment using unweighted-pair group method with arithmetic mean (UPGMA). The standardized index of association values obtained in both B. cenocepacia IIIB and BCC6 suggests an epidemic population structure in which occasional clones emerge and spread. Conclusions Taken together our data demonstrate a wide dispersal of certain B. cenocepacia IIIB and BCC6 isolates in Mexican and Italian maize rhizospheres. Despite the clear relationship found between the geographic origin of isolates and grouping, identical RTs and closely related isolates were observed in geographically distant regions. Ecological factors and selective pressure may preferably promote some genotypes within each local microbial

  2. Role for Surgical Resection in the Multi-Disciplinary Treatment of Stage IIIB Non-Small Cell Lung Cancer

    PubMed Central

    Bott, Matthew J.; Patel, Aalok P.; Crabtree, Traves D.; Morgensztern, Daniel; Robinson, Cliff G.; Colditz, Graham A.; Waqar, Saiama; Kreisel, Daniel; Krupnick, A. Sasha; Patterson, G. Alexander; Broderick, Stephen; Meyers, Bryan F.; Puri, Varun

    2015-01-01

    Background The role of multi-modality therapy in stage IIIB NSCLC remains inadequately studied. Although chemoradiation is currently the mainstay of treatment, randomized trials evaluating surgery are lacking and resection is offered selectively. Methods Data of clinical stage IIIB NSCLC patients (T4N2 or any N3) undergoing definitive multimodality therapy were obtained from the National Cancer Database (NCDB). Multivariable Cox regression models were fitted to evaluate variables influencing overall survival (OS). Results From 1998-2010, 7,459 clinical stage IIIB NSCLC patients were treated with definitive chemoradiation (CR group), while 1,714 patients underwent chemotherapy, radiation, and surgery in any sequence (CRS group). CRS patients were more likely to be younger, Caucasian, and have slightly smaller tumors (all p < 0.01). There was no difference in Charlson Comorbidity Index (CCI) between the groups (p = 0.5). In the CRS group, 79% of patients received neoadjuvant therapy. Thirty-day surgical mortality was 3%. Factors associated with improved OS in multivariate analysis included younger age, female gender, decreased CCI, smaller tumor size, and surgical resection (HR 0.57, 95% CI 0.52-0.63). Among patients treated with surgery, incomplete resection was associated with decreased OS (HR 1.52, 95% CI 1.20-1.92). Median OS was longer in CRS patients (25.9 months vs. 16.3 months, p<0.001). Propensity matched analysis on 631 patient-pairs treated with CRS vs. CR confirmed these findings (median OS = 28.9 vs. 17.2 months, p<0.001). Conclusions Surgical resection as a part of multimodality therapy may be associated with improved overall survival in highly selected patients with stage IIIB NSCLC. Multidisciplinary evaluation of these patients is critical. PMID:25912748

  3. Membrane-permeabilizing activities of Bacillus thuringiensis coleopteran-active toxin CryIIIB2 and CryIIIB2 domain I peptide.

    PubMed Central

    Von Tersch, M A; Slatin, S L; Kulesza, C A; English, L H

    1994-01-01

    Bacillus thuringiensis toxin CryIIIB2 exhibits activity against two agriculturally important pests, the Colorado potato beetle, Leptinotarsa decemlineata, and the Southern corn rootworm, Diabrotica undecimpunctata. CryIIIB2 shows significant structural similarity to Colorado potato beetle-active toxin CryIIIA, whose crystal structure has been determined elsewhere [J. Li, J. Carrol, and D. J. Ellar, Nature (London) 353:815-821, 1991]. A clone limited to the putative 7-alpha-helical bundle domain I peptide of CryIIIB2 was constructed by PCR. The truncated protein was expressed at high levels in Escherichia coli. Domain I peptide was isolated and compared with native CryIIIB2 toxin in promoting ion efflux from synthetic phospholipid vesicles and formation of ion channels in black lipid membranes. The results showed that CryIIIB2 domain I peptide is sufficient for ion channel formation and promotes ion efflux. Both native CryIIIB2 toxin and domain I peptide were inefficient channel-forming proteins that produced noisy ion channels of various conductance states. In ion efflux assays, native toxin promoted greater ion efflux from synthetic vesicles than did the truncated peptide. Images PMID:7527203

  4. [Tolerance of riluzole in a phase IIIb clinical trial].

    PubMed

    Lacomblez, L; Dib, M; Doppler, V; Faudet, A; Robin, V; Salachas, F; Bensimon, G; Meininger, V

    2002-01-01

    Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile. PMID:12090150

  5. Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer

    ClinicalTrials.gov

    2014-08-04

    Adenocarcinoma of the Lung; Bronchoalveolar Cell Lung Cancer; Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  6. Combined type IIIB with bilateral type I thyroplasty for pitch lowering with maintenance of vocal fold tension

    PubMed Central

    Hoffman, Matthew R.; Devine, Erin E.; Remacle, Marc; Ford, Charles N.; Wadium, Elizabeth; Jiang, Jack J.

    2013-01-01

    Objective To evaluate type IIIB thyroplasty using the excised larynx bench apparatus and determine how altering vocal fold contour by performing bilateral medialization of the inferior vocal fold affects phonation. This procedure could be performed in patients for whom pitch lowering is desirable, such as female-to-male transsexuals or male patients with mutational falsetto in whom intensive voice therapy was insufficient. Methods Aerodynamic, acoustic, and high-speed videokymographic data were collected for nine larynges at three subglottal pressure inputs for each of three conditions: normal; type IIIB thyroplasty; and combined type IIIB with modified bilateral type I thyroplasty intended to create a more rectangular glottal configuration. Each larynx served as its own control. Results Phonation threshold flow (p=0.005), phonation threshold power (p=0.031), and airflow varied across conditions with highest values for type IIIB thyroplasty and lowest for the combined procedure. Fundamental frequency was significantly different (p<0.001), decreasing by approximately 100 Hz from control to type IIIB trials, and then by approximately 15 Hz from IIIB to combined procedure trials. Vibratory amplitudes and intrafold phase difference were highest for type IIIB trials. Conclusions Addition of bilateral inferior medialization to type IIIB thyroplasty provided some further decrease in frequency, but mostly served to increase tension, reduce airflow, and produce a vibratory pattern which more closely mirrored control trials. Exploration of this combined procedure in patients may be warranted if not completely satisfied with the results from type IIIB thyroplasty alone. PMID:24241252

  7. Calculation of atmospheric transmittance by IBM 3033 computer code LOWTRAN IIIB

    NASA Astrophysics Data System (ADS)

    Shin, M. S.

    1983-06-01

    LOWTRAN IIIB is a FORTRAN computer program for prediction of atmospheric optical transmittance, developed at the U.S. Air Force Geophysics Laboratory (AFGL). The LOWTRAN IIIB was received in the modified form developed by naval weapons center China Lake for use on the UNIVAC 1110 computer, and has now been interfaced to the IBM 3033 computer. Due to complier storage limitation in the IBM computer, the atmospheric data are read into common storage at the beginning of the program. The two dimensional block data submodule has been replaced with a linear data array, and a new subroutine (array) written to reformat the data. The basic logic structure is unchanged. Comparisons of NPS LOWTRAN IIIB computations with direct optical extinctions measurement over Monterey Bay and at San Nicolas Island indicate that under these circumstances LOWTRAN IIIB underestimates the extinction due to aerosols while the computed molecular absorption is in substantial agreement with experiment. LOWTRAN IIIB is presently available as a method of predicting atmospheric transmittance at low resolutions at NPS and is suitable for incorporation in simulations and studies of electrooptic weapon/sensor systems performance.

  8. Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

    PubMed Central

    Valstar, Marlies J.; Bruggenwirth, Hennie T.; Olmer, Renske; Wevers, Ron A.; Verheijen, Frans W.; Poorthuis, Ben J.; Halley, Dicky J.

    2010-01-01

    Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetyl-α-D-glucosaminidase (NAGLU). Information on the natural course of MPS IIIB is scarce but much needed in view of emerging therapies. To improve knowledge on the natural course, data on all 52 MPS IIIB patients ever identified by enzymatic studies in the Netherlands were gathered. Clinical data on 44 patients could be retrieved. Only a small number (n = 9; 21%) presented with a classical MPS III phenotype; all other patients showed a much more attenuated course of the disease characterized by a significantly slower regression of intellectual and motor abilities. The majority of patients lived well into adulthood. First signs of the disease, usually mild developmental delay, were observed at a median age of 4 years. Subsequently, patients showed a slowing and eventually a stagnation of development. Patients with the attenuated phenotype had a stable intellectual disability for many years. Molecular analysis was performed in 24 index patients. The missense changes p.R643C, p.S612G, p.E634K, and p.L497V were exclusively found in patients with the attenuated phenotype. MPS IIIB comprises a remarkably wide spectrum of disease severity, and an unselected cohort including all Dutch patients showed a large proportion (79%) with an attenuated phenotype. MPS IIIB must be considered in patients with a developmental delay, even in the absence of a progressive decline in intellectual abilities. A key feature, necessitating metabolic studies, is the coexistence of behavioral problems. PMID:20852935

  9. Factors Influencing the Readability of Student-Generated Texts.

    ERIC Educational Resources Information Center

    Allen, JoBeth

    An investigation examined student-generated texts in terms of both traditional and more theoretically valid readability to determine what factors influence comprehension when children read their own, peer, and adult-written texts. Seventy dictated stories created in an earlier study, along with 4 first-grade level stories from the "Reader's Digest…

  10. RADGEN: A radiation exchange factor generator for rod bundles

    SciTech Connect

    Rector, D.R.

    1987-10-01

    The RADGEN computer program has been developed at Pacific Northwest Laboratory (PNL) to generate input required for the thermal radiation models used in the COBRA-SFS (Spent Fuel Storage) computer program. The COBRA-SFS program uses radiation exchange factors to describe the net amount of energy transferred from each surface to every other surface in an enclosure. The RADGEN program generates radiation exchange factors for arrays of rods on a square or triangular pitch as well as open channel geometries. This report describes the input requirements for the RADGEN code, which may be executed in a batch or interactive mode, and outlines the solution procedure used to obtain the exchange factors. 4 refs., 25 figs., 13 tabs.

  11. SIMILARITIES BETWEEN PROTEIN IIIA AND PROTEIN IIIB, TWO PROMINENT SYNAPTIC VESICLE-ASSOCIATED PHOSPHOPROTEINS (JOURNAL VERSION)

    EPA Science Inventory

    Protein IIIa (Mr 74,000) and protein IIIb (Mr 55,000) are two major phosphoproteins found in mammalian brain. It was previously shown in intact nerve cells that the phosphorylation state of these two proteins could be increased by electrical stimulation, by depolarizing agents in...

  12. Isolated Limb Perfusion With Melphalan in Treating Patients With Stage IIIB-IV Melanoma or Sarcoma

    ClinicalTrials.gov

    2015-07-22

    Basal Cell Carcinoma of the Skin; Eccrine Carcinoma of the Skin; Recurrent Adult Soft Tissue Sarcoma; Recurrent Melanoma; Recurrent Skin Cancer; Squamous Cell Carcinoma of the Skin; Stage III Adult Soft Tissue Sarcoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Melanoma

  13. Selected Findings from Phase III-B. BTES. Beginning Teacher Evaluation Study. Supplement. Preliminary Version.

    ERIC Educational Resources Information Center

    Fisher, Charles W.; And Others

    This series of six papers concerning the Beginning Teacher Evaluation Study (BTES) starts with Teaching Behaviors, Academic Learning Time and Student Achievement: An Overview of Phase III-B of the Beginning Teacher Evaluation Study by the project director, Charles Fisher. As an introduction, it describes a model of classroom instruction based on…

  14. Interaction of sugarbeet host resistance and Rhizoctonia solani AG-2-2 IIIB strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Rhizoctonia root rot caused by Rhizoctonia solani can cause serious economic losses in sugarbeet fields. Preliminary evidence suggests there could be interactions between different strains and resistance sources. Thus, field studies were conducted to determine if nine R. solani AG-2-2 IIIB str...

  15. Results of a conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy, and external and interstitial irradiation in 98 patients with locally advanced breast cancer (IIIA-IIIB)

    SciTech Connect

    Jacquillat, C.; Baillet, F.; Weil, M.; Auclerc, G.; Housset, M.; Auclerc, M.; Sellami, M.; Jindani, A.; Thill, L.; Soubrane, C.

    1988-05-15

    Ninety-eight patients with locally advanced breast cancer (Stage IIIA-IIIB) were entered into a pilot study combining intensive induction (neoadjuvant) chemotherapy (VTMFAP) with or without hormonochemotherapy, external and interstitial radiotherapy, and consolidation chemotherapy with or without hormonochemotherapy. Tumor regression over 50% was observed in 91% patients after chemotherapy, and complete clinical remission occurred in 100% patients after irradiation. The rate of local relapse is 13%. The 3-year disease-free survival is 62% and 3-year global survival is 77%. Initial chemotherapeutic tumor regression greater than 75% is the main predictive factor for disease-free survival.

  16. Heparin coating of tantalum coronary stents reduces surface thrombin generation but not factor IXa generation.

    PubMed

    Blezer, R; Cahalan, L; Cahalan, P T; Lindhout, T

    1998-07-01

    In the present study we used an in-vitro technique to examine initiation and propagation of blood coagulation at the surface of tantalum coronary stents exposed to flowing platelet-rich and platelet-free plasma. The time course of factor IXa production at the surface of the stent was not influenced by platelets. In spite of a significant factor IXa production, no thrombin activity was detected when the tantalum stent was exposed to platelet-free plasma; only when the stent was exposed to platelet-rich plasma was extensive thrombin production observed. These findings indicate that tantalum triggers blood coagulation, but that (adherent) platelets are essential for thrombin generation. Heparin-coated tantalum stents exposed to flowing platelet-rich plasma showed that factor IXa generation was slightly reduced compared with the bare stent. However, the heparin coating drastically delayed the onset of thrombin generation and largely reduced the steady-state production of thrombin. We found a clear relationship between the antithrombin binding capacity and the antithrombogenic potential of the heparin-coated stents. The mode of action of immobilized heparin is thought to abrogate thrombin generation by inhibiting thrombin-dependent positive feedback reactions at the surface of the coronary stent. PMID:9712292

  17. Global factors generate the McCollough effect.

    PubMed

    Dodwell, P C; O'Shea, R P

    1987-01-01

    It has recently been demonstrated that certain globally orthogonal pattern pairs derived from Hoffman's Lie Transformation Group Model of Neuropsychology (LTG/NP) are sufficient to generate McCollough effects (pattern-contingent colour aftereffects: PCCAES). We now provide evidence that the global factors postulated to generate these particular PCCAEs are also necessary. In Experiment 1 observers made controlled eye movements over the induction patterns and subsequently showed PCCAEs which were as strong as those obtained under central fixation. The induction process therefore did not depend on selectively adapting local oriented and colour-specific edge detectors. The global structure of the inducing patterns appears to be a necessary component of the generation of such aftereffects. In Experiment 2, a number of pattern pairs having various degrees of global organization were used as induction patterns, but in every case there was an equal degree of local orthogonality. Local orthogonality was shown not to be sufficient to induce PCCAEs, but global orthogonality was. These results lend strong support to the notion that McCollough-type PCCAEs are generated in a structure of the visual system somewhat above the level of strictly local operations, whether defined as edge and bar detectors or, equivalently, as units selectively tuned to different spatial frequencies and orientations. The global nature of the effects, and the particular pattern structures involved, lead us to suggest that Hoffman's LTG/NP provides a sound basis for explaining our findings. PMID:3660619

  18. Studies on the high-sulphur proteins of reduced Merino wool. Amino acid sequence of protein SCMKB-IIIB4

    PubMed Central

    Swart, L. S.; Haylett, T.

    1971-01-01

    The complete amino acid sequence of protein SCMKB-IIIB4 is presented. It is closely related to the sequence of protein SCMKB-IIIB3 (Haylett, Swart & Parris, 1971) differing in only four positions. The peptic and thermolysin peptides of protein SCMKB-IIIB4 were analysed by the dansyl–Edman method (Gray, 1967) and by tritium-labelling of C-terminal residues (Matsuo, Fujimoto & Tatsuno, 1966). This protein is the third member of a group of high-sulphur wool proteins with molecular weight of about 11400. It consists of 98 residues and has acetylalanine and carboxymethylcysteine as N- and C-terminal residues respectively. PMID:4942536

  19. Developing the Next Generation Shell Buckling Design Factors and Technologies

    NASA Technical Reports Server (NTRS)

    Hilburger, Mark W.

    2012-01-01

    NASA s Shell Buckling Knockdown Factor (SBKF) Project was established in the spring of 2007 by the NASA Engineering and Safety Center (NESC) in collaboration with the Constellation Program and Exploration Systems Mission Directorate. The SBKF project has the current goal of developing less-conservative, robust shell buckling design factors (a.k.a. knockdown factors) and design and analysis technologies for light-weight stiffened metallic launch vehicle (LV) structures. Preliminary design studies indicate that implementation of these new knockdown factors can enable significant reductions in mass and mass-growth in these vehicles and can help mitigate some of NASA s LV development and performance risks. In particular, it is expected that the results from this project will help reduce the reliance on testing, provide high-fidelity estimates of structural performance, reliability, robustness, and enable increased payload capability. The SBKF project objectives and approach used to develop and validate new design technologies are presented, and provide a glimpse into the future of design of the next generation of buckling-critical launch vehicle structures.

  20. Link community detection using generative model and nonnegative matrix factorization.

    PubMed

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities. PMID:24489803

  1. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  2. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  3. Link Community Detection Using Generative Model and Nonnegative Matrix Factorization

    PubMed Central

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities. PMID:24489803

  4. Implant Materials Generate Different Peri-implant Inflammatory Factors

    PubMed Central

    Olivares-Navarrete, Rene; Hyzy, Sharon L.; Slosar, Paul J.; Schneider, Jennifer M.; Schwartz, Zvi

    2015-01-01

    Study Design. An in vitro study examining factors produced by human mesenchymal stem cells on spine implant materials. Objective. The aim of this study was to examine whether the inflammatory microenvironment generated by cells on titanium-aluminum-vanadium (Ti-alloy, TiAlV) surfaces is affected by surface microtexture and whether it differs from that generated on poly-ether-ether-ketone (PEEK). Summary of Background Data. Histologically, implants fabricated from PEEK have a fibrous connective tissue surface interface whereas Ti-alloy implants demonstrate close approximation with surrounding bone. Ti-alloy surfaces with complex micron/submicron scale roughness promote osteoblastic differentiation and foster a specific cellular environment that favors bone formation whereas PEEK favors fibrous tissue formation. Methods. Human mesenchymal stem cells were cultured on tissue culture polystyrene, PEEK, smooth TiAlV, or macro-/micro-/nano-textured rough TiAlV (mmnTiAlV) disks. Osteoblastic differentiation and secreted inflammatory interleukins were assessed after 7 days. Fold changes in mRNAs for inflammation, necrosis, DNA damage, or apoptosis with respect to tissue culture polystyrene were measured by low-density polymerase chain reaction array. Data were analyzed by analysis of variance, followed by Bonferroni's correction of Student's t-test. Results. Cells on PEEK upregulated mRNAs for chemokine ligand-2, interleukin (IL) 1β, IL6, IL8, and tumor necrosis factor. Cells grown on the mmnTiAlV had an 8-fold reduction in mRNAs for toll-like receptor-4. Cells grown on mmnTiAlV had reduced levels of proinflammatory interleukins. Cells on PEEK had higher mRNAs for factors strongly associated with cell death/apoptosis, whereas cells on mmnTiAlV exhibited reduced cytokine factor levels. All results were significant (P < 0.05). Conclusion. These results suggest that fibrous tissue around PEEK implants may be due to several factors: reduced osteoblastic differentiation of

  5. Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

    PubMed Central

    Wilkinson, Fiona L.; Holley, Rebecca J.; Langford-Smith, Kia J.; Badrinath, Soumya; Liao, Aiyin; Langford-Smith, Alex; Cooper, Jonathan D.; Jones, Simon A.; Wraith, J. Ed; Wynn, Rob F.; Merry, Catherine L. R.; Bigger, Brian W.

    2012-01-01

    Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events. Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend

  6. Increased number of negative lymph nodes is associated with improved cancer specific survival in pathological IIIB and IIIC rectal cancer treated with preoperative radiotherapy

    PubMed Central

    Li, Qingguo; Zhuo, Changhua; Cai, Guoxiang; Li, Dawei; Liang, Lei; Cai, Sanjun

    2014-01-01

    Preoperative radiation significantly decreases the number of retrieved lymph nodes (LNs) in rectal cancer, but little is known with respect to the prognostic significance of negative LN (NLN) counts under these circumstances. In this study, Surveillance, Epidemiology, and End Results Program (SEER)-registered ypIII stage rectal cancer patients, and patients from Fudan University Shanghai Cancer Center (FDSCC) were combined and analyzed. The results showed that the survival rate of patients with n (cutoff) or more NLNs increased gradually when n ranged from two to nine. After n reached 10 or greater, survival rates were approximately equivalent. Furthermore, the optimal cutoff value of 10 was validated as an independent prognostic factor in stage ypIIIB and ypIIIC patients by both univariate and multivariate analysis (P < 0.001); the number of NLNs could also stratify the prognosis of ypN(+) patients in more detail. Patients in the FDSCC set validated these findings and confirmed that NLN count was not decreased in the good tumor regression group relative to the poor tumor regression group. These results suggest that NLN count is an independent prognostic factor for ypIIIB and ypIIIC rectal cancer patients, and, together with the number of positive LNs, this will provide better prognostic information than the number of positive LNs alone. PMID:25514596

  7. Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10

    PubMed Central

    Gilkes, J A; Bloom, M D; Heldermon, C D

    2016-01-01

    Sanfilippo syndrome type B (mucopolysaccharidosis IIIB, MPS IIIB) is a lysosomal storage disease resulting from deficiency of N-acetyl-glucosaminidase (NAGLU) activity. To determine the possible therapeutic utility of recombinant adeno-associated virus (rAAV) in early gene therapy-based interventions, we performed a comprehensive assessment of transduction and biodistribution profiles of four central nervous system (CNS) administered rAAV serotypes, -5, -8, -9 and -rh10. To simulate optimal earliest treatment of the disease, each rAAV serotype was injected into the CNS of neonatal MPS IIIB and control animals. We observed marked differences in biodistribution and transduction profiles between the serotypes and this differed in MPS IIIB compared with healthy control mice. Overall, in control mice, all serotypes performed comparably, although some differences were observed in certain focal areas. In MPS IIIB mice, AAV8 was more efficient than AAV5, -9 and -rh10 for gene delivery to most structures analyzed, including the cerebral cortex, hippocampus and thalamus. Noteworthy, the pattern of biodistribution within the CNS varied by serotype and genotype. Interestingly, AAV8 also produced the highest green fluorescent protein intensity levels compared with any other serotype and demonstrated improved transduction in NAGLU compared with control brains. Importantly, we also show leakage of AAV8, -9 and -rh10, but not AAV5, from CNS parenchyma to systemic organs. Overall, our data suggest that AAV8 represents the best therapeutic gene transfer vector for early intervention in MPS IIIB. PMID:26674264

  8. Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10.

    PubMed

    Gilkes, J A; Bloom, M D; Heldermon, C D

    2016-03-01

    Sanfilippo syndrome type B (mucopolysaccharidosis IIIB, MPS IIIB) is a lysosomal storage disease resulting from deficiency of N-acetyl-glucosaminidase (NAGLU) activity. To determine the possible therapeutic utility of recombinant adeno-associated virus (rAAV) in early gene therapy-based interventions, we performed a comprehensive assessment of transduction and biodistribution profiles of four central nervous system (CNS) administered rAAV serotypes, -5, -8, -9 and -rh10. To simulate optimal earliest treatment of the disease, each rAAV serotype was injected into the CNS of neonatal MPS IIIB and control animals. We observed marked differences in biodistribution and transduction profiles between the serotypes and this differed in MPS IIIB compared with healthy control mice. Overall, in control mice, all serotypes performed comparably, although some differences were observed in certain focal areas. In MPS IIIB mice, AAV8 was more efficient than AAV5, -9 and -rh10 for gene delivery to most structures analyzed, including the cerebral cortex, hippocampus and thalamus. Noteworthy, the pattern of biodistribution within the CNS varied by serotype and genotype. Interestingly, AAV8 also produced the highest green fluorescent protein intensity levels compared with any other serotype and demonstrated improved transduction in NAGLU compared with control brains. Importantly, we also show leakage of AAV8, -9 and -rh10, but not AAV5, from CNS parenchyma to systemic organs. Overall, our data suggest that AAV8 represents the best therapeutic gene transfer vector for early intervention in MPS IIIB. PMID:26674264

  9. Generation and characterization of transgenic mice expressing cobra venom factor.

    PubMed

    Andrä, Jörg; Halter, Roman; Kock, Michael A; Niemann, Heiner; Vogel, Carl-Wilhelm; Paul, Dieter

    2002-10-01

    Cobra venom factor (CVF), the anticomplementary protein in cobra venom, activates the alternative complement pathway, eventually leading to complement consumption. Here, we describe the development of a transgenic mouse model for CVF. We generated a DNA construct containing the full-length cDNA for single-chain pre-pro-CVF. Expression of CVF was controlled by the alpha(1)-antitrypsin promoter to achieve liver-specific expression. Linearized DNA was microinjected into murine ovary cells (strain CD(2)F(1) (BALB/cxDBA/2J)) and the newborn mice were analyzed for stable integration of CVF DNA. After establishing the transgene, mice were propagated in a BALB/c background. The CVF mRNA was detected in the liver and, in some animals, in the kidney. CVF protein was detected in small amounts in the serum. Serum complement hemolytic activity in CVF-transgenic mice was virtually absent. The concentration of plasma C3 was significantly reduced. The CVF-transgenic animals show no unusual phenotype. They provide an animal model to study the effect of long-term complement depletion by continued activation, as well as the role of complement in host immune response and pathogenesis of disease. PMID:12220893

  10. The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure

    PubMed Central

    De Pasquale, Valeria; Cocchiaro, Pasquale; Paciello, Orlando; Avallone, Luigi; Belfiore, Maria Paola; Iacobellis, Francesca; Di Napoli, Daniele; Magliulo, Fabio; Perrino, Cinzia; Trimarco, Bruno; Esposito, Giovanni; Di Natale, Paola; Pavone, Luigi Michele

    2015-01-01

    Mucopolysaccharidosis (MPS) IIIB is a lysosomal disease due to the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The disease is characterized by mild somatic features and severe neurological disorders. Very little is known on the cardiac dysfunctions in MPS IIIB. In this study, we used the murine model of MPS IIIB (NAGLU knockout mice, NAGLU-/-) in order to investigate the cardiac involvement in the disease. Echocardiographic analysis showed a marked increase in left ventricular (LV) mass, reduced cardiac function and valvular defects in NAGLU-/- mice as compared to wild-type (WT) littermates. The NAGLU-/- mice exhibited a significant increase in aortic and mitral annulus dimension with a progressive elongation and thickening of anterior mitral valve leaflet. A severe mitral regurgitation with reduction in mitral inflow E-wave-to-A-wave ratio was observed in 32-week-old NAGLU-/- mice. Compared to WT mice, NAGLU-/- mice exhibited a significantly lower survival with increased mortality observed in particular after 25 weeks of age. Histopathological analysis revealed a significant increase of myocardial fiber vacuolization, accumulation of HS in the myocardial vacuoles, recruitment of inflammatory cells and collagen deposition within the myocardium, and an increase of LV fibrosis in NAGLU-/- mice compared to WT mice. Biochemical analysis of heart samples from affected mice showed increased expression levels of cardiac failure hallmarks such as calcium/calmodulin-dependent protein kinase II, connexin43, α-smooth muscle actin, α-actinin, atrial and brain natriuretic peptides, and myosin heavy polypeptide 7. Furthermore, heart samples from NAGLU-/- mice showed enhanced expression of the lysosome-associated membrane protein-2 (LAMP2), and the autophagic markers Beclin1 and LC3 isoform II (LC3-II). Overall, our findings demonstrate that NAGLU-/- mice develop heart disease, valvular abnormalities and cardiac

  11. Cue Set Stimulation as a Factor in Human Response Generation.

    ERIC Educational Resources Information Center

    Petelle, John L.

    The hypotheses that there will be a significant difference (1) in the number of responses generated according to economic issues, (2) in the number of responses generated according to social issues, (3) in the number of responses generated between the category of economic issues and the category of social issues, (4) in cue ranking by response…

  12. Electrophysiological and Histological Characterization of Rod-Cone Retinal Degeneration and Microglia Activation in a Mouse Model of Mucopolysaccharidosis Type IIIB

    PubMed Central

    Tse, Dennis Y.; Lotfi, Parisa; Simons, David L.; Sardiello, Marco; Wu, Samuel M.

    2015-01-01

    Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies. PMID:26607664

  13. Electrophysiological and Histological Characterization of Rod-Cone Retinal Degeneration and Microglia Activation in a Mouse Model of Mucopolysaccharidosis Type IIIB.

    PubMed

    Tse, Dennis Y; Lotfi, Parisa; Simons, David L; Sardiello, Marco; Wu, Samuel M

    2015-01-01

    Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46 th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies. PMID:26607664

  14. Epilepsy and electrophysiological findings in polish twins with glycogenosis type IIIb.

    PubMed

    Kroczka, Sławomir; Biedroń, Agnieszka; Kaciński, Marek

    2014-07-01

    Glycogen storage diseases are rare genetic disorders, mostly autosomal recessively inherited. Abnormal accumulation is because of the lack of one of the enzymes involved in glycogen metabolism. Neurological manifestation of the diseases involves muscle weakness and hypoglycemia-induced seizures. In this article, we present a history of twin sisters with unusual coincidence of glycogenosis type IIIb and epilepsy. Hypoglycemic background of seizures and organic changes of the central nervous system were excluded. Since the introduction of antiepileptic treatment, the patients have been seizure-free; however, paroxysmal electroencephalographic (EEG) changes have persisted. A high-protein and low-carbohydrate diet has protected them against hypoglycemia. PMID:24357677

  15. FGFR2IIIb-MAPK Activity Is Required for Epithelial Cell Fate Decision in the Lower Müllerian Duct.

    PubMed

    Terakawa, Jumpei; Rocchi, Altea; Serna, Vanida A; Bottinger, Erwin P; Graff, Jonathan M; Kurita, Takeshi

    2016-07-01

    Cell fate of lower Müllerian duct epithelium (MDE), to become uterine or vaginal epithelium, is determined by the absence or presence of ΔNp63 expression, respectively. Previously, we showed that SMAD4 and runt-related transcription factor 1 (RUNX1) were independently required for MDE to express ΔNp63. Here, we report that vaginal mesenchyme directs vaginal epithelial cell fate in MDE through paracrine activation of fibroblast growth factor (FGF) receptor-MAPK pathway. In the developing reproductive tract, FGF7 and FGF10 were enriched in vaginal mesenchyme, whereas FGF receptor 2IIIb was expressed in epithelia of both the uterus and vagina. When Fgfr2 was inactivated, vaginal MDE underwent uterine cell fate, and this differentiation defect was corrected by activation of MEK-ERK pathway. In vitro, FGF10 in combination with bone morphogenetic protein 4 and activin A (ActA) was sufficient to induce ΔNp63 in MDE, and ActA was essential for induction of RUNX1 through SMAD-independent pathways. Accordingly, inhibition of type 1 receptors for activin in neonatal mice induced uterine differentiation in vaginal epithelium by down-regulating RUNX1, whereas conditional deletion of Smad2 and Smad3 had no effect on vaginal epithelial differentiation. In conclusion, vaginal epithelial cell fate in MDE is induced by FGF7/10-MAPK, bone morphogenetic protein 4-SMAD, and ActA-RUNX1 pathway activities, and the disruption in any one of these pathways results in conversion from vaginal to uterine epithelial cell fate. PMID:27164167

  16. Thoracic Endovascular Aortic Repair for Chronic DeBakey IIIb Aortic Dissection

    PubMed Central

    Hughes, G. Chad; Ganapathi, Asvin M.; Keenan, Jeffrey E.; Englum, Brian R.; Hanna, Jennifer M.; Schechter, Matthew A.; Wang, Hanghang; McCann, Richard L.

    2015-01-01

    Background Thoracic endovascular aortic repair (TEVAR) for chronic DeBakey IIIb dissection with associated descending aneurysm remains controversial. This study examines long-term results of TEVAR for this disorder including examination of anatomic features associated with TEVAR outcomes. Methods Between July 2005 and January 2013, 32 patients underwent TEVAR for chronic (>30 days) DeBakey IIIb dissection involving the descending thoracic aorta at a single institution and constituted the study cohort. Results The mean interval from dissection to TEVAR was 32 ± 44 months (range, 1 to 146 months). There were no 30-day or in-hospital deaths, strokes, or paraplegia. During a 54-month median follow-up, there were no aortic-related deaths. Significant thoracic aneurysm sac regression (>1 cm) in the intervened segment was observed in 89%. Thoracic remodeling was not correlated with the number of visceral vessels arising from the true lumen or the number or size of residual distal fenestrations; failure of thoracic remodeling was associated with fenestrations distal to the endograft(s) in the descending thoracic aorta, most often stent graft-induced new entry tears. Complete resolution of the thoracic and abdominal false lumen after TEVAR was observed in 15.6% (n = 5). All patients in this group had all visceral vessels arising from the true lumen and fewer than three residual distal fenestrations. Conclusions Thoracic endovascular aortic repair is effective for chronic DeBakey IIIb dissection with associated descending aneurysm, with excellent 30-day and long-term outcomes and significant aortic remodeling in the vast majority of patients. Thoracic remodeling does not appear dependent on distal anatomic characteristics of the true and false lumens, although care should be taken to cover all thoracic fenestrations and avoid creation of stent graft-induced new entry tears to ensure clinical success. Complete aortic remodeling was observed only in the setting of all

  17. Literature Review: Factors Affecting the Development of Generation X and Millennials. Societal Factors Affecting Education.

    ERIC Educational Resources Information Center

    Denham, Thomas J.; adbow, Nancy

    Generation X, or "Xers," refers to those born in the United States between 1960 and 1980 and Generation Y, also known as "Millennials," refers to those born between 1980 and 2000. An examination of these two generations is important to educators as the new generation of Millennials begins to access higher education. A large and growing body of…

  18. 77 FR 39388 - Removal of Category IIIa, IIIb, and IIIc Definitions; Confirmation of Effective Date and Response...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-03

    ... confirms the effective date of the direct final rule published on February 16, 2012 (77 FR 9163), and..., entitled ``Removal of Category IIIa, IIIb, and IIIc Definitions'' (77 FR 9163). The direct final rule..._policies/ or 3. Access the Government Printing Office's Web page at...

  19. Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2016-02-08

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  20. Metabolome profiling to understand the defense response to sugar beet (Beta vulgaris) to Rhizoctonia solani AG 2-2 IIIB

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rhizoctonia crown and root rot, caused by Rhizoctonia solani Kühn AG 2-2 IIIB, is an important disease of sugar beet (Beta vulgaris L.). The molecular processes that mediate sugar beet resistance to R. solani are largely unknown and identifying the metabolites associated with R. solani infection ma...

  1. Coenzyme A Binding to the Aminoglycoside Acetyltransferase (3)-IIIb Increases Conformational Sampling of Antibiotic Binding Site

    SciTech Connect

    Hu, Xiaohu; Norris, Adrianne; Baudry, Jerome Y; Serpersu, Engin H

    2011-01-01

    NMR spectroscopy experiments and molecular dynamics simulations were performed to describe the dynamic properties of the aminoglycoside acetyltransferase (3)-IIIb (AAC) in its apo and coenzyme A (CoASH) bound forms. The {sup 15}N-{sup 1}H HSQC spectra indicate a partial structural change and coupling of the CoASH binding site with another region in the protein upon the CoASH titration into the apo enzyme. Molecular dynamics simulations indicate a significant structural and dynamic variation of the long loop in the antibiotic binding domain in the form of a relatively slow (250 ns), concerted opening motion in the CoASH enzyme complex and that binding of the CoASH increases the structural flexibility of the loop, leading to an interchange between several similar equally populated conformations.

  2. RNA-activated DNA cleavage by the Type III-B CRISPR-Cas effector complex.

    PubMed

    Estrella, Michael A; Kuo, Fang-Ting; Bailey, Scott

    2016-02-15

    The CRISPR (clustered regularly interspaced short palindromic repeat) system is an RNA-guided immune system that protects prokaryotes from invading genetic elements. This system represents an inheritable and adaptable immune system that is mediated by multisubunit effector complexes. In the Type III-B system, the Cmr effector complex has been found to cleave ssRNA in vitro. However, in vivo, it has been implicated in transcription-dependent DNA targeting. We show here that the Cmr complex from Thermotoga maritima can cleave an ssRNA target that is complementary to the CRISPR RNA. We also show that binding of a complementary ssRNA target activates an ssDNA-specific nuclease activity in the histidine-aspartate (HD) domain of the Cmr2 subunit of the complex. These data suggest a mechanism for transcription-coupled DNA targeting by the Cmr complex and provide a unifying mechanism for all Type III systems. PMID:26848046

  3. A Qualitative Study of Recovery from Type III-B and III-C Tibial Fractures

    PubMed Central

    Shauver, Melissa S.; Aravind, Maya S.; Chung, Kevin C.

    2011-01-01

    The literature has shown that long-term outcomes for both below-knee amputation and reconstruction following type III-B and III-C tibial fracture are poor. Yet, patients often report satisfaction with their treatment and/or outcomes. The aim of this study is to explore the relationship between patient outcomes and satisfaction after open tibial fractures via qualitative methodology. Twenty patients who were treated for open tibial fractures at one institution were selected using purposeful sampling and interviewed in-person in a semi-structured manner. Data were analyzed using grounded theory methodology. Despite reporting marked physical and psychosocial deficits, participants relayed high satisfaction. We hypothesize that the use adaptive coping techniques successfully reduces stress, which leads to an increase in coping self-efficacy that results in the further use of adaptive coping strategies, culminating in personal growth. This stress reduction and personal growth leads to satisfaction despite poor functional and emotional outcomes. PMID:20948418

  4. Exploring First Generation African American Graduate Students: Motivating Factors for Pursuing a Doctoral Degree

    ERIC Educational Resources Information Center

    Adams, Stephanie G.

    2011-01-01

    The purpose for conducting the study was to examine the factors that motivate African-American first-generation students to pursue doctoral education at a four-year public university. There has been little research on the influence academic or nonacademic factors have on first-generation graduate student motivation. Similarly, little research…

  5. Factors associated with the satisfaction of millennial generation dental residents.

    PubMed

    Lam, Hwai-Tai C; O'Toole, Terry G; Arola, Patricia E; Kashner, T Michael; Chang, Barbara K

    2012-11-01

    Data from the 2010 Learners' Perceptions Survey (LPS) administered through the Office of Academic Affiliations, Department of Veterans Affairs (VA) were analyzed to identify factors associated with dental residents' satisfaction with the VA as a clinical training environment. Satisfaction scores were linked to clinic workloads, dental procedure complexity levels, staffing patterns, and facility infrastructure data to explore conditions that may improve residents' satisfaction. Findings supported the construct validity of the LPS survey data and underscored the importance of maintaining optimal ratios of attending dentists, dental assistants, and administrative staff to residents so that each trainee will have opportunities to perform an adequate level of dental workload. As programs strive to improve the quality of graduate dental education, findings from this study are vital for setting curriculum design guidelines and for providing infrastructure support for dental resident education. PMID:23144476

  6. Limestone: high-throughput candidate phenotype generation via tensor factorization.

    PubMed

    Ho, Joyce C; Ghosh, Joydeep; Steinhubl, Steve R; Stewart, Walter F; Denny, Joshua C; Malin, Bradley A; Sun, Jimeng

    2014-12-01

    The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in

  7. A Review of Operational Water Consumption and Withdrawal Factors for Electricity Generating Technologies

    SciTech Connect

    Macknick, Jordan; Newmark, Robin; Heath, Garvin; Hallett, K. C.

    2011-03-01

    This report provides estimates of operational water withdrawal and water consumption factors for electricity generating technologies in the United States. Estimates of water factors were collected from published primary literature and were not modified except for unit conversions. The presented water factors may be useful in modeling and policy analyses where reliable power plant level data are not available.

  8. Historical and contemporary factors generate unique butterfly communities on islands.

    PubMed

    Vodă, Raluca; Dapporto, Leonardo; Dincă, Vlad; Shreeve, Tim G; Khaldi, Mourad; Barech, Ghania; Rebbas, Khellaf; Sammut, Paul; Scalercio, Stefano; Hebert, Paul D N; Vila, Roger

    2016-01-01

    The mechanisms shaping island biotas are not yet well understood mostly because of a lack of studies comparing eco-evolutionary fingerprints over entire taxonomic groups. Here, we linked community structure (richness, frequency and nestedness) and genetic differentiation (based on mitochondrial DNA) in order to compare insular butterfly communities occurring over a key intercontinental area in the Mediterranean (Italy-Sicily-Maghreb). We found that community characteristics and genetic structure were influenced by a combination of contemporary and historical factors, and among the latter, connection during the Pleistocene had an important impact. We showed that species can be divided into two groups with radically different properties: widespread taxa had high dispersal capacity, a nested pattern of occurrence, and displayed little genetic structure, while rare species were mainly characterized by low dispersal, high turnover and genetically differentiated populations. These results offer an unprecedented view of the distinctive butterfly communities and of the main processes determining them on each studied island and highlight the importance of assessing the phylogeographic value of populations for conservation. PMID:27353723

  9. Historical and contemporary factors generate unique butterfly communities on islands

    NASA Astrophysics Data System (ADS)

    Vodă, Raluca; Dapporto, Leonardo; Dincă, Vlad; Shreeve, Tim G.; Khaldi, Mourad; Barech, Ghania; Rebbas, Khellaf; Sammut, Paul; Scalercio, Stefano; Hebert, Paul D. N.; Vila, Roger

    2016-06-01

    The mechanisms shaping island biotas are not yet well understood mostly because of a lack of studies comparing eco-evolutionary fingerprints over entire taxonomic groups. Here, we linked community structure (richness, frequency and nestedness) and genetic differentiation (based on mitochondrial DNA) in order to compare insular butterfly communities occurring over a key intercontinental area in the Mediterranean (Italy-Sicily-Maghreb). We found that community characteristics and genetic structure were influenced by a combination of contemporary and historical factors, and among the latter, connection during the Pleistocene had an important impact. We showed that species can be divided into two groups with radically different properties: widespread taxa had high dispersal capacity, a nested pattern of occurrence, and displayed little genetic structure, while rare species were mainly characterized by low dispersal, high turnover and genetically differentiated populations. These results offer an unprecedented view of the distinctive butterfly communities and of the main processes determining them on each studied island and highlight the importance of assessing the phylogeographic value of populations for conservation.

  10. Factors that influence the generation of autobiographical memory conjunction errors.

    PubMed

    Devitt, Aleea L; Monk-Fromont, Edwin; Schacter, Daniel L; Addis, Donna Rose

    2016-01-01

    The constructive nature of memory is generally adaptive, allowing us to efficiently store, process and learn from life events, and simulate future scenarios to prepare ourselves for what may come. However, the cost of a flexibly constructive memory system is the occasional conjunction error, whereby the components of an event are authentic, but the combination of those components is false. Using a novel recombination paradigm, it was demonstrated that details from one autobiographical memory (AM) may be incorrectly incorporated into another, forming AM conjunction errors that elude typical reality monitoring checks. The factors that contribute to the creation of these conjunction errors were examined across two experiments. Conjunction errors were more likely to occur when the corresponding details were partially rather than fully recombined, likely due to increased plausibility and ease of simulation of partially recombined scenarios. Brief periods of imagination increased conjunction error rates, in line with the imagination inflation effect. Subjective ratings suggest that this inflation is due to similarity of phenomenological experience between conjunction and authentic memories, consistent with a source monitoring perspective. Moreover, objective scoring of memory content indicates that increased perceptual detail may be particularly important for the formation of AM conjunction errors. PMID:25611492

  11. Historical and contemporary factors generate unique butterfly communities on islands

    PubMed Central

    Vodă, Raluca; Dapporto, Leonardo; Dincă, Vlad; Shreeve, Tim G.; Khaldi, Mourad; Barech, Ghania; Rebbas, Khellaf; Sammut, Paul; Scalercio, Stefano; Hebert, Paul D. N.; Vila, Roger

    2016-01-01

    The mechanisms shaping island biotas are not yet well understood mostly because of a lack of studies comparing eco-evolutionary fingerprints over entire taxonomic groups. Here, we linked community structure (richness, frequency and nestedness) and genetic differentiation (based on mitochondrial DNA) in order to compare insular butterfly communities occurring over a key intercontinental area in the Mediterranean (Italy-Sicily-Maghreb). We found that community characteristics and genetic structure were influenced by a combination of contemporary and historical factors, and among the latter, connection during the Pleistocene had an important impact. We showed that species can be divided into two groups with radically different properties: widespread taxa had high dispersal capacity, a nested pattern of occurrence, and displayed little genetic structure, while rare species were mainly characterized by low dispersal, high turnover and genetically differentiated populations. These results offer an unprecedented view of the distinctive butterfly communities and of the main processes determining them on each studied island and highlight the importance of assessing the phylogeographic value of populations for conservation. PMID:27353723

  12. Combination Chemotherapy and Peripheral Blood Stem Cell Transplant Followed By Aldesleukin and Sargramostim in Treating Patients With Inflammatory Stage IIIB or Metastatic Stage IV Breast Cancer

    ClinicalTrials.gov

    2011-07-08

    Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; Inflammatory Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIB Breast Cancer; Stage IV Breast Cancer

  13. Effectiveness of composition based on oxidized dextran in the treatment of grade IIIB skin burns.

    PubMed

    Shkurupy, V A; Karpov, M A; Troitskii, A V; Arkhipov, S A; Neshchadim, D V

    2015-03-01

    Grade IIIB skin burns were treated with a composition based on oxidized dextran with a molecular weight of 40 kDa (oxidation of 7% glucose residues). On day 32 after burn infliction and from the start of the treatment, the area of skin defect in rats was 30% less than in the group without treatment and by 2.3 times less than in rats treated with panthenol. In rats treated with dextran-based composition or panthenol, the eschar was absent on day 21 after the start of the treatment; by day 32, we found cells of surface epithelium, hair follicles, and sebaceous glands above the scar tissue that were absent in untreated animals; in rats treated with the composition, their number was higher by 2.5 times than in animals treated with panthenol. Treatment with the composition increased volume density (by 2.5 times) and numerical density (by more than 3 times) of blood vessels in the wound and reduced signs of inflammation and fibroplastic activity of fibroblasts in comparison with the corresponding parameters in untreated animals or animals treated with panthenol. PMID:25778648

  14. Institutional Factors Influencing First-Generation College Students in the First Year: A Case Study

    ERIC Educational Resources Information Center

    Todd, Preston

    2013-01-01

    External stakeholders hold higher education institutions accountable for the rate students persist and graduate. When identifying at-risk student populations, one group involves students whose parents did not graduate. These students are known as first-generation students. There are many challenging factors facing first-generation college students…

  15. The Meaning of Work for Older Adults Seeking Employment: The Generativity Factor.

    ERIC Educational Resources Information Center

    Mor-Barak, Michal E.

    1995-01-01

    Examines the meaning of work for older adults in a sample of 146 older job seekers. Proposes four factors to the meaning of work: financial, personal, social, and generativity. Indicates ethnic and employment differences regarding the meaning of work. Jobs providing opportunities for transfer of knowledge and experience to younger generations may…

  16. Saprolegnia species in Norwegian salmon hatcheries: field survey identifies S. diclina sub-clade IIIB as the dominating taxon.

    PubMed

    Thoen, E; Vrålstad, T; Rolén, E; Kristensen, R; Evensen, Ø; Skaar, I

    2015-06-01

    Saprolegnia isolates within the recognized clades encompassing the taxa S. parasitica and S. diclina act as opportunist and aggressive pathogens to both fish and their eggs. They are responsible for significant economic losses in aquaculture, particularly in salmonid hatcheries. However, the identity, distribution and pathogenic significance of involved species often remain unexplored. In this study, 89 Saprolegnia isolates were recovered from water, eggs and salmon tissue samples that originated from salmon (Salmo salar) hatcheries along the coast of Norway. The cultures were characterized morphologically and molecularly in order to provide an overview of the species composition of Saprolegnia spp. present in Norwegian salmon hatcheries. We demonstrate that S. diclina clearly dominated and contributed to 79% of the recovered isolates. Parsimony analyses of the nuclear ribosomal internal transcribed spacer (ITS) region split these isolates into 2 strongly supported sub-clades, S. diclina sub-clade IIIA and IIIB, where sub-clade IIIB accounted for 66% of all isolates. A minor portion of the isolates constituted other taxa that were either conspecific or showed strong affinity to S. parasitica, S. ferax, S. hypogyna and Scoliolegnia asterophora. The unique sub-clade IIIB of S. diclina was most prevalent in water and salmon eggs, while S. parasitica isolates were more frequently isolated from post hatching stages. The study demonstrated that morphological criteria in many cases were insufficient for species delimitation due to lack of sexual structures or incoherent morphological expression of such features within the tested replicates. PMID:26036826

  17. High-power optical millimeter-wave signal generation with tunable frequency multiplication factor

    NASA Astrophysics Data System (ADS)

    Han, Yi-shi; Zheng, Zhenyu; Luo, Zhixiao; Min, Zhixuan; Xu, Ou; Liu, Jie

    2015-01-01

    This work demonstrates a simple and novel scheme for millimeter-wave (MMW) signal generation using optical multi-sidebands (OMSB) modulation. In the proposed methods, several pairs of optical sidebands can be generated by employing parallel phase modulators driven by a low frequency radio frequency (RF) signal. The optical sidebands will beat at a photodetector (PD) to generate high frequency MMW signal with tunable frequency multiplication factor, such as frequency octupling, 12-tupling, 16-tupling and 18-tupling. Since no optical filters or DC bias are used, the MMW signal has the evident character of high-power output. A generalized analytic expression and simulation verification for generating the frequency multi-tupling MMW signal are developed. The influences caused by non-ideal factors are discussed in detail, and undesired power ratios versus non-ideal factors are plotted and analyzed.

  18. Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.

    PubMed

    Ribera, Albert; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Motas, Sandra; Villacampa, Pilar; Maggioni, Luca; León, Xavier; Molas, Maria; Sánchez, Víctor; Muñoz, Sergio; Leborgne, Christian; Moll, Xavier; Pumarola, Martí; Mingozzi, Federico; Ruberte, Jesús; Añor, Sònia; Bosch, Fatima

    2015-04-01

    Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB. PMID:25524704

  19. Three-dimensional surface grid generation for calculation of thermal radiation shape factors

    NASA Technical Reports Server (NTRS)

    Aly, Hany M.

    1992-01-01

    A technique is described to generate three dimensional surface grids suitable for calculating shape factors for thermal radiative heat transfer. The surface under consideration is approximated by finite triangular elements generated in a special manner. The grid is generated by dividing the surface into a two dimensional array of nodes. Each node is defined by its coordinates. Each set of four adjacent nodes is used to construct two triangular elements. Each triangular element is characterized by the vector representation of its vertices. Vector algebra is used to calculate all desired geometric properties of grid elements. The properties are used to determine the shape factor between the element and an area element in space. The grid generation can be graphically displayed using any software with three dimensional features. DISSPLA was used to view the grids.

  20. Factors affecting respirable dust generation from longwall roof supports. Information circular/1985

    SciTech Connect

    Organiscak, J.A.; Listak, J.M.; Jankowski, R.A.

    1985-01-01

    The Bureau of Mines conducted a survey of eight shearer longwall operations to identify factors that affect respirable dust generation from longwall roof supports. The longwalls surveyed were in coal seams located in different geographic regions of the United States. Data were collected on mining (geologic) conditions, support design, operational characteristics, and amount of respirable dust generated from roof supports. Several practices are currently employed to effectively control roof support dust.

  1. Recurrent infections in partial complement factor I deficiency: evaluation of three generations of a Brazilian family

    PubMed Central

    Grumach, A S; Leitão, M F; Arruk, V G; Kirschfink, M; Condino-Neto, A

    2006-01-01

    We report here on the evaluation of a factor I-deficient Brazilian family (three generations, 39 members) with strong consanguinity. The complete factor I-deficient patients (n = 3) presented recurrent respiratory infections, skin infections and meningitis; one of them died after sepsis. They presented an impaired total haemolytic activity (CH50), low C3, low factor H and undetectable C3dg/C3d. Partial factor I deficiency was detected in 16 family members (normal low cut-off value was 25 µg/ml). Respiratory infections were the most common clinical occurrence among partial factor I-deficient relatives. Two of them were submitted to nephrectomy following recurrent urinary tract infections. An additional two heterozygous relatives presented with arthritis and rheumatic fever. Apparently, patients with partial factor I deficiency are also at higher risk for recurrent infections. Vaccination against capsulated bacteria and the eventual use of prophylactic antibiotics should be considered individually in this patient group. PMID:16412054

  2. Robot-assisted laparoscopic retroperitoneal lymph node dissection for stage IIIb mixed germ cell testicular cancer after chemotherapy.

    PubMed

    Lee, Sang Hyub; Kim, Dong Soo; Chang, Sung-Goo; Jeon, Seung Hyun

    2015-07-01

    Laparoscopic retroperitoneal lymph node dissection, especially when performed with the da Vinci Surgical System (Intuitive Surgical), has shown excellent cosmetic results with similar oncologic outcomes to those of open surgery. In this study, we present a case of robot-assisted retroperitoneal lymph node dissection performed in an 18-year-old man who was diagnosed with a stage IIIb mixed germ cell tumor and who was initially treated with radical orchiectomy, followed by chemotherapy. This case shows that robot-assisted retroperitoneal lymph node dissection is technically feasible, safe, and cosmetically favorable, even when performed on patients with high-stage disease or after chemotherapy. PMID:26175874

  3. Comparison of Retention Factors between First-Generation and Second- and Third-Generation College Students and Development of the Likelihood of Success Model

    ERIC Educational Resources Information Center

    Williams, Gerri Brown

    2009-01-01

    The purpose of this study was to compare the retention factors between first-generation college students and second- and third-generation college students in the postsecondary educational setting. This study examined the differences in the preselected retention factors: faculty-student interaction, college mentor, academic support, residential…

  4. Effect of Sugar Beet Variety and Nonhost Plant on Rhizoctonia solani AG2-2IIIB Soil Inoculum Potential Measured in Soil DNA Extracts.

    PubMed

    Schulze, Sascha; Koch, Heinz-Josef; Märländer, Bernward; Varrelmann, Mark

    2016-09-01

    A direct soil DNA extraction method from soil samples (250 g) was applied for detection of the soilborne sugar-beet-infecting pathogen Rhizoctonia solani anastomosis group (AG) 2-2IIIB using a newly developed real-time polymerase chain reaction assay that showed specificity to AG2-2IIIB when tested against various R. solani AG. The assay showed a good relation between cycle threshold and amount of AG2-2IIIB sclerotia detected in three spiked field soils and was also able to detect the pathogen in naturally infested field soil samples. A field trial was conducted to quantify R. solani AG2-2IIIB soil inoculum potential (IP) before and after growing a susceptible and a resistant sugar beet variety as well as after subsequent growth of an expected nonhost winter rye. Plants of the susceptible sugar beet variety displayed a higher disease severity. A more than sixfold increase of the R. solani AG2-2IIIB soil IP was observed in contrast to the resistant variety that resulted in a constant IP. Growing winter rye significantly reduced soil IP to the initial level at sowing. Further research is required to better understand the interaction between disease occurrence and soil IP as well as the environmental influence on IP development. PMID:27143412

  5. Factors That Relate to the Persistence of First-Generation Undergraduate Students in a Public University

    ERIC Educational Resources Information Center

    Thachil, Shoba Anne

    2013-01-01

    This study examined factors that relate to the persistence of first-generation undergraduate students in a 4-year public university in the Southeastern United States. Results were analyzed from a 2011 two-part survey: CARES-I (College Assessment of Readiness for Entering Students-Intent) and CARES-A (College Assessment of Readiness for Entering…

  6. Factors Influencing College Decision-Making for First-Generation Appalachian Students

    ERIC Educational Resources Information Center

    Wood, Kristy Lynn

    2012-01-01

    This investigation determined the degree of importance for selected personal-psychological, academic, peer, financial, and family factors influencing the decision to attend college by first-generation, Appalachian (FGA) sophomore students. Outcomes were further related to the degree of academic and social integration in college and the likelihood…

  7. Generation Y Student-Teachers' Motivational Factors: Retention Implications for K-12 Educational Leaders

    ERIC Educational Resources Information Center

    Bontempo, Brian

    2010-01-01

    Generation Y represents a growing number of student-teachers who will impact the future of educational practice, yet little research has been conducted for this demographic group. The purpose of this mixed-method study was to identify motivational factors of neophyte teachers and the retention implications these findings had on Kindergarten…

  8. The lifting factorization and construction of wavelet bi-frames with arbitrary generators and scaling.

    PubMed

    Shi, Yan; Yang, Xiaoyuan

    2011-09-01

    In this paper, we present the lifting factorization and construction of wavelet bi-frames with arbitrary generators and scaling. We show that an arbitrary polyphase matrix of a wavelet bi-frame can be factorized into a series of lifting steps. Based on the proposed factorization, we present a general construction of bi-frames. Especially, we give an explicit formula to construct the bi-frames of two scaling and two generators with symmetry and one vanishing moment. This paper does not involve many theories of wavelet frames in mathematics, but focuses on the algebraic issues related to Laurent polynomials, which are efficient expressions in redundant filter banks associated with wavelet frames. As an extension of the classical two-channel filter bank, the redundant filter bank is more complicated but also more flexible. Furthermore, we present an algorithm to increase the number of vanishing moments to arbitrary order by lifting, which is iterated and is straightforward in implementation. PMID:21356617

  9. Inhibition by CāINH of Hageman Factor Fragment Activation of Coagulation, Fibrinolysis, and Kinin Generation

    PubMed Central

    Schreiber, Alan D.; Kaplan, Allen P.; Austen, K. Frank

    1973-01-01

    Highly purified inhibitor of the first component of complement (CāINH) was shown to inhibit the capacity of active Hageman factor fragments to initiate kinin generation, fibrinolysis, and coagulation. The inhibition of prealbumin Hageman factor fragments observed was dependent upon the time of interaction of the fragments with CāINH and not to an effect upon kallikrein or plasmin generated. The inhibition of the coagulant activity of the intermediate sized Hageman factor fragment by CāINH was not due to an effect on PTA or other clotting factors. The inhibition by CāINH of both the prealbumin and intermediate sized Hageman factor fragments occurred in a dose response fashion. The CāINH did not appear to be consumed when the activity of the Hageman factor fragments was blocked, although the fragments themselves could no longer be recovered functionally or as a protein on alkaline disc gel electrophoretic analysis. These results suggest that the CāINH may have an enzymatic effect on the fragments or that an additional site on CāINH is involved in Cā inactivation. Images PMID:4703226

  10. Factors influencing municipal solid waste generation in China: a multiple statistical analysis study.

    PubMed

    Liu, Chen; Wu, Xin-wu

    2011-04-01

    A relationship between the waste production and socio-economic factors is essential in waste management. In the present study, the factors influencing municipal solid waste generation in China were investigated by multiple statistical analysis. Twelve items were chosen for investigation: GDP, per capita GDP, urban population, the proportion of urban population, the area of urban construction, the area of paved roads, the area of urban gardens and green areas, the number of the large cities, annual per capita disposable income of urban households, annual per capita consumption expenditure of urban households, total energy consumption and annual per capital consumption for households. Two methodologies from multiple statistical analysis were selected; specifically principal components analysis (PCA) and cluster analysis (CA). Three new dimensions were identified by PCA: component 1: economy and urban development; component 2: energy consumption; and component 3: urban scale. The three components together accounted for 99.1% of the initial variance. The results show that economy and urban development are important items influencing MSW generation. The proportion of urban population and urban population had the highest loadings in all factors. The relationship between growth of gross domestic product (GDP) and production of MSW was not as clear-cut as often assumed in China, a situation that is more likely to apply to developed countries. Energy consumption was another factor considered in our study of MSW generation. In addition, the annual MSW quantity variation was investigated by cluster analysis. PMID:20699292

  11. Optical rectification and third harmonic generation of spherical quantum dots: Controlling via external factors

    NASA Astrophysics Data System (ADS)

    Vaseghi, B.; Sadri, M.; Rezaei, G.; Gharaati, A.

    2015-01-01

    In this paper simultaneous effects of pressure, temperature, external electric field and laser radiation on the optical rectification and third harmonic generation of a spherical quantum dot with parabolic confinement and dressed impurity are studied. By means of matrix diagonalization technique, energy eigenvalues and functions are evaluated and used to find the optical rectification coefficient and third harmonic generation of the system via density operator method. It is shown that these nonlinear optical quantities strongly depend on pressure, temperature, electric field, confinement frequency and dressing laser intensity. Obvious effects of these external factors propose new facilities with different effects to control nonlinear optical properties of such systems.

  12. Europium-activated phosphors containing oxides of rare-earth and group-IIIB metals and method of making the same

    DOEpatents

    Comanzo, Holly Ann; Setlur, Anant Achyut; Srivastava, Alok Mani; Manivannan, Venkatesan

    2004-07-13

    Europium-activated phosphors comprise oxides of at least a rare-earth metal selected from the group consisting of gadolinium, yttrium, lanthanum, and combinations thereof and at least a Group-IIIB metal selected from the group consisting of aluminum, gallium, indium, and combinations thereof. A method for making such phosphors comprises adding at least a halide of at least one of the selected Group-IIIB metals in a starting mixture. The method further comprises firing the starting mixture in an oxygen-containing atmosphere. The phosphors produced by such a method exhibit improved absorption in the UV wavelength range and improved quantum efficiency.

  13. Europium-activated phosphors containing oxides of rare-earth and group-IIIB metals and method of making the same

    DOEpatents

    Comanzo, Holly Ann; Setlur, Anant Achyut; Srivastava, Alok Mani

    2006-04-04

    Europium-activated phosphors comprise oxides of at least a rare-earth metal selected from the group consisting of gadolinium, yttrium, lanthanum, and combinations thereof and at least a Group-IIIB metal selected from the group consisting of aluminum, gallium, indium, and combinations thereof. A method for making such phosphors comprises adding at least a halide of at least one of the selected Group-IIIB metals in a starting mixture. The method further comprises firing the starting mixture in an oxygen-containing atmosphere. The phosphors produced by such a method exhibit improved absorption in the UV wavelength range and improved quantum efficiency.

  14. The immunological generation of a platelet-activating factor and a platet-lytic factor in the rat.

    PubMed Central

    Valone, F H; Whitmer, D I; Pickett, W C; Austen, K F; Goetzl, E J

    1979-01-01

    Antigen challenge of the rat peritoneal cavity which had been prepared with IgGa-rich antiserum generated activities which released [14C]-serotonin from pre-labelled human platelets. After adsorption of these activities onto Amberlite XAD-8 and elution in 80% ethanol, two factors of differing polarity were resolved by chromatography on diethylaminoethyl cellulose in organic solvents. The activity eluting in the 7:1 chloroform:methanol solvent contained a platelet-lytic factor (PLF) assessed by the parallel release of lactic acid dehydrogenase and [14C]-serotonin; the cytotoxicity of this fraction was confirmed by phase-contrast microscopy examination which demonstrated fragmentation of the exposed platelets. The activity eluting in the 1:1 methanol: aqueous 1.0 M ammonium carbonate solvent was a platelet-activating factor (PAF) as defined by release of [14C]-serotonin without lactic acid dehydrogenase. Both the lytic and the activating principles were separable from slow reacting substance of anaphylaxis and polymorphonuclear leucocyte chemotactic activity, and each presented a single activity peak of differing mobility when chromatographed on silica gel H plates. Human eosinophil phospholipase D inactivated the lytic factor by more than 85% in 2 h at 37 degrees without affecting the activity of the activating factor. The release of [14C]-serotonin induced by the PAF was not affected by the absence of calcium from the medium or by elevations in the platelet concentrations of cyclic AMP or cyclic GMP that resulted from pre-incubation of platelets with prostaglandin D2 or sodium ascorbate, respectively. PMID:227784

  15. Factors affecting hydrocarbon generation, migration, and accumulation in Norwegian Central Graben and northern Viking graben

    SciTech Connect

    Leonard, R.C.

    1986-05-01

    The Norwegian Central graben and northern Viking graben are among the most prolific hydrocarbon provinces in Europe, with proved reserves exceeding 8 billion bbl of oil and 61 tcf of gas. Although are several successful plays are found in both grabens, this study concentrates on factors controlling accumulations in the most prolific trends - the Late Cretaceous to Danian chalk fields of the Central graben, and the Jurassic and Triassic sandstone fields of the northern Viking graben. Detailed modeling of hydrocarbon generation and migration in the two grabens demonstrates some similarities and major differences in the geochemical factors that control the accumulations.

  16. A global fouling factor methodology for analyzing steam generator thermal performance degradation

    SciTech Connect

    Kreider, M.A.; White, G.A.; Varrin, R.D. Jr.

    1998-06-01

    Over the past few years, steam generator (SG) thermal performance degradation has led to decreased plant efficiency and power output at numerous PWR nuclear power plants with recirculating-type SGs. The authors have developed and implemented methodologies for quantitatively evaluating the various sources of SG performance degradation, both internal and external to the SG pressure boundary. These methodologies include computation of the global fouling factor history, evaluation of secondary deposit thermal resistance using deposit characterization data, and consideration of pressure loss causes unrelated to the tube bundle, such as hot-leg temperature streaming and SG moisture separator fouling. In order to evaluate the utility of the global fouling factor methodology, the authors performed case studies for a number of PWR SG designs. Key results from two of these studies are presented here. In tandem with the fouling-factor analyses, a study evaluated for each plant the potential causes of pressure loss. The combined results of the global fouling factor calculations and the pressure-loss evaluations demonstrated two key points: (1) that the available thermal margin against fouling, which can vary substantially from plant to plant, has an important bearing on whether a given plant exhibits losses in electrical generating capacity, and (2) that a wide variety of causes can result in SG thermal performance degradation.

  17. Operational water consumption and withdrawal factors for electricity generating technologies: a review of existing literature

    NASA Astrophysics Data System (ADS)

    Macknick, J.; Newmark, R.; Heath, G.; Hallett, K. C.

    2012-12-01

    This report provides estimates of operational water withdrawal and water consumption factors for electricity generating technologies in the United States. Estimates of water factors were collected from published primary literature and were not modified except for unit conversions. The water factors presented may be useful in modeling and policy analyses where reliable power plant level data are not available. Major findings of the report include: water withdrawal and consumption factors vary greatly across and within fuel technologies, and water factors show greater agreement when organized according to cooling technologies as opposed to fuel technologies; a transition to a less carbon-intensive electricity sector could result in either an increase or a decrease in water use, depending on the choice of technologies and cooling systems employed; concentrating solar power technologies and coal facilities with carbon capture and sequestration capabilities have the highest water consumption values when using a recirculating cooling system; and non-thermal renewables, such as photovoltaics and wind, have the lowest water consumption factors. Improved power plant data and further studies into the water requirements of energy technologies in different climatic regions would facilitate greater resolution in analyses of water impacts of future energy and economic scenarios. This report provides the foundation for conducting water use impact assessments of the power sector while also identifying gaps in data that could guide future research.

  18. Improvement of force factor of magnetostrictive vibration power generator for high efficiency

    SciTech Connect

    Kita, Shota Ueno, Toshiyuki; Yamada, Sotoshi

    2015-05-07

    We develop high power magnetostrictive vibration power generator for battery-free wireless electronics. The generator is based on a cantilever of parallel beam structure consisting of coil-wound Galfenol and stainless plates with permanent magnet for bias. Oscillating force exerted on the tip bends the cantilever in vibration yields stress variation of Galfenol plate, which causes flux variation and generates voltage on coil due to the law of induction. This generator has advantages over conventional, such as piezoelectric or moving magnet types, in the point of high efficiency, highly robust, and low electrical impedance. Our concern is the improvement of energy conversion efficiency dependent on the dimension. Especially, force factor, the conversion ratio of the electromotive force (voltage) on the tip velocity in vibration, has an important role in energy conversion process. First, the theoretical value of the force factor is formulated and then the validity was verified by experiments, where we compare four types of prototype with parameters of the dimension using 7.0 × 1.5 × 50 mm beams of Galfenol with 1606-turn wound coil. In addition, the energy conversion efficiency of the prototypes depending on load resistance was measured. The most efficient prototype exhibits the maximum instantaneous power of 0.73 W and energy of 4.7 mJ at a free vibration of frequency of 202 Hz in the case of applied force is 25 N. Further, it was found that energy conversion efficiency depends not only on the force factor but also on the damping (mechanical loss) of the vibration.

  19. Improvement of force factor of magnetostrictive vibration power generator for high efficiency

    NASA Astrophysics Data System (ADS)

    Kita, Shota; Ueno, Toshiyuki; Yamada, Sotoshi

    2015-05-01

    We develop high power magnetostrictive vibration power generator for battery-free wireless electronics. The generator is based on a cantilever of parallel beam structure consisting of coil-wound Galfenol and stainless plates with permanent magnet for bias. Oscillating force exerted on the tip bends the cantilever in vibration yields stress variation of Galfenol plate, which causes flux variation and generates voltage on coil due to the law of induction. This generator has advantages over conventional, such as piezoelectric or moving magnet types, in the point of high efficiency, highly robust, and low electrical impedance. Our concern is the improvement of energy conversion efficiency dependent on the dimension. Especially, force factor, the conversion ratio of the electromotive force (voltage) on the tip velocity in vibration, has an important role in energy conversion process. First, the theoretical value of the force factor is formulated and then the validity was verified by experiments, where we compare four types of prototype with parameters of the dimension using 7.0 × 1.5 × 50 mm beams of Galfenol with 1606-turn wound coil. In addition, the energy conversion efficiency of the prototypes depending on load resistance was measured. The most efficient prototype exhibits the maximum instantaneous power of 0.73 W and energy of 4.7 mJ at a free vibration of frequency of 202 Hz in the case of applied force is 25 N. Further, it was found that energy conversion efficiency depends not only on the force factor but also on the damping (mechanical loss) of the vibration.

  20. Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work.

    PubMed

    So, R H Y; Lam, S T

    2014-01-01

    This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed. PMID:23726141

  1. Correction of Neurological Disease of Mucopolysaccharidosis IIIB in Adult Mice by rAAV9 Trans-Blood–Brain Barrier Gene Delivery

    PubMed Central

    Fu, Haiyan; DiRosario, Julianne; Killedar, Smruti; Zaraspe, Kimberly; McCarty, Douglas M

    2011-01-01

    The greatest challenge in developing therapies for mucopolysaccharidosis (MPS) IIIB is to achieve efficient central nervous system (CNS) delivery across the blood–brain barrier (BBB). In this study, we used the novel ability of adeno-associated virus serotype 9 (AAV9) to cross the BBB from the vasculature to achieve long-term global CNS, and widespread somatic restoration of α-N-acetylglucosaminidase (NAGLU) activity. A single intravenous (IV) injection of rAAV9-CMV-hNAGLU, without extraneous treatment to disrupt the BBB, restored NAGLU activity to normal or above normal levels in adult MPS IIIB mice, leading to the correction of lysosomal storage pathology in the CNS and periphery, and correction of astrocytosis and neurodegeneration. The IV delivered rAAV9 vector also transduced abundant neurons in the myenteric and submucosal plexus, suggesting peripheral nervous system (PNS) targeting. While CNS entry did not depend on osmotic disruption of the BBB, it was significantly enhanced by pretreatment with an IV infusion of mannitol. Most important, we demonstrate that a single systemic rAAV9-NAGLU gene delivery provides long-term (>18 months) neurological benefits in MPS IIIB mice, resulting in significant improvement in behavioral performance, and extension of survival. These data suggest promising clinical potential using the trans-BBB neurotropic rAAV9 vector for treating MPS IIIB and other neurogenetic diseases. PMID:21386820

  2. Bond-stretching and bond-bending force constant of binary tetrahedral (A IIIB V and A IIB VI) semiconductors

    NASA Astrophysics Data System (ADS)

    Verma, A. S.

    2008-12-01

    In this Letter we present the two expressions relating the bond-stretching force constant ( α in N/m) and bond-bending force constant ( β in N/m) for the A IIIB V and A IIB VI semiconductors with the product of ionic charges ( ZZ) and nearest neighbor distance d (Å). Interatomic force constants of these compounds exhibit a linear relationship when plotted on a log-log scale against the nearest neighbor distance d (Å), but fall on different straight lines according to the ionic charge product of the compounds. A fairly good agreement has been found between the observed and calculated values of the α and β for binary tetrahedral semiconductors.

  3. Draft genome sequence of the sugar beet pathogen Rhizoctonia solani AG2-2IIIB strain BBA69670.

    PubMed

    Wibberg, Daniel; Andersson, Louise; Rupp, Oliver; Goesmann, Alexander; Pühler, Alfred; Varrelmann, Mark; Dixelius, Christina; Schlüter, Andreas

    2016-03-20

    Rhizoctonia solani is a widespread plant pathogenic fungus featuring a broad host range including several economically important crops. Accordingly, genome analyses of R. solani isolates are important to uncover their pathogenic potential. Draft genome sequences for four R. solani isolates representing three of the 14 R. solani anastomosis groups (AGs) are available. Here, we present the first draft genome sequence for an R. solani AG2-2IIIB isolate that is pathogenic on sugar beet. The fungal genome was assembled in 2065 scaffolds consisting of 5826 contigs amounting to a size of about 52 Mb which is larger than any other R. solani isolate known today. Genes potentially encoding cellulolytic, lignolytic and pectinolytic enzymes were identified. PMID:26851388

  4. Pathological and biochemical studies of mucopolysaccharidosis type IIIB (Sanfilippo syndrome type B) in juvenile emus (Dromaius novaehollandiae).

    PubMed

    Palmieri, C; Giger, U; Wang, P; Pizarro, M; Shivaprasad, H L

    2015-01-01

    Mucopolysaccharidosis (MPS) type IIIB was diagnosed in 14 juvenile emus (Dromaius novaehollandiae), ages 3 weeks to 6 months, based on pathological and biochemical analyses. The animals had a history of neurological signs or sudden death; one of the birds with neurological signs and 3 others experienced acute hemoabdomen. Histopathologically, neuronal swelling and vacuolation in the cerebrum, cerebellum, brainstem, and spinal cord (80%-92%); retina (100%); autonomic ganglia of the intestine (71%); gizzard (50%); adrenal gland (27%); and ear (50%) were noted in affected but not healthy emus. Cytoplasmic vacuoles were also observed in the pancreas, liver, intestine, adrenal glands, and kidneys. The intracytoplasmic inclusions were periodic acid-Schiff and Luxol Fast Blue positive, consistent with a storage disease. Foamy macrophages infiltrated the liver, intestine, tunica media of the aorta, and spleen. By transmission electron microscopy, typical lamellated cytoplasmic bodies were detected in neurons of the brain and retina, while electron-dense bodies consistent with glycosaminoglycan inclusions were observed in hepatocytes and/or hepatic macrophages. The livers of the 2 affected emus studied contained large amounts of heparan sulfate, which is suggestive of MPS type III. Compared with normal controls, hepatic and serum α-N-acetylglucosaminidase activity was very low (<8% of control), while other enzyme activities were normal to increased in the 2 affected emus studied. Moreover, affected emus were homozygous for a 2-bp deletion in the NAGLU gene. This study characterizes the pathology of MPS type IIIB in emus, which is one of the rare inborn errors in birds, showing the homology of this condition to Sanfilippo syndrome in humans. PMID:24723233

  5. Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria

    PubMed Central

    Iking-Konert, Christof; Aringer, Martin; Wollenhaupt, Jürgen; Mosch, Thomas; Tuerk, Stefan; Feist, Eugen; Burmester, Gerd R

    2011-01-01

    Background Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28) <2.6, more stringent criteria may imply the absence of disease activity. The 2011 ACR/EULAR remission criteria provide the newest and most stringent definition of remission. Objectives To evaluate post hoc the remission by ACR/EULAR criteria and compare the criteria with the conventional DAS28 in TAMARA, an open-label phase IIIb tocilizumab (TCZ) trial including patients with active RA receiving inadequate disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor α (TNFα) inhibitor treatment. Results 286 patients were enrolled, 99.7% of patients were receiving a conventional DMARD and 41.6% had TNFα inhibitor pretreatment. Baseline mean DAS28 of 6.0 ± 1.0 fell to 2.6 ± 1.5 at week 24. DAS28 <2.6 was achieved by 47.6% at week 24. Remission rates with the new ACR/EULAR Boolean-based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks. Of note, 13.5% of patients with previous TNFα blocker inadequate response still achieved remission according to the new ACR/EULAR criteria after 24 weeks. Clinical Disease Activity Index and Simplified Disease Activity Index remission rates were 24.1% and 25.2%, respectively. Conclusions Under the definition of the new stringent 2011 ACR/EULAR remission criteria, patients with active RA despite DMARD treatment and even after inadequate response to TNFα inhibitors, receiving TCZ showed significant rates of remission. Similar remission rates were achieved, when clinical practice criteria, not inclusive of acute phase reactants, were used. PMID:21875873

  6. Generation of primitive neural stem cells from human fibroblasts using a defined set of factors

    PubMed Central

    Miura, Takumi; Sugawara, Tohru; Fukuda, Atsushi; Tamoto, Ryo; Kawasaki, Tomoyuki; Umezawa, Akihiro; Akutsu, Hidenori

    2015-01-01

    ABSTRACT In mice, leukemia inhibitory factor (LIF)-dependent primitive neural stem cells (NSCs) have a higher neurogenic potential than bFGF-dependent definitive NSCs. Therefore, expandable primitive NSCs are required for research and for the development of therapeutic strategies for neurological diseases. There is a dearth of suitable techniques for the generation of human long-term expandable primitive NSCs. Here, we have described a method for the conversion of human fibroblasts to LIF-dependent primitive NSCs using a strategy based on techniques for the generation of induced pluripotent stem cells (iPSCs). These LIF-dependent induced NSCs (LD-iNSCs) can be expanded for >100 passages. Long-term cultured LD-iNSCs demonstrated multipotent neural differentiation potential and could generate motor neurons and dopaminergic neurons, as well as astrocytes and oligodendrocytes, indicating a high level of plasticity. Furthermore, LD-iNSCs easily reverted to human iPSCs, indicating that LD-iNSCs are in an intermediate iPSC state. This method may facilitate the generation of patient-specific human neurons for studies and treatment of neurodegenerative diseases. PMID:26490674

  7. Generation of a Felinized Swine Endothelial Cell Line by Expression of Feline Decay-Accelerating Factor

    PubMed Central

    Izuhara, Luna; Tatsumi, Norifumi; Miyagawa, Shuji; Iwai, Satomi; Watanabe, Masahito; Yamanaka, Shuichiro; Katsuoka, Yuichi; Nagashima, Hiroshi; Okano, Hirotaka J.; Yokoo, Takashi

    2015-01-01

    Embryonic stem cell research has facilitated the generation of many cell types for the production of tissues and organs for both humans and companion animals. Because ≥30% of pet cats suffer from chronic kidney disease (CKD), xenotransplantation between pigs and cats has been studied. For a successful pig to cat xenotransplant, the immune reaction must be overcome, especially hyperacute rejection. In this study, we isolated the gene for feline decay-accelerating factor (fDAF), an inhibitor of complement proteins, and transfected a swine endothelial cell line with fDAF to “felinize” the pig cells. These fDAF-expressing cells were resistant to feline serum containing anti-pig antibodies, suggesting that felinized pig cells were resistant to hyperacute rejection. Our results suggest that a “felinized” pig kidney can be generated for the treatment of CKD in cats in the future. PMID:25671605

  8. Generating Pedestrian Trajectories Consistent with the Fundamental Diagram Based on Physiological and Psychological Factors

    PubMed Central

    Narang, Sahil; Best, Andrew; Curtis, Sean; Manocha, Dinesh

    2015-01-01

    Pedestrian crowds often have been modeled as many-particle system including microscopic multi-agent simulators. One of the key challenges is to unearth governing principles that can model pedestrian movement, and use them to reproduce paths and behaviors that are frequently observed in human crowds. To that effect, we present a novel crowd simulation algorithm that generates pedestrian trajectories that exhibit the speed-density relationships expressed by the Fundamental Diagram. Our approach is based on biomechanical principles and psychological factors. The overall formulation results in better utilization of free space by the pedestrians and can be easily combined with well-known multi-agent simulation techniques with little computational overhead. We are able to generate human-like dense crowd behaviors in large indoor and outdoor environments and validate the results with captured real-world crowd trajectories. PMID:25875932

  9. A Progenitor Cell Expressing Transcription Factor RORγt Generates All Human Innate Lymphoid Cell Subsets.

    PubMed

    Scoville, Steven D; Mundy-Bosse, Bethany L; Zhang, Michael H; Chen, Li; Zhang, Xiaoli; Keller, Karen A; Hughes, Tiffany; Chen, Luxi; Cheng, Stephanie; Bergin, Stephen M; Mao, Hsiaoyin C; McClory, Susan; Yu, Jianhua; Carson, William E; Caligiuri, Michael A; Freud, Aharon G

    2016-05-17

    The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development. PMID:27178467

  10. Generation of a felinized swine endothelial cell line by expression of feline decay-accelerating factor.

    PubMed

    Izuhara, Luna; Tatsumi, Norifumi; Miyagawa, Shuji; Iwai, Satomi; Watanabe, Masahito; Yamanaka, Shuichiro; Katsuoka, Yuichi; Nagashima, Hiroshi; Okano, Hirotaka J; Yokoo, Takashi

    2015-01-01

    Embryonic stem cell research has facilitated the generation of many cell types for the production of tissues and organs for both humans and companion animals. Because ≥30% of pet cats suffer from chronic kidney disease (CKD), xenotransplantation between pigs and cats has been studied. For a successful pig to cat xenotransplant, the immune reaction must be overcome, especially hyperacute rejection. In this study, we isolated the gene for feline decay-accelerating factor (fDAF), an inhibitor of complement proteins, and transfected a swine endothelial cell line with fDAF to "felinize" the pig cells. These fDAF-expressing cells were resistant to feline serum containing anti-pig antibodies, suggesting that felinized pig cells were resistant to hyperacute rejection. Our results suggest that a "felinized" pig kidney can be generated for the treatment of CKD in cats in the future. PMID:25671605

  11. The Impact of Local and Regional Disease Extent on Overall Survival in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Carcinoma

    SciTech Connect

    Higginson, Daniel S.; Chen, Ronald C.; Tracton, Gregg; Morris, David E.; Halle, Jan; Rosenman, Julian G.; Stefanescu, Mihaela; Pham, Erica; Socinski, Mark A.; Marks, Lawrence B.

    2012-11-01

    Purpose: Patients with advanced stage IIIB or stage IV non-small cell lung carcinoma are typically treated with initial platinum-based chemotherapy. A variety of factors (eg, performance status, gender, age, histology, weight loss, and smoking history) are generally accepted as predictors of overall survival. Because uncontrolled pulmonary disease constitutes a major cause of death in these patients, we hypothesized that clinical and radiographic factors related to intrathoracic disease at diagnosis may be prognostically significant in addition to conventional factors. The results have implications regarding the selection of patients for whom palliative thoracic radiation therapy may be of most benefit. Methods and Materials: We conducted a pooled analysis of 189 patients enrolled at a single institution into 9 prospective phase II and III clinical trials involving first-line, platinum-based chemotherapy. Baseline clinical and radiographic characteristics before trial enrollment were analyzed as possible predictors for subsequent overall survival. To assess the relationship between anatomic location and volume of disease within the thorax and its effect on survival, the pre-enrollment computed tomography images were also analyzed by contouring central and peripheral intrapulmonary disease. Results: On univariate survival analysis, multiple pulmonary-related factors were significantly associated with worse overall survival, including pulmonary symptoms at presentation (P=.0046), total volume of intrathoracic disease (P=.0006), and evidence of obstruction of major bronchi or vessels on prechemotherapy computed tomography (P<.0001). When partitioned into central and peripheral volumes, central (P<.0001) but not peripheral (P=.74) disease was associated with worse survival. On multivariate analysis with known factors, pulmonary symptoms (hazard ratio, 1.46; P=.042), central disease volume (hazard ratio, 1.47; P=.042), and bronchial/vascular compression (hazard ratio, 1

  12. Using data linkage to generate 30-day crash-fatality adjustment factors for Taiwan.

    PubMed

    Lai, Ching-Huei; Huang, Wei-Shin; Chang, Kai-Kuo; Jeng, Ming-Chang; Doong, Ji-Liang

    2006-07-01

    Different countries have their own police reporting time standards for counting the number of fatalities in reported crashes. A rapid estimation method (such as adjustment factor) for the comparison is important. The data-linkage technique was used to combine police-reported crash data and vital registration data, in order to generate 30-day fatality adjustment factors for various reporting time standards, which could also shed light on the fatal injury trend over time. The major findings were as follows. Firstly, a conservative 30-day fatality adjustment factor for the first day (or 24 h) would be 1.54 (or 1.35) in an area with a large motorcycle population, like Taiwan. This produced 20-40% higher 30-day fatalities than UK Transport Research Laboratory predicted, and 15-25% higher fatalities than those in Europe/Japan. Secondly, after excluding motorcycle impacts, the Taiwanese factors suggested 8-14% higher fatalities within 30 days than those in Europe/Japan. Third, motorcycle fatalities influenced the overall 30-day fatality trend within 3 days. In the future, both the police under-reporting problem and the motorcycle/overall fatal injury pattern within 3 days after crashing in developing countries like Taiwan merit further investigation. PMID:16430844

  13. Measurement of microparticle tissue factor activity in clinical samples: A summary of two tissue factor-dependent FXa generation assays.

    PubMed

    Hisada, Yohei; Alexander, Wyeth; Kasthuri, Raj; Voorhees, Peter; Mobarrez, Fariborz; Taylor, Angela; McNamara, Coleen; Wallen, Hakan; Witkowski, Marco; Key, Nigel S; Rauch, Ursula; Mackman, Nigel

    2016-03-01

    Thrombosis is a leading cause of morbidity and mortality. Detection of a prothrombotic state using biomarkers would be of great benefit to identify patients at risk of thrombosis that would benefit from thromboprophylaxis. Tissue factor (TF) is a highly procoagulant protein that under normal conditions is not present in the blood. However, increased levels of TF in the blood in the form of microparticles (MPs) (also called extracellular vesicles) are observed under various pathological conditions. In this review, we will discuss studies that have measured MP-TF activity in a variety of diseases using two similar FXa generation assay. One of the most robust signals for MP-TF activity (16-26 fold higher than healthy controls) is observed in pancreatic cancer patients with venous thromboembolism. In this case, the TF+ MPs appear to be derived from the cancer cells. Surprisingly, cirrhosis and acute liver injury are associated with 17-fold and 38-fold increases in MP-TF activity, respectively. Based on mouse models, we speculate that the TF+ MPs are derived from hepatocytes. More modest increases are observed in patients with urinary tract infections (6-fold) and in a human endotoxemia model (9-fold) where monocytes are the likely source of the TF+ MPs. Finally, there is no increase in MP-TF activity in the majority of cardiovascular disease patients. These studies indicate that MP-TF activity may be a useful biomarker to identify patients with particular diseases that have an increased risk of thrombosis. PMID:26916302

  14. Generation of induced pluripotent stem cells from buffalo (Bubalus bubalis) fetal fibroblasts with buffalo defined factors.

    PubMed

    Deng, Yanfei; Liu, Qingyou; Luo, Chan; Chen, Shibei; Li, Xiangping; Wang, Caizhu; Liu, Zhenzhen; Lei, Xiaocan; Zhang, Huina; Sun, Hongliang; Lu, Fenghua; Jiang, Jianrong; Shi, Deshun

    2012-09-01

    Ectopically, expression of defined factors could reprogram mammalian somatic cells into induced pluripotent stem cells (iPSCs), which initiates a new strategy to obtain pluripotent stem cell lines. Attempts have been made to generate buffalo pluripotent stem cells by culturing primary germ cells or inner cell mass, but the efficiency is extremely low. Here, we report a successful method to reprogram buffalo fetal fibroblasts (BFFs) into pluripotent stem cells [buffalo induced pluripotent stem cell (biPSCs)] by transduction of buffalo defined factors (Oct4, Sox2, Klf4, and c-Myc) using retroviral vectors. The established biPSCs displayed typical morphological characteristics of pluripotent stem cells, normal karyotype, positive staining of alkaline phosphatase, and expressed pluripotent markers including Oct4, Sox2, Nanog, Lin28, E-Cadherin, SSEA-1, SSEA-4, TRA-1-81, STAT3, and FOXD3. They could form embryoid bodies (EBs) in vitro and teratomas after injecting into the nude BALB/C mice, and 3 germ layers were identified in the EBs and teratomas. Methylation assay revealed that the promoters of Oct4 and Nanog were hypomethylated in biPSCs compared with BFFs and pre-biPSCs, while the promoters of Sox2 and E-Cadherin were hypomethylated in both BFFs and biPSCs. Further, inhibiting p53 expression by coexpression of SV40 large T antigen and buffalo defined factors in BFFs or treating BFFs with p53 inhibitor pifithrin-a (PFT) could increase the efficiency of biPSCs generation up to 3-fold, and nuclear transfer embryos reconstructed with biPSCs could develop to blastocysts. These results indicate that BFFs can be reprogrammed into biPSCs by buffalo defined factors, and the generation efficiency of biPSCs can be increased by inhibition of p53 expression. These efforts will provide a feasible approach for investigating buffalo stem cell signal pathways, establishing buffalo stem cell lines, and producing genetic modification buffaloes in the future. PMID:22420535

  15. An alternative strategy to generate coding sequence of macrophage migration inhibitory factor-2 of Wuchereria bancrofti

    PubMed Central

    Chauhan, Nikhil; Hoti, S.L.

    2016-01-01

    Background & objectives: Different developmental stages of Wuchereria bancrofti, the major causal organism of lymphatic filariasis (LF), are difficult to obtain. Beside this limitation, to obtain complete coding sequence (CDS) of a gene one has to isolate mRNA and perform subsequent cDNA synthesis which is laborious and not successful at times. In this study, an alternative strategy employing polymerase chain reaction (PCR) was optimized and validated, to generate CDS of Macrophage migration Inhibitory Factor-2 (wbMIF-2), a gene expressed in the transition stage between L3 to L4. Methods: The genomic DNA of W. bancrofti microfilariae was extracted and used to amplify the full length wbMIF-2 gene (4.275 kb). This amplified product was used as a template for amplifying the exons separately, using the overlapping primers, which were then assembled through another round of PCR. Results: A simple strategy was developed based on PCR, which is used routinely in molecular biology laboratories. The amplified CDS of 363 bp of wbMIF-2 generated using genomic DNA splicing technique was devoid of any intronic sequence. Interpretation & conclusions: The cDNA of wbMIF-2 gene was successfully amplified from genomic DNA of microfilarial stage of W. bancrofti thus circumventing the use of inaccessible L3-L4 transitional stage of this parasite. This strategy is useful for generating CDS of genes from parasites that have restricted availability. PMID:27121522

  16. UVB Generates Microvesicle Particle Release in Part Due to Platelet-activating Factor Signaling.

    PubMed

    Bihl, Ji C; Rapp, Christine M; Chen, Yanfang; Travers, Jeffrey B

    2016-05-01

    The lipid mediator platelet-activating factor (PAF) and oxidized glycerophosphocholine PAF agonists produced by ultraviolet B (UVB) have been demonstrated to play a pivotal role in UVB-mediated processes, from acute inflammation to delayed systemic immunosuppression. Recent studies have provided evidence that microvesicle particles (MVPs) are released from cells in response to various signals including stressors. Importantly, these small membrane fragments can interact with various cell types by delivering bioactive molecules. The present studies were designed to test if UVB radiation can generate MVP release from epithelial cells, and the potential role of PAF receptor (PAF-R) signaling in this process. We demonstrate that UVB irradiation of the human keratinocyte-derived cell line HaCaT resulted in the release of MVPs. Similarly, treatment of HaCaT cells with the PAF-R agonist carbamoyl PAF also generated equivalent amounts of MVP release. Of note, pretreatment of HaCaT cells with antioxidants blocked MVP release from UVB but not PAF-R agonist N-methyl carbamyl PAF (CPAF). Importantly, UVB irradiation of the PAF-R-negative human epithelial cell line KB and KB transduced with functional PAF-Rs resulted in MVP release only in PAF-R-positive cells. These studies demonstrate that UVB can generate MVPs in vitro and that PAF-R signaling appears important in this process. PMID:26876152

  17. Socioeconomic and Sociodemographic Factors Associated with Asthma Related Outcomes in Early Childhood: The Generation R Study

    PubMed Central

    Hafkamp-de Groen, Esther; Sonnenschein-van der Voort, Agnes M. M.; Mackenbach, Johan P.; Duijts, Liesbeth; Jaddoe, Vincent W. V.; Moll, Henriëtte A.; Hofman, Albert; de Jongste, Johan C.; Raat, Hein

    2013-01-01

    Rationale Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied. Methods The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models. Results At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18–2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24–2.15, aOR = 1.85, 95% CI:1.11–3.09, aOR = 1.58, 95% CI:1.24–2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained. Conclusions This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 years. Several socioeconomic and sociodemographic factors were independently associated with wheezing and asthma. Child's ethnicity was the only factor independently associated with FeNO. We

  18. Generations.

    PubMed

    Chambers, David W

    2005-01-01

    Groups naturally promote their strengths and prefer values and rules that give them an identity and an advantage. This shows up as generational tensions across cohorts who share common experiences, including common elders. Dramatic cultural events in America since 1925 can help create an understanding of the differing value structures of the Silents, the Boomers, Gen Xers, and the Millennials. Differences in how these generations see motivation and values, fundamental reality, relations with others, and work are presented, as are some applications of these differences to the dental profession. PMID:16623137

  19. Modeling and analysis of PM2.5 generation for key factors identification in China

    NASA Astrophysics Data System (ADS)

    Xia, Dehong; Jiang, Binfan; Xie, Yulei

    2016-06-01

    Recently, the PM2.5 pollution in China has occurred frequently and caused widely concern. In order to identify the key factors for PM2.5 generation, the formation characteristics of PM2.5 would be revealed. A property of electric neutrality of PM2.5 was proposed under the least-energy principle and verified through electricity-charge calculation in this paper. It indicated that PM2.5 is formed by the effect of electromagnetic force, including the effect of ionic bond, hydrogen bond and polarization. According to the analysis of interactive forces among different chemical components, a simulation model is developed for describing the random process of PM2.5 generation. In addition, an orthogonal test with two levels and four factors has been designed and carried out through the proposed model. From the text analysis, PM2.5 would be looser and suspend longer in atmosphere due to Organic Compound (OC) existing (OC can reduce about 67% of PM2.5 density). Considering that NH4+ is the only cation in the main chemical components of PM2.5, it would be vital for anions (such as SO42- and NO3-) to aggregate together for facilitating PM2.5 growing. Therefore, in order to relieve PM2.5 pollution, control strategies for OC and NH4+ would be enhanced by government through improving the quality of oils and solvent products, decreasing the amount of nitrogenous fertilizer utilization, or changing the fertilizing environment from dry condition to wet condition.

  20. Factors Influencing the Creation of a Wiki Culture for Knowledge Management in a Cross-Generational Organizational Setting

    ERIC Educational Resources Information Center

    Macro, Kenneth L., Jr.

    2011-01-01

    Initiatives within organizations that promote sharing of knowledge may be hampered by generational differences. Research on relationships between generations and technology-based knowledge sharing campaigns provides little managerial guidance for practitioners. The purpose of this ethnographic study was to identify the factors that influence the…

  1. Methods and analysis of factors impact on the efficiency of the photovoltaic generation

    NASA Astrophysics Data System (ADS)

    Tianze, Li; Xia, Zhang; Chuan, Jiang; Luan, Hou

    2011-02-01

    First of all, the thesis elaborates two important breakthroughs which happened In the field of the application of solar energy in the 1950s.The 21st century the development of solar photovoltaic power generation will have the following characteristics: the continued high growth of industrial development, the significantly reducing cost of the solar cell, the large-scale high-tech development of photovoltaic industries, the breakthroughs of the film battery technology, the rapid development of solar PV buildings integration and combined to the grids. The paper makes principles of solar cells the theoretical analysis. On the basis, we study the conversion efficiency of solar cells, find the factors impact on the efficiency of the photovoltaic generation, solve solar cell conversion efficiency of technical problems through the development of new technology, and open up new ways to improve the solar cell conversion efficiency. Finally, the paper connecting with the practice establishes policies and legislation to the use of encourage renewable energy, development strategy, basic applied research etc.

  2. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor.

    PubMed

    Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A; Ferracini, Matheus; Touloukian, Christopher E; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C; Althouse, Sandra K; Perkins, Susan M; Speicher, Paul J; Tyler, Douglas S; Konger, Raymond L; Travers, Jeffrey B

    2014-12-01

    Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. PMID:25304264

  3. Generation and gene expression profiling of 48 transcription-factor-inducible mouse embryonic stem cell lines

    PubMed Central

    Yamamizu, Kohei; Sharov, Alexei A.; Piao, Yulan; Amano, Misa; Yu, Hong; Nishiyama, Akira; Dudekula, Dawood B.; Schlessinger, David; Ko, Minoru S. H.

    2016-01-01

    Mouse embryonic stem cells (ESCs) can differentiate into a wide range – and possibly all cell types in vitro, and thus provide an ideal platform to study systematically the action of transcription factors (TFs) in cell differentiation. Previously, we have generated and analyzed 137 TF-inducible mouse ESC lines. As an extension of this “NIA Mouse ESC Bank,” we generated and characterized 48 additional mouse ESC lines, in which single TFs in each line could be induced in a doxycycline-controllable manner. Together, with the previous ESC lines, the bank now comprises 185 TF-manipulable ESC lines (>10% of all mouse TFs). Global gene expression (transcriptome) profiling revealed that the induction of individual TFs in mouse ESCs for 48 hours shifts their transcriptomes toward specific differentiation fates (e.g., neural lineages by Myt1 Isl1, and St18; mesodermal lineages by Pitx1, Pitx2, Barhl2, and Lmx1a; white blood cells by Myb, Etv2, and Tbx6, and ovary by Pitx1, Pitx2, and Dmrtc2). These data also provide and lists of inferred target genes of each TF and possible functions of these TFs. The results demonstrate the utility of mouse ESC lines and their transcriptome data for understanding the mechanism of cell differentiation and the function of TFs. PMID:27150017

  4. Generation of Mice With a Conditional Allele for the Transforming Growth Factor Beta3 Gene

    PubMed Central

    Doetschman, Thomas; Georgieva, Teodora; Li, Hongqi; Reed, Thomas D.; Grisham, Christina; Friel, Jacqueline; Estabrook, Mark A.; Gard, Connie; Sanford, L.P.; Azhar, Mohamad

    2013-01-01

    Summary The transforming growth factor beta (TGFβ) pathway is involved in embryonic development and several inherited and acquired human diseases. The gene for TGFβ3 (Tgfb3) encodes one of the three ligands for TGF b receptors. It is widely expressed in the embryo and its mutation or misexpression is found in human diseases. Tgfb3−/− mice die at birth from cleft palate, precluding functional studies in adults. Here, we generated mice in which exon 6 of Tgfb3 was flanked with LoxP sites (Tgfb3flox/flox). The adult mice were normal and fertile. EIIa-Cre-mediated deletion of exon 6 in Tgfb3flox/flox mice efficiently generated Tgfb3 conditional knockout (Tgfb3cko/cko) mice which died at birth from the same cleft palate defect as Tgfb3−/− mice, indicating that the conditional and knockout alleles are functionally equivalent. This Tgfb3cko allele will now enable studies of TGFβ3 function in different cell or tissue types in embryonic development and during adulthood. genesis 50:59-66, 2012. PMID:22223248

  5. [The effect of piperazine analogs of aryloxyaminopropanol (IIIq and IIIb) on the occurrence of reperfusion dysrhythmias in an in vivo experiment on rats].

    PubMed

    Jadronová, O; Kuzelová, M; Seginko, J; Celková, H; Svec, P

    1996-11-01

    The present experimental study reports the beneficial effects of newly synthetized substances IIIq and IIIb in vivo. These aryloxyaminopropanol drugs have been shown to antagonize the contraction caused by calcium comparable to verapamil and flunarizine in the model of the isolated guinea pig terminal ileum. Effects of substances on both the incidence of arrhythmias during ischemia and the reperfusion period and mortality were investigated in the rat model ischemia-reperfusion injury. We can conclude that compound IIIq in a dose of 10(-6) mol/kg is effective in reducing the incidence of reperfusion-induced arrhythmias. Substance IIIb (10(-6) mol/kg) administered before ischemia was not able to suppress arrhythmias in the rat model of myocardial infarction and reperfusion. PMID:8998610

  6. Novel SOX2 partner-factor domain mutation in a four-generation family

    PubMed Central

    Mihelec, Marija; Abraham, Peter; Gibson, Kate; Krowka, Renata; Susman, Rachel; Storen, Rebecca; Chen, Yongjuan; Donald, Jenny; Tam, Patrick PL; Grigg, John R; Flaherty, Maree; Gole, Glen A; Jamieson, Robyn V

    2009-01-01

    Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development. PMID:19471311

  7. CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface

    PubMed Central

    Martínez-Muñoz, Laura; Barroso, Rubén; Dyrhaug, Sunniva Y.; Navarro, Gemma; Lucas, Pilar; Soriano, Silvia F.; Vega, Beatriz; Costas, Coloma; Muñoz-Fernández, M. Ángeles; Santiago, César; Frade, José Miguel Rodríguez; Franco, Rafael; Mellado, Mario

    2014-01-01

    CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/CXCR4-mediated cell-cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4+ T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention. PMID:24778234

  8. Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report

    PubMed Central

    YEO, SEUNG-GU

    2015-01-01

    Hyperthermia enhances the susceptibility of tumors to radiotherapy (RT) and chemotherapy. Oncothermia, also known as electro-hyperthermia, is a new treatment modality developed to overcome the problems of traditional hyperthermia by selectively delivering energy to the malignant tissues. The present study reports the outcome of combined oncothermia and RT in a 75-year-old patient with stage IIIB non-small-cell lung cancer (NSCLC). Due to the advanced age and the performance status of the patient, the combination of systemic chemotherapy and RT was deemed infeasible; therefore, the patient instead decided to undergo oncothermia concurrently with definitive RT. The RT was administered at a dose of 64.8 Gy in 36 fractions using a three-dimensional conformal plan technique. Oncothermia was started concomitantly with RT and was performed for 60 min per session, two sessions per week, for a total of 12 sessions. No severe toxicities developed, with the exception of mild odynophagia, which resolved soon after the treatments. Follow-up computed tomography showed complete tumor response, and the patient was alive with no evidence of the disease 18 months after the completion of the treatment. In conclusion, the present case report suggests that oncothermia combined with RT, with the former possessing radiosensitizing potential and no additional toxicities, may be a promising alternative for advanced-age and/or frail patients with locally advanced NSCLC. PMID:26622391

  9. A Gustilo type IIIB open forearm fracture treated by negative pressure wound therapy and locking compression plates: a case report.

    PubMed

    Takeuchi, Naohide; Mae, Takao; Hotokezaka, Shunsuke; Sasaki, Kosuke; Matsushita, Akinobu; Miake, Go; Kuchiishi, Rintaro; Noguchi, Yasuo

    2011-10-01

    A 91-year-old female sustained injuries to her left forearm while walking across a crosswalk. X-rays showed left radial shaft and ulna shaft fractures, and the injury was a type IIIB open fracture. On the day of admission, irrigation and debridement of the open wound, and temporary fixation of the radius and ulna using an external fixator and a Kirschner wire were peformed. Six days after the surgery, we used negative pressure wound therapy (NPWT) using the V.A.C.ATS system for the open wound. Thirteen days after the first surgery, definitive fixation was performed by using locking compression plates, and full thickness skin grafting was undertaken for the open wound. NPWT is a treatment that accelerates the wound healing process through the delivery of continuous subatmospheric pressure within a closed environment. In our case, we could reduce the healing period of the soft tissue and could convert to the definitive fixation in a timely fashion. NPWT is thought to be a useful adjunct in the management of the soft tissues of open fractures. PMID:22171501

  10. Structure and activity of the RNA-targeting Type III-B CRISPR-Cas complex of Thermus thermophilus

    PubMed Central

    Zhu, Yifan; Taylor, David W.; van Duijn, Esther; Barendregt, Arjan; Vlot, Marnix; Koehorst, Jasper J.; Sakamoto, Keiko; Masuda, Akiko; Dohmae, Naoshi; Schaap, Peter J.; Doudna, Jennifer A.; Heck, Albert J.R.; Yonekura, Koji; van der Oost, John; Shinkai, Akeo

    2014-01-01

    Summary The CRISPR-Cas system is a prokaryotic host defense system against genetic elements. The Type III-B CRISPR-Cas system of the bacterium Thermus thermophilus, the TtCmr complex, is composed of six different protein subunits (Cmr1-6) and one crRNA with a stoichiometry of Cmr112131445361:crRNA1. The TtCmr complex co-purifies with crRNA species of 40 and 46 nt, originating from a distinct subset of CRISPR loci and spacers. The TtCmr complex cleaves the target RNA at multiple sites with 6 nt intervals via a 5’ ruler mechanism. Electron microscopy revealed that the structure of TtCmr resembles a ‘sea worm’ and is composed of a Cmr2-3 heterodimer ‘tail’, a helical backbone of Cmr4 subunits capped by Cmr5 subunits, and a curled ‘head’ containing Cmr1 and Cmr6. Despite having a backbone of only four Cmr4 subunits and being both longer and narrower, the overall architecture of TtCmr resembles that of Type I Cascade complexes. PMID:24119403

  11. Definitive extended field intensity-modulated radiotherapy and concurrent cisplatin chemosensitization in the treatment of IB2-IIIB cervical cancer

    PubMed Central

    Zhang, Guangyu; He, Fangfang; Fu, Chunli; Zhang, Youzhong; Yang, Qiuan; Wang, Jianbo

    2014-01-01

    Objective To assess the toxicity of delivering extended field intensity-modulated radiotherapy (EF-IMRT) and concurrent cisplatin chemotherapy for locally advanced cervical carcinoma. Methods Forty-five patients who underwent EF-IMRT and concurrent cisplatin chemotherapy for the treatment of stage IB2 to IIIB cervical cancer were retrospectively reviewed. The clinical target volume included all areas of gross and potentially microscopic disease and regional lymph node regions. All patients underwent high-dose-rate brachytherapy. The acute and late toxicity were scored using the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group late radiation morbidity scoring criteria, respectively. Results The median follow-up was 28 months (range, 5 to 62 months). Forty-two patients had a complete response, and three had a persistent disease. Of those 42 patients, 15 patients (35.7%) had recurrence. The regions of recurrence were in-field in 2 patients and out-field in 13 patients. Acute grade ≥3 gastrointestinal, genitourinary and hematologic toxicity occurred in 3, 1, and 9 patients, respectively. Three patients (6.7%) suffered from late grade 3 toxicities. Seven patients experienced ovarian transposition, 5 of those patients (71%) maintained ovarian function. Thirty-eight patients (84.4%) were alive at the last follow-up. Conclusion Concurrent cisplatin chemotherapy with EF-IMRT was safe. The acute and late toxicities are acceptable. EF-IMRT provides an opportunity to preserve endocrine function for patients with ovarian transposition. PMID:24459576

  12. Mutation Scanning of D1705 and D1709 in the RNAse IIIb Domain of MicroRNA Processing Enzyme Dicer in Cutaneous Melanoma.

    PubMed

    Sand, Michael; Bechara, Falk G; Skrygan, Marina; Sand, Daniel; Gambichler, Thilo; Bromba, Michael; Stockfleth, Eggert; Hessam, Schapoor

    2016-07-01

    Since the discovery of microRNAs (miRNAs) there have been performed several studies showing perturbations in the expression of miRNAs and the miRNA expression machinery in cutaneous melanoma. Dicer, a pivotal cytosolic enzyme of miRNA maturation has shown to be affected by both somatic and germline mutations in a variety of cancers. Recent studies have shown that recurrent somatic mutations of Dicer frequently affect the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain, therefore called hot spot mutations. The present study investigates metal-ion-binding sites D1709 and D1705 of the Dicer RNase IIIb domain in cutaneous melanomas and melanoma metastasis by Sanger sequencing. All investigated samples showed wildtype sequence and no single mutation was detected. The miRNA processing enzyme Dicer of melanoma and melanoma metastasis does not appear to be affected by mutation in the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain. PMID:26683837

  13. Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)

    PubMed Central

    Ejarque, Miriam; Mir-Coll, Joan; Gomis, Ramon; German, Michael S.; Lynn, Francis C.; Gasa, Rosa

    2016-01-01

    Atonal Homolog 8 (Atoh8) is a basic helix-loop-helix (bHLH) transcription factor that is highly conserved across species and expressed in multiple tissues during embryogenesis. In the developing pancreas, Atoh8 is expressed in endocrine progenitors but declines in hormone-positive cells, suggesting a role during early stages of the endocrine differentiation program. We previously generated a whole-body Atoh8 knockout but early lethality of null embryos precluded assessment of Atoh8 functions during organ development. Here we report the generation of a conditional Atoh8 knockout mouse strain by insertion of two loxP sites flanking exon 1 of the Atoh8 gene. Pancreas-specific Atoh8 knockout (Atoh8 Δpanc) mice were obtained by mating this strain with a Pdx1-Cre transgenic line. Atoh8 Δpanc mice were born at the expected mendelian ratio and showed normal appearance and fertility. Pancreas weight and gross pancreatic morphology were normal. All pancreatic cell lineages were present, although endocrine δ (somatostatin) cells were modestly augmented in Atoh8 Δpanc as compared to control neonates. This increase did not affect whole-body glucose tolerance in adult knockout animals. Gene expression analysis in embryonic pancreases at the time of the major endocrine differentiation wave revealed modest alterations in several early endocrine differentiation markers. Together, these data argue that Atoh8 modulates activation of the endocrine program but it is not essential for pancreas formation or endocrine differentiation in the mouse. Given the ubiquitous expression pattern of Atoh8, the availability of a mouse strain carrying a conditional allele for this gene warrants further studies using temporally regulated Cre transgenic lines to elucidate time or cell-autonomous functions of Atoh8 during development and in the adult. PMID:26752640

  14. Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design

    PubMed Central

    Fjellström, Ola; Akkaya, Sibel; Beisel, Hans-Georg; Eriksson, Per-Olof; Erixon, Karl; Gustafsson, David; Jurva, Ulrik; Kang, Daiwu; Karis, David; Knecht, Wolfgang; Nerme, Viveca; Nilsson, Ingemar; Olsson, Thomas; Redzic, Alma; Roth, Robert; Sandmark, Jenny; Tigerström, Anna; Öster, Linda

    2015-01-01

    Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1’-S2’ FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1’-S2’ binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1’-S2’ binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds. PMID:25629509

  15. Cave spiders choose optimal environmental factors with respect to the generated entropy when laying their cocoon

    NASA Astrophysics Data System (ADS)

    Chiavazzo, Eliodoro; Isaia, Marco; Mammola, Stefano; Lepore, Emiliano; Ventola, Luigi; Asinari, Pietro; Pugno, Nicola Maria

    2015-01-01

    The choice of a suitable area to spiders where to lay eggs is promoted in terms of Darwinian fitness. Despite its importance, the underlying factors behind this key decision are generally poorly understood. Here, we designed a multidisciplinary study based both on in-field data and laboratory experiments focusing on the European cave spider Meta menardi (Araneae, Tetragnathidae) and aiming at understanding the selective forces driving the female in the choice of the depositional area. Our in-field data analysis demonstrated a major role of air velocity and distance from the cave entrance within a particular cave in driving the female choice. This has been interpreted using a model based on the Entropy Generation Minimization - EGM - method, without invoking best fit parameters and thanks to independent lab experiments, thus demonstrating that the female chooses the depositional area according to minimal level of thermo-fluid-dynamic irreversibility. This methodology may pave the way to a novel approach in understanding evolutionary strategies for other living organisms.

  16. Review of Operational Water Consumption and Withdrawal Factors for Electricity Generating Technologies

    SciTech Connect

    Macknick, J.; Newmark, R.; Heath, G.; Hallett, K. C.

    2011-03-01

    Various studies have attempted to consolidate published estimates of water use impacts of electricity generating technologies, resulting in a wide range of technologies and values based on different primary sources of literature. The goal of this work is to consolidate the various primary literature estimates of water use during the generation of electricity by conventional and renewable electricity generating technologies in the United States to more completely convey the variability and uncertainty associated with water use in electricity generating technologies.

  17. A qualitative study of factors influencing different generations of Newfoundland and Saskatchewan trained physicians to leave a work location

    PubMed Central

    2012-01-01

    Background Some studies have suggested that young physicians may have different expectations and practice behaviours than their older generational counterparts, including their reasons for wanting to remain or leave a community. This study examined the factors associated with a physician’s decision to leave a work location. We compared different generations of physicians to assess whether these factors have changed over generations. Methods We conducted semi-structured, qualitative interviews with 48 physicians who graduated from two Canadian medical schools. We asked each physician about the number and nature of work location changes and the factors related to their decisions to leave each location. Interview transcripts and notes were analysed using a thematic analysis approach. Results Dissatisfaction with the working environment was the most frequently cited reason for leaving a location for physicians of all generations. Elements which contributed to the quality of the work environment included the collaborative nature of the practice, the relationship with administrators, and access to resources and personnel. For younger physicians, the work environment had to meet their personal expectations for work-life balance. While remuneration level was given by some physicians as the key reason for leaving a location, for others it was the “last straw” if the work environment was poor. A small number of older generation physicians moved in response to political events and/or policies Conclusions We documented generational differences in physicians’ reasons for choosing a work location. We found that a poor work environment was universally the most important reason why a physician chose to leave a location. A few physicians who were unsatisfied with their work location identified level of remuneration as an additional reason for leaving. Some older generation physicians cited political climate as a reason for leaving a work location. While economic factors

  18. Universal risk factors for multifactorial diseases: LifeLines: a three-generation population-based study.

    PubMed

    Stolk, Ronald P; Rosmalen, Judith G M; Postma, Dirkje S; de Boer, Rudolf A; Navis, Gerjan; Slaets, Joris P J; Ormel, Johan; Wolffenbuttel, Bruce H R

    2008-01-01

    The risk for multifactorial diseases is determined by risk factors that frequently apply across disorders (universal risk factors). To investigate unresolved issues on etiology of and individual's susceptibility to multifactorial diseases, research focus should shift from single determinant-outcome relations to effect modification of universal risk factors. We present a model to investigate universal risk factors of multifactorial diseases, based on a single risk factor, a single outcome measure, and several effect modifiers. Outcome measures can be disease overriding, such as clustering of disease, frailty and quality of life. "Life course epidemiology" can be considered as a specific application of the proposed model, since risk factors and effect modifiers of multifactorial diseases typically have a chronic aspect. Risk factors are categorized into genetic, environmental, or complex factors, the latter resulting from interactions between (multiple) genetic and environmental factors (an example of a complex factor is overweight). The proposed research model of multifactorial diseases assumes that determinant-outcome relations differ between individuals because of modifiers, which can be divided into three categories. First, risk-factor modifiers that determine the effect of the determinant (such as factors that modify gene-expression in case of a genetic determinant). Second, outcome modifiers that determine the expression of the studied outcome (such as medication use). Third, generic modifiers that determine the susceptibility for multifactorial diseases (such as age). A study to assess disease risk during life requires phenotype and outcome measurements in multiple generations with a long-term follow up. Multiple generations will also enable to separate genetic and environmental factors. Traditionally, representative individuals (probands) and their first-degree relatives have been included in this type of research. We put forward that a three-generation

  19. Favorable outcome of rivaroxaban-associated intracerebral hemorrhage reversed by 4-factor prothrombin complex concentrate: impact on thrombin generation.

    PubMed

    Kauffmann, Sophie; Chabanne, Russell; Coste, Aurélien; Longeras, François; Sinegre, Thomas; Schmidt, Jeannot; Samama, Charles-Marc; Constantin, Jean-Michel; Lebreton, Aurélien

    2015-06-01

    The management of life-threatening bleeding associated with rivaroxaban remains a challenge for physicians due to the lack of evidence about clinically effective options for anticoagulation reversal. We report a favorable outcome in a patient receiving rivaroxaban prophylaxis, who developed a spontaneous subdural hematoma treated by a surgical evacuation and administration of 4-factor prothrombin complex concentrate. Classical coagulation variables were associated with impaired thrombin generation. Reversal with prothrombin complex concentrates improved all thrombin generation measures. Thrombin generation tests may be suitable for assessing the clinical utility of reversal drugs on rivaroxaban-induced coagulopathy. PMID:26035221

  20. Dependent Personality Disorder: Comparing an Expert Generated and Empirically Derived Five-Factor Model Personality Disorder Count

    ERIC Educational Resources Information Center

    Miller, Joshua D.; Lynam, Donald R.

    2008-01-01

    Assessment of the "Diagnostic and Statistical Manual of Mental Disorders" (4th Ed.; "DSM-IV") personality disorders (PDs) using five-factor model (FFM) prototypes and counts has shown substantial promise, with a few exceptions. Miller, Reynolds, and Pilkonis suggested that the expert-generated FFM dependent prototype might be misspecified in…

  1. A GLP-Compliant Toxicology and Biodistribution Study: Systemic Delivery of an rAAV9 Vector for the Treatment of Mucopolysaccharidosis IIIB.

    PubMed

    Meadows, Aaron S; Duncan, F Jason; Camboni, Marybeth; Waligura, Kathryn; Montgomery, Chrystal; Zaraspe, Kimberly; Naughton, Bartholomew J; Bremer, William G; Shilling, Christopher; Walker, Christopher M; Bolon, Brad; Flanigan, Kevin M; McBride, Kim L; McCarty, Douglas M; Fu, Haiyan

    2015-12-01

    No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU gene delivery in WT C57BL/6 mice at 1 × 10(14) vg/kg and 2 × 10(14) vg/kg (n = 30/group, M:F = 1:1), and non-GLP testing in MPS IIIB mice at 2 × 10(14) vg/kg. Importantly, no adverse clinical signs or chronic toxicity were observed through the 6 month study duration. The rAAV9-mediated rNAGLU expression was rapid and persistent in virtually all tested CNS and somatic tissues. However, acute liver toxicity occurred in 33% (5/15) WT males in the 2 × 10(14) vg/kg cohort, which was dose-dependent, sex-associated, and genotype-specific, likely due to hepatic rNAGLU overexpression. Interestingly, a significant dose response was observed only in the brain and spinal cord, whereas in the liver at 24 weeks postinfection (pi), NAGLU activity was reduced to endogenous levels in the high dose cohort but remained at supranormal levels in the low dose group. The possibility of rAAV9 germline transmission appears to be minimal. The vector delivery resulted in transient T-cell responses and characteristic acute antibody responses to both AAV9 and rNAGLU in all rAAV9-treated animals, with no detectable impacts on tissue transgene expression. This study demonstrates a generally safe and effective profile, and may have identified the upper dosing limit of rAAV9-CMV-hNAGLU via systemic delivery for the treatment of MPS IIIB. PMID:26684447

  2. Factors Associated with College Students' Intentions to Vaccinate Their Daughters Against HPV: Protecting the Next Generation.

    PubMed

    Wilson, Kelly L; White, Alice; Rosen, Brittany L; Chiappone, Alethea; Pulczinski, Jairus C; Ory, Marcia G; Smith, Matthew Lee

    2016-10-01

    Human papillomavirus (HPV) is a contemporary public health concern because of its association with cervical cancer. Despite evidence about HPV vaccination benefits, debate surrounds whether or not to vaccinate American youth. While no nationwide mandate exists, understanding the behaviors and intentions of future parents may provide insight about our ability to protect the next generation of school-aged youth. The purposes of this study were to examine factors associated with unmarried college students' intentions to: (1) vaccinate their daughters against HPV and (2) give their daughters the choice about whether or not to be vaccinated. Data were analyzed from 1606 college students aged 18-26 using an internet-delivered questionnaire. Two binary logistic regression analyses were performed identifying predictor variables associated with participants' intentions when having daughters in the future to vaccinate them against HPV and whether or not they would let their daughters decide to get the vaccination. Relative to those who did not intend to vaccinate their daughters against HPV, participants who were female (OR 1.55, P = 0.018), sexually active (OR 1.62, P = 0.001), diagnosed with HPV (OR 2.64, P < 0.001), received a flu shot in the past 12 months (OR 1.63, P = 0.002), perceived the HPV vaccine to be safe (OR 1.19, P < 0.001), and supported HPV vaccination mandates for school-aged youth (OR 2.58, P < 0.001) were more likely to report intentions of vaccinating their daughters against HPV. Participants who were sexually active (OR 1.45, P = 0.002) and perceived the HPV vaccine to be safe (OR 1.05, P = 0.012) were more likely to report they would allow their daughters to choose whether to be vaccinated against HPV. Until HPV vaccination mandates are enacted, parental support of vaccines are among the most effective way of increasing vaccine uptake. Identifying HPV vaccination support among future parents has potential to inform parent vaccination

  3. Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists.

    PubMed Central

    Di Marco, A; Gloaguen, I; Graziani, R; Paonessa, G; Saggio, I; Hudson, K R; Laufer, R

    1996-01-01

    Ciliary neurotrophic factor (CNTF) drives the sequential assembly of a receptor complex containing the ligand-specific alpha-receptor subunit (CNTFR alpha) and the signal transducers gp130 and leukemia inhibitory factor receptor-beta (LIFR). The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR. The functional importance of these residues was assessed by alanine mutagenesis. Substitution of either F152 or K155 with alanine was found to specifically inhibit cytokine interaction with LIFR without affecting binding to CNTFR alpha or gp130. The resulting variants behaved as partial agonists with varying degrees of residual bioactivity in different cell-based assays. Simultaneous alanine substitution of both F152 and K155 totally abolished biological activity. Combining these mutations with amino acid substitutions in the D-helix, which enhance binding affinity for the CNTFR alpha, gave rise to a potent competitive CNTF receptor antagonist. This protein constitutes a new tool for studies of CNTF function in normal physiology and disease. Images Fig. 1 Fig. 6 PMID:8799186

  4. Wind Power predictability a risk factor in the design, construction and operation of Wind Generation Turbines

    NASA Astrophysics Data System (ADS)

    Thiesen, J.; Gulstad, L.; Ristic, I.; Maric, T.

    2010-09-01

    Summit: The wind power predictability is often a forgotten decision and planning factor for most major wind parks, both onshore and offshore. The results of the predictability are presented after having examined a number of European offshore and offshore parks power predictability by using three(3) mesoscale model IRIE_GFS and IRIE_EC and WRF. Full description: It is well known that the potential wind production is changing with latitude and complexity in terrain, but how big are the changes in the predictability and the economic impacts on a project? The concept of meteorological predictability has hitherto to some degree been neglected as a risk factor in the design, construction and operation of wind power plants. Wind power plants are generally built in places where the wind resources are high, but these are often also sites where the predictability of the wind and other weather parameters is comparatively low. This presentation addresses the question of whether higher predictability can outweigh lower average wind speeds with regard to the overall economy of a wind power project. Low predictability also tends to reduce the value of the energy produced. If it is difficult to forecast the wind on a site, it will also be difficult to predict the power production. This, in turn, leads to increased balance costs and a less reduced carbon emission from the renewable source. By investigating the output from three(3) mesoscale models IRIE and WRF, using ECMWF and GFS as boundary data over a forecasting period of 3 months for 25 offshore and onshore wind parks in Europe, the predictability are mapped. Three operational mesoscale models with two different boundary data have been chosen in order to eliminate the uncertainty with one mesoscale model. All mesoscale models are running in a 10 km horizontal resolution. The model output are converted into "day a head" wind turbine generation forecasts by using a well proven advanced physical wind power model. The power models

  5. Updated greenhouse gas and criteria air pollutant emission factors and their probability distribution functions for electricity generating units

    SciTech Connect

    Cai, H.; Wang, M.; Elgowainy, A.; Han, J.

    2012-07-06

    Greenhouse gas (CO{sub 2}, CH{sub 4} and N{sub 2}O, hereinafter GHG) and criteria air pollutant (CO, NO{sub x}, VOC, PM{sub 10}, PM{sub 2.5} and SO{sub x}, hereinafter CAP) emission factors for various types of power plants burning various fuels with different technologies are important upstream parameters for estimating life-cycle emissions associated with alternative vehicle/fuel systems in the transportation sector, especially electric vehicles. The emission factors are typically expressed in grams of GHG or CAP per kWh of electricity generated by a specific power generation technology. This document describes our approach for updating and expanding GHG and CAP emission factors in the GREET (Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation) model developed at Argonne National Laboratory (see Wang 1999 and the GREET website at http://greet.es.anl.gov/main) for various power generation technologies. These GHG and CAP emissions are used to estimate the impact of electricity use by stationary and transportation applications on their fuel-cycle emissions. The electricity generation mixes and the fuel shares attributable to various combustion technologies at the national, regional and state levels are also updated in this document. The energy conversion efficiencies of electric generating units (EGUs) by fuel type and combustion technology are calculated on the basis of the lower heating values of each fuel, to be consistent with the basis used in GREET for transportation fuels. On the basis of the updated GHG and CAP emission factors and energy efficiencies of EGUs, the probability distribution functions (PDFs), which are functions that describe the relative likelihood for the emission factors and energy efficiencies as random variables to take on a given value by the integral of their own probability distributions, are updated using best-fit statistical curves to characterize the uncertainties associated with GHG and CAP emissions in life

  6. Factor XIa and Thrombin Generation Are Elevated in Patients with Acute Coronary Syndrome and Predict Recurrent Cardiovascular Events

    PubMed Central

    Loeffen, Rinske; van Oerle, René; Leers, Mathie P. G.; Kragten, Johannes A.; Crijns, Harry; Spronk, Henri M. H.; ten Cate, Hugo

    2016-01-01

    Objective In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS. Methods We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis. Results Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]). Conclusion ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events. PMID:27419389

  7. Hyperbaric oxygen therapy for carcinoma of the cervix - Stages IIB, IIIA, IIIB, and IVA: results of a randomized study by the radiation therapy oncology group

    SciTech Connect

    Brady, L.W.; Plenk,H.P.; Hanley, J.A.

    1981-08-01

    A total of 65 patients with Stage IIB, IIIA, IIIB or IVA carcinoma of the cervix were randomized to receive conventional radiation therapy in air or hyperbaric oxygen therapy with radiation at optimal schedules. Seven patients could not be evaluated. Of the 19 patients treated in oxygen, 14 (73%) were living or had died without evidence of disease. Of the 29 patients treated with radiation alone 15 (52%) were alive or had died without evidence of tumor. Two of 29 patients treated in air and 5 of 19 patients treated in oxygen were dead of complications or intercurrent disease. No significant difference in survival could be demonstrated.

  8. Interaction of Platelet Activating Factor, Reactive Oxygen Species Generated by Xanthine Oxidase, and Leukocytes in the Generation of Hepatic Injury After Shock/Resuscitation

    PubMed Central

    Yamakawa, Yasuhiko; Takano, Manabu; Patel, Mayur; Tien, Nevin; Takada, Tadahiro; Bulkley, Gregory B.

    2000-01-01

    Objective To evaluate the putative relation of platelet activating factor (PAF), xanthine oxidase, reactive oxidants, and leukocytes in the pathogenesis of hepatic injury after shock/resuscitation (S/R) in vivo. Background Reactive oxygen metabolites generated by xanthine oxidase at reperfusion have been found to trigger postischemic injury in many organs, including the liver. However, the precise linear sequence of the mechanism of consequent hepatic injury after S/R remains to be characterized. Methods Unheparinized male rats were bled to a mean blood pressure of 45 ± 3 mmHg. After 2 hours of shock, they were resuscitated by reinfusion of shed blood (anticoagulated with citrate-phosphate-dextrose) and crystalloid and observed for the next 6 or 24 hours. Results S/R caused the oxidation of hepatic glutathione and generated centrolobular leukocyte accumulation at 6 hours, followed by predominantly centrolobular hepatocellular injury at 24 hours. Each of these components was attenuated by PAF inhibition with WEB 2170, xanthine oxidase inhibition with allopurinol, antioxidant treatment with N-acetylcysteine, or severe leukopenia induced by vinblastine. In each case, the degree of leukocyte accumulation at 6 hours correlated with the hepatocellular injury seen at 24 hours. However, xanthine oxidase inhibition with allopurinol failed to attenuate further the small level of residual hepatocellular injury seen in leukopenic rats. Conclusion These findings suggest that reactive oxidants generated by xanthine oxidase at reperfusion, stimulated by PAF, mediate hepatocellular injury by triggering leukocyte accumulation, primarily within the centrolobular sinusoids. PMID:10714632

  9. First-Generation Freshman College Students: Factors Impacting Retention for the Subsequent Year

    ERIC Educational Resources Information Center

    McLean, Laura Colson

    2013-01-01

    Against all odds, first-generation college students continue to enroll in postsecondary schools with aspirations of obtaining a bachelor's degree. Unfortunately, many have not successfully reached their goal, which in turn has affected retention rates of colleges and universities. There are programs that provide academic support and advising to…

  10. Contextual Factors Contributing to Ethnic Identity Development of Second-Generation Iranian American Adolescents

    ERIC Educational Resources Information Center

    Daha, Maryam

    2011-01-01

    The data drawn from interviews with 55 second-generation Iranian American adolescents revealed that pride in ancient Persian culture, the adolescents' physical characteristics, perceived stereotypes, and community point of reference all combined to affect ethnic identity as well as to reinforce a sense of ethnic loyalty. The contextual factors…

  11. Viewing Generativity and Social Capital as Underlying Factors of Parent Involvement

    ERIC Educational Resources Information Center

    Stevens, Sharon; Patel, Nimisha

    2015-01-01

    Parent involvement in education is a multifaceted support that has many well-documented benefits for students of all ages. Parent involvement is also a common expression of generativity as defined in Erik Erikson's theory of psychosocial development. The activities parents engage in during their children's educational pursuits, as well as their…

  12. Concurrent Phosphorus Recovery and Energy Generation in Mediator-Less Dual Chamber Microbial Fuel Cells: Mechanisms and Influencing Factors

    PubMed Central

    Almatouq, Abdullah; Babatunde, Akintunde O.

    2016-01-01

    This study investigated the mechanism and key factors influencing concurrent phosphorus (P) recovery and energy generation in microbial fuel cells (MFC) during wastewater treatment. Using a mediator-less dual chamber microbial fuel cell operated for 120 days; P was shown to precipitate as struvite when ammonium and magnesium chloride solutions were added to the cathode chamber. Monitoring data for chemical oxygen demand (COD), pH, oxidation reduction potential (ORP) and aeration flow rate showed that a maximum 38% P recovery was achieved; and this corresponds to 1.5 g/L, pH > 8, −550 ± 10 mV and 50 mL/min respectively, for COD, pHcathode, ORP and cathode aeration flow rate. More importantly, COD and aeration flow rate were shown to be the key influencing factors for the P recovery and energy generation. Results further show that the maximum P recovery corresponds to 72 mW/m2 power density. However, the energy generated at maximum P recovery was not the optimum; this shows that whilst P recovery and energy generation can be concurrently achieved in a microbial fuel cell, neither can be at the optimal value. PMID:27043584

  13. Concurrent Phosphorus Recovery and Energy Generation in Mediator-Less Dual Chamber Microbial Fuel Cells: Mechanisms and Influencing Factors.

    PubMed

    Almatouq, Abdullah; Babatunde, Akintunde O

    2016-04-01

    This study investigated the mechanism and key factors influencing concurrent phosphorus (P) recovery and energy generation in microbial fuel cells (MFC) during wastewater treatment. Using a mediator-less dual chamber microbial fuel cell operated for 120 days; P was shown to precipitate as struvite when ammonium and magnesium chloride solutions were added to the cathode chamber. Monitoring data for chemical oxygen demand (COD), pH, oxidation reduction potential (ORP) and aeration flow rate showed that a maximum 38% P recovery was achieved; and this corresponds to 1.5 g/L, pH > 8, -550 ± 10 mV and 50 mL/min respectively, for COD, pH(cathode), ORP and cathode aeration flow rate. More importantly, COD and aeration flow rate were shown to be the key influencing factors for the P recovery and energy generation. Results further show that the maximum P recovery corresponds to 72 mW/m² power density. However, the energy generated at maximum P recovery was not the optimum; this shows that whilst P recovery and energy generation can be concurrently achieved in a microbial fuel cell, neither can be at the optimal value. PMID:27043584

  14. Enhanced hemangioblast generation and improved vascular repair and regeneration from embryonic stem cells by defined transcription factors.

    PubMed

    Liu, Fang; Bhang, Suk Ho; Arentson, Elizabeth; Sawada, Atsushi; Kim, Chan Kyu; Kang, Inyoung; Yu, Jinsheng; Sakurai, Nagisa; Kim, Suk Hyung; Yoo, Judy Ji Woon; Kim, Paul; Pahng, Seong Ho; Xia, Younan; Solnica-Krezel, Lilianna; Choi, Kyunghee

    2013-01-01

    The fetal liver kinase 1 (FLK-1)(+) hemangioblast can generate hematopoietic, endothelial, and smooth muscle cells (SMCs). ER71/ETV2, GATA2, and SCL form a core transcriptional network in hemangioblast development. Transient coexpression of these three factors during mesoderm formation stage in mouse embryonic stem cells (ESCs) robustly enhanced hemangioblast generation by activating bone morphogenetic protein (BMP) and FLK-1 signaling while inhibiting phosphatidylinositol 3-kinase, WNT signaling, and cardiac output. Moreover, etsrp, gata2, and scl inhibition converted hematopoietic field of the zebrafish anterior lateral plate mesoderm to cardiac. FLK-1(+) hemangioblasts generated by transient coexpression of the three factors (ER71-GATA2-SCL [EGS]-induced FLK-1(+)) effectively produced hematopoietic, endothelial, and SMCs in culture and in vivo. Importantly, EGS-induced FLK-1(+) hemangioblasts, when codelivered with mesenchymal stem cells as spheroids, were protected from apoptosis and generated functional endothelial cells and SMCs in ischemic mouse hindlimbs, resulting in improved blood perfusion and limb salvage. ESC-derived, EGS-induced FLK-1(+) hemangioblasts could provide an attractive cell source for future hematopoietic and vascular repair and regeneration. PMID:24052951

  15. Factors affecting eluation characteristics of sorption generators of technetium-99m

    NASA Astrophysics Data System (ADS)

    Skuridin, V. S.; Chernov, V. I.; Sadkin, V. L.; Stasyuk, E. S.; Varlamova, N. V.; Rogov, A. S.; Nesterov, E. A.; Ilina, E. A.; Larionova, L. A.; Medvedeva, A. A.

    2016-08-01

    The influence of the adsorbed mass of molybdenum on the width of eluation profiles of generators and the patterns of molybdenum distribution in the amount of chromatographic columns by scanning them on the germanium-gallium detector using collimating device are studied. The boundary conditions under which the maximum value of 99mTc yield from generators Ye = 1 are defined. After scanning the columns, it was found out that the degree of filling the columns with molybdenum Q and the value of its maximum adsorption depend naturally on the total weight of the adsorbed mass. In order to achieve the condition Ye = 1 the value of Q should be at least 85%.

  16. Perceived Factors Influencing the Pursuit of Higher Education among First-Generation College Students

    ERIC Educational Resources Information Center

    Coy-Ogan, Lynne

    2009-01-01

    Students who are first in their families to pursue higher education are often less likely to receive the academic, social, and financial support needed to experience success when compared to students from college-educated families. This study examined the perceived differences among salient factors influencing the pursuit of higher education…

  17. Key Motivational Factors in the Retention of Three Generations of Public High School Mathematics Teachers

    ERIC Educational Resources Information Center

    Pospichal, Wendy

    2011-01-01

    Purpose: The purpose of this study was to describe and compare the similarities and differences between five key motivational factors: (a) new teacher induction, (b) noninduction mentor support in the early years of teaching, (c) salary and benefits, (d) working conditions, and (e) administrative support influential in retention of employment in…

  18. Factors Related to Perceived Status in the Campus Community for First Generation Students at an HBCU

    ERIC Educational Resources Information Center

    Longmire-Avital, Buffie; Miller-Dyce, Cherrel

    2013-01-01

    Research that has examined the complexities of within-group difference as they related to socioeconomic diversity has been necessary to fully understand the myriad of factors that affected college experience, persistence, and graduation rates of Black students not just at predominately White institutions (PWI's), but also at the Historically Black…

  19. Complicating factors in safety testing of drug metabolites: Kinetic differences between generated and preformed metabolites

    SciTech Connect

    Prueksaritanont, Thomayant . E-mail: thomayant_prueksaritanont@merck.com; Lin, Jiunn H.; Baillie, Thomas A.

    2006-12-01

    This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.

  20. Application of a microscale emission factor model for particulate matter to calculate vehicle-generated contributions to fine particulate emissions.

    PubMed

    Singh, Rakesh B; Desloges, Catherine; Sloan, James J

    2006-01-01

    This paper discusses the evaluation and application of a new generation of particulate matter (PM) emission factor model (MicroFacPM). MicroFacPM that was evaluated in Tuscarora Mountain Tunnel, Pennsylvania Turnpike, PA shows good agreement between measured and modeled emissions. MicroFacPM application is presented to the vehicle traffic on the main approach road to the Ambassador Bridge, which is one of the most important international border entry points in North America, connecting Detroit, MI, with Windsor, Ontario, Canada. An increase in border security has forced heavy-duty diesel vehicles to line up for several kilometers through the city of Windsor causing concern about elevated concentrations of ambient PM. MicroFacPM has been developed to model vehicle-generated PM (fine [PM2.5] and coarse < or = 10 microm [PM10]) from the on-road vehicle fleet, which in this case includes traffic at very low speeds (10 km/h). The Windsor case study gives vehicle generated PM2.5 sources and their breakdown by vehicle age and class. It shows that the primary sources of vehicle-generated PM2.5 emissions are the late-model heavy-duty diesel vehicles. We also applied CALINE4 and AERMOD in conjunction with MicroFacPM, using Canadian traffic and climate conditions, to describe the vehicle-generated PM2.5 dispersion near this roadway during the month of May in 2003. PMID:16499145

  1. Environmental and sustainability factors associated with next-generation biofuels in the U.S.: what do we really know?

    PubMed

    Williams, Pamela R D; Inman, Daniel; Aden, Andy; Heath, Garvin A

    2009-07-01

    In this paper, we assess what is known or anticipated about environmental and sustainability factors associated with next-generation biofuels relative to the primary conventional biofuels (i.e., corn grain-based ethanol and soybean-based diesel) in the United States during feedstock production and conversion processes. Factors considered include greenhouse (GHG) emissions, air pollutant emissions, soil health and quality, water use and water quality, wastewater and solid waste streams, and biodiversity and land-use changes. Based on our review of the available literature, we find that the production of next-generation feedstocks in the U.S. (e.g., municipal solid waste, forest residues, dedicated energy crops, microalgae) are expected to fare better than corn-grain or soybean production on most of these factors, although the magnitude of these differences may vary significantly among feedstocks. Ethanol produced using a biochemical or thermochemical conversion platform is expected to result in fewer GHG and air pollutant emissions, but to have similar or potentially greater water demands and solid waste streams than conventional ethanol biorefineries in the U.S. However, these conversion-related differences are likely to be small, particularly relative to those associated with feedstock production. Modeling performed for illustrative purposes and to allow for standardized quantitative comparisons across feedstocks and conversion technologies generally confirms the findings from the literature. Despite current expectations, significant uncertainty remains regarding how well next-generation biofuels will fare on different environmental and sustainability factors when produced on a commercial scale in the U.S. Additional research is needed in several broad areas including quantifying impacts, designing standardized metrics and approaches, and developing decision-support tools to identify and quantify environmental trade-offs and ensure sustainable biofuels production

  2. State-level Greenhouse Gas Emission Factors for Electricity Generation, Updated

    EIA Publications

    2001-01-01

    To assist reporters in estimating emissions and emission reductions, The Energy Information Administration (EIA) has made available in the instructions to Forms EIA-1605 and EIA-1605EZ emission coefficients for most commonly used fossil fuels and electricity. These coefficients were based on 1992 emissions and generation data. In 1999, updated coefficients were prepared based on the most recent data (1998) then available; however, the updated coefficients were not included in the instructions for the 1999 data year. This year, they have been updated again, but based on three years worth of data (1997, 1998, and 1999) rather than a single year.

  3. Generation of in vivo activating factors in the ischemic intestine by pancreatic enzymes

    NASA Astrophysics Data System (ADS)

    Mitsuoka, Hiroshi; Kistler, Erik B.; Schmid-Schönbein, Geert W.

    2000-02-01

    One of the early events in physiological shock is the generation of activators for leukocytes, endothelial cells, and other cells in the cardiovascular system. The mechanism by which these activators are produced has remained unresolved. We examine here the hypothesis that pancreatic digestive enzymes in the ischemic intestine may be involved in the generation of activators during intestinal ischemia. The lumen of the small intestine of rats was continuously perfused with saline containing a broadly acting pancreatic enzyme inhibitor (6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfate, 0.37 mM) before and during ischemia of the small intestine by splanchnic artery occlusion. This procedure inhibited activation of circulating leukocytes during occlusion and reperfusion. It also prevented the appearance of activators in portal venous and systemic artery plasma and attenuated initiating symptoms of multiple organ injury in shock. Intestinal tissue produces only low levels of activators in the absence of pancreatic enzymes, whereas in the presence of enzymes, activators are produced in a concentration- and time-dependent fashion. The results indicate that pancreatic digestive enzymes in the ischemic intestine serve as an important source for cell activation and inflammation, as well as multiple organ failure.

  4. Impact of Prophylactic Cranial Irradiation Timing on Brain Relapse Rates in Patients With Stage IIIB Non-Small-Cell Lung Carcinoma Treated With Two Different Chemoradiotherapy Regimens

    SciTech Connect

    Topkan, Erkan; Parlak, Cem; Kotek, Ayse; Yuksel, Oznur; Cengiz, Mustafa; Ozsahin, Mahmut; Pehlivan, Berrin

    2012-07-15

    Purpose: To retrospectively assess the influence of prophylactic cranial irradiation (PCI) timing on brain relapse rates in patients treated with two different chemoradiotherapy (CRT) regimens for Stage IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: A cohort of 134 patients, with Stage IIIB NSCLC in recursive partitioning analysis Group 1, was treated with PCI (30 Gy at 2 Gy/fr) following one of two CRT regimens. Regimen 1 (n = 58) consisted of three cycles of induction chemotherapy (ICT) followed by concurrent CRT (C-CRT). Regimen 2 (n = 76) consisted of immediate C-CRT during thoracic radiotherapy. Results: At a median follow-up of 27.6 months (range, 7.2-40.4), 65 patients were alive. Median, progression-free, and brain metastasis-free survival (BMFS) times for the whole study cohort were 23.4, 15.4, and 23.0 months, respectively. Median survival time and the 3-year survival rate for regimens 1 and 2 were 19.3 vs. 26.1 months (p = 0.001) and 14.4% vs. 34.4% (p < .001), respectively. Median time from the initiation of primary treatment to PCI was 123.2 (range, 97-161) and 63.4 (range, 55-74) days for regimens 1 and 2, respectively (p < 0.001). Overall, 11 (8.2%) patients developed brain metastasis (BM) during the follow-up period: 8 (13.8%) in regimen 1 and 3 (3.9%) in regimen 2 (p = 0.03). Only 3 (2.2%) patients developed BM at the site of first failure, and for 2 of them, it was also the sole site of recurrence. Median BMFS for regimens 1 and 2 were 17.4 (13.5-21.3) vs. 26.0 (22.9-29.1 months), respectively (p < 0.001). Conclusion: These results suggest that in Stage IIIB NSCLC patients treated with PCI, lower BM incidence and longer survival rates result from immediate C-CRT rather than ITC-first regimens. This indicates the benefit of earlier PCI use without delay because of induction protocols.

  5. TRANSCRIPTION FACTOR Bmsage PLAYS A CRUCIAL ROLE IN SILK GLAND GENERATION IN SILKWORM, Bombyx mori.

    PubMed

    Xin, Hu-hu; Zhang, Deng-pan; Chen, Rui-ting; Cai, Zi-zheng; Lu, Yan; Liang, Shuang; Miao, Yun-gen

    2015-10-01

    Salivary gland secretion is altered in Drosophila embryos with loss of function of the sage gene. Saliva has a reduced volume and an increased electron density according to transmission electron microscopy, resulting in regions of tube dilation and constriction with intermittent tube closure. However, the precise functions of Bmsage in silkworm (Bombyx mori) are unknown, although its sequence had been deposited in SilkDB. From this, Bmsage is inferred to be a transcription factor that regulates the synthesis of silk fibroin and interacts with another silk gland-specific transcription factor, namely, silk gland factor-1. In this study, we introduced a germline mutation of Bmsage using the Cas9/sgRNA system, a genome-editing technology, resulting in deletion of Bmsage from the genome of B. mori. Of the 15 tested samples, seven displayed alterations at the target site. The mutagenesis efficiency was about 46.7% and there were no obvious off-target effects. In the screened homozygous mutants, silk glands developed poorly and the middle and posterior silk glands (MSG and PSG) were absent, which was significantly different from the wild type. The offspring of G0 mosaic silkworms had indel mutations causing 2- or 9-bp deletions at the target site, but exhibited the same abnormal silk gland structure. Mutant larvae containing different open-reading frames of Bmsage had the same silk gland phenotype. This illustrated that the mutant phenotype was due to Bmsage knockout. We conclude that Bmsage participates in embryonic development of the silk gland. PMID:25917878

  6. Generation and Characterization of Small Single Domain Antibodies Inhibiting Human Tumor Necrosis Factor Receptor 1*

    PubMed Central

    Steeland, Sophie; Puimège, Leen; Vandenbroucke, Roosmarijn E.; Van Hauwermeiren, Filip; Haustraete, Jurgen; Devoogdt, Nick; Hulpiau, Paco; Leroux-Roels, Geert; Laukens, Debby; Meuleman, Philip; De Vos, Martine; Libert, Claude

    2015-01-01

    The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named “TNF Receptor-One Silencer” (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin-α/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients. PMID:25538244

  7. Aberrant DNA methylation reprogramming during induced pluripotent stem cell generation is dependent on the choice of reprogramming factors.

    PubMed

    Planello, Aline C; Ji, Junfeng; Sharma, Vivek; Singhania, Rajat; Mbabaali, Faridah; Müller, Fabian; Alfaro, Javier A; Bock, Christoph; De Carvalho, Daniel D; Batada, Nizar N

    2014-01-01

    The conversion of somatic cells into pluripotent stem cells via overexpression of reprogramming factors involves epigenetic remodeling. DNA methylation at a significant proportion of CpG sites in induced pluripotent stem cells (iPSCs) differs from that of embryonic stem cells (ESCs). Whether different sets of reprogramming factors influence the type and extent of aberrant DNA methylation in iPSCs differently remains unknown. In order to help resolve this critical question, we generated human iPSCs from a common fibroblast cell source using either the Yamanaka factors (OCT4, SOX2, KLF4 and cMYC) or the Thomson factors (OCT4, SOX2, NANOG and LIN28), and determined their genome-wide DNA methylation profiles. In addition to shared DNA methylation aberrations present in all our iPSCs, we identified Yamanaka-iPSC (Y-iPSC)-specific and Thomson-iPSC (T-iPSC)-specific recurrent aberrations. Strikingly, not only were the genomic locations of the aberrations different but also their types: reprogramming with Yamanaka factors mainly resulted in failure to demethylate CpGs, whereas reprogramming with Thomson factors mainly resulted in failure to methylate CpGs. Differences in the level of transcripts encoding DNMT3b and TET3 between Y-iPSCs and T-iPSCs may contribute partially to the distinct types of aberrations. Finally, de novo aberrantly methylated genes in Y-iPSCs were enriched for NANOG targets that are also aberrantly methylated in some cancers. Our study thus reveals that the choice of reprogramming factors influences the amount, location, and class of DNA methylation aberrations in iPSCs. These findings may provide clues into how to produce human iPSCs with fewer DNA methylation abnormalities. PMID:25408883

  8. Ambient but not incremental oxidant generation effects intercellular adhesion molecule 1 induction by tumour necrosis factor alpha in endothelium.

    PubMed

    Arai, T; Kelly, S A; Brengman, M L; Takano, M; Smith, E H; Goldschmidt-Clermont, P J; Bulkley, G B

    1998-05-01

    Proinflammatory cytokines upregulate endothelial adhesion molecule expression, thereby initiating the microvascular inflammatory response. We re-evaluated the reported role of reactive oxygen metabolites (ROMs) in signalling upregulation of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by tumour necrosis factor alpha (TNF-alpha) in vitro. TNF-alpha upregulation of endothelial-cell ICAM-1 expression was inhibited by the cell-permeable antioxidants, or by the adenovirus-mediated intracellular overexpression of Cu,Zn-superoxide dismutase, but not by the exogenous (extracellular) administration of the cell-impermeable antioxidants, superoxide dismutase and/or catalase. This ICAM-1 upregulation was also inhibited by inhibitors of NADH dehydrogenase, cytochrome bc1 complex and NADPH oxidase. However, a measurable increase in net cellular ROM generation in response to TNF-alpha was not seen using four disparate sensitive ROM assays. Moreover, the stimulation of exogenous or endogenous ROM generation did not upregulate ICAM-1, nor enhance ICAM-1 upregulation by TNF-alpha. These findings suggest that an ambient background flux of ROMs, generated intracellularly, but not their net incremental generation, is necessary for TNF-alpha to induce ICAM-1 expression in endothelium in vitro. PMID:9560314

  9. The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer.

    PubMed

    Steuer, Conor E; Khuri, Fadlo R; Ramalingam, Suresh S

    2015-04-15

    The discovery of "driver" genomic alterations in patients with non-small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First-generation and second-generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR-mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third-generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third-generation agents in the treatment of patients with advanced NSCLC. PMID:25521095

  10. Bioactive saponins and glycosides. XII. Horse chestnut. (2): Structures of escins IIIb, IV, V, and VI and isoescins Ia, Ib, and V, acylated polyhydroxyoleanene triterpene oligoglycosides, from the seeds of horse chestnut tree (Aesculus hippocastanum L., Hippocastanaceae).

    PubMed

    Yoshikawa, M; Murakami, T; Yamahara, J; Matsuda, H

    1998-11-01

    New acylated polyhydroxyoleanene triterpene oligoglycosides, escins IIIb, IV, V, and VI and isoescins Ia, Ib, and V, were isolated from the seeds of horse chestnut tree (Aesculus hippocastanum L.). Their structures were elucidated on the basis of chemical and physicochemical evidence. PMID:9845957

  11. Radiation Therapy and Cisplatin With or Without Triapine in Treating Patients With Newly Diagnosed Stage IB2, II, or IIIB-IVA Cervical Cancer or Stage II-IVA Vaginal Cancer

    ClinicalTrials.gov

    2016-09-09

    Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Stage IB2 Cervical Cancer; Stage II Vaginal Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage III Vaginal Cancer; Stage IIIB Cervical Cancer; Stage IVA Cervical Cancer; Stage IVA Vaginal Cancer; Stage IVB Vaginal Cancer

  12. Non-viral generation of marmoset monkey iPS cells by a six-factor-in-one-vector approach.

    PubMed

    Debowski, Katharina; Warthemann, Rita; Lentes, Jana; Salinas-Riester, Gabriela; Dressel, Ralf; Langenstroth, Daniel; Gromoll, Jörg; Sasaki, Erika; Behr, Rüdiger

    2015-01-01

    Groundbreaking studies showed that differentiated somatic cells of mouse and human origin could be reverted to a stable pluripotent state by the ectopic expression of only four proteins. The resulting pluripotent cells, called induced pluripotent stem (iPS) cells, could be an alternative to embryonic stem cells, which are under continuous ethical debate. Hence, iPS cell-derived functional cells such as neurons may become the key for an effective treatment of currently incurable degenerative diseases. However, besides the requirement of efficacy testing of the therapy also its long-term safety needs to be carefully evaluated in settings mirroring the clinical situation in an optimal way. In this context, we chose the long-lived common marmoset monkey (Callithrix jacchus) as a non-human primate species to generate iPS cells. The marmoset monkey is frequently used in biomedical research and is gaining more and more preclinical relevance due to the increasing number of disease models. Here, we describe, to our knowledge, the first-time generation of marmoset monkey iPS cells from postnatal skin fibroblasts by non-viral means. We used the transposon-based, fully reversible piggyback system. We cloned the marmoset monkey reprogramming factors and established robust and reproducible reprogramming protocols with a six-factor-in-one-construct approach. We generated six individual iPS cell lines and characterized them in comparison with marmoset monkey embryonic stem cells. The generated iPS cells are morphologically indistinguishable from marmoset ES cells. The iPS cells are fully reprogrammed as demonstrated by differentiation assays, pluripotency marker expression and transcriptome analysis. They are stable for numerous passages (more than 80) and exhibit euploidy. In summary, we have established efficient non-viral reprogramming protocols for the derivation of stable marmoset monkey iPS cells, which can be used to develop and test cell replacement therapies in

  13. Factors affecting the pore space transformation during hydrocarbon generation in source rock (shales): laboratory experiment

    NASA Astrophysics Data System (ADS)

    Giliazetdinova, D. R.; Korost, D. V.

    2014-12-01

    Oil and gas generation is a set of processes which taking place in the interior, the processes can't be observable in nature. In the process of dumping the source rock, organic matter is transformed into a complex of high-molecular compounds - precursors of oil and gas (kerogen). Entering of a source column for specific thermobaric conditions, triggers the formation of low molecular weight hydrocarbon compounds. Generation of sufficient quantities of hydrocarbons leads to the primary fluid migration within the source rock. For the experiment were selected mainly siliceous-carbonate composition rocks from Domanic horizon South-Tatar arch. The main aim of experiment was heating the rocks in the pyrolyzer to temperatures which correspond katagenes stages. For monitoring changes in the morphology of the pore space X-ray microtomography method was used. As a result, when was made a study of the composition of mineral and organic content of the rocks, as well as textural and structural features, have been identified that the majority of the rock samples within the selected collection are identical. However, characteristics such as organic content and texture of rocks are different. Thus, the experiment was divided into two parts: 1) the study of the influence of organic matter content on the morphology of the rock in the process of thermal effects; 2) study the effect of texture on the primary migration processes for the same values of organic matter. Also, an additional experiment was conducted to study the dynamics of changes in the structure of the pore space. At each stage of the experiment morphology of altered rocks characterized by the formation of new pores and channels connecting the primary voids. However, it was noted that the samples with a relatively low content of the organic matter had less changes in pore space morphology, in contrast to rocks with a high organic content. At the second stage of the research also revealed that the conversion of the pore

  14. Generation of serrated and wavy petals by inhibition of the activity of TCP transcription factors in Arabidopsis thaliana

    PubMed Central

    Ohme-Takagi, Masaru; Sato, Fumihiko

    2011-01-01

    The final shape of shoot lateral organs, namely, leaves and flowers, is determined by coordinated growth after the initiation of primordia from shoot meristems in seed plants. This coordination is achieved by the complex action of many transcription factors, which include the TEOSINTE BRANCHED1, CYCLOIDEA and PCF (TCP) family. We have recently reported that CINCINNATA-like (CIN-like) TCP genes act dose-dependently to regulate the flat and smooth morphology of leaves in Arabidopsis thaliana. In contrast, the roles of CIN-like TCP genes in flower development are poorly understood. In this report, using multiple tcp mutants and transgenic plants in which the activity of CIN-like TCP transcription factors is dominantly inhibited, we found that these TCPs regulate the smooth and flat morphology of petals. Based on these findings, we discuss a possible strategy to generate a fringed morphology in floricultural plants. PMID:21455021

  15. Feasibility and Safety of Systemic rAAV9-hNAGLU Delivery for Treating Mucopolysaccharidosis IIIB: Toxicology, Biodistribution, and Immunological Assessments in Primates

    PubMed Central

    Murrey, Darren A.; Naughton, Bartholomew J.; Duncan, F. Jason; Meadows, Aaron S.; Ware, Tierra A.; Campbell, Katie J.; Bremer, William G.; Walker, Christopher M.; Goodchild, Laurie; Bolon, Brad; La Perle, Krista; Flanigan, Kevin M.; McBride, Kim L.; McCarty, Douglas M.

    2014-01-01

    Abstract No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease caused by autosomal recessive defect in α-N-acetylglucosaminidase (NAGLU). In anticipation of a clinical gene therapy treatment for MPS IIIB in humans, we tested the rAAV9-CMV-hNAGLU vector administration to cynomolgus monkeys (n=8) at 1E13 vg/kg or 2E13 vg/kg via intravenous injection. No adverse events or detectable toxicity occurred over a 6-month period. Gene delivery resulted in persistent global central nervous system and broad somatic transduction, with NAGLU activity detected at 2.9–12-fold above endogenous levels in somatic tissues and 1.3–3-fold above endogenous levels in the brain. Secreted rNAGLU was detected in serum. Low levels of preexisting anti-AAV9 antibodies (Abs) did not diminish vector transduction. Importantly, high-level preexisting anti-AAV9 Abs lead to reduced transduction in liver and other somatic tissues, but had no detectable impact on transgene expression in the brain. Enzyme-linked immunoabsorbent assay showed Ab responses to both AAV9 and rNAGLU in treated animals. Serum anti-hNAGLU Abs, but not anti-AAV9 Abs, correlated with the loss of circulating rNAGLU enzyme. However, serum Abs did not affect tissue rNAGLU activity levels. Weekly or monthly peripheral blood interferon-γ enzyme-linked immunospot assays detected a CD4+ T-cell (Th-1) response to rNAGLU only at 4 weeks postinjection in one treated subject, without observable correlation to tissue transduction levels. The treatment did not result in detectable CTL responses to either AAV9 or rNAGLU. Our data demonstrate an effective and safe profile for systemic rAAV9-hNAGLU vector delivery in nonhuman primates, supporting its clinical potential in humans. PMID:24720466

  16. Outcomes of anterolateral thigh-free flaps and conversion from external to internal fixation with bone grafting in gustilo type IIIB open tibial fractures.

    PubMed

    Lee, Jae Hoon; Chung, Duke Whan; Han, Chung Soo

    2012-09-01

    The purpose of this study was to analyze the utility and the clinical outcomes of anterolateral thigh (ALT)-free flaps and conversion from external to internal fixation with plating and bone grafting in Gustilo type IIIB open tibial fractures. A total of 21 patients were analyzed retrospectively. The mean follow-up period was 18 months and the mean age was 46.7 years. There were 18 men and three women. The mean time from injury to flap coverage was 11.6 days. The mean size of flaps used was 15.3 × 8.2 cm. The mean size of bone defects was 2.26 cm. Segmental bone defects were observed in 5 five cases, for which bone transport or vascularized fibular graft were performed. When flaps were successful and the fracture sites did not have any evidence of infection, internal fixation with plates and bone grafting were performed. Flaps survived in 20 cases. In the 20 cases with successful flaps, two cases developed osteomyelitis, but the 20 cases achieved solid bone union at a mean of 8.6 months after the injury, salvaging the lower extremity in 100% of the cases. At the last follow-up, 9 nine cases were measured excellent or good; 6, fair; and 6, poor in the functional assessment based on the method developed by Puno et al. ALT- free flaps to cover soft tissue defects in Gustilo type IIIB open tibial fractures are considered as useful option for the treatment of composite defects. In addition, conversion to internal fixation and bone grafting can be an alternative method in order to reduce the risk of complications and inconvenience of external fixators. PMID:22434519

  17. Coupling Factor Determination in the Control of Unintentionally Generated RF Fields

    NASA Technical Reports Server (NTRS)

    McCollum, Matthew B.; Clark, Tony L.

    1999-01-01

    Radiated emissions and susceptibility requirements imposed in bands where intentional RF reception or transmission does not occur is problematical. It is often desired to compare radiated emissions with radiated susceptibility performance to assess system level compatibility. For reasons purely theoretical and because of practical measurement limitations, this not realistic. McCollum and Clark proposed a limit and test method that provided a direct comparison of radiated emissions and radiated susceptibility performance in those cases where only unintentional emissions and reception are of interest (non-tunable electronics). This test method, referred to as bulk current emissions (BCE) testing, and its associated limit is a complementary test method to bulk current injection testing and radiated susceptibility testing. Previous work utilized victim and culprit circuits with low common-mode loop impedance. Forward work identified in this publication was to determine how different loop impedance on culprit and victim circuits affected cable-to-cable coupling and the corresponding BCE test limit. Cable coupling factors for victim and culprit circuits with different loop impedance are investigated.

  18. Interactions of disulfide-deficient selenocysteine analogs of μ-conotoxin BuIIIB with the α-subunit of the voltage-gated sodium channel subtype 1.3.

    PubMed

    Green, Brad R; Zhang, Min-Min; Chhabra, Sandeep; Robinson, Samuel D; Wilson, Michael J; Redding, Addison; Olivera, Baldomero M; Yoshikami, Doju; Bulaj, Grzegorz; Norton, Raymond S

    2014-07-01

    Inhibitors of the α-subunit of the voltage-gated sodium channel subtype 1.3 (NaV 1.3) are of interest as pharmacological tools for the study of neuropathic pain associated with spinal cord injury and have potential therapeutic applications. The recently described μ-conotoxin BuIIIB (μ-BuIIIB) from Conus bullatus was shown to block NaV 1.3 with submicromolar potency (Kd = 0.2 μm), making it one of the most potent peptidic inhibitors of this subtype described to date. However, oxidative folding of μ-BuIIIB results in numerous folding isoforms, making it difficult to obtain sufficient quantities of the active form of the peptide for detailed structure-activity studies. In the present study, we report the synthesis and characterization of μ-BuIIIB analogs incorporating a disulfide-deficient, diselenide-containing scaffold designed to simplify synthesis and facilitate structure-activity studies directed at identifying amino acid residues involved in NaV 1.3 blockade. Our results indicate that, similar to other μ-conotoxins, the C-terminal residues (Trp16, Arg18 and His20) are most crucial for NaV 1 blockade. At the N-terminus, replacement of Glu3 by Ala resulted in an analog with an increased potency for NaV 1.3 (Kd = 0.07 μm), implicating this position as a potential site for modification for increased potency and/or selectivity. Further examination of this position showed that increased negative charge, through γ-carboxyglutamate replacement, decreased potency (Kd = 0.33 μm), whereas replacement with positively-charged 2,4-diamonobutyric acid increased potency (Kd = 0.036 μm). These results provide a foundation for the design and synthesis of μ-BuIIIB-based analogs with increased potency against NaV 1.3. PMID:24814369

  19. Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model

    PubMed Central

    Brenneman, Mark; Field, Amanda; Yang, Jiandong; Williams, Gretchen; Doros, Leslie; Rossi, Christopher; Schultz, Kris Ann; Rosenberg, Avi; Ivanovich, Jennifer; Turner, Joyce; Gordish-Dressman, Heather; Stewart, Douglas; Yu, Weiying; Harris, Anne; Schoettler, Peter; Goodfellow, Paul; Dehner, Louis; Messinger, Yoav; Hill, D. Ashley

    2015-01-01

    Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition,  DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of  DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of  DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing  DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or  de novo germline LOF mutations, most of which truncate the  DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing  DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of  DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in  DICER1-associated  tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development. PMID:26925222

  20. Stimulus-specific deactivation of chemotactic factor-induced cyclic AMP response and superoxide generation by human neutrophils.

    PubMed Central

    Simchowitz, L; Atkinson, J P; Spilberg, I

    1980-01-01

    The responses of isolated human peripheral neutrophils to either simultaneous or sequential additions of two chemotactic factors were studied. Simultaneous additions of formyl-methionyl-leucyl-phenylalanine (10-100 nM) and the fifth component of complement, C5a (1-10 microliters/ml), evoked partially additive responses of membrane depolarization as measured by the fluorescent dye 3,3'-dipropyl-thiocarbocyanine, a transient elevation of intracellular cyclic AMP (cAMP), and superoxide (O2-) generation as assessed by ferricytochrome c reduction. Preincubation of the cells with either formyl-methionyl-leucyl-phenylalanine or C5a alone caused dose-dependent inhibition of the depolarization, the cAMP increase, and O2- release induced by a subsequent exposure to an optimal dose of the same stimulus, i.e., deactivation occurred. In contrast, when cells were treated with one chemotactic factor and then exposed to the other stimulus, the cells exhibited a normal response of peak depolarization, the rise in cAMP, and O2-0 production i.e., cross-deactivation failed to occur. The results imply that deactivation of these phenomena is stimulus specific. Further, these observations are consistent with the hypothesis that cross-deactivation of chemotaxis is mediated by one or more processes that are irrelevant to O2- generation, and that occur distal to the depolarization and cAMP steps in the sequence of neutrophil activation: possibly microtubule polymerization and orientation. PMID:6252250

  1. Analysis of Pre-Analytic Factors Affecting the Success of Clinical Next-Generation Sequencing of Solid Organ Malignancies

    PubMed Central

    Chen, Hui; Luthra, Rajyalakshmi; Goswami, Rashmi S.; Singh, Rajesh R.; Roy-Chowdhuri, Sinchita

    2015-01-01

    Application of next-generation sequencing (NGS) technology to routine clinical practice has enabled characterization of personalized cancer genomes to identify patients likely to have a response to targeted therapy. The proper selection of tumor sample for downstream NGS based mutational analysis is critical to generate accurate results and to guide therapeutic intervention. However, multiple pre-analytic factors come into play in determining the success of NGS testing. In this review, we discuss pre-analytic requirements for AmpliSeq PCR-based sequencing using Ion Torrent Personal Genome Machine (PGM) (Life Technologies), a NGS sequencing platform that is often used by clinical laboratories for sequencing solid tumors because of its low input DNA requirement from formalin fixed and paraffin embedded tissue. The success of NGS mutational analysis is affected not only by the input DNA quantity but also by several other factors, including the specimen type, the DNA quality, and the tumor cellularity. Here, we review tissue requirements for solid tumor NGS based mutational analysis, including procedure types, tissue types, tumor volume and fraction, decalcification, and treatment effects. PMID:26343728

  2. Generation of Potent Anti-Vascular Endothelial Growth Factor Neutralizing Antibodies from Mouse Phage Display Library for Cancer Therapy.

    PubMed

    Lai, Yan-Da; Wu, Yen-Yu; Tsai, Yi-Jiue; Tsai, Yi-San; Lin, Yu-Ying; Lai, Szu-Liang; Huang, Chao-Yang; Lok, Ying-Yung; Hu, Chih-Yung; Lai, Jiann-Shiun

    2016-01-01

    Vascular endothelial growth factor (VEGF) is an important stimulator for angiogenesis in solid tumors. Blocking VEGF activity is an effective therapeutic strategy to inhibit tumor growth and metastasis. Avastin, a humanized monoclonal antibody recognizes VEGF, has been approved by the US Food and Drug Administration. To generate potential VEGF-recognizing antibodies with better tumor regression ability than that of Avastin, we have designed a systematic antibody selection plan. From mice immunized with recombinant human VEGF, we generated three phage display libraries, scFv-M13KO7, Fab-M13KO7, and scFv-Hyperphage, in single-chain Fv (scFv) or Fab format, displayed using either M13KO7 helper phage or Hyperphage. Solid-phase and solution-phase selection strategies were then applied to each library, generating six panning combinations. A total of sixty-four antibodies recognizing VEGF were obtained. Based on the results of epitope mapping, binding affinity, and biological functions in tumor inhibition, eight antibodies were chosen to examine their abilities in tumor regression in a mouse xenograft model using human COLO 205 cancer cells. Three of them showed improvement in the inhibition of tumor growth (328%-347% tumor growth ratio (% of Day 0 tumor volume) on Day 21 vs. 435% with Avastin). This finding suggests a potential use of these three antibodies for VEGF-targeted therapy. PMID:26861297

  3. Generation of Potent Anti-Vascular Endothelial Growth Factor Neutralizing Antibodies from Mouse Phage Display Library for Cancer Therapy

    PubMed Central

    Lai, Yan-Da; Wu, Yen-Yu; Tsai, Yi-Jiue; Tsai, Yi-San; Lin, Yu-Ying; Lai, Szu-Liang; Huang, Chao-Yang; Lok, Ying-Yung; Hu, Chih-Yung; Lai, Jiann-Shiun

    2016-01-01

    Vascular endothelial growth factor (VEGF) is an important stimulator for angiogenesis in solid tumors. Blocking VEGF activity is an effective therapeutic strategy to inhibit tumor growth and metastasis. Avastin, a humanized monoclonal antibody recognizes VEGF, has been approved by the US Food and Drug Administration. To generate potential VEGF-recognizing antibodies with better tumor regression ability than that of Avastin, we have designed a systematic antibody selection plan. From mice immunized with recombinant human VEGF, we generated three phage display libraries, scFv-M13KO7, Fab-M13KO7, and scFv-Hyperphage, in single-chain Fv (scFv) or Fab format, displayed using either M13KO7 helper phage or Hyperphage. Solid-phase and solution-phase selection strategies were then applied to each library, generating six panning combinations. A total of sixty-four antibodies recognizing VEGF were obtained. Based on the results of epitope mapping, binding affinity, and biological functions in tumor inhibition, eight antibodies were chosen to examine their abilities in tumor regression in a mouse xenograft model using human COLO 205 cancer cells. Three of them showed improvement in the inhibition of tumor growth (328%–347% tumor growth ratio (% of Day 0 tumor volume) on Day 21 vs. 435% with Avastin). This finding suggests a potential use of these three antibodies for VEGF-targeted therapy. PMID:26861297

  4. An in vivo model to assess factors that may stimulate the generation of an immune reaction to erythropoietin.

    PubMed

    Ryan, Mary H; Heavner, George A; Brigham-Burke, Michael; McMahon, Frank; Shanahan, Mary F; Gunturi, Srinivas R; Sharma, Basant; Farrell, Francis X

    2006-04-01

    The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (s.c.) administration of epoetin alfa (EPREX) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, in vivo models were developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). It was difficult to generate anti-EPO antibodies in mice. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to increase both the frequency of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some mice exhibited a reduction in hematocrit, suggesting neutralization of endogenous EPO by anti-EPO antibodies. To evaluate the primary lead identified in the technical investigation, leachates from the uncoated syringe stoppers of EPREX syringes, a surrogate antigen (chicken egg albumin, OVA) was used to avoid possible interferences that could arise from the use of an endogenous protein like EPO. These leachates yielded a positive, concentration-dependent antibody response in the OVA animal model, demonstrating their adjuvant properties and providing support for the hypothesis generated through the technical investigation that leachates were capable of enhancing the immune response to rHuEPO. PMID:16504928

  5. Generation of leukemia inhibitory factor and basic fibroblast growth factor-dependent induced pluripotent stem cells from canine adult somatic cells.

    PubMed

    Luo, Jiesi; Suhr, Steven T; Chang, Eun Ah; Wang, Kai; Ross, Pablo J; Nelson, Laura L; Venta, Patrick J; Knott, Jason G; Cibelli, Jose B

    2011-10-01

    For more than thirty years, the dog has been used as a model for human diseases. Despite efforts made to develop canine embryonic stem cells, success has been elusive. Here, we report the generation of canine induced pluripotent stem cells (ciPSCs) from canine adult fibroblasts, which we accomplished by introducing human OCT4, SOX2, c-MYC, and KLF4. The ciPSCs expressed critical pluripotency markers and showed evidence of silencing the viral vectors and normal karyotypes. Microsatellite analysis indicated that the ciPSCs showed the same profile as the donor fibroblasts but differed from cells taken from other dogs. Under culture conditions favoring differentiation, the ciPSCs could form cell derivatives from the ectoderm, mesoderm, and endoderm. Further, the ciPSCs required leukemia inhibitory factor and basic fibroblast growth factor to survive, proliferate, and maintain pluripotency. Our results demonstrate an efficient method for deriving canine pluripotent stem cells, providing a powerful platform for the development of new models for regenerative medicine, as well as for the study of the onset, progression, and treatment of human and canine genetic diseases. PMID:21495906

  6. Generation of Leukemia Inhibitory Factor and Basic Fibroblast Growth Factor-Dependent Induced Pluripotent Stem Cells from Canine Adult Somatic Cells

    PubMed Central

    Luo, Jiesi; Suhr, Steven T.; Chang, Eun Ah; Wang, Kai; Ross, Pablo J.; Nelson, Laura L.; Venta, Patrick J.; Knott, Jason G.

    2011-01-01

    For more than thirty years, the dog has been used as a model for human diseases. Despite efforts made to develop canine embryonic stem cells, success has been elusive. Here, we report the generation of canine induced pluripotent stem cells (ciPSCs) from canine adult fibroblasts, which we accomplished by introducing human OCT4, SOX2, c-MYC, and KLF4. The ciPSCs expressed critical pluripotency markers and showed evidence of silencing the viral vectors and normal karyotypes. Microsatellite analysis indicated that the ciPSCs showed the same profile as the donor fibroblasts but differed from cells taken from other dogs. Under culture conditions favoring differentiation, the ciPSCs could form cell derivatives from the ectoderm, mesoderm, and endoderm. Further, the ciPSCs required leukemia inhibitory factor and basic fibroblast growth factor to survive, proliferate, and maintain pluripotency. Our results demonstrate an efficient method for deriving canine pluripotent stem cells, providing a powerful platform for the development of new models for regenerative medicine, as well as for the study of the onset, progression, and treatment of human and canine genetic diseases. PMID:21495906

  7. Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

    PubMed Central

    Mocca, Brian

    2012-01-01

    In mammalian cells, nitric oxide (NO·) is an important signal molecule with concentration-dependent and often controversial functions of promoting cell survival and inducing cell death. An inducible nitric oxide synthase (iNOS) in various mammalian cells produces higher levels of NO· from l-arginine upon infections to eliminate pathogens. In this study, we reveal novel pathogenic roles of NO· generated by bacteria in bacterium-host cell cocultures using Moraxella catarrhalis, a respiratory tract disease-causing bacterium, as a biological producer of NO·. We recently demonstrated that M. catarrhalis cells that express the nitrite reductase (AniA protein) can produce NO· by reducing nitrite. Our study suggests that, in the presence of pathophysiological levels of nitrite, this opportunistic pathogen hijacks host cell signaling and modulates host gene expression through its ability to produce NO· from nitrite. Bacterium-generated NO· significantly increases the secretion of tumor necrosis factor alpha (TNF-α) and modulates the expression of apoptotic proteins, therefore triggering host cell programmed death partially through TNF-α signaling. Furthermore, our study reveals that bacterium-generated NO· stalls host cell division and directly results in the death of dividing cells by reducing the levels of an essential regulator of cell division. This study provides unique insight into why NO· may exert more severe cytotoxic effects on fast growing cells, providing an important molecular basis for NO·-mediated pathogenesis in infections and possible therapeutic applications of NO·-releasing molecules in tumorigenesis. This study strongly suggests that bacterium-generated NO· can play important pathogenic roles during infections. PMID:22636782

  8. Factors expressed by murine embryonic pancreatic mesenchyme enhance generation of insulin-producing cells from hESCs.

    PubMed

    Guo, Tingxia; Landsman, Limor; Li, Na; Hebrok, Matthias

    2013-05-01

    Islet transplantation has proven to be a successful strategy to restore normoglycemia in patients with type 1 diabetes (T1D). However, the dearth of cadaveric islets available for transplantation hampers the widespread application of this treatment option. Although human embryonic stem cells and induced pluripotent stem cells are capable of generating insulin-producing cells in vitro when provided with the appropriate inductive cues, the insulin-expressing cells that develop behave more like immature β-cells with minimal sensitivity to glucose stimulation. Here, we identify a set of signaling factors expressed in mouse embryonic mesenchyme during the time when foregut and pancreatic progenitors are specified and test their activities during in vitro differentiation of human embryonic stem cells. Several of the identified factors work in concert to expand the pancreatic progenitor pool. Interestingly, transforming growth factor (TGF)-β ligands, most potent in inducing pancreatic progenitors, display strong inhibitory effects on subsequent endocrine cell differentiation. Treatment with TGF-β ligands, followed by the addition of a TGF-β receptor antagonist, dramatically increased the number of insulin-producing cells in vitro, demonstrating the need for dynamic temporal regulation of TGF-β signaling during in vitro differentiation. These studies illustrate the need to precisely mimic the in vivo conditions to fully recapitulate pancreatic lineage specification in vitro. PMID:23305648

  9. Experience with a third generation recombinant factor VIII concentrate (Advate) for immune tolerance induction in patients with haemophilia A.

    PubMed

    Valentino, L A; Recht, M; Dipaola, J; Shapiro, A D; Pipe, S W; Ewing, N; Urgo, J; Bullock, T; Simmons, M; Deguzman, C

    2009-05-01

    The development of an inhibitor represents one of the most challenging complications in patients with haemophilia A. Optimal management is immune tolerance induction (ITI), typically through the administration of high doses of factor VIII (FVIII) concentrate. Among 12 patients who underwent ITI using Advate, a third-generation recombinant FVIII product that is free of animal and human protein additives, tolerance was achieved in nine (75%), including seven of 10 patients (70%) with high-titre inhibitors. ITI is ongoing in two patients and not yet successful; immune tolerance failed in the third patient. The median time to success was 4.0 months for group as a whole and for patients with high-titre inhibitors. Treatment was well tolerated, and no adverse events were observed. Advate was found to be equivalent to other FVIII products with regard to both ITI success rates and the incidence of adverse effects when used in these immune tolerance regimens. PMID:19298383

  10. Impact of experimental haemodilution on platelet function, thrombin generation and clot firmness: effects of different coagulation factor concentrates

    PubMed Central

    Caballo, Carolina; Escolar, Gines; Diaz-Ricart, Maribel; Lopez-Vílchez, Irene; Lozano, Miguel; Cid, Joan; Pino, Marcos; Beltrán, Joan; Basora, Misericordia; Pereira, Arturo; Galan, Ana M.

    2013-01-01

    Background Haemodilution during resuscitation after massive haemorrhage may worsen the coagulopathy and perpetuate bleeding. Materials and methods Blood samples from healthy donors were diluted (30 and-60%) using crystalloids (saline, Ringer’s lactate, PlasmalyteTM) or colloids (6% hydroxyethylstarch [HES130/0.4], 5% human albumin, and gelatin). The effects of haemodilution on platelet adhesion (Impact R), thrombin generation (TG), and thromboelastometry (TEM) parameters were analysed as were the effects of fibrinogen, prothrombin complex concentrates (PCC), activated recombinant factor VII (FVIIa), and cryoprecipates on haemodilution. Results Platelet interactions was already significantly reduced at 30% haemodilution. Platelet reactivity was not improved by addition of any of the concentrates tested. A decrease in TG and marked alterations of TEM parameters were noted at 60% haemodilution. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCC whereas rFVIIa only caused a mild acceleration of TG initiation. Fibrinogen restored the alterations of TEM parameters caused by haemodilution including those caused by HES 130/0.4. Cryoprecipitates significantly improved the alterations caused by haemodilution on TG and TEM parameters; the effects on TG disappeared after ultracentrifugation of the cryoprecipitates. Discussion The haemostatic alterations caused by haemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 had the most deleterious effect on haemostasis parameters. Coagulation factor concentrates did not improve platelet interactions in the Impact R, but did have favourable effects on coagulation parameters measured by TG and TEM. Fibrinogen notably improved TEM parameters without increasing thrombin generation, suggesting that this concentrate may help to preserve blood clotting abilities during haemodilution without enhancing the prothrombotic risk. PMID

  11. Enrollment Factors that Predict Persistence of At-Risk (Low Income and First Generation) Students' Journey towards Completion of a Baccalaureate Degree at Idaho State University

    ERIC Educational Resources Information Center

    Yizar, James H., Jr.

    2010-01-01

    The purpose of this study was to explore, track, and predict longitudinal differences (over the course of six years beginning fall semester 2001) between and among ISU low income, first generation, or the combination of low income and first generation freshman students; regarding persistence rate, and associated persistence factors, such as ACT…

  12. Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors

    PubMed Central

    2010-01-01

    Background The use of lentiviruses to reprogram human somatic cells into induced pluripotent stem (iPS) cells could limit their therapeutic usefulness due to the integration of viral DNA sequences into the genome of the recipient cell. Recent work has demonstrated that human iPS cells can be generated using episomal plasmids, excisable transposons, adeno or sendai viruses, mRNA, or recombinant proteins. While these approaches offer an advance, the protocols have some drawbacks. Commonly the procedures require either subcloning to identify human iPS cells that are free of exogenous DNA, a knowledge of virology and safe handling procedures, or a detailed understanding of protein biochemistry. Results Here we report a simple approach that facilitates the reprogramming of human somatic cells using standard techniques to transfect expression plasmids that encode OCT4, NANOG, SOX2, and LIN28 without the need for episomal stability or selection. The resulting human iPS cells are free of DNA integration, express pluripotent markers, and form teratomas in immunodeficient animals. These iPS cells were also able to undergo directed differentiation into hepatocyte-like and cardiac myocyte-like cells in culture. Conclusions Simple transient transfection of plasmid DNA encoding reprogramming factors is sufficient to generate human iPS cells from primary fibroblasts that are free of exogenous DNA integrations. This approach is highly accessible and could expand the use of iPS cells in the study of human disease and development. PMID:20682060

  13. Neutrophil Elastase-Generated Fragment of Vascular Endothelial Growth Factor-A Stimulates Macrophage and Endothelial Progenitor Cell Migration

    PubMed Central

    Kurtagic, Elma; Rich, Celeste B.; Buczek-Thomas, Jo Ann; Nugent, Matthew A.

    2015-01-01

    Elastase released from neutrophils as part of the innate immune system has been implicated in chronic diseases such as emphysema and cardiovascular disease. We have previously shown that neutrophil elastase targets vascular endothelial growth factor-A (VEGF) for partial degradation to generate a fragment of VEGF (VEGFf) that has distinct activities. Namely, VEGFf binds to VEGF receptor 1 but not to VEGF receptor 2 and shows altered signaling compared to intact VEGF. In the present study we investigated the chemotactic function of VEGF and VEGFf released from cells by neutrophil elastase. We found that endothelial cells migrated in response to intact VEGF but not VEGFf whereas RAW 264.7 macrophages/monocytes and embryonic endothelial progenitor cells were stimulated to migrate by either VEGF or VEGFf. To investigate the role of elastase-mediated release of VEGF from cells/extracellular matrices, a co-culture system was established. High or low VEGF producing cells were co-cultured with macrophages, endothelial or endothelial progenitor cells and treated with neutrophil elastase. Elastase treatment stimulated macrophage and endothelial progenitor cell migration with the response being greater with the high VEGF expressing cells. However, elastase treatment led to decreased endothelial cell migration due to VEGF cleavage to VEGF fragment. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment. PMID:26672607

  14. Identification of deep intronic variants in 15 haemophilia A patients by next generation sequencing of the whole factor VIII gene.

    PubMed

    Bach, J Elisa; Wolf, Beat; Oldenburg, Johannes; Müller, Clemens R; Rost, Simone

    2015-10-01

    Current screening methods for factor VIII gene (F8) mutations can reveal the causative alteration in the vast majority of haemophilia A patients. Yet, standard diagnostic methods fail in about 2% of cases. This study aimed at analysing the entire intronic sequences of the F8 gene in 15 haemophilia A patients by next generation sequencing. All patients had a mild to moderate phenotype and no mutation in the coding sequence and splice sites of the F8 gene could be diagnosed so far. Next generation sequencing data revealed 23 deep intronic candidate variants in several F8 introns, including six recurrent variants and three variants that have been described before. One patient additionally showed a deletion of 9.2 kb in intron 1, mediated by Alu-type repeats. Several bioinformatic tools were used to score the variants in comparison to known pathogenic F8 mutations in order to predict their deleteriousness. Pedigree analyses showed a correct segregation pattern for three of the presumptive mutations. In each of the 15 patients analysed, at least one deep intronic variant in the F8 gene was identified and predicted to alter F8 mRNA splicing. Reduced F8 mRNA levels and/or stability would be well compatible with the patients' mild to moderate haemophilia A phenotypes. The next generation sequencing approach used proved an efficient method to screen the complete F8 gene and could be applied as a one-stop sequencing method for molecular diagnostics of haemophilia A. PMID:25948085

  15. Next-generation sequencing of genomic DNA fragments bound to a transcription factor in vitro reveals its regulatory potential.

    PubMed

    Kurihara, Yukio; Makita, Yuko; Kawashima, Mika; Hamasaki, Hidefumi; Yamamoto, Yoshiharu Y; Matsui, Minami

    2014-01-01

    Several transcription factors (TFs) coordinate to regulate expression of specific genes at the transcriptional level. In Arabidopsis thaliana it is estimated that approximately 10% of all genes encode TFs or TF-like proteins. It is important to identify target genes that are directly regulated by TFs in order to understand the complete picture of a plant's transcriptome profile. Here, we investigate the role of the LONG HYPOCOTYL5 (HY5) transcription factor that acts as a regulator of photomorphogenesis. We used an in vitro genomic DNA binding assay coupled with immunoprecipitation and next-generation sequencing (gDB-seq) instead of the in vivo chromatin immunoprecipitation (ChIP)-based methods. The results demonstrate that the HY5-binding motif predicted here was similar to the motif reported previously and that in vitro HY5-binding loci largely overlapped with the HY5-targeted candidate genes identified in previous ChIP-chip analysis. By combining these results with microarray analysis, we identified hundreds of HY5-binding genes that were differentially expressed in hy5. We also observed delayed induction of some transcripts of HY5-binding genes in hy5 mutants in response to blue-light exposure after dark treatment. Thus, an in vitro gDNA-binding assay coupled with sequencing is a convenient and powerful method to bridge the gap between identifying TF binding potential and establishing function. PMID:25534860

  16. Changes in the Factors Influencing Public Acceptance of Nuclear Power Generation in Japan Since the 2011 Fukushima Daiichi Nuclear Disaster.

    PubMed

    Tsujikawa, Norifumi; Tsuchida, Shoji; Shiotani, Takamasa

    2016-01-01

    Public support for nuclear power generation has decreased in Japan since the Fukushima Daiichi nuclear accident in March 2011. This study examines how the factors influencing public acceptance of nuclear power changed after this event. The influence factors examined are perceived benefit, perceived risk, trust in the managing bodies, and pro-environmental orientation (i.e., new ecological paradigm). This study is based on cross-sectional data collected from two online nationwide surveys: one conducted in November 2009, before the nuclear accident, and the other in October 2011, after the accident. This study's target respondents were residents of Aomori, Miyagi, and Fukushima prefectures in the Tohoku region of Japan, as these areas were the epicenters of the Great East Japan Earthquake and the locations of nuclear power stations. After the accident, trust in the managing bodies was found to have a stronger influence on perceived risk, and pro-environmental orientation was found to have a stronger influence on trust in the managing bodies; however, perceived benefit had a weaker positive influence on public acceptance. We also discuss the theoretical and practical implications of these findings. PMID:26224041

  17. Generation and Characterization of Leukemia Inhibitory Factor-Dependent Equine Induced Pluripotent Stem Cells from Adult Dermal Fibroblasts

    PubMed Central

    Ovchinnikov, Dmitry A.; Sun, Jane; Fortuna, Patrick R.J.; Wolvetang, Ernst J.

    2014-01-01

    In this study we have reprogrammed dermal fibroblasts from an adult female horse into equine induced pluripotent stem cells (equiPSCs). These equiPSCs are dependent only on leukemia inhibitory factor (LIF), placing them in striking contrast to previously derived equiPSCs that have been shown to be co-dependent on both LIF and basic fibroblast growth factor (bFGF). These equiPSCs have a normal karyotype and have been maintained beyond 60 passages. They possess alkaline phosphatase activity and express eqNANOG, eqOCT4, and eqTERT mRNA. Immunocytochemistry confirmed that they produce NANOG, REX1, SSEA4, TRA1-60, and TRA1-81. While our equiPSCs are LIF dependent, bFGF co-stimulates their proliferation via the PI3K/AKT pathway. EquiPSCs lack expression of eqXIST and immunostaining for H3K27me3, suggesting that during reprogramming the inactive X chromosome has likely been reactivated to generate cells that have two active X chromosomes. EquiPSCs form embryoid bodies and in vitro teratomas that contain derivatives of all three germ layers. These LIF-dependent equiPSCs likely reflect a more naive state of pluripotency than equiPSCs that are co-dependent on both LIF and bFGF and so provide a novel resource for understanding pluripotency in the horse. PMID:24555755

  18. Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients.

    PubMed

    Sun, A S; Yeh, H C; Wang, L H; Huang, Y P; Maeda, H; Pivazyan, A; Hsu, C; Lewis, E R; Bruckner, H W; Fasy, T M

    2001-01-01

    Previously, a specific dietary supplement, selected vegetables (SV), was found to be associated with prolonged survival of stage III and IV non-small cell lung cancer (NSCLC) patients. In this study, several anticancer components in SV were measured; the anticancer activity of SV was assessed using a lung tumor model, line 1 in BALB/c mice. SV was also used in conjunction with conventional therapies by stage IIIB and IV NSCLC patients whose survival and clinical responses were evaluated. A daily portion (283 g) of SV was found to contain 63 mg of inositol hexaphosphate, 4.4 mg of daidzein, 2.6 mg of genistein, and 16 mg of coumestrol. Mouse food containing 5% SV (wt/wt) was associated with a 53-74% inhibition of tumor growth rate. Fourteen of the 18 patients who ingested SV daily for 2-46 months were included in the analyses; none showed evidence of toxicity. The first lead case remained tumor free for > 133 months; the second case showed complete regression of multiple brain lesions after using SV and radiotherapy. The median survival time of the remaining 12 patients was 33.5 months, and one-year survival was > 70%. The median survival time of the 16 "intent-to-treat" patients (including ineligible patients) was 20 months, and one-year survival was 55%. The Karnofsky performance status of eligible patients was 55 +/- 13 at entry but improved to 92 +/- 9 after use of SV for five months or longer (p < 0.01). Five patients had stable lesions for 30, 30, 20, 12, and 2 months; two of them, whose primary tumor was resected, used SV alone and demonstrated an objective response of their metastatic tumors. In addition to the two lead cases, eight patients had no new metastases after using SV. Three patients had complete regression of brain metastases after using radiotherapy and SV. In this study, daily ingestion of SV was associated with objective responses, prolonged survival, and attenuation of the normal pattern of progression of stage IIIB and IV NSCLC. A large

  19. The African Experience. Volume I: Syllabus Lectures; Volume II: Bibliographic References; Volume IIIA: Introductory Essays; Volume IIIB: Introductory Essays.

    ERIC Educational Resources Information Center

    Paden, John N.; Soja, Edward W.

    In response to demands for more and better teaching about Africa in American higher education, the US Office of Education requested that the Program of African Studies at Northwestern University generate a set of teaching materials which could be used in introductory undergraduate courses. Included in these volumes, these materials provide…

  20. Generational diversity.

    PubMed

    Kramer, Linda W

    2010-01-01

    Generational diversity has proven challenges for nurse leaders, and generational values may influence ideas about work and career planning. This article discusses generational gaps, influencing factors and support, and the various generational groups present in today's workplace as well as the consequences of need addressing these issues. The article ends with a discussion of possible solutions. PMID:20395729

  1. Hemobilia secondary to hepatic artery pseudoaneurysm: an unusual complication of bile leakage in a patient with a history of a resected IIIb Klatskin tumor.

    PubMed

    Siablis, Dimitrios; Papathanassiou, Zafiria G; Karnabatidis, Dimitrios; Christeas, Nikolaos; Vagianos, Constantine

    2005-09-01

    We report a case of a 74-year-old woman with a 16-year history of a double bilo-enteric anastomosis due to resected hilar cholangiocarcinoma (Type IIIb Klatskin tumor). The patient presented with cholangitis secondary to benign anastomotic stenosis which resulted in a large intrahepatic biloma. In order to restore the patency of the anastomosis and overcome cholangitis, several attempts took place, including endobiliary stenting, balloon-assisted biloplasty and transhepatic billiary drainage. Anastomotic patency was achieved, complicated, however, by persistent upper gastro-intestinal bleeding, presented as hemobilia. A biloma-induced pseudoaneurysm of the left hepatic artery was diagnosed. This had ruptured into the biliary tract, and presented the actual cause of the hemobilia. Selective embolism of the pseudoaneurysm resulted in control of the hemorrhage, and was successfully combined with transhepatic dilatation of the anastomosis and percutaneous drainage of the biloma. The patient was ultimately cured and seems to be in excellent condition, 5 mo after treatment. PMID:16127759

  2. Generation rates and emission factors of particulate matter and particle-bound polycyclic aromatic hydrocarbons of incense sticks.

    PubMed

    Lung, Shih-Chun Candice; Hu, Shu-Chuan

    2003-02-01

    The generation rates and emission factors of particulate matter and associated polycyclic aromatic hydrocarbons (PAHs) from incense burning were assessed in a laboratory setting. The differences among different segments of the same stick, among different sticks of the same kind of incense, and between two kinds of manually made Chih-Chen incense sticks (A and B) were evaluated. Joss sticks were burned inside a 44 cm long elutriator; personal environmental monitors fitted into the top of the elutriator were used to take PM2.5 and PM10 samples of incense smoke. Samples were analyzed for PAHs by gas chromatography-flame ionization Detector. It was found that particle and associated PAHs were generated approximately at 561 microg/min (geometric standard deviation (GSD) = 1.1) and 0.56 microg/min (GSD = 1.1) from Incense A, and at 661 microg/min (GSD = 1.7) and 0.46 microg/min (GSD = 1.3) from Incense B, respectively. One gram of Incense A emitted about 19.8 mg (GSD = 1.1) particulate matter and 17.1 microg (GSD = 1.2) particulate-phase PAHs, while one gram of Incense B produced around 43.6 mg (GSD = 1.1) of particles and 25.2 microg (GSD = 1.2) of particle-bound PAHs. There were significant differences in emissions between Incenses A and B, although they belong to the same class of incense. A 10-20% variability in emissions was observed in the main part of the manually produced stick, and a larger variation was found at both tips of the combustible part. PMID:12685744

  3. Changes in hormone and lipid levels in male patients with focal seizures when switched from carbamazepine to lacosamide as adjunctive treatment to levetiracetam: A small phase IIIb, prospective, multicenter, open-label trial.

    PubMed

    Elger, Christian E; Rademacher, Michael; Brandt, Christian; Elmoufti, Sami; Dedeken, Peter; Eckhardt, Klaus; Tennigkeit, Frank; De Backer, Marc

    2016-09-01

    Treatment with enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine (CBZ) can lead to changes in reproductive, endocrine, and lipid parameters, resulting in clinical symptoms for some patients. Previous studies indicate that these changes can be reversed by switching to a nonenzyme-inducing AED. Lacosamide is a newer-generation AED, not known to induce or strongly inhibit cytochrome P450 (CYP450) enzymes. In this phase IIIb, prospective, multicenter, open-label, single-arm trial (NCT01375374), the serum concentrations of CYP-related reproductive hormones, thyroid hormones, and lipids were assessed in otherwise healthy male patients with focal seizures (N=11), before and after a switch from CBZ (600-1200mg/day at baseline) to lacosamide (target dose: 400mg/day by the end of titration) as adjunctive treatment to the nonenzyme-inducing AED levetiracetam (LEV, stable dosage of >1000mg/day throughout). Cross titration took place over 4weeks, followed by an 8-week maintenance period. Serum measurements were conducted at baseline and at the end of maintenance. The median serum sex-hormone-binding globulin (SHBG) concentration was towards the higher end of the normal range at baseline and decreased following the switch (61.7 to 47.5nmol/L, N=10, p=0.027 by Wilcoxon signed-rank test). Free androgen index (100×testosterone/SHBG) and free thyroxine serum concentration increased (25.4 to 36.4 and 13.0 to 14.9pmol/L, respectively, both N=10 and p=0.002). At baseline, the median progesterone serum concentration was below the normal range (0.7nmol/L), whereas median cholesterol and low-density lipoprotein concentrations were above the normal range (5.5 and 3.6mmol/L, respectively). By the end of maintenance, all measured parameters were within the normal range. The safety and tolerability profile of lacosamide was consistent with that observed in previous studies. Furthermore, antiseizure efficacy appeared to be maintained, suggesting that deinduction of CYP enzymes

  4. Family Aggregation and Risk Factors in Phobic Disorders over Three-Generations in a Nation-Wide Study

    PubMed Central

    Steinhausen, Hans-Christoph; Jakobsen, Helle; Meyer, Andrea; Jørgensen, Povl Munk; Lieb, Roselind

    2016-01-01

    Objective This nation-wide register-based study investigated how often phobic disorders (PHO) and co-morbid disorders occur in affected families compared to control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. Method A total of N = 746 child and adolescent psychiatric participants born between 1969 and 1986 and registered in the Danish Psychiatric Central Research Register (DPCRR) with a diagnosis of a mental disorder before the age of 18, and developed PHO at some point during their life-time until a maximum age of 40 years were included. In addition, N = 2229 controls without any diagnosis of mental disorders before age 18 and that were matched for age, sex, and residential region were included. Diagnoses of mental disorders were also obtained from the first- degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. Results PHO occurred significantly more often in case than in control families, in particular, in mothers and siblings. Substance use disorders (SUD), Depressive disorders (DEP), anxiety disorders (ANX) and personality disorders (PERS) in the family were significantly associated with specific phobia in the case-probands. After controlling for various mental disorders comorbid to PHO it was found that some of the family transmission could be caused by various other mental disorders in family members rather than the PHO itself. Female sex and more recent year of birth were further risk factors while region of residence was not related to the manifestation of PHO. Case-relatives did not develop PHO earlier than control relatives. After adjusting for various additional explanatory variables, the family load explained only 0.0013% of the variance in the manifestation of PHO in the case-probands Discussion These findings, based on a very large and representative dataset, provide

  5. Application of spatial and non-spatial data analysis in determination of the factors that impact municipal solid waste generation rates in Turkey.

    PubMed

    Keser, Saniye; Duzgun, Sebnem; Aksoy, Aysegul

    2012-03-01

    In studies focusing on the factors that impact solid waste generation habits and rates, the potential spatial dependency in solid waste generation data is not considered in relating the waste generation rates to its determinants. In this study, spatial dependency is taken into account in determination of the significant socio-economic and climatic factors that may be of importance for the municipal solid waste (MSW) generation rates in different provinces of Turkey. Simultaneous spatial autoregression (SAR) and geographically weighted regression (GWR) models are used for the spatial data analyses. Similar to ordinary least squares regression (OLSR), regression coefficients are global in SAR model. In other words, the effect of a given independent variable on a dependent variable is valid for the whole country. Unlike OLSR or SAR, GWR reveals the local impact of a given factor (or independent variable) on the waste generation rates of different provinces. Results show that provinces within closer neighborhoods have similar MSW generation rates. On the other hand, this spatial autocorrelation is not very high for the exploratory variables considered in the study. OLSR and SAR models have similar regression coefficients. GWR is useful to indicate the local determinants of MSW generation rates. GWR model can be utilized to plan waste management activities at local scale including waste minimization, collection, treatment, and disposal. At global scale, the MSW generation rates in Turkey are significantly related to unemployment rate and asphalt-paved roads ratio. Yet, significances of these variables may diminish at local scale for some provinces. At local scale, different factors may be important in affecting MSW generation rates. PMID:22104614

  6. Dysregulation of the Transforming Growth Factor β Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia

    PubMed Central

    Ge, Jingping; Apicella, Marisa; Mills, Jason A.; Garçon, Loïc; French, Deborah L.; Weiss, Mitchell J.; Bessler, Monica; Mason, Philip J.

    2015-01-01

    Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome with clinical features of red cell aplasia and variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations in ribosomal protein genes but the pathogenic mechanism is still unknown. We generated induced pluripotent stem cells from DBA patients carrying RPS19 or RPL5 mutations. Transcriptome analysis revealed the striking dysregulation of the transforming growth factor β (TGFβ) signaling pathway in DBA lines. Expression of TGFβ target genes, such as TGFBI, BAMBI, COL3A1 and SERPINE1 was significantly increased in the DBA iPSCs. We quantified intermediates in canonical and non-canonical TGFβ pathways and observed a significant increase in the levels of the non-canonical pathway mediator p-JNK in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. Surprisingly, nuclear levels of SMAD4, a mediator of canonical TGFβ signaling, were decreased in DBA cells due to increased proteolytic turnover. We also observed the up-regulation of TGFβ1R, TGFβ2, CDKN1A and SERPINE1 mRNA, and the significant decrease of GATA1 mRNA in the primitive multilineage progenitors. In summary our observations identify for the first time a dysregulation of the TGFβ pathway in the pathobiology of DBA. PMID:26258650

  7. A chimeric repressor of petunia PH4 R2R3-MYB family transcription factor generates margined flowers in torenia.

    PubMed

    Kasajima, Ichiro; Sasaki, Katsutomo

    2016-05-01

    The development of new phenotypes is key to the commercial development of the main floricultural species and cultivars. Important new phenotypes include features such as multiple-flowers, color variations, increased flower size, new petal shapes, variegation and distinctive petal margin colourations. Although their commercial use is not yet common, the transgenic technologies provide a potentially rapid means of generating interesting new phenotypes. In this report, we construct 5 vectors which we expected to change the color of the flower anthocyanins, from purple to blue, regulating vacuolar pH. When these constructs were transformed into purple torenia, we unexpectedly recovered some genotypes having slightly margined petals. These transgenic lines expressed a chimeric repressor of the petunia PhPH4 gene under the control of Cauliflower mosaic virus 35 S RNA promoter. PhPH4 is an R2R3-type MYB transcription factor. The transgenic lines lacked pigmentation in the petal margin cells both on the adaxial and abaxial surfaces. Expressions of Flavanone 3-hydroxylase (F3H), Flavonoid 3'-hydroxylase (F3'H) and Flavonoid 3'5'-hydroxylase (F3'5'H) genes were reduced in the margins of these transgenic lines, suggesting an inhibitory effect of PhPH4 repressor on anthocyanin synthesis. PMID:27089475

  8. Intracerebral infusion of a second-generation ciliary neurotrophic factor reduces neuronal loss in rat striatum following experimental intracerebral hemorrhage.

    PubMed

    Del Bigio, M R; Yan, H J; Xue, M

    2001-11-15

    Neuronal and glial cell death in the striatum of a rat model of collagenase-induced intracerebral hemorrhage begins at 1 day and continues for at least 3 weeks. We hypothesized that administration of a neurotrophic agent would reduce neuronal loss in this experimental model. Because it has been shown to protect striatal neurons against excitotoxic injury, a second-generation ciliary neurotrophic factor (CNTF) (AXOKINE) was administered by continuous intracerebral infusion (2 microg/day) beginning 28 h after hemorrhage and continuing for 2 weeks. Magnetic resonance imaging showed that the hematoma size was comparable in control and treated rats prior to treatment. Counts of medium-sized striatal neurons within 320 microm of the hematoma 8 weeks after the hemorrhage revealed a slight but statistically significant benefit with a 42.5% loss in treated rats compared to 51.7% loss in controls. The results suggest that AXOKINE might be protective of striatal neurons in the vicinity of a hemorrhagic lesion. PMID:11701153

  9. Dysregulation of the Transforming Growth Factor β Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia.

    PubMed

    Ge, Jingping; Apicella, Marisa; Mills, Jason A; Garçon, Loïc; French, Deborah L; Weiss, Mitchell J; Bessler, Monica; Mason, Philip J

    2015-01-01

    Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome with clinical features of red cell aplasia and variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations in ribosomal protein genes but the pathogenic mechanism is still unknown. We generated induced pluripotent stem cells from DBA patients carrying RPS19 or RPL5 mutations. Transcriptome analysis revealed the striking dysregulation of the transforming growth factor β (TGFβ) signaling pathway in DBA lines. Expression of TGFβ target genes, such as TGFBI, BAMBI, COL3A1 and SERPINE1 was significantly increased in the DBA iPSCs. We quantified intermediates in canonical and non-canonical TGFβ pathways and observed a significant increase in the levels of the non-canonical pathway mediator p-JNK in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. Surprisingly, nuclear levels of SMAD4, a mediator of canonical TGFβ signaling, were decreased in DBA cells due to increased proteolytic turnover. We also observed the up-regulation of TGFβ1R, TGFβ2, CDKN1A and SERPINE1 mRNA, and the significant decrease of GATA1 mRNA in the primitive multilineage progenitors. In summary our observations identify for the first time a dysregulation of the TGFβ pathway in the pathobiology of DBA. PMID:26258650

  10. Factorbook.org: a Wiki-based database for transcription factor-binding data generated by the ENCODE consortium.

    PubMed

    Wang, Jie; Zhuang, Jiali; Iyer, Sowmya; Lin, Xin-Ying; Greven, Melissa C; Kim, Bong-Hyun; Moore, Jill; Pierce, Brian G; Dong, Xianjun; Virgil, Daniel; Birney, Ewan; Hung, Jui-Hung; Weng, Zhiping

    2013-01-01

    The Encyclopedia of DNA Elements (ENCODE) consortium aims to identify all functional elements in the human genome including transcripts, transcriptional regulatory regions, along with their chromatin states and DNA methylation patterns. The ENCODE project generates data utilizing a variety of techniques that can enrich for regulatory regions, such as chromatin immunoprecipitation (ChIP), micrococcal nuclease (MNase) digestion and DNase I digestion, followed by deeply sequencing the resulting DNA. As part of the ENCODE project, we have developed a Web-accessible repository accessible at http://factorbook.org. In Wiki format, factorbook is a transcription factor (TF)-centric repository of all ENCODE ChIP-seq datasets on TF-binding regions, as well as the rich analysis results of these data. In the first release, factorbook contains 457 ChIP-seq datasets on 119 TFs in a number of human cell lines, the average profiles of histone modifications and nucleosome positioning around the TF-binding regions, sequence motifs enriched in the regions and the distance and orientation preferences between motif sites. PMID:23203885

  11. New role for Kruppel-like factor 14 as a transcriptional activator involved in the generation of signaling lipids.

    PubMed

    de Assuncao, Thiago M; Lomberk, Gwen; Cao, Sheng; Yaqoob, Usman; Mathison, Angela; Simonetto, Douglas A; Huebert, Robert C; Urrutia, Raul A; Shah, Vijay H

    2014-05-30

    Sphingosine kinase 1 (SK1) is an FGF-inducible gene responsible for generation of sphingosine-1-phosphate, a critical lipid signaling molecule implicated in diverse endothelial cell functions. In this study, we identified SK1 as a target of the canonical FGF2/FGF receptor 1 activation pathway in endothelial cells and sought to identify novel transcriptional pathways that mediate lipid signaling. Studies using the 1.9-kb SK1 promoter and deletion mutants revealed that basal and FGF2-stimulated promoter activity occurred through two GC-rich regions located within 633 bp of the transcription start site. Screening for GC-rich binding transcription factors that could activate this site demonstrated that KLF14, a gene implicated in obesity and the metabolic syndrome, binds to this region. Congruently, overexpression of KLF14 increased basal and FGF2-stimulated SK1 promoter activity by 3-fold, and this effect was abrogated after mutation of the GC-rich sites. In addition, KLF14 siRNA transfection decreased SK1 mRNA and protein levels by 3-fold. Congruently, SK1 mRNA and protein levels were decreased in livers from KLF14 knock-out mice. Combined, luciferase, gel shift, and chromatin immunoprecipitation assays showed that KLF14 couples to p300 to increase the levels of histone marks associated with transcriptional activation (H4K8ac and H3K14ac), while decreasing repressive marks (H3K9me3 and H3K27me3). Collectively, the results demonstrate a novel mechanism whereby SK1 lipid signaling is regulated by epigenetic modifications conferred by KLF14 and p300. Thus, this is the first description of the activity and mechanisms underlying the function of KLF14 as an activator protein and novel regulator of lipid signaling. PMID:24759103

  12. New Role for Kruppel-like Factor 14 as a Transcriptional Activator Involved in the Generation of Signaling Lipids*

    PubMed Central

    de Assuncao, Thiago M.; Lomberk, Gwen; Cao, Sheng; Yaqoob, Usman; Mathison, Angela; Simonetto, Douglas A.; Huebert, Robert C.; Urrutia, Raul A.; Shah, Vijay H.

    2014-01-01

    Sphingosine kinase 1 (SK1) is an FGF-inducible gene responsible for generation of sphingosine-1-phosphate, a critical lipid signaling molecule implicated in diverse endothelial cell functions. In this study, we identified SK1 as a target of the canonical FGF2/FGF receptor 1 activation pathway in endothelial cells and sought to identify novel transcriptional pathways that mediate lipid signaling. Studies using the 1.9-kb SK1 promoter and deletion mutants revealed that basal and FGF2-stimulated promoter activity occurred through two GC-rich regions located within 633 bp of the transcription start site. Screening for GC-rich binding transcription factors that could activate this site demonstrated that KLF14, a gene implicated in obesity and the metabolic syndrome, binds to this region. Congruently, overexpression of KLF14 increased basal and FGF2-stimulated SK1 promoter activity by 3-fold, and this effect was abrogated after mutation of the GC-rich sites. In addition, KLF14 siRNA transfection decreased SK1 mRNA and protein levels by 3-fold. Congruently, SK1 mRNA and protein levels were decreased in livers from KLF14 knock-out mice. Combined, luciferase, gel shift, and chromatin immunoprecipitation assays showed that KLF14 couples to p300 to increase the levels of histone marks associated with transcriptional activation (H4K8ac and H3K14ac), while decreasing repressive marks (H3K9me3 and H3K27me3). Collectively, the results demonstrate a novel mechanism whereby SK1 lipid signaling is regulated by epigenetic modifications conferred by KLF14 and p300. Thus, this is the first description of the activity and mechanisms underlying the function of KLF14 as an activator protein and novel regulator of lipid signaling. PMID:24759103

  13. Second Generation Reusable Launch Vehicle Development and Global Competitiveness of US Space Transportation Industry: Critical Success Factors Assessment

    NASA Technical Reports Server (NTRS)

    Enyinda, Chris I.

    2002-01-01

    In response to the unrelenting call in both public and private sectors fora to reduce the high cost associated with space transportation, many innovative partially or fully RLV (Reusable Launch Vehicles) designs (X-34-37) were initiated. This call is directed at all levels of space missions including scientific, military, and commercial and all aspects of the missions such as nonrecurring development, manufacture, launch, and operations. According to Wertz, tbr over thirty years, the cost of space access has remained exceedingly high. The consensus in the popular press is that to decrease the current astronomical cost of access to space, more safer, reliable, and economically viable second generation RLVs (SGRLV) must be developed. Countries such as Brazil, India, Japan, and Israel are now gearing up to enter the global launch market with their own commercial space launch vehicles. NASA and the US space launch industry cannot afford to lag behind. Developing SGRLVs will immeasurably improve the US's space transportation capabilities by helping the US to regain the global commercial space markets while supporting the transportation capabilities of NASA's space missions, Developing the SGRLVs will provide affordable commercial space transportation that will assure the competitiveness of the US commercial space transportation industry in the 21st century. Commercial space launch systems are having difficulty obtaining financing because of the high cost and risk involved. Access to key financial markets is necessary for commercial space ventures. However, public sector programs in the form of tax incentives and credits, as well as loan guarantees are not yet available. The purpose of this paper is to stimulate discussion and assess the critical success factors germane for RLVs development and US global competitiveness.

  14. Generation of Wheat Transcription Factor FOX Rice Lines and Systematic Screening for Salt and Osmotic Stress Tolerance

    PubMed Central

    Zhang, Qian; Liu, Yayun; Zhu, Butuo; Cao, Jian; Li, Zhanpeng; Han, Longzhi; Jia, Jizeng; Zhao, Guangyao; Sun, Xuehui

    2015-01-01

    Transcription factors (TFs) play important roles in plant growth, development, and responses to environmental stress. In this study, we collected 1,455 full-length (FL) cDNAs of TFs, representing 45 families, from wheat and its relatives Triticum urartu, Aegilops speltoides, Aegilops tauschii, Triticum carthlicum, and Triticum aestivum. More than 15,000 T0 TF FOX (Full-length cDNA Over-eXpressing) rice lines were generated; of these, 10,496 lines set seeds. About 14.88% of the T0 plants showed obvious phenotypic changes. T1 lines (5,232 lines) were screened for salt and osmotic stress tolerance using 150 mM NaCl and 20% (v/v) PEG-4000, respectively. Among them, five lines (591, 746, 1647, 1812, and J4065) showed enhanced salt stress tolerance, five lines (591, 746, 898, 1078, and 1647) showed enhanced osmotic stress tolerance, and three lines (591, 746, and 1647) showed both salt and osmotic stress tolerance. Further analysis of the T-DNA flanking sequences showed that line 746 over-expressed TaEREB1, line 898 over-expressed TabZIPD, and lines 1812 and J4065 over-expressed TaOBF1a and TaOBF1b, respectively. The enhanced salt and osmotic stress tolerance of lines 898 and 1812 was confirmed by retransformation of the respective genes. Our results demonstrate that a heterologous FOX system may be used as an alternative genetic resource for the systematic functional analysis of the wheat genome. PMID:26176782

  15. Complement factor H modulates the activation of human neutrophil granulocytes and the generation of neutrophil extracellular traps.

    PubMed

    Schneider, Andrea E; Sándor, Noémi; Kárpáti, Éva; Józsi, Mihály

    2016-04-01

    Factor H (FH) is a major inhibitor of the alternative pathway of complement activation in plasma and on certain host surfaces. In addition to being a complement regulator, FH can bind to various cells via specific receptors, including binding to neutrophil granulocytes through complement receptor type 3 (CR3; CD11b/CD18), and modulate their function. The cellular roles of FH are, however, poorly understood. Because neutrophils are important innate immune cells in inflammatory processes and the host defense against pathogens, we aimed at studying the effects of FH on various neutrophil functions, including the generation of extracellular traps. FH co-localized with CD11b on the surface of neutrophils isolated from peripheral blood of healthy individuals, and cell-bound FH retained its cofactor activity and enhanced C3b degradation. Soluble FH supported neutrophil migration and immobilized FH induced cell spreading. In addition, immobilized but not soluble FH enhanced IL-8 release from neutrophils. FH alone did not trigger the cells to produce neutrophil extracellular traps (NETs), but NET formation induced by PMA and by fibronectin plus fungal β-glucan were inhibited by immobilized, but not by soluble, FH. Moreover, in parallel with NET formation, immobilized FH also inhibited the production of reactive oxygen species induced by PMA and by fibronectin plus β-glucan. Altogether, these data indicate that FH has multiple regulatory roles on neutrophil functions. While it can support the recruitment of neutrophils, FH may also exert anti-inflammatory effects and influence local inflammatory and antimicrobial reactions, and reduce tissue damage by modulating NET formation. PMID:26938503

  16. Mid-Infrared (MIR) and Near-Infrared (NIR) Detection of Rhizoctonia solani AG 2-2 IIIB on Barley-Based Artificial Inoculum.

    PubMed

    Webb, Kimberly M; Calderón, Francisco J

    2015-10-01

    The amount of Rhizoctonia solani in the soil and how much must be present to cause disease in sugar beet (Beta vulgaris L.) is relatively unknown. This is mostly because of the usually low inoculum densities found naturally in soil and the low sensitivity of traditional serial dilution assays. We investigated the usefulness of Fourier transform mid-infrared (MIR) and near-infrared (NIR) spectroscopic properties in identifying the artificial colonization of barley grains with R. solani AG 2-2 IIIB and in detecting R. solani populations in plant tissues and inoculants. The objectives of this study were to compare the ability of traditional plating assays to NIR and MIR spectroscopies to identify R. solani in different-size fractions of colonized ground barley (used as an artificial inoculum) and to differentiate colonized from non-inoculated barley. We found that NIR and MIR spectroscopies were sensitive in resolving different barley particle sizes, with particles that were <0.25 and 0.25-0.5 mm having different spectral properties than coarser particles. Moreover, we found that barley colonized with R. solani had different MIR spectral properties than the non-inoculated samples for the larger fractions (0.5-1.0, 1.0-2.0, and >2.0 mm) of the ground barley. This colonization was confirmed using traditional plating assays. Comparisons with the spectra from pure fungal cultures and non-inoculated barley suggest that the MIR spectrum of colonized barley is different because of the consumption of C substrates by the fungus rather than because of the presence of fungal bands in the spectra of the colonized samples. We found that MIR was better than NIR spectroscopy in differentiating the colonized from the control samples. PMID:26449805

  17. Application of spatial and non-spatial data analysis in determination of the factors that impact municipal solid waste generation rates in Turkey

    SciTech Connect

    Keser, Saniye; Duzgun, Sebnem; Aksoy, Aysegul

    2012-03-15

    Highlights: Black-Right-Pointing-Pointer Spatial autocorrelation exists in municipal solid waste generation rates for different provinces in Turkey. Black-Right-Pointing-Pointer Traditional non-spatial regression models may not provide sufficient information for better solid waste management. Black-Right-Pointing-Pointer Unemployment rate is a global variable that significantly impacts the waste generation rates in Turkey. Black-Right-Pointing-Pointer Significances of global parameters may diminish at local scale for some provinces. Black-Right-Pointing-Pointer GWR model can be used to create clusters of cities for solid waste management. - Abstract: In studies focusing on the factors that impact solid waste generation habits and rates, the potential spatial dependency in solid waste generation data is not considered in relating the waste generation rates to its determinants. In this study, spatial dependency is taken into account in determination of the significant socio-economic and climatic factors that may be of importance for the municipal solid waste (MSW) generation rates in different provinces of Turkey. Simultaneous spatial autoregression (SAR) and geographically weighted regression (GWR) models are used for the spatial data analyses. Similar to ordinary least squares regression (OLSR), regression coefficients are global in SAR model. In other words, the effect of a given independent variable on a dependent variable is valid for the whole country. Unlike OLSR or SAR, GWR reveals the local impact of a given factor (or independent variable) on the waste generation rates of different provinces. Results show that provinces within closer neighborhoods have similar MSW generation rates. On the other hand, this spatial autocorrelation is not very high for the exploratory variables considered in the study. OLSR and SAR models have similar regression coefficients. GWR is useful to indicate the local determinants of MSW generation rates. GWR model can be utilized to

  18. The Effect of a Narrative Intervention on Story Retelling and Personal Story Generation Skills of Preschoolers with Risk Factors and Narrative Language Delays

    ERIC Educational Resources Information Center

    Spencer, Trina D.; Slocum, Timothy A.

    2010-01-01

    Narration, or storytelling, is an important aspect of language. Narrative skills have academic and social importance. This study evaluated the effects of a narrative intervention on story retelling and personal story generation skills of preschoolers with risk factors and narrative language delays. Narrative intervention was delivered in a small…

  19. Factor Analysis of the ESL/EFL Strategy Inventory for Language Learning: Generation 1.5 Korean Immigrant College Students' Language Learning Strategies

    ERIC Educational Resources Information Center

    Heo, Misook; Stoffa, Rosa; Kush, Joseph C.

    2012-01-01

    This study explores factors related to the language learning strategies of second language learners, specifically Generation 1.5 Korean immigrant students--the seventh-largest and one of the fastest growing foreign-born groups in the USA. Participants in this study were members of the Korean communities located in Pittsburgh and Philadelphia who…

  20. Generation of Induced Pluripotent Stem Cells from Human Amniotic Fluid Cells by Reprogramming with Two Factors in Feeder-free Conditions

    PubMed Central

    LI, Qing; FAN, Yong; SUN, Xiaofang; YU, Yanhong

    2012-01-01

    Abstract The ectopic expression of transcription factors for reprogramming human somatic cells to a pluripotent state represents a valuable resource for the development of in vitro-based models for human disease and has great potential in regenerative therapies. However, the majority of studies have used skin fibroblasts to generate induced pluripotent stem cells (iPSCs) that typically require the enforced expression of several transcription factors, thereby posing a mutagenesis risk by the insertion of viral transgenes. To reduce this risk, iPSCs have been generated with OCT4 and KLF4 from human neural stem cells that endogenously express the remaining reprogramming factors. However, human neural stem cells are rare and difficult to obtain. Here, we show that iPSCs can be generated from human amniotic fluid cells (hAFCs) with two transcription factors: OCT4 and KLF4. Furthermore, iPSCs can be readily derived from hAFCs in a feeder-free conditions, thereby eliminating the potential variability caused by using feeder cells. Our results indicate that hAFCs represent an accessible source of cells that can be reprogrammed into pluripotent stem cells with two Yamanaka factors. Therefore, hAFCs may become a preferred cell type in the future for safe reprogramming without any exogenous genetic material. PMID:23138118

  1. Human factors engineering control-room-design review/audit report: Palo Verde Nuclear Generating Station, Arizona Public Service Company

    SciTech Connect

    Savage, J.W.; Lappa, D.A.

    1981-10-09

    A human factors engineering design review of the Palo Verde control room simulator was performed at the site on September 15 through September 17, 1981. Observed human factors design discrepancies were given priority ratings. This report summarizes the team's observations of the control room design and layout and of the control room operators' interface with the control room environment. A list of the human factors strengths observed in the Palo Verde control room simulator is given.

  2. Shared Genetic Aetiology between Cognitive Ability and Cardiovascular Disease Risk Factors: Generation Scotland's Scottish Family Health Study

    ERIC Educational Resources Information Center

    Luciano, Michelle; Batty, G. David; McGilchrist, Mark; Linksted, Pamela; Fitzpatrick, Bridie; Jackson, Cathy; Pattie, Alison; Dominiczak, Anna F.; Morris, Andrew D.; Smith, Blair H.; Porteous, David; Deary, Ian J.

    2010-01-01

    People with higher general cognitive ability in early life have more favourable levels of cardiovascular disease (CVD) risk factors in adulthood and CVD itself. The mechanism of these associations is not known. Here we examine whether general cognitive ability and CVD risk factors share genetic and/or environmental aetiology. In this large,…

  3. Benefits of switching from latanoprost to preservative-free tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials

    PubMed Central

    Uusitalo, Hannu; Egorov, Evgeniy; Kaarniranta, Kai; Astakhov, Yuri; Ropo, Auli

    2016-01-01

    Introduction Glaucoma patients frequently exhibit ocular surface side effects during treatment with prostaglandin eye drops. The present work investigated whether glaucoma patients suffering from signs and symptoms of ocular surface disease while using preserved latanoprost eye drops benefited from switching to preservative-free tafluprost eye drops. Patients and methods The analysis was based on 339 glaucoma patients enrolled in two Phase IIIb trials. The patients were required to have two symptoms, or one sign and one symptom of ocular surface disease at baseline, and at least 6 months preceding treatment with latanoprost eye drops preserved with benzalkonium chloride. All eligible patients were switched from latanoprost to preservative-free tafluprost for a total of 12 weeks. Ocular symptoms and ocular signs were evaluated at baseline and at 2 weeks, 6 weeks, and 12 weeks after commencing treatment with tafluprost. Intraocular pressure (IOP), drop discomfort, and treatment preference were evaluated to investigate the clinical efficacy and patient-related outcomes. Results After 12 weeks of treatment with preservative-free tafluprost, the incidences of irritation/burning/stinging, foreign body sensation, tearing, itching, and dry eye sensation had diminished to one-third of those reported for preserved latanoprost at baseline. The incidences of blepharitis and corneal/conjunctival fluorescein staining had in turn decreased to one-half of those reported for preserved latanoprost. Severity of conjunctival hyperemia was halved during treatment with preservative-free tafluprost, and there was significant improvement in tear break-up time and tear production. A further reduction in IOP (~1 mmHg) was seen with preservative-free tafluprost compared with preserved latanoprost. Drop discomfort was alleviated during preservative-free tafluprost treatment, and an outstanding majority of patients (72%) preferred preservative-free tafluprost over preserved latanoprost

  4. Consolidative Involved-Node Proton Therapy for Stage IA-IIIB Mediastinal Hodgkin Lymphoma: Preliminary Dosimetric Outcomes From a Phase II Study

    SciTech Connect

    Hoppe, Bradford S.; Flampouri, Stella; Su Zhong; Morris, Christopher G.; Latif, Naeem

    2012-05-01

    Purpose: To compare the dose reduction to organs at risk (OARs) with proton therapy (PT) versus three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in patients with mediastinal Hodgkin lymphoma (HL) enrolled on a Phase II study of involved-node radiotherapy (INRT). Methods and Materials: Between June 2009 and October 2010, 10 patients were enrolled on a University of Florida institutional review board-approved protocol for de novo 'classical' Stage IA-IIIB HL with mediastinal (bulky or nonbulky) involvement after chemotherapy. INRT was planned per European Organization for Research and Treatment of Cancer guidelines. Three separate optimized plans were developed for each patient: 3D-CRT, IMRT, and PT. The primary end point was a 50% reduction in the body V4 with PT compared with 3D-CRT or IMRT. Results: The median relative reduction with PT in the primary end point, body V4, was 51% compared with 3D-CRT (p = 0.0098) and 59% compared with IMRT (p = 0.0020), thus all patients were offered treatment with PT. PT provided the lowest mean dose to the heart, lungs, and breasts for all 10 patients compared with either 3D-CRT or IMRT. The median difference in the OAR mean dose reduction with PT compared with 3D-CRT were 10.4 Gy/CGE for heart; 5.5 Gy/CGE for lung; 0.9 Gy/CGE for breast; 8.3 Gy/CGE for esophagus; and 4.1 Gy/CGE for thyroid. The median differences for mean OAR dose reduction for PT compared with IMRT were 4.3 Gy/CGE for heart, 3.1 Gy/CGE for lung, 1.4 Gy/CGE for breast, 2.8 Gy/CGE for esophagus, and 2.7 Gy/CGE for thyroid. Conclusions: All 10 patients benefitted from dose reductions to OARs with PT compared with either 3D-CRT or IMRT. It is anticipated that these reductions in dose to OAR will translate into lower rates of late complications, but long-term follow-up on this Phase II INRT study is needed.

  5. Differences in problem behaviour among ethnic minority and majority preschoolers in the Netherlands and the role of family functioning and parenting factors as mediators: the Generation R Study

    PubMed Central

    2012-01-01

    Background Studies have shown that, compared to native counterparts, preschoolers from ethnic minorities are at an increased risk of problem behaviour. Socio-economic factors only partly explain this increased risk. This study aimed to further unravel the differences in problem behaviour among ethnic minority and native preschoolers by examining the mediating role of family functioning and parenting factors. Methods We included 4,282 preschoolers participating in the Generation R Study, an ethnically-diverse cohort study with inclusion in early pregnancy. At child age 3 years, parents completed the Child Behavior Checklist (CBCL/1,5-5); information on demographics, socio-economic status and measures of family functioning (maternal psychopathology; general family functioning) and parenting (parenting stress; harsh parenting) were retrieved from questionnaires. CBCL Total Problems scores in each ethnic subgroup were compared with scores in the Dutch reference population. Mediation was evaluated using multivariate regression models. Results After adjustment for confounders, preschoolers from ethnic minorities were more likely to present problem behaviour than the Dutch subgroup (e.g. CBCL Total Problems Turkish subgroup (OR 7.0 (95% CI 4.9; 10.1)). When considering generational status, children of first generation immigrants were worse off than the second generation (P<0.01). Adjustment for socio-economic factors mediated the association between the ethnic minority status and child problem behaviour (e.g. attenuation in OR by 54.4% (P<0.05) from OR 5.1 (95% CI 2.8; 9.4) to OR 2.9 (95% CI 1.5; 5.6) in Cape Verdean subgroup). However, associations remained significant in most ethnic subgroups. A final adjustment for family functioning and parenting factors further attenuated the association (e.g. attenuation in OR by 55.5% (P<0.05) from OR 2.2 (95% CI 1.3; 4.4) to OR 1.5 (95% CI 1.0; 2.4) in European other subgroup). Conclusions This study showed that preschoolers from

  6. Space factor of "excess" heat generation in the Earth and planetary interiors. Article 2. Space-time patterns of distribution of the heat generating zones in the Earth interior

    NASA Astrophysics Data System (ADS)

    Makarenko, O. M.

    Besides radiogenic energy, the "supplementary" energy source occurs in the Earth interior. This source is of cosmic origin and modulated by position and direction of the Solar system motion in the Galaxy. It can be called as "cosmic furnace", which works in the Earth internal and outer cores as well as in mantle. The specific thermal generation per unit of volume is about 10 W/km3 in the Earth mantle and some 50 W/km3 in the Earth core. Excess heat generation occurs mainly in the latitudinal zone between 650 of northern latitude and 650 of southern latitude. More active heat generation occurs in the northern and southern hemispheres alternately with intervals about 200 million years that is equal to the period of revolution about the Galaxy center. The latitudinal zone of maximal heat generation moves in time along the sinusoidal curve in accordance with displacement of projection of the Solar system apex on the Earth surface. Maximal intensity of heat generation occurs when projection of the Earth motion in the Galaxy achieves the Earth equator (every 100 million years). At this particular time the direction of the Solar system motion in the Galaxy is in the plane of ecliptic and heat generation - of maximal intensity. This results in existence of equatorial hot belt in the Earth interior, distinctly exhibited in the core and mantle. The fact of alternate heating of the Earth semi-spheres allows us to assume that heat-generating factor influencing our planet from galactic space is absorbed largely while passing through the planetary interior.

  7. Retraction Notice: Generation of Knock down Tools for Transcription Factor 7-like-2 (TCF7L2) and Evaluation of its Expression Pattern in Developing Chicken Optic Tectum.

    PubMed

    2016-01-01

    The publishers have decided to retract the manuscript entitled "Generation of Knock Down Tools for Transcription Factor 7-Like-2 (TCF7L2) and Evaluation of its Expression Pattern in Developing Chicken Optic Tectum" published in MicroRNA, volume 4, issue 3, page numbers 209-216, 2015, for the following reasons. • Due to conflict of interests between authors and the Principal Investigator. PMID:26861895

  8. Technique for information retrieval using enhanced latent semantic analysis generating rank approximation matrix by factorizing the weighted morpheme-by-document matrix

    DOEpatents

    Chew, Peter A; Bader, Brett W

    2012-10-16

    A technique for information retrieval includes parsing a corpus to identify a number of wordform instances within each document of the corpus. A weighted morpheme-by-document matrix is generated based at least in part on the number of wordform instances within each document of the corpus and based at least in part on a weighting function. The weighted morpheme-by-document matrix separately enumerates instances of stems and affixes. Additionally or alternatively, a term-by-term alignment matrix may be generated based at least in part on the number of wordform instances within each document of the corpus. At least one lower rank approximation matrix is generated by factorizing the weighted morpheme-by-document matrix and/or the term-by-term alignment matrix.

  9. Comparison of methods for generation of absolute reflectance-factor values for bidirectional reflectance-distribution function studies.

    PubMed

    Feng, X; Schott, J R; Gallagher, T

    1993-03-01

    Currently, spectrophotometric standard reference materials are calibrated only by using the illumination and viewing geometries recommended by the Commission Internationale de l'Eclairage, and for some geometries the spectral range is limited to the visible wavelengths. A need exists for procedures that calibrate standards at many other geometries and for a broader spectral range. Two methods for calibrating the spectral bidirectional reflectance factor are described. The absolute bidirectional reflectance factor of a sintered polytetrafluoroethylene (PTFE) sample is determined for nearly all the possible illumination and viewing geometries from 400 nm to 2500 nm. The references are a 45/0 reflectance standard calibrated by the National Institute of Standards and Technology and a sintered PTFE sample with a directional, hemispherical reflectance factor traceable to the Institute. The results of the two methods agree to within 0.01 in reflectance factor values. With this PTFE sample as a transfer standard, the instrument described can also be used to measure the absolute bidirectional reflectance factor at nearly all the illumination and viewing geometries from 400 nm to 2500 nm. PMID:20820258

  10. Zinc Finger Nuclease-Expressing Baculoviral Vectors Mediate Targeted Genome Integration of Reprogramming Factor Genes to Facilitate the Generation of Human Induced Pluripotent Stem Cells

    PubMed Central

    Phang, Rui-Zhe; Tay, Felix Chang; Goh, Sal-Lee; Lau, Cia-Hin; Zhu, Haibao; Tan, Wee-Kiat; Liang, Qingle; Chen, Can; Du, Shouhui; Li, Zhendong; Tay, Johan Chin-Kang; Wu, Chunxiao; Zeng, Jieming; Fan, Weimin; Toh, Han Chong

    2013-01-01

    Integrative gene transfer using retroviruses to express reprogramming factors displays high efficiency in generating induced pluripotent stem cells (iPSCs), but the value of the method is limited because of the concern over mutagenesis associated with random insertion of transgenes. Site-specific integration into a preselected locus by engineered zinc-finger nuclease (ZFN) technology provides a potential way to overcome the problem. Here, we report the successful reprogramming of human fibroblasts into a state of pluripotency by baculoviral transduction-mediated, site-specific integration of OKSM (Oct3/4, Klf4, Sox2, and c-myc) transcription factor genes into the AAVS1 locus in human chromosome 19. Two nonintegrative baculoviral vectors were used for cotransduction, one expressing ZFNs and another as a donor vector encoding the four transcription factors. iPSC colonies were obtained at a high efficiency of 12% (the mean value of eight individual experiments). All characterized iPSC clones carried the transgenic cassette only at the ZFN-specified AAVS1 locus. We further demonstrated that when the donor cassette was flanked by heterospecific loxP sequences, the reprogramming genes in iPSCs could be replaced by another transgene using a baculoviral vector-based Cre recombinase-mediated cassette exchange system, thereby producing iPSCs free of exogenous reprogramming factors. Although the use of nonintegrating methods to generate iPSCs is rapidly becoming a standard approach, methods based on site-specific integration of reprogramming factor genes as reported here hold the potential for efficient generation of genetically amenable iPSCs suitable for future gene therapy applications. PMID:24167318

  11. [Analysis of the risk factors for severe neutropenia in advanced non-small cell lung cancer after the first course of chemotherapy with third-generation agents].

    PubMed

    Shibuya, Midori; Kogo, Mari; Kurihara, Tatsuya; Shikama, Yusuke; Nakajima, Hiroaki; Yoneyama, Keiichiro; Kiuchi, Yuji

    2013-01-01

      We retrospectively evaluated clinical data before therapy to determine the risk factors for severe neutropenia in advanced non-small-cell lung cancer (NSCLC) patients treated with third-generation agents. We analyzed 100 patients who received such agents (paclitaxel, docetaxel, gemcitabine, irinotecan, or vinorelbine) for advanced NSCLC. The endpoint of the survey was the occurrence of severe neutropenia (grade 4). Risk factors significantly related to severe neutropenia were identified using logistic regression analysis. Of the 100 patients studied, the median age was 62.0 (32-81 years), and 77 (77.0%) were male. CEA 6.6 (0-2220) ng/dL and cytokeratin 19 fragment 21-1 (CYFRA) 4.8 (0.2-173.8) ng/dL before chemotherapy were higher than normal range. Severe neutropenia occurred in 36.0%, the incidence being highest in the first cycle (61.1%). In the univariate analysis, variables associated with severe neutropenia were sex, chest pain, absolute neutrophil count (ANC), Cr, CRP, and CYFRA. In the multivariate analysis, low CYFRA level was identified as a significant risk factor that contributed independently to chemotherapy-induced severe neutropenia (p<0.05). Our analysis suggests that low CYFRA level is the most important risk factor for severe neutropenia in advanced NSCLC patients after the first course of chemotherapy with third-generation agents. PMID:23728094

  12. Human factors in the presentation of computer-generated information - Aspects of design and application in automated flight traffic

    NASA Technical Reports Server (NTRS)

    Roske-Hofstrand, Renate J.

    1990-01-01

    The man-machine interface and its influence on the characteristics of computer displays in automated air traffic is discussed. The graphical presentation of spatial relationships and the problems it poses for air traffic control, and the solution of such problems are addressed. Psychological factors involved in the man-machine interface are stressed.

  13. Immigrant Parents' Choice of a Bilingual versus Monolingual Kindergarten for Second-Generation Children: Motives, Attitudes, and Factors

    ERIC Educational Resources Information Center

    Schwartz, Mila; Moin, Victor; Leikin, Mark; Breitkopf, Anna

    2010-01-01

    This study investigated how immigrant parents describe and explain their family language policy concerning their child's preschool bilingual development, and also explored the factors linked to the parents' choice of bilingual or monolingual kindergarten for their child. The study design was based on a comparison of 2 groups of parents: those who…

  14. Generation of reactive oxygen species (ROS) is a key factor for stimulation of macrophage proliferation by ceramide 1-phosphate

    SciTech Connect

    Arana, Lide; Gangoiti, Patricia; Ouro, Alberto; Rivera, Io-Guane; Ordonez, Marta; Trueba, Miguel; Lankalapalli, Ravi S.; Bittman, Robert; Gomez-Munoz, Antonio

    2012-02-15

    We previously demonstrated that ceramide 1-phosphate (C1P) is mitogenic for fibroblasts and macrophages. However, the mechanisms involved in this action were only partially described. Here, we demonstrate that C1P stimulates reactive oxygen species (ROS) formation in primary bone marrow-derived macrophages, and that ROS are required for the mitogenic effect of C1P. ROS production was dependent upon prior activation of NADPH oxidase by C1P, which was determined by measuring phosphorylation of the p40phox subunit and translocation of p47phox from the cytosol to the plasma membrane. In addition, C1P activated cytosolic calcium-dependent phospholipase A{sub 2} and protein kinase C-{alpha}, and NADPH oxidase activation was blocked by selective inhibitors of these enzymes. These inhibitors, and inhibitors of ROS production, blocked the mitogenic effect of C1P. By using BHNB-C1P (a photolabile caged-C1P analog), we demonstrate that all of these C1P actions are caused by intracellular C1P. It can be concluded that the enzyme responsible for C1P-stimulated ROS generation in bone marrow-derived macrophages is NADPH oxidase, and that this enzyme is downstream of PKC-{alpha} and cPLA{sub 2}-{alpha} in this pathway. -- Highlights: Black-Right-Pointing-Pointer Ceramide 1-phosphate (C1P) stimulates reactive oxygen species (ROS) formation. Black-Right-Pointing-Pointer The enzyme responsible for ROS generation by C1P in macrophages is NADPH oxidase. Black-Right-Pointing-Pointer NADPH oxidase lies downstream of cPLA{sub 2}-{alpha} and PKC-{alpha} in this pathway. Black-Right-Pointing-Pointer ROS generation is essential for the stimulation of macrophage proliferation by C1P.

  15. Changes in the pattern of distribution of von Willebrand factor in rat aortic endothelial cells following thrombin generation in vivo.

    PubMed

    Senis, Y A; Richardson, M; Tinlin, S; Maurice, D H; Giles, A R

    1996-04-01

    The pattern of distribution of von Willebrand factor (VWF) in relatively large sheets of rat aortic endothelial cells (EC) obtained by the Häutchen technique were analysed by immunocytochemistry and light microscopy. EC were examined pre and post administration of a procoagulant mixture of factor Xa (F.Xa) and phosphotidylcholine/phosphotidylserine (PCPS) vesicles which was demonstrated to result in the selective loss of high molecular weight multimers (HMWM) of plasma VWF in the rat. In placebo animals the pattern was heterogenous both in overall distribution and in individual cells which showed both a diffuse and granular pattern. Groups of intensely stained EC were oriented parallel to the longitudinal axis of the aorta and staining was particularly prominent around the orifices of the intercostal arteries, implicating shear-stress as a possible factor in VWF expression by EC. Changes in the pattern of distribution of staining were observed at various time points post-infusion of F.Xa/PCPS, suggesting the immediate release of VWF from EC stores followed by the recruitment of EC to synthesize and store VWF. These changes are consistent with the decrease in EC Weibel-Palade Body (WPB) content observed by EM in previously reported studies using this model. PMID:8611460

  16. Generation of dendritic cells in vitro from peripheral blood mononuclear cells with granulocyte-macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha for use in cancer immunotherapy.

    PubMed Central

    Morse, M A; Zhou, L J; Tedder, T F; Lyerly, H K; Smith, C

    1997-01-01

    OBJECTIVE: The purpose of the study was to characterize the requirements in terms of precursors, developmental pathways, and media for the generation of large numbers of mature dendritic cells (DC) under conditions acceptable for use in adjuvant, active immunotherapy strategies for surgically treated malignancies. SUMMARY BACKGROUND DATA: Although limited previously by the small numbers accessible, DC-based immunotherapies for malignancy have become more realistic with the development of methods for efficiently generating larger numbers of DC from peripheral blood mononuclear cells (PBMC) in vitro, but these methods rely on clinically unacceptable culture conditions (such as inclusion of fetal bovine serum), necessitating the development of methods for generating functionally equivalent DC in serum-free conditions. METHODS: Plastic-adherent PBMC (from healthy donors and patients with cancer) were incubated for 7 days with granulocyte-macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) with and without tumor necrosis factor-alpha (TNF-alpha) in fetal bovine serum-containing and serum-free media and were analyzed by Wright's stain for morphology, flow cytometry for phenotype, and mixed lymphocyte reaction for allostimulatory function. RESULTS: Growth in either serum-containing or serum-free media supplemented with GM-CSF and IL-4 yielded a similarly heterogeneous population of cells, 6% to 10% of which had the morphology (large cells with thin projections), immunophenotype (including CD83+), and function of mature DC. Tumor necrosis factor-alpha significantly augmented the number of these mature DC, whereas preculture depletion of CD14+ PBMC virtually eliminated them. CONCLUSIONS: Generation of mature DC in the authors' serum-free clinically applicable conditions is similar to serum-containing conditions and requires CD14+ precursors, differentiation through a CD14-CD83- immature stage under the influence of GM-CSF and IL-4, and maturation into a

  17. Monitoring Low Molecular Weight Heparins at Therapeutic Levels: Dose-Responses of, and Correlations and Differences between aPTT, Anti-Factor Xa and Thrombin Generation Assays

    PubMed Central

    Thomas, Owain; Lybeck, Emanuel; Strandberg, Karin; Tynngård, Nahreen; Schött, Ulf

    2015-01-01

    Background Low molecular weight heparins (LMWH’s) are used to prevent and treat thrombosis. Tests for monitoring LMWH’s include anti-factor Xa (anti-FXa), activated partial thromboplastin time (aPTT) and thrombin generation. Anti-FXa is the current gold standard despite LMWH’s varying affinities for FXa and thrombin. Aim To examine the effects of two different LMWH’s on the results of 4 different aPTT-tests, anti-FXa activity and thrombin generation and to assess the tests’ concordance. Method Enoxaparin and tinzaparin were added ex-vivo in concentrations of 0.0, 0.5, 1.0 and 1.5 anti-FXa international units (IU)/mL, to blood from 10 volunteers. aPTT was measured using two whole blood methods (Free oscillation rheometry (FOR) and Hemochron Jr (HCJ)) and an optical plasma method using two different reagents (ActinFSL and PTT-Automat). Anti-FXa activity was quantified using a chromogenic assay. Thrombin generation (Endogenous Thrombin Potential, ETP) was measured on a Ceveron Alpha instrument using the TGA RB and more tissue-factor rich TGA RC reagents. Results Methods’ mean aPTT at 1.0 IU/mL LMWH varied between 54s (SD 11) and 69s (SD 14) for enoxaparin and between 101s (SD 21) and 140s (SD 28) for tinzaparin. ActinFSL gave significantly shorter aPTT results. aPTT and anti-FXa generally correlated well. ETP as measured with the TGA RC reagent but not the TGA RB reagent showed an inverse exponential relationship to the concentration of LMWH. The HCJ-aPTT results had the weakest correlation to anti-FXa and thrombin generation (Rs0.62–0.87), whereas the other aPTT methods had similar correlation coefficients (Rs0.80–0.92). Conclusions aPTT displays a linear dose-respone to LMWH. There is variation between aPTT assays. Tinzaparin increases aPTT and decreases thrombin generation more than enoxaparin at any given level of anti-FXa activity, casting doubt on anti-FXa’s present gold standard status. Thrombin generation with tissue factor-rich activator is

  18. Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection.

    PubMed

    Martinez, Gustavo J; Hu, Joyce K; Pereira, Renata M; Crampton, Jordan S; Togher, Susan; Bild, Nicholas; Crotty, Shane; Rao, Anjana

    2016-03-01

    Follicular CD4(+) Th (Tfh) cells provide B cell help in germinal center reactions that support class switching, somatic hypermutation, and the generation of high-affinity Abs. In this article, we show that deficiency in NFAT1 and NFAT2 in CD4(+) T cells leads to impaired germinal center reactions upon viral infection because of reduced Tfh cell differentiation and defective expression of proteins involved in T/B interactions and B cell help, including ICOS, PD-1, and SLAM family receptors. Genome-wide chromatin immunoprecipitation data suggest that NFAT proteins likely directly participate in regulation of genes important for Tfh cell differentiation and function. NFAT proteins are important TCR and Ca(2+)-dependent regulators of T cell biology, and in this article we demonstrate a major positive role of NFAT family members in Tfh differentiation. PMID:26851216

  19. Hysteresis behavior of Kerr frequency comb generation in a high-quality-factor whispering-gallery-mode microcavity

    NASA Astrophysics Data System (ADS)

    Kato, Takumi; Chen-Jinnai, Akitoshi; Nagano, Takuma; Kobatake, Tomoya; Suzuki, Ryo; Yoshiki, Wataru; Tanabe, Takasumi

    2016-07-01

    A numerical and experimental study of Kerr frequency comb generation in a silica toroid microcavity is presented. We use a generalized mean-field Lugiato–Lefever equation and solve it with the split-step Fourier method. We observe that a stable mode-locked regime can be accessed when we reduce the input power after strong pumping due to the bistable nature of the nonlinear cavity system used. The experimental results agree well with the results of the numerical analysis, where we obtain a low-noise Kerr comb spectrum by gradually reducing the pumping input after strong pumping. This finding complements the results obtained by a previous wavelength scanning method and clarifies the procedure for achieving mode-locked states in such high-Q microcavity systems.

  20. Modifications of human growth differentiation factor 9 to improve the generation of embryos from low competence oocytes.

    PubMed

    Li, Jing-Jie; Sugimura, Satoshi; Mueller, Thomas D; White, Melissa A; Martin, Georgia A; Ritter, Lesley J; Liang, Xiao-Yan; Gilchrist, Robert B; Mottershead, David G

    2015-01-01

    Growth differentiation factor 9 (GDF9) is an oocyte-derived growth factor that plays a critical role in ovarian folliculogenesis and oocyte developmental competence and belongs to the TGF-β family of proteins. Recombinant human GDF9 (hGDF9) is secreted in a latent form, which in the case of the fully processed protein, has the proregion noncovalently associated with the mature region. In this study, we investigated a number of amino acid residues in the mature region of hGDF9 that are different from the corresponding residues in the mouse protein, which is not latent. We designed, expressed, and purified 4 forms of chimeric hGDF9 (M1-M4) that we found to be active in a granulosa cell bioassay. Using a porcine in vitro maturation model with inherent low developmental competence (yielding 10%-20% blastocysts), we tested the ability of the chimeric hGDF9 proteins to improve oocyte maturation and developmental competence. Interestingly, one of the chimeric proteins, M3, was able to significantly increase the level of embryo production using such low competence oocytes. Our molecular modeling studies suggest that in the case of hGDF9 the Gly(391)Arg mutation probably increases receptor binding affinity, thereby creating an active protein for granulosa cells in vitro. However, for an improvement in oocyte developmental competence, a second mutation (Ser(412)Pro), which potentially decreases the affinity of the mature region for the proregion, is also required. PMID:25394262

  1. Identification of caveolin-1 as a potential causative factor in the generation of trastuzumab resistance in breast cancer cells.

    PubMed

    Sekhar, Sreeja C; Kasai, Tomonari; Satoh, Ayano; Shigehiro, Tsukasa; Mizutani, Akifumi; Murakami, Hiroshi; El-Aarag, Bishoy Ya; Salomon, David S; Massaguer, Anna; de Llorens, Rafael; Seno, Masaharu

    2013-01-01

    The oncogenic tyrosine kinase receptor ErbB2 is a prognostic factor and target for breast cancer therapeutics. In contrast with the other ErbB receptors, ErbB2 is hardly internalized by ligand induced mechanisms, indicating a prevalent surface expression. Elevated levels of ErbB2 in tumor cells are associated with its defective endocytosis and down regulation. Here we show that caveolin-1 expression in breast cancer derived SKBR-3 cells (SKBR-3/Cav-1) facilitates ligand induced ErbB2 endocytosis using an artificial peptide ligand EC-eGFP. Similarly, stimulation with humanized anti ErbB2 antibody Trastuzumab (Herceptin) was found to be internalized and co-localized with caveolin-1 in SKBR-3/Cav-1 cells. Internalized EC-eGFP and Trastuzumab in SKBR-3/Cav-1 cells were then delivered via caveolae to the caveolin-1 containing early endosomes. Consequently, attenuated Fc receptor mediated ADCC functions were observed when exposed to Trastuzumab and EC-Fc (EC-1 peptide conjugated to Fc part of human IgG). On the other hand, this caveolae dependent endocytic synergy was not observed in parental SKBR-3 cells. Therefore, caveolin-1 expression in breast cancer cells could be a predictive factor to estimate how cancer cells are likely to respond to Trastuzumab treatment. PMID:23833684

  2. Use of mice tolerant to lipopolysaccharide to demonstrate requirement of cooperation between macrophages and lymphocytes to generate lipopolysaccharide-induced colony-stimulating factor in vivo.

    PubMed Central

    Williams, Z; Hertogs, C F; Pluznik, D H

    1983-01-01

    Injection of lipopolysaccharide (LPS) into mice was followed by a rapid elevation of colony-stimulating factor (CSF) in the serum. A second, challenging injection of LPS given 3 to 4 days later failed to induce elevated levels of CSF in the serum. Such mice tolerant to LPS were used as an experimental tool to identify the CSF-producing cells which respond to LPS. We observed that generation of LPS-induced CSF in mice tolerant to LPS could be restored by an intraperitoneal injection of spleen cells 24 h before the challenging injection of LPS. Depletion of the adherent cells from the spleen cells reduced the ability of the splenic lymphocytes to restore the capacity of the mice tolerant to LPS to generate serum CSF. Reconstitution of the splenic lymphocytes with 5% thioglycolate-elicited peritoneal macrophages, however, reestablished the restorative capacity of these cells, whereas almost no restoration was observed after direct injection of elicited peritoneal macrophages. These data suggest that the spleen cells are active in generating CSF, provided that macrophages are present and can interact with the splenic lymphocytes to generate LPS-induced CSF in the serum. PMID:6602767

  3. The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)

    PubMed Central

    Xu, Meng; Xie, Yiqun; Ni, Songshi

    2015-01-01

    First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, produce reliable responses and survival benefits in selected patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who initially respond to first-line therapy with EGFR TKIs will experience disease progression in 1-2 years. To overcome the resistance of EGFR TKIs, the potent resistance mechanisms and novel therapeutic strategies have been developed. T790M mutation and activation of bypass signaling pathway are identified the predominant mechanisms of acquired resistance to TKIs. Several approaches have shown promise, such as next-generation EGFR TKIs, immunotherapy, and combinational therapies. And the limited clinical data suggest that all drugs are acceptable safe. Additionally, this review will also focus on the increasingly importance of re-biopsy at the time of disease progression, and the matching effective therapies is related to the identification of specific molecular types of tumors. PMID:26015938

  4. Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

    PubMed

    Mathieu, Sophie; Crampe, Carine; Dargaud, Yesim; Lavigne-Lissalde, Géraldine; Escuriola-Ettingshausen, Carmen; Tardy, Brigitte; Meley, Roland; Thouvenin, Sandrine; Stephan, Jean L; Berger, Claire

    2015-12-01

    Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI. PMID:26517064

  5. The basic helix-loop-helix transcription factor HEBAlt is expressed in pro-T cells and enhances the generation of T cell precursors.

    PubMed

    Wang, Duncheng; Claus, Carol L; Vaccarelli, Giovanna; Braunstein, Marsela; Schmitt, Thomas M; Zúñiga-Pflücker, Juan Carlos; Rothenberg, Ellen V; Anderson, Michele K

    2006-07-01

    The basic helix-loop-helix (bHLH) transcription factors HEB and E2A are critical mediators of gene regulation during lymphocyte development. We have cloned a new transcription factor, called HEBAlt, from a pro-T cell cDNA library. HEBAlt is generated by alternative transcriptional initiation and splicing from the HEB gene locus, which also encodes the previously characterized E box protein HEBCan. HEBAlt contains a unique N-terminal coding exon (the Alt domain) that replaces the first transactivation domain of HEBCan. Downstream of the Alt domain, HEBAlt is identical to HEBCan, including the DNA binding domain. HEBAlt is induced in early thymocyte precursors and down-regulated permanently at the double negative to double positive (DP) transition, whereas HEBCan mRNA expression peaks at the DP stage of thymocyte development. HEBAlt mRNA is up-regulated synergistically by a combination of HEBCan activity and Delta-Notch signaling. Retroviral transduction of HEBAlt or HEBCan into hemopoietic stem cells followed by OP9-DL1 coculture revealed that HEBAlt-transduced precursors generated more early T lineage precursors and more DP pre-T cells than control transduced cells. By contrast, HEBCan-transduced cells that maintained high level expression of the HEBCan transgene were inhibited in expansion and progression through T cell development. HEB(-/-) fetal liver precursors transduced with HEBAlt were rescued from delayed T cell specification, but HEBCan-transduced HEB(-/-) precursors were not. Therefore, HEBAlt and HEBCan are functionally distinct transcription factors, and HEBAlt is specifically required for the efficient generation of early T cell precursors. PMID:16785505

  6. SU-E-P-15: Technique Factor Modulation and Reference Plane Air Kerma Rates in Response to Simulated Patient Thickness Variations for a Sample of Current Generation Fluoroscopes

    SciTech Connect

    Wunderle, K; Rakowski, J; Dong, F

    2015-06-15

    Purpose: To evaluate and compare approaches to technique factor modulation and air kerma rates in response to simulated patient thickness variations for four state-of-the-art and one previous-generation interventional fluoroscopes. Methods: A polymethyl methacrylate (PMMA) phantom was used as a tissue surrogate for the purposes of determining fluoroscopic reference plane air kerma rates, kVp, mA, and spectral filtration over a wide range of simulated tissue thicknesses. Data were acquired for each fluoroscopic and acquisition dose curve within a default abdomen or body imaging protocol. Results: The data obtained indicated vendor- and model-specific variations in the approach to technique factor modulation and reference plane air kerma rates across a range of tissue thicknesses. Some vendors have made hardware advances increasing the radiation output capabilities of their fluoroscopes; this was evident in the acquisition air kerma rates. However, in the imaging protocol evaluated, all of the state-of-the-art systems had relatively low air kerma rates in the fluoroscopic low-dose imaging mode as compared to the previous-generation unit. Each of the newest-generation systems also employ copper filtration in the selected protocol in the acquisition mode of imaging; this is a substantial benefit, reducing the skin entrance dose to the patient in the highest dose-rate mode of fluoroscope operation. Conclusion: Understanding how fluoroscopic technique factors are modulated provides insight into the vendor-specific image acquisition approach and provides opportunities to optimize the imaging protocols for clinical practice. The enhanced radiation output capabilities of some of the fluoroscopes may, under specific conditions, may be beneficial; however, these higher output capabilities also have the potential to lead to unnecessarily high dose rates. Therefore, all parties involved in imaging, including the clinical team, medical physicists, and imaging vendors, must work

  7. Transforming growth factor-beta1 inhibits tissue engineering cartilage absorption via inducing the generation of regulatory T cells.

    PubMed

    Li, Chichi; Bi, Wei; Gong, Yiming; Ding, Xiaojun; Guo, Xuehua; Sun, Jian; Cui, Lei; Yu, Youcheng

    2016-02-01

    The objective of the present study was to explore the mechanisms of transforming growth factor (TGF)-β1 inhibiting the absorption of tissue engineering cartilage. We transfected TGF-β1 gene into bone marrow mesenchymal stem cells (BMMSCs) and co-cultured with interferon (IFN)-γ and tumour necrosis factor (TNF)-α and CD4(+) CD25(-) T lymphocytes. We then characterized the morphological changes, apoptosis and characterization of chondrogenic-committed cells from TGF-β1(+) BMMSCs and explored their mechanisms. Results showed that BMMSCs apoptosis and tissue engineering cartilage absorption in the group with added IFN-γ and TNF-α were greater than in the control group. In contrast, there was little BMMSC apoptosis and absorption by tissue engineering cartilage in the group with added CD4(+) CD25(-) T lymphocytes; Foxp3(+) T cells and CD25(+) CD39(+) T cells were found. In contrast, no type II collagen or Foxp3(+) T cells or CD25(+) CD39(+) T cells was found in the TGF-β1(-) BMMSC group. The data suggest that IFN-γ and TNF-α induced BMMSCs apoptosis and absorption of tissue engineering cartilage, but the newborn regulatory T (Treg) cells inhibited the function of IFN-γ and TNF-α and protected BMMSCs and tissue engineering cartilage. TGF-β1not only played a cartilage inductive role, but also inhibited the absorption of tissue engineering cartilage. The pathway proposed in our study may simulate the actual reaction procedure after implantation of BMMSCs and tissue engineering cartilage in vivo. PMID:23868873

  8. Computer generation and application of 3-D model porous media: From pore-level geostatistics to the estimation of formation factor

    SciTech Connect

    Ioannidis, M.; Kwiecien, M.; Chatzis, I.

    1995-12-31

    This paper describes a new method for the computer generation of 3-D stochastic realizations of porous media using geostatistical information obtained from high-contrast 2-D images of pore casts. The stochastic method yields model porous media with statistical properties identical to those of their real counterparts. Synthetic media obtained in this manner can form the basis for a number of studies related to the detailed characterization of the porous microstructure and, ultimately, the prediction of important petrophysical and reservoir engineering properties. In this context, direct computer estimation of the formation resistivity factor is examined using a discrete random walk algorithm. The dependence of formation factor on measureable statistical properties of the pore space is also investigated.

  9. The effectiveness of power-generating complexes constructed on the basis of nuclear power plants combined with additional sources of energy determined taking risk factors into account

    NASA Astrophysics Data System (ADS)

    Aminov, R. Z.; Khrustalev, V. A.; Portyankin, A. V.

    2015-02-01

    The effectiveness of combining nuclear power plants equipped with water-cooled water-moderated power-generating reactors (VVER) with other sources of energy within unified power-generating complexes is analyzed. The use of such power-generating complexes makes it possible to achieve the necessary load pickup capability and flexibility in performing the mandatory selective primary and emergency control of load, as well as participation in passing the night minimums of electric load curves while retaining high values of the capacity utilization factor of the entire power-generating complex at higher levels of the steam-turbine part efficiency. Versions involving combined use of nuclear power plants with hydrogen toppings and gas turbine units for generating electricity are considered. In view of the fact that hydrogen is an unsafe energy carrier, the use of which introduces additional elements of risk, a procedure for evaluating these risks under different conditions of implementing the fuel-and-hydrogen cycle at nuclear power plants is proposed. Risk accounting technique with the use of statistical data is considered, including the characteristics of hydrogen and gas pipelines, and the process pipelines equipment tightness loss occurrence rate. The expected intensities of fires and explosions at nuclear power plants fitted with hydrogen toppings and gas turbine units are calculated. In estimating the damage inflicted by events (fires and explosions) occurred in nuclear power plant turbine buildings, the US statistical data were used. Conservative scenarios of fires and explosions of hydrogen-air mixtures in nuclear power plant turbine buildings are presented. Results from calculations of the introduced annual risk to the attained net annual profit ratio in commensurable versions are given. This ratio can be used in selecting projects characterized by the most technically attainable and socially acceptable safety.

  10. Tissue Destruction Induced by Porphyromonas gingivalis Infection in a Mouse Chamber Model Is Associated with Host Tumor Necrosis Factor Generation

    PubMed Central

    Lin, Yuh-Yih; Huang, Jan-Hung; Lai, Yo-Yin; Huang, Han-Ching; Hu, Suh-Woan

    2005-01-01

    Intrachamber challenge with Porphyromonas gingivalis strain 381 in a mouse subcutaneous chamber model results in a local infection that progresses to exfoliation of the chambers within 15 days. This study was designed to elucidate the contribution of host reactions to tissue destruction manifested by chamber exfoliation in animals infected with P. gingivalis. Chamber fluids showed increasing levels of prostaglandin E2 with infection, and the levels of tumor necrosis factor (TNF) in chamber fluids peaked just before chamber exfoliation. Intraperitoneal injection of a TNF inhibitor, thalidomide (TH), reduced the number of exfoliated chambers, while indomethacin had no effect. Exogenous TNF in chambers without bacterial infection did not cause chamber exfoliation but induced neutrophil infiltration. In a dual-chamber model, two chambers were implanted in the same mouse. One chamber was infected with P. gingivalis, and 9 days later exogenous TNF was added to the other chamber. Altogether, 66.67% of uninfected chambers were exfoliated between day 11 and day 16, although no bacteria were recovered from uninfected chambers. TH treatment alleviated both infected and uninfected chamber exfoliation. In this study, tissue destruction caused by P. gingivalis 381 infection was due to the elevation of the TNF levels and not due to local bacterial activities. Our results further indicate that local infection by P. gingivalis 381, a nondisseminating strain, actually has systemic effects on the host pathological outcome. PMID:16299286