Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.

PubMed

Tsai, Jordan C; Miller-Vedam, Lakshmi E; Anand, Aditya A; Jaishankar, Priyadarshini; Nguyen, Henry C; Renslo, Adam R; Frost, Adam; Walter, Peter

2018-03-30

Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a substrate to a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, thereby inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation, and in rodents it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and ISRIB promoted this step by cross-bridging a central symmetry interface. Thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Expression of the Eukaryotic Translation Initiation Factors 4E and 2α in Non-Hodgkin’s Lymphomas

PubMed Central

Wang, Songtao; Rosenwald, Igor B.; Hutzler, Michael J.; Pihan, German A.; Savas, Lou; Chen, Jane-Jane; Woda, Bruce A.

1999-01-01

Transition of cells from quiescence to proliferation requires an increase in the rate of protein synthesis, which is regulated in part by two key translation initiation factors, 4E and 2α. The expression and activity of both factors are increased transiently when normal resting cells are stimulated to proliferate. They are constitutively elevated in oncogene transformed cultured cells, and overexpression of either initiation factor in rodent cells makes them tumorigenic. In this study we investigate an association between the expression of translation initiation factors and lymphomagenesis. We have analyzed the expression of the protein synthesis initiation factors 4E and 2α by immunohistochemistry in reactive lymph nodes and several types of non-Hodgkin’s lymphoma representing a wide range of clinical behaviors based on the Revised European-American Lymphoma behavioral classification. The study included 7 benign lymph nodes with follicular hyperplasia, 26 indolent lymphomas (6 marginal zone lymphomas, 7 small lymphocytic lymphomas, and 13 follicular lymphomas, grades 1 and 2), 16 moderately aggressive lymphomas (8 mantle cell lymphomas and 8 follicular lymphomas, grade 3), 24 aggressive lymphomas (14 large-B-cell lymphomas and 10 anaplastic large-cell lymphomas), and 15 highly aggressive lymphomas (7 lymphoblastic lymphomas and 8 Burkitt’s lymphomas). Strong expression of initiation factors 4E and 2α was demonstrated in the germinal centers of reactive follicles. Minimal or no expression was seen in the mantle zones and surrounding paracortices, indicating that high expression of initiation factors 4E and 2α is associated with the active proliferation of lymphocytes. Most cases of aggressive and highly aggressive lymphomas showed strong expression of initiation factors 4E and 2α, in contrast to the cases of indolent and moderately aggressive lymphoma, in which their expression was intermediate between the germinal centers and the mantles of reactive follicles. A positive correlation was found between the expression of both initiation factors 4E and 2α and the Revised European-American Lymphoma behavior classification (P < 0.05). Thus, constitutively increased expression of initiation factors 4E and 2α may play an important role in the development of lymphomas and is correlated with their biological aggressiveness. PMID:10393856

Initial Bacterial Adhesion on Different Yttria-Stabilized Tetragonal Zirconia Implant Surfaces in Vitro

PubMed Central

Karygianni, Lamprini; Jähnig, Andrea; Schienle, Stefanie; Bernsmann, Falk; Adolfsson, Erik; Kohal, Ralf J.; Chevalier, Jérôme; Hellwig, Elmar; Al-Ahmad, Ali

2013-01-01

Bacterial adhesion to implant biomaterials constitutes a virulence factor leading to biofilm formation, infection and treatment failure. The aim of this study was to examine the initial bacterial adhesion on different implant materials in vitro. Four implant biomaterials were incubated with Enterococcus faecalis, Staphylococcus aureus and Candida albicans for 2 h: 3 mol % yttria-stabilized tetragonal zirconia polycrystal surface (B1a), B1a with zirconium oxide (ZrO2) coating (B2a), B1a with zirconia-based composite coating (B1b) and B1a with zirconia-based composite and ZrO2 coatings (B2b). Bovine enamel slabs (BES) served as control. The adherent microorganisms were quantified and visualized using scanning electron microscopy (SEM); DAPI and live/dead staining. The lowest bacterial count of E. faecalis was detected on BES and the highest on B1a. The fewest vital C. albicans strains (42.22%) were detected on B2a surfaces, while most E. faecalis and S. aureus strains (approximately 80%) were vital overall. Compared to BES; coated and uncoated zirconia substrata exhibited no anti-adhesive properties. Further improvement of the material surface characteristics is essential. PMID:28788415

Translation Initiation Factor eIF4B Interacts with a Picornavirus Internal Ribosome Entry Site in both 48S and 80S Initiation Complexes Independently of Initiator AUG Location

PubMed Central

Ochs, Kerstin; Rust, René C.; Niepmann, Michael

1999-01-01

Most eukaryotic initiation factors (eIFs) are required for internal translation initiation at the internal ribosome entry site (IRES) of picornaviruses. eIF4B is incorporated into ribosomal 48S initiation complexes with the IRES RNA of foot-and-mouth disease virus (FMDV). In contrast to the weak interaction of eIF4B with capped cellular mRNAs and its release upon entry of the ribosomal 60S subunit, eIF4B remains tightly associated with the FMDV IRES during formation of complete 80S ribosomes. Binding of eIF4B to the IRES is energy dependent, and binding of the small ribosomal subunit to the IRES requires the previous energy-dependent association of initiation factors with the IRES. The interaction of eIF4B with the IRES in 48S and 80S complexes is independent of the location of the initiator AUG and thus independent of the mechanism by which the small ribosomal subunit is placed at the actual start codon, either by direct internal ribosomal entry or by scanning. eIF4B does not greatly rearrange its binding to the IRES upon entry of the ribosomal subunits, and the interaction of eIF4B with the IRES is independent of the polypyrimidine tract-binding protein, which enhances FMDV translation. PMID:10438840

Phosphorylation of Wheat Germ Initiation Factors and Ribosomal Proteins 1

PubMed Central

Browning, Karen S.; Yan, Tyan Fuh J.; Lauer, Stephen J.; Aquino, Lu Ann; Tao, Mariano; Ravel, Joanne M.

1985-01-01

The ability of the wheat germ initiation factors and ribosomes to serve as substrates for a wheat germ protein kinase (Yan and Tao 1982 J Biol Chem 257: 7037-7043) has been investigated. The wheat germ kinase catalyzes the phosphorylation of the 42,000 dalton subunit of eukaryotic initiation factor (eIF)-2 and the 107,000 dalton subunit of eIF-3. Other initiation factors, eIF-4B and eIF-4A, and elongation factors, EF-1 and EF-2, are not phosphorylated by the kinase. Quantitative analysis indicates that the kinase catalyzes the incorporation of about 0.5 to 0.6 mole of phosphate per mole of the 42,000 dalton subunit of eIF-2 and about 6 moles of phosphate per mole of the 107,000 dalton subunit of eIF-3. Three proteins (Mr = 38,000, 14,800, and 12,600) of the 60S ribosomal subunit are phosphorylated by the kinase, but none of the 40S ribosomal proteins are substrates of the kinase. No effects of phosphorylation on the activities of eIF-2, eIF-3, or 60S ribosomal subunits could be demonstrated in vitro. Images Fig. 1 Fig. 3 Fig. 4 PMID:16664060

Reliability Estimating Procedures for Electric and Thermochemical Propulsion Systems. Volume 2

DTIC Science & Technology

1977-02-01

final form. For some components, the parameters are calculated from design factors (e.g., design life) that must be input when requested. Each component...Components Components are regarded as statis- tically identical if they are drawn from the same production lot because the initial and sub- sequent...table yields b 0.0023 The - factors are obtained from Tables 2.2.4-1 through 2.2.4-5: Factor Value rE Space, flight 1 JANTXV quality 0.5 7A Small signal

B cell helper factors. II. Synergy among three helper factors in the response of T cell- and macrophage-depleted B cells.

PubMed

Liebson, H J; Marrack, P; Kappler, J

1982-10-01

The concanavalin A- (Con A) stimulated supernatant of normal spleen cells (normal Con A SN) was shown to contain a set of helper factors sufficient to allow T cell- and macrophage- (M phi) depleted murine splenic B cells to produce a plaque-forming cell response to the antigen sheep red blood cells (SRBC). The activity of normal Con A SN could be reconstituted by a mixture of three helper factor preparations. The first was the interleukin 2- (IL 2) containing Con A SN of the T cell hybridoma, FS6-14.13. The second was a normal Con A SN depleted of IL 2 by extended culture with T cell blasts from which the 30,000 to 50,000 m.w. factors were isolated (interleukin X, IL X). The third was a SN either from the M phi tumor cell line P388D1 or from normal M phi taken from Corynebacterium parvum-immune mice. The combination of all three helper factor preparations was required to equal the activity of normal Con A SN; however, the M phi SN had the least overall effect. The M phi SN and IL 2 had to be added at the initiation of the culture period for a maximal effect, but the IL X preparation was most effective when added 24 hr after the initiation of culture. These results indicate that at least three nonspecific helper factors contribute to the helper activity in normal Con A SN.

Identification of a Kinase in Wheat Germ that Phosphorylates the Large Subunit of Initiation Factor 4F 1

PubMed Central

Humphreys, Jean; Browning, Karen S.; Ravel, Joanne M.

1988-01-01

A kinase has been isolated from wheat (Triticum aestivum) germ that phosphorylates the 220 kilodaltons (kD) subunit of wheat germ initiation factor (eIF) 4F, the 80 kD subunit of eIF-4B (an isozyme form of eIF-4F) and eIF-4G (the functional equivalent to mammalian eIF-4B). The kinase elutes from Sephacryl S-200 slightly in front of ovalbumin. The kinase phosphorylates casein and histone IIA to a small extent, but does not phosphorylate phosvitin. Of the wheat germ initiation factors, elongation factors, and small and large ribosomal subunits, only eIF-4F, eIF-4B, and eIF-4G are phosphorylated to a significant extent. The kinase phosphorylates eIF-4F to the extent of two phosphates per mole of the 220 kD subunit and phosphorylates eIF-4B to the extent of one phosphate per mole of the 80 kD subunit. The 26 kD subunit of eIF-4F and the 28 kD subunit of eIF-4B are not phosphorylated by the kinase. The kinase phosphorylates the 59 kD component of eIF-4G to the extent of 0.25 phosphate per mole of eIF-4G. Phosphorylation of eIF-4F and eIF-4B does not affect their ability to support the binding of mRNA to small ribosomal subunits in vitro. Images Fig. 2 Fig. 3 PMID:16666331

Multiple Sclerosis and EIF2B5: A Paradox or a Missing Link.

PubMed

Zahoor, Insha; Haq, Ehtishamul; Asimi, Ravouf

2017-01-01

Multiple sclerosis (MS) is an encumbering inflammatory condition of the central nervous system (CNS) caused by axonal demyelination. There is sufficient evidence suggesting role of eukaryotic translation initiation factor 2B (EIF2B) gene family encoding the five subunits of eIF2B complex-α, β, γ, δ and ε respectively, in causing vanishing white matter (VWM) disease of the brain. Incidentally researchers have proposed overlapping between MS and VWM in terms of clinical, biochemical and genetic aspects, which incited us to write this chapter to explore the association between EIF2B5 and MS. eIF2B plays an essential role in translation initiation and its regulation in eukaryotes. Among EIF2B gene family, EIF2B5 gene encodes the catalytic and a crucial epsilon subunit of the eIF2B protein as most of the alterations have been found in this gene. The recent findings on the association between EIF2B5 and MS susceptibility point towards unfathomable and contentious role of EIF2B5 in MS development. This chapter briefly reviews the insights gleaned from recent studies conducted in understanding the association between EIF2B5 and MS risk. The need of hour is to conduct large scale conclusive studies aimed at expounding the mechanisms behind this relationship.

40 CFR 1033.320 - Calculation and reporting of test results.

Code of Federal Regulations, 2010 CFR

2010-07-01

... applicable non-deterioration adjustments such as a Green Engine Factor or regeneration adjustment factor... following are true: (1) The catalyst was in a green condition when tested initially. (2) The locomotive met... locomotive, including: (A) Configuration and engine family identification. (B) Year, make, and build date. (C...

Initial Bacterial Adhesion on Different Yttria-Stabilized Tetragonal Zirconia Implant Surfaces in Vitro.

PubMed

Karygianni, Lamprini; Jähnig, Andrea; Schienle, Stefanie; Bernsmann, Falk; Adolfsson, Erik; Kohal, Ralf J; Chevalier, Jérôme; Hellwig, Elmar; Al-Ahmad, Ali

2013-12-04

Bacterial adhesion to implant biomaterials constitutes a virulence factor leading to biofilm formation, infection and treatment failure. The aim of this study was to examine the initial bacterial adhesion on different implant materials in vitro . Four implant biomaterials were incubated with Enterococcus faecalis , Staphylococcus aureus and Candida albicans for 2 h: 3 mol % yttria-stabilized tetragonal zirconia polycrystal surface (B1a), B1a with zirconium oxide (ZrO₂) coating (B2a), B1a with zirconia-based composite coating (B1b) and B1a with zirconia-based composite and ZrO₂ coatings (B2b). Bovine enamel slabs (BES) served as control. The adherent microorganisms were quantified and visualized using scanning electron microscopy (SEM); DAPI and live/dead staining. The lowest bacterial count of E. faecalis was detected on BES and the highest on B1a. The fewest vital C. albicans strains (42.22%) were detected on B2a surfaces, while most E. faecalis and S. aureus strains (approximately 80%) were vital overall. Compared to BES; coated and uncoated zirconia substrata exhibited no anti-adhesive properties. Further improvement of the material surface characteristics is essential.

Cyclophilin B expression in renal proximal tubules of hypertensive rats.

PubMed

Kainer, D B; Doris, P A

2000-04-01

Rat cyclophilin-like protein (Cy-LP) is a candidate hypertension gene initially identified by differential hybridization and implicated in renal mechanisms of salt retention and high blood pressure. We report the molecular characterization of rat cyclophilin B (CypB) and demonstrate, through sequence analysis and an allele-specific polymerase chain reaction primer assay, that CypB but not Cy-LP is expressed in rat kidney. CypB is an endoplasmic reticulum-localized prolyl-isomerase that interacts with elongation initiation factor 2-beta, an important regulator of protein translation and a central component of the endoplasmic reticulum stress response to hypoxia or ATP depletion. Active renal transport of sodium is increased in the spontaneously hypertensive rat (SHR), and there is evidence that this coincides with hypoxia and ATP depletion in the renal cortex. In the present studies we have examined expression of CypB in rat proximal tubules, which contributes to the increased renal sodium reabsorption in this model of hypertension. We report that CypB transcript abundance is significantly elevated in proximal convoluted tubules from SHR compared with the control Wistar-Kyoto strain. This upregulation occurs in weanling animals and precedes the development of hypertension, indicating that it is not a simple response to hypertension in SHR. Further, CypB expression is also higher in a proximal tubule cell line derived from SHR compared with a similar line derived from Wistar-Kyoto rats, indicating that this difference is genetically determined. No sequence differences were observed in the CypB cDNA from these 2 strains. These observations suggest that a genetically determined alteration in proximal tubules from SHR occurs that leads to increased expression of CypB. In view of evidence linking CypB to the regulation of elongation initiation factor-2, the upregulation of CypB may result from metabolic stress.

Alcohols inhibit translation to regulate morphogenesis in C. albicans

PubMed Central

Egbe, Nkechi E.; Paget, Caroline M.; Wang, Hui; Ashe, Mark P.

2015-01-01

Many molecules are secreted into the growth media by microorganisms to modulate the metabolic and physiological processes of the organism. For instance, alcohols like butanol, ethanol and isoamyl alcohol are produced by the human pathogenic fungus, Candida albicans and induce morphological differentiation. Here we show that these same alcohols cause a rapid inhibition of protein synthesis. More specifically, the alcohols target translation initiation, a complex stage of the gene expression process. Using molecular techniques, we have identified the likely translational target of these alcohols in C. albicans as the eukaryotic translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, which supports the exchange reaction where eIF2.GDP is converted to eIF2.GTP. Even minimal regulation at this step will lead to alterations in the levels of specific proteins that may allow the exigencies of the fungus to be realised. Indeed, similar to the effects of alcohols, a minimal inhibition of protein synthesis with cycloheximide also causes an induction of filamentous growth. These results suggest a molecular basis for the effect of various alcohols on morphological differentiation in C. albicans. PMID:25843913

Factors affecting UV/H2O2 inactivation of Bacillus atrophaeus spores in drinking water.

PubMed

Zhang, Yongji; Zhang, Yiqing; Zhou, Lingling; Tan, Chaoqun

2014-05-05

This study aims at estimating the performance of the Bacillus atrophaeus spores inactivation by the UV treatment with addition of H2O2. The effect of factors affecting the inactivation was investigated, including initial H2O2 dose, UV irradiance, initial cell density, initial solution pH and various inorganic anions. Under the experimental conditions, the B. atrophaeus spores inactivation followed both the modified Hom Model and the Chick's Model. The results revealed that the H2O2 played dual roles in the reactions, while the optimum reduction of 5.88lg was received at 0.5mM H2O2 for 10min. The inactivation effect was affected by the UV irradiance, while better inactivation effect was achieved at higher irradiance. An increase in the initial cell density slowed down the inactivation process. A slight acid condition at pH 5 was considered as the optimal pH value. The inactivation effect within 10min followed the order of pH 5>pH 7>pH 9>pH 3>pH 11. The effects of three added inorganic anions were investigated and compared, including sulfate (SO4(2)(-)), nitrate (NO3(-)) and carbonate (CO3(2)(-)). The sequence of inactivation effect within 10min followed the order of control group>SO4(2)(-)>NO3(-)>CO3(2)(-). Copyright © 2014 Elsevier B.V. All rights reserved.

Primate Lentiviruses Modulate NF-κB Activity by Multiple Mechanisms to Fine-Tune Viral and Cellular Gene Expression

PubMed Central

Heusinger, Elena; Kirchhoff, Frank

2017-01-01

The transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) plays a complex role during the replication of primate lentiviruses. On the one hand, NF-κB is essential for induction of efficient proviral gene expression. On the other hand, this transcription factor contributes to the innate immune response and induces expression of numerous cellular antiviral genes. Recent data suggest that primate lentiviruses cope with this challenge by boosting NF-κB activity early during the replication cycle to initiate Tat-driven viral transcription and suppressing it at later stages to minimize antiviral gene expression. Human and simian immunodeficiency viruses (HIV and SIV, respectively) initially exploit their accessory Nef protein to increase the responsiveness of infected CD4+ T cells to stimulation. Increased NF-κB activity initiates Tat expression and productive replication. These events happen quickly after infection since Nef is rapidly expressed at high levels. Later during infection, Nef proteins of HIV-2 and most SIVs exert a very different effect: by down-modulating the CD3 receptor, an essential factor for T cell receptor (TCR) signaling, they prevent stimulation of CD4+ T cells via antigen-presenting cells and hence suppress further induction of NF-κB and an effective antiviral immune response. Efficient LTR-driven viral transcription is maintained because it is largely independent of NF-κB in the presence of Tat. In contrast, human immunodeficiency virus type 1 (HIV-1) and its simian precursors have lost the CD3 down-modulation function of Nef and use the late viral protein U (Vpu) to inhibit NF-κB activity by suppressing its nuclear translocation. In this review, we discuss how HIV-1 and other primate lentiviruses might balance viral and antiviral gene expression through a tight temporal regulation of NF-κB activity throughout their replication cycle. PMID:28261165

Genomic organization and chromosomal localization of the gene TCF15 encoding the early mesodermal basic helix-loop-helix factor bHLH-EC2

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

Hidai, H.; Quertermous, E.E.; Quertermous, T.

1995-12-10

bHLH-EC2 is a recently characterized member of a growing family of basic helix-loop-helix transcription factors. This family includes bHLH factors such as twist, which appear to be primarily involved in early mesodermal differentiation, and bHLH factors such as TAL-1, which have been characterized through their association with chromosomal breakpoints associated with T-cell leukemias. To provide for studies aimed at understanding the genetic regulation of bHLH-EC2, we have characterized the organization of this gene and conducted preliminary studies of the transcriptional activity of the upstream promoter region. The mouse bHLH-EC2 gene was found to consist of two exons separated by amore » 5-kb intron, an organization pattern similar to the mouse twist gene. The transcription initiation site was identified by RNase protection assay and primer extension analysis. Linked promoter-reporter gene transfection experiments in cultured cells indicated that while the identified upstream sequence can function to promote transcription, it does not function in a cell-specific fashion. To investigate the possible association of bHLH-EC2 with hematological malignancy, the chromosomal location of this gene in the human was mapped by fluorescence in situ hybridization and assigned to chromosome band 20p13. 16 refs., 3 figs.« less

Plant recognition of Bradyrhizobium japonicum nod factors. Final report, September 15, 1992--March 14, 1997

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

Stacey, G.

1998-01-01

This grant had three objectives: (1) isolate and identify the unique nod factor metabolites made by different wild-type B. japonicum strains; (2) investigate the biological activity of these unique nod factors, especially as it relates to host range; and (3) initiate studies to define the mechanism of plant recognition of the nod factors. This report summarizes the results of this research.

Crosstalk between Two bZIP Signaling Pathways Orchestrates Salt-Induced Metabolic Reprogramming in Arabidopsis Roots

PubMed Central

Hartmann, Laura; Pedrotti, Lorenzo; Weiste, Christoph; Fekete, Agnes; Schierstaedt, Jasper; Göttler, Jasmin; Kempa, Stefan; Krischke, Markus; Dietrich, Katrin; Mueller, Martin J.; Vicente-Carbajosa, Jesus; Hanson, Johannes; Dröge-Laser, Wolfgang

2015-01-01

Soil salinity increasingly causes crop losses worldwide. Although roots are the primary targets of salt stress, the signaling networks that facilitate metabolic reprogramming to induce stress tolerance are less understood than those in leaves. Here, a combination of transcriptomic and metabolic approaches was performed in salt-treated Arabidopsis thaliana roots, which revealed that the group S1 basic leucine zipper transcription factors bZIP1 and bZIP53 reprogram primary C- and N-metabolism. In particular, gluconeogenesis and amino acid catabolism are affected by these transcription factors. Importantly, bZIP1 expression reflects cellular stress and energy status in roots. In addition to the well-described abiotic stress response pathway initiated by the hormone abscisic acid (ABA) and executed by SnRK2 (Snf1-RELATED-PROTEIN-KINASE2) and AREB-like bZIP factors, we identify a structurally related ABA-independent signaling module consisting of SnRK1s and S1 bZIPs. Crosstalk between these signaling pathways recruits particular bZIP factor combinations to establish at least four distinct gene expression patterns. Understanding this signaling network provides a framework for securing future crop productivity. PMID:26276836

Mechanism of Promoter Melting by the Xeroderma Pigmentosum Complementation Group B Helicase of Transcription Factor IIH Revealed by Protein-DNA Photo-Cross-Linking

PubMed Central

Douziech, Maxime; Coin, Frédéric; Chipoulet, Jean-Marc; Arai, Yoko; Ohkuma, Yoshiaki; Egly, Jean-Marc; Coulombe, Benoit

2000-01-01

The p89/xeroderma pigmentosum complementation group B (XPB) ATPase-helicase of transcription factor IIH (TFIIH) is essential for promoter melting prior to transcription initiation by RNA polymerase II (RNAPII). By studying the topological organization of the initiation complex using site-specific protein-DNA photo-cross-linking, we have shown that p89/XPB makes promoter contacts both upstream and downstream of the initiation site. The upstream contact, which is in the region where promoter melting occurs (positions −9 to +2), requires tight DNA wrapping around RNAPII. The addition of hydrolyzable ATP tethers the template strand at positions −5 and +1 to RNAPII subunits. A mutation in p89/XPB found in a xeroderma pigmentosum patient impairs the ability of TFIIH to associate correctly with the complex and thereby melt promoter DNA. A model for open complex formation is proposed. PMID:11027286

The delta-subunit of murine guanine nucleotide exchange factor eIF-2B. Characterization of cDNAs predicts isoforms differing at the amino-terminal end.

PubMed

Henderson, R A; Krissansen, G W; Yong, R Y; Leung, E; Watson, J D; Dholakia, J N

1994-12-02

Protein synthesis in mammalian cells is regulated at the level of the guanine nucleotide exchange factor, eIF-2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. We have isolated and sequenced cDNA clones encoding the delta-subunit of murine eIF-2B. The cDNA sequence encodes a polypeptide of 544 amino acids with molecular mass of 60 kDa. Antibodies against a synthetic polypeptide of 30 amino acids deduced from the cDNA sequence specifically react with the delta-subunit of mammalian eIF-2B. The cDNA-derived amino acid sequence shows significant homology with the yeast translational regulator Gcd2, supporting the hypothesis that Gcd2 may be the yeast homolog of the delta-subunit of mammalian eIF-2B. Primer extension studies and anchor polymerase chain reaction analysis were performed to determine the 5'-end of the transcript for the delta-subunit of eIF-2B. Results of these experiments demonstrate two different mRNAs for the delta-subunit of eIF-2B in murine cells. The isolation and characterization of two different full-length cDNAs also predicts the presence of two alternate forms of the delta-subunit of eIF-2B in murine cells. These differ at their amino-terminal end but have identical nucleotide sequences coding for amino acids 31-544.

KH-type splicing regulatory protein is regulated by nuclear factor-κB signaling to mediate innate immunity in Caco-2 cells infected by Salmonella enteritidis.

PubMed

Nie, Yuanyang; Cao, Mei; Wu, Daoyan; Li, Ningzhe; Peng, Jingshan; Yi, Sijun; Yang, Xiaofan; Zhang, Mao; Hu, Guoku; Zhao, Jian

2018-05-04

Salmonella enteritidis infection occurs in enterogenous diseases, such as gastroenteritis and parenteral focal infection, which often involve inflammation of intestinal epithelial cells. The nuclear factor kappa B (NF-κB) pathway participates in the innate immune response to many gram-negative pathogenic bacteria and initiates inflammation in epithelial cells. KH-type splicing regulatory protein (KSRP) is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for inflammatory response factors. However, it remains unclear whether KSRP is regulated by NF-κB signaling pathway in response to S. enteritidis infection and affects the development of inflammation. Accordingly, in this study, we investigated the role of KSRP in mediating the response to S. enteritidis in Caco-2 cells. The data revealed that S. enteritidis infection decreased KSRP expression, which was suppressed by blocking the NF-κB pathway. Additionally, S. enteritidis infection significantly increased the expression of inducible nitric oxide synthase and cyclooxygenase-2. Overexpression of KSRP reduced the expression levels of inflammatory factors in Caco-2 cells. KSRP was regulated by the NF-κB signaling pathway and participated in mediating the innate immune response to S. enteritidis infection in Caco-2 cells, and KSRP acted as a negative regulator of inflammatory gene expression.

Transgenic analysis of the medaka mesp-b enhancer in somitogenesis.

PubMed

Terasaki, Harumi; Murakami, Ryohei; Yasuhiko, Yukuto; Shin-I, Tadasu; Kohara, Yuji; Saga, Yumiko; Takeda, Hiroyuki

2006-04-01

Somitogenesis is a critical step during the formation of metameric structures in vertebrates. Recent studies in mouse, chick, zebrafish and Xenopus have revealed that several factors, such as T-box genes, Notch/Delta, Wnt, retinoic acid and FGF signaling, are involved in the specification of nascent somites. By interacting with these pathways, the Mesp2-like bHLH transcription factors are transiently expressed in the anterior presomitic mesoderm and play a crucial role in somite formation. The regulatory mechanisms of Mesp2 and its related genes during somitogenesis have been studied in mouse and Xenopus. However, the precise mechanism that regulates the transcriptional activity of Mesp2 has yet to be determined. In our current report, we identify the essential enhancer element of medaka mesp-b, an orthologue of mouse Mesp2, using transgenic techniques and embryo manipulation. Our results demonstrate that a region of approximately 2.8 kb, upstream of the mesp-b gene, is responsible for both the initiation and anterior localization of mesp-b transcription within a somite primordium. Furthermore, putative motifs for both T-box transcription factors and Notch/Delta signaling are present in this enhancer region and are essential for activity.

Systems approach to the study of brain damage in the very preterm newborn

PubMed Central

Leviton, Alan; Gressens, Pierre; Wolkenhauer, Olaf; Dammann, Olaf

2015-01-01

Background: A systems approach to the study of brain damage in very preterm newborns has been lacking. Methods: In this perspective piece, we offer encephalopathy of prematurity as an example of the complexity and interrelatedness of brain-damaging molecular processes that can be initiated inflammatory phenomena. Results: Using three transcription factors, nuclear factor-kappa B (NF-κB), Notch-1, and nuclear factor erythroid 2 related factor 2 (NRF2), we show the inter-connectedness of signaling pathways activated by some antecedents of encephalopathy of prematurity. Conclusions: We hope that as biomarkers of exposures and processes leading to brain damage in the most immature newborns become more readily available, those who apply a systems approach to the study of neuroscience can be persuaded to study the pathogenesis of brain disorders in the very preterm newborn. PMID:25926780

Phloretin Inhibits Phorbol Ester–Induced Tumor Promotion and Expression of Cyclooxygenase-2 in Mouse Skin: Extracellular Signal-Regulated Kinase and Nuclear Factor-κB as Potential Targets

PubMed Central

Shin, Jun-Wan; Kundu, Joydeb Kumar

2012-01-01

Abstract The present study investigated the effect of phloretin [2′,4′,6′-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)–induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. PMID:22181070

Phloretin inhibits phorbol ester-induced tumor promotion and expression of cyclooxygenase-2 in mouse skin: extracellular signal-regulated kinase and nuclear factor-κB as potential targets.

PubMed

Shin, Jun-Wan; Kundu, Joydeb Kumar; Surh, Young-Joon

2012-03-01

The present study investigated the effect of phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.

Fractionation and reconstitution of factors required for accurate transcription of mammalian ribosomal RNA genes: identification of a species-dependent initiation factor.

PubMed Central

Mishima, Y; Financsek, I; Kominami, R; Muramatsu, M

1982-01-01

Mouse and human cell extracts (S100) can support an accurate and efficient transcription initiation on homologous ribosomal RNA gene (rDNA) templates. The cell extracts were fractionated with the aid of a phosphocellulose column into four fractions (termed A, B, C and D), including one containing a major part of the RNA polymerase I activity. Various reconstitution experiments indicate that fraction D is an absolute requirement for the correct and efficient transcription initiation by RNA polymerase I on both mouse and human genes. Fraction B effectively suppresses random initiation on these templates. Fraction A appears to further enhance the transcription which takes place with fractions C and D. Although fractions A, B and C are interchangeable between mouse and human extracts, fraction D is not; i.e. initiation of transcription required the presence of a homologous fraction D for both templates. The factor(s) in fraction D, however, is not literally species-specific, since mouse D fraction is capable of supporting accurate transcription initiation on a rat rDNA template in the presence of all the other fractions from human cell extract under the conditions where human D fraction is unable to support it. We conclude from these experiments that a species-dependent factor in fraction D plays an important role in the initiation of rDNA transcription in each animal species. Images PMID:7177852

Distribution of ureteral stones and factors affecting their location and expulsion in patients with renal colic.

PubMed

Moon, Young Joon; Kim, Hong-Wook; Kim, Jin Bum; Kim, Hyung Joon; Chang, Young-Seop

2015-10-01

To evaluate the distribution of ureteral stones and to determine their characteristics and expulsion rate based on their location. We retrospectively reviewed computed tomography (CT) findings of 246 patients who visited our Emergency Department (ED) for renal colic caused by unilateral ureteral stones between January 2013 and April 2014. Histograms were constructed to plot the distribution of stones based on initial CT findings. Data from 144 of the 246 patients who underwent medical expulsive therapy (MET) for 2 weeks were analyzed to evaluate the factors responsible for the stone distribution and expulsion. The upper ureter and ureterovesical junction (UVJ) were 2 peak locations at which stones initially lodged. Stones lodged at the upper ureter and ureteropelvic junction (group A) had a larger longitudinal diameter (4.21 mm vs. 3.56 mm, p=0.004) compared to those lodged at the lower ureter and UVJ (group B). The expulsion rate was 75.6% and 94.9% in groups A and B, respectively. There was no significant difference in the time interval from initiation of renal colic to arrival at the ED between groups A and B (p=0.422). Stone diameter was a significant predictor of MET failure (odds ratio [OR], 1.795; p=0.005) but the initial stone location was not (OR, 0.299; p=0.082). The upper ureter and UVJ are 2 peak sites at which stones lodge. For stone size 10 mm or less, initial stone lodge site is not a significant predictor of MET failure in patients who have no previous history of active stone treatment in the ureter.

Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction.

PubMed

Miki, Takanori; Kusaka, Takashi; Yokoyama, Toshifumi; Ohta, Ken-ichi; Suzuki, Shingo; Warita, Katsuhiko; Jamal, Mostofa; Wang, Zhi-Yu; Ueki, Masaaki; Liu, Jun-Qian; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

2014-02-01

Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor α1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription-polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction.

Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response

PubMed Central

Sidrauski, Carmela; Tsai, Jordan C; Kampmann, Martin; Hearn, Brian R; Vedantham, Punitha; Jaishankar, Priyadarshini; Sokabe, Masaaki; Mendez, Aaron S; Newton, Billy W; Tang, Edward L; Verschueren, Erik; Johnson, Jeffrey R; Krogan, Nevan J; Fraser, Christopher S; Weissman, Jonathan S; Renslo, Adam R; Walter, Peter

2015-01-01

The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate eIF2 serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, a potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function in rodents by blocking long-term depression. ISRIB was identified in a phenotypic cell-based screen, and its mechanism of action remained unknown. We now report that ISRIB is an activator of eIF2B. Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity. Our results define ISRIB as a symmetric molecule, show ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (δ-subunit) contributes to the ISRIB binding site. We also developed new ISRIB analogs, improving its EC50 to 600 pM in cell culture. By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases. DOI: http://dx.doi.org/10.7554/eLife.07314.001 PMID:25875391

The BCL11A Transcription Factor Directly Activates RAG Gene Expression and V(D)J Recombination

PubMed Central

Lee, Baeck-seung; Dekker, Joseph D.; Lee, Bum-kyu; Iyer, Vishwanath R.; Sleckman, Barry P.; Shaffer, Arthur L.; Ippolito, Gregory C.

2013-01-01

Recombination-activating gene 1 protein (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining (VDJ) segment recombination, an essential process for antigen receptor expression and lymphocyte development. The transcription factor BCL11A is required for B cell development, but its molecular function(s) in B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds the RAG1 promoter and Erag enhancer to activate RAG1 and RAG2 transcription in pre-B cells. We employed BCL11A overexpression with recombination substrates in a cultured pre-B cell line as well as Cre recombinase-mediated Bcl11alox/lox deletion in explanted murine pre-B cells to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination. PMID:23438597

Moco biosynthesis and the ATAC acetyltransferase engage translation initiation by inhibiting latent PKR activity.

PubMed

Suganuma, Tamaki; Swanson, Selene K; Florens, Laurence; Washburn, Michael P; Workman, Jerry L

2016-02-01

Molybdenum cofactor (Moco) biosynthesis is linked to c-Jun N-terminal kinase (JNK) signaling in Drosophila through MoaE, a molybdopterin (MPT) synthase subunit that is also a component of the Ada Two A containing (ATAC) acetyltransferase complex. Here, we show that human MPT synthase and ATAC inhibited PKR, a double-stranded RNA-dependent protein kinase, to facilitate translation initiation of iron-responsive mRNA. MPT synthase and ATAC directly interacted with PKR and suppressed latent autophosphorylation of PKR and its downstream phosphorylation of JNK and eukaryotic initiation factor 2α (eIF2α). The suppression of eIF2α phosphorylation via MPT synthase and ATAC prevented sequestration of the guanine nucleotide exchange factor eIF2B, which recycles eIF2-GDP to eIF2-GTP, resulting in the promotion of translation initiation. Indeed, translation of the iron storage protein, ferritin, was reduced in the absence of MPT synthase or ATAC subunits. Thus, MPT synthase and ATAC regulate latent PKR signaling and link transcription and translation initiation. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Regulation of the human ascorbate transporter SVCT2 exon 1b gene by zinc-finger transcription factors

PubMed Central

Qiao, Huan; May, James M.

2011-01-01

The sodium-dependent vitamin C transporter (SVCT) 2 is crucial for ascorbate uptake in metabolically active and specialized tissues. The present study focused on the gene regulation of the SVCT2 exon 1b, which is ubiquitously expressed in human and mouse tissues. Although the human SVCT2 exon 1b promoter doesn’t contain a classical TATA-box, we found that it does contain a functional initiator (Inr) that binds YY1 and interacts with upstream Sp1/Sp3 elements in the proximal promoter region. These elements in turn play a critical role in regulating YY1-mediated transcription of the exon 1b gene. Formation of YY1/Sp complexes on the promoter is required for its optional function. YY1 with Sp1 or Sp3 synergistically enhanced exon 1b promoter activity as well as the endogenous SVCT2 protein expression. Further, in addition to Sp1/Sp3 both EGR-1 and -2 were detected in the protein complexes that bound the three GC boxes bearing overlapping binding sites for EGR/WT1 and Sp1/3. The EGR family factors, WT1 and MAZ were found to differentially regulate exon 1b promoter activity. These results show that differential occupancy of transcription factors on the GC-rich consensus sequences in SVCT2 exon 1b promoter contributes to the regulation of cell and tissue expression of SVCT2. PMID:21335086

The small molecule '1-(4-biphenylylcarbonyl)-4-(5-bromo-2-methoxybenzyl) piperazine oxalate' and its derivatives regulate global protein synthesis by inactivating eukaryotic translation initiation factor 2-alpha.

PubMed

Hong, Mi-Na; Nam, Ky-Youb; Kim, Kyung Kon; Kim, So-Young; Kim, InKi

2016-05-01

By environmental stresses, cells can initiate a signaling pathway in which eukaryotic translation initiation factor 2-alpha (eIF2-α) is involved to regulate the response. Phosphorylation of eIF2-α results in the reduction of overall protein neogenesis, which allows cells to conserve resources and to reprogram energy usage for effective stress control. To investigate the role of eIF2-α in cell stress responses, we conducted a viability-based compound screen under endoplasmic reticulum (ER) stress condition, and identified 1-(4-biphenylylcarbonyl)-4-(5-bromo-2-methoxybenzyl) piperazine oxalate (AMC-01) and its derivatives as eIF2-α-inactivating chemical. Molecular characterization of this signaling pathway revealed that AMC-01 induced inactivation of eIF2-α by phosphorylating serine residue 51 in a dose- and time-dependent manner, while the negative control compounds did not affect eIF2-α phosphorylation. In contrast with ER stress induction by thapsigargin, phosphorylation of eIF2-α persisted for the duration of incubation with AMC-01. By pathway analysis, AMC-01 clearly induced the activation of protein kinase RNA-activated (PKR) kinase and nuclear factor-κB (NF-κB), whereas it did not modulate the activity of PERK or heme-regulated inhibitor (HRI). Finally, we could detect a lower protein translation rate in cells incubated with AMC-01, establishing AMC-01 as a potent chemical probe that can regulate eIF2-α activity. We suggest from these data that AMC-01 and its derivative compounds can be used as chemical probes in future studies of the role of eIF2-α in protein synthesis-related cell physiology.

Development and Initial Evaluation of 7 Tesla Q-Ball Imaging of the Human Brain

PubMed Central

Mukherjee, Pratik; Hess, Christopher P.; Xu, Duan; Han, Eric T.; Kelley, Douglas A.; Vigneron, Daniel B.

2010-01-01

Diffusion tensor imaging (DTI) noninvasively depicts white matter connectivity in regions where the Gaussian model of diffusion is valid, but yields inaccurate results where diffusion has a more complex distribution, such as fiber crossings. Q-ball imaging (QBI) overcomes this limitation of DTI by more fully characterizing the angular dependence of intravoxel diffusion with larger numbers of diffusion-encoding directional measurements at higher diffusion-weighting factors (b values). However, the former results in longer acquisition times and the latter results in lower signal-to-noise ratio (SNR). In this project, we developed specialized 7 Tesla acquisition methods utilizing novel radiofrequency pulses, 8-channel parallel imaging EPI, and high-order shimming with a phase-sensitive multichannel B0 field map reconstruction. These methods were applied in initial healthy adult volunteer studies which demonstrated the feasibility of performing 7T QBI. Preliminary comparisons of 3T with 7T within supratentorial crossing white matter tracts document a 79.5% SNR increase for b=3000 s/mm2 (p=0.0001), and a 38.6% SNR increase for b=6000 s/mm2 (p=0.015). Using spherical harmonic reconstruction of the q-ball orientation distribution function at b=3000 s/mm2, 7T QBI allowed accurate visualization of crossing fiber tracts with fewer diffusion-encoding acquisitions than at 3T. The improvement of 7T QBI at b factors as high as 6000 s/mm2 resulted in better angular resolution than 3T for depicting fibers crossing at shallow angles. Although the increased susceptibility effects at 7T caused problematic distortions near brain-air interfaces at the skull base and posterior fossa, these initial 7T QBI studies demonstrated excellent quality in much of the supratentorial brain with significant improvements as compared to 3T acquisitions in the same individuals. PMID:17692489

Population age and initial density in a patchy environment affect the occurrence of abrupt transitions in a birth-and-death model of Taylor's law

USGS Publications Warehouse

Jiang, Jiang; DeAngelis, Donald L.; Zhang, B.; Cohen, J.E.

2014-01-01

Taylor's power law describes an empirical relationship between the mean and variance of population densities in field data, in which the variance varies as a power, b, of the mean. Most studies report values of b varying between 1 and 2. However, Cohen (2014a) showed recently that smooth changes in environmental conditions in a model can lead to an abrupt, infinite change in b. To understand what factors can influence the occurrence of an abrupt change in b, we used both mathematical analysis and Monte Carlo samples from a model in which populations of the same species settled on patches, and each population followed independently a stochastic linear birth-and-death process. We investigated how the power relationship responds to a smooth change of population growth rate, under different sampling strategies, initial population density, and population age. We showed analytically that, if the initial populations differ only in density, and samples are taken from all patches after the same time period following a major invasion event, Taylor's law holds with exponent b=1, regardless of the population growth rate. If samples are taken at different times from patches that have the same initial population densities, we calculate an abrupt shift of b, as predicted by Cohen (2014a). The loss of linearity between log variance and log mean is a leading indicator of the abrupt shift. If both initial population densities and population ages vary among patches, estimates of b lie between 1 and 2, as in most empirical studies. But the value of b declines to ~1 as the system approaches a critical point. Our results can inform empirical studies that might be designed to demonstrate an abrupt shift in Taylor's law.

Mapping shallow waters habitats using OBIA by applying several approaches of depth invariant index in North Kepulauan Seribu

NASA Astrophysics Data System (ADS)

Siregar, V. P.; Agus, S. B.; Subarno, T.; Prabowo, N. W.

2018-05-01

The availability of satellite imagery with a variety of spatial resolution, both free access and commercial become as an option in utilizing the remote sensing technology. Variability of the water column is one of the factors affecting the interpretation results when mapping marine shallow waters. This study aimed to evaluate the influence of water column correction (depth-invariant index) on the accuracy of shallow water habitat classification results using OBIA. This study was conducted in North of Kepulauan Seribu, precisely in Harapan Island and its surrounding areas. Habitat class schemes were based on field observations, which were then used to build habitat classes on satellite imagery. The water column correction was applied to the three pairs of SPOT-7 multispectral bands, which were subsequently used in object-based classification. Satellite image classification was performed with four different approaches, namely (i) using DII transformed bands with single pair band input (B1B2), (ii) multi pairs bands (B1B2, B1B3, and B2B3), (iii) combination of multi pairs band and initial bands, and (iv) only using initial bands. The accuracy test results of the four inputs show the values of Overall Accuracy and Kappa Statistics, respectively 55.84 and 0.48; 68.53 and 0.64; 78.68 and 0.76; 77.66 and 0.74. It shows that the best results when using DII and initial band combination for shallow water benthic classification in this study site.

Structure of the protein core of translation initiation factor 2 in apo, GTP-bound and GDP-bound forms

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

Simonetti, Angelita; Marzi, Stefano; Fabbretti, Attilio

2013-06-01

The crystal structures of the eubacterial translation initiation factor 2 in apo form and with bound GDP and GTP reveal conformational changes upon nucleotide binding and hydrolysis, notably of the catalytically important histidine in the switch II region. Translation initiation factor 2 (IF2) is involved in the early steps of bacterial protein synthesis. It promotes the stabilization of the initiator tRNA on the 30S initiation complex (IC) and triggers GTP hydrolysis upon ribosomal subunit joining. While the structure of an archaeal homologue (a/eIF5B) is known, there are significant sequence and functional differences in eubacterial IF2, while the trimeric eukaryotic IF2more » is completely unrelated. Here, the crystal structure of the apo IF2 protein core from Thermus thermophilus has been determined by MAD phasing and the structures of GTP and GDP complexes were also obtained. The IF2–GTP complex was trapped by soaking with GTP in the cryoprotectant. The structures revealed conformational changes of the protein upon nucleotide binding, in particular in the P-loop region, which extend to the functionally relevant switch II region. The latter carries a catalytically important and conserved histidine residue which is observed in different conformations in the GTP and GDP complexes. Overall, this work provides the first crystal structure of a eubacterial IF2 and suggests that activation of GTP hydrolysis may occur by a conformational repositioning of the histidine residue.« less

Pit initiation on nitinol in simulated physiological solutions.

PubMed

Pound, Bruce G

2018-05-01

Inclusions appear to play a crucial role in the initiation of pitting on nitinol, but the reason remains unclear. Furthermore, it has not been established whether the type of inclusion is a central factor. In this study, potentiodynamic polarization together with scanning electron microscopy and energy dispersive X-ray spectroscopy were used to provide more insight into the initiation of pits on electropolished nitinol wire. Corrosion was limited to a single primary pit on each of the few wire samples that exhibited breakdown. The pit contained numerous Ti 2 NiO x inclusions, but secondary pits that developed within the primary pit provided evidence that these inclusions were the sites of pit initiation. Although several theories have been proposed to account for pit initiation at inclusions in mechanically polished and electropolished nitinol, titanium depletion in the adjacent alloy matrix appears to provide the most viable explanation. The key factor appears to be the size of the inclusion and therefore the extent of titanium depletion in the alloy matrix. The type of inclusion evidently plays a secondary role at most. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1605-1610, 2018. © 2017 Wiley Periodicals, Inc.

No evidence for a role of Ile587Val polymorphism of EIF2B5 gene in multiple sclerosis in Kashmir Valley of India.

PubMed

Zahoor, Insha; Asimi, Ravouf; Haq, Ehtishamul

2015-12-15

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the nervous system with a profound genetic element. It is already known that alterations in Eukaryotic Translation Initiation Factor 2B (EIF2B) gene encoding the five subunits of eIF2B complex cause Vanishing White Matter (VWM) disease of the brain and emerging evidences have advocated certain resemblances between MS and VWM in terms of clinical and epidemiological characteristics, thus validating the association study between EIF2B and MS. Moreover, a recent study has implicated EIF2B5 Ile587Val (rs843358) polymorphism as a susceptibility factor for MS. In order to investigate the association of EIF2B5 Ile587Val polymorphism with MS susceptibility in Kashmir region in India, we screened EIF2B5 Exon 13 in 30 MS patients and 65 controls (a total of 95 participants). During the present course of study, we could not find statistically significant difference in the frequency of Ile587Val between MS patients and controls, thus indicating that such alteration does not appear to influence MS development in Kashmiri population. Our results provide evidence against a major role for Ile587Val polymorphism in MS susceptibility. Copyright © 2015 Elsevier B.V. All rights reserved.

G-actin provides substrate-specificity to eukaryotic initiation factor 2α holophosphatases

PubMed Central

Chen, Ruming; Rato, Cláudia; Yan, Yahui; Crespillo-Casado, Ana; Clarke, Hanna J; Harding, Heather P; Marciniak, Stefan J; Read, Randy J; Ron, David

2015-01-01

Dephosphorylation of eukaryotic translation initiation factor 2a (eIF2a) restores protein synthesis at the waning of stress responses and requires a PP1 catalytic subunit and a regulatory subunit, PPP1R15A/GADD34 or PPP1R15B/CReP. Surprisingly, PPP1R15-PP1 binary complexes reconstituted in vitro lacked substrate selectivity. However, selectivity was restored by crude cell lysate or purified G-actin, which joined PPP1R15-PP1 to form a stable ternary complex. In crystal structures of the non-selective PPP1R15B-PP1G complex, the functional core of PPP1R15 made multiple surface contacts with PP1G, but at a distance from the active site, whereas in the substrate-selective ternary complex, actin contributes to one face of a platform encompassing the active site. Computational docking of the N-terminal lobe of eIF2a at this platform placed phosphorylated serine 51 near the active site. Mutagenesis of predicted surface-contacting residues enfeebled dephosphorylation, suggesting that avidity for the substrate plays an important role in imparting specificity on the PPP1R15B-PP1G-actin ternary complex. DOI: http://dx.doi.org/10.7554/eLife.04871.001 PMID:25774600

FASTPM: a new scheme for fast simulations of dark matter and haloes

NASA Astrophysics Data System (ADS)

Feng, Yu; Chu, Man-Yat; Seljak, Uroš; McDonald, Patrick

2016-12-01

We introduce FASTPM, a highly scalable approximated particle mesh (PM) N-body solver, which implements the PM scheme enforcing correct linear displacement (1LPT) evolution via modified kick and drift factors. Employing a two-dimensional domain decomposing scheme, FASTPM scales extremely well with a very large number of CPUs. In contrast to Comoving-Lagrangian (COLA) approach, we do not require to split the force or track separately the 2LPT solution, reducing the code complexity and memory requirements. We compare FASTPM with different number of steps (Ns) and force resolution factor (B) against three benchmarks: halo mass function from friends-of-friends halo finder; halo and dark matter power spectrum; and cross-correlation coefficient (or stochasticity), relative to a high-resolution TREEPM simulation. We show that the modified time stepping scheme reduces the halo stochasticity when compared to COLA with the same number of steps and force resolution. While increasing Ns and B improves the transfer function and cross-correlation coefficient, for many applications FASTPM achieves sufficient accuracy at low Ns and B. For example, Ns = 10 and B = 2 simulation provides a substantial saving (a factor of 10) of computing time relative to Ns = 40, B = 3 simulation, yet the halo benchmarks are very similar at z = 0. We find that for abundance matched haloes the stochasticity remains low even for Ns = 5. FASTPM compares well against less expensive schemes, being only 7 (4) times more expensive than 2LPT initial condition generator for Ns = 10 (Ns = 5). Some of the applications where FASTPM can be useful are generating a large number of mocks, producing non-linear statistics where one varies a large number of nuisance or cosmological parameters, or serving as part of an initial conditions solver.

Transcriptional requirements of the distal heavy-strand promoter of mtDNA

PubMed Central

Zollo, Ornella; Tiranti, Valeria; Sondheimer, Neal

2012-01-01

The heavy strand of mtDNA contains two promoters with nonoverlapping functions. The role of the minor heavy-strand promoter (HSP2) is controversial, because the promoter has been difficult to activate in an in vitro system. We have isolated HSP2 by excluding its interaction with the more powerful HSP1 promoter, and we find that it is transcribed efficiently by recombinant mtRNA polymerase and mitochondrial transcription factor B2. The mitochondrial transcription factor A is not required for initiation, but it has the ability to alternatively activate and repress the HSP2 transcriptional unit depending on the ratio between mitochondrial transcription factor A and other transcription factors. The positioning of transcriptional initiation agrees with our current understanding of HSP2 activity in vivo. Serial deletion of HSP2 shows that only proximal sequences are required. Several mutations, including the disruption of a polycytosine track upstream of the HSP2 initiation site, influence transcriptional activity. Transcription from HSP2 is also observed when HeLa cell mitochondrial extract is used as the source of mitochondrial polymerase, and this transcription is maintained when HSP2 is provided in proper spacing and context to the HSP1 promoter. Studies of the linked heavy-strand promoters show that they are differentially regulated by ATP dosage. We conclude that HSP2 is transcribed and has features that allow it to regulate mitochondrial mRNA synthesis. PMID:22454497

40 CFR Appendix B to Part 132 - Great Lakes Water Quality Initiative

Code of Federal Regulations, 2011 CFR

2011-07-01

... WATER QUALITY GUIDANCE FOR THE GREAT LAKES SYSTEM Pt. 132, App. B Appendix B to Part 132—Great Lakes Water Quality Initiative Methodology for Deriving Bioaccumulation Factors Great Lakes States and Tribes... system. For log KOW, the log of the octanol-water partition coefficient is a base 10 logarithm. Uptake...

40 CFR Appendix B to Part 132 - Great Lakes Water Quality Initiative

Code of Federal Regulations, 2010 CFR

2010-07-01

... WATER QUALITY GUIDANCE FOR THE GREAT LAKES SYSTEM Pt. 132, App. B Appendix B to Part 132—Great Lakes Water Quality Initiative Methodology for Deriving Bioaccumulation Factors Great Lakes States and Tribes... system. For log KOW, the log of the octanol-water partition coefficient is a base 10 logarithm. Uptake...

Cloning, expression, purification, crystallization and X-ray crystallographic analysis of CofB, the minor pilin subunit of CFA/III from human enterotoxigenic Escherichia coli.

PubMed

Kawahara, Kazuki; Oki, Hiroya; Fukakusa, Shunsuke; Maruno, Takahiro; Kobayashi, Yuji; Motooka, Daisuke; Taniguchi, Tooru; Honda, Takeshi; Iida, Tetsuya; Nakamura, Shota; Ohkubo, Tadayasu

2015-06-01

Colonization factor antigen III (CFA/III) is one of the virulence factors of human enterotoxigenic Escherichia coli (ETEC) that forms the long, thin, proteinaceous fibres of type IV pili through assembly of its major and minor subunits CofA and CofB, respectively. The crystal structure of CofA has recently been reported; however, the lack of structural information for CofB, the largest among the known type IV pilin subunits, hampers a comprehensive understanding of CFA/III pili. In this study, constructs of wild-type CofB with an N-terminal truncation and the corresponding SeMet derivative were cloned, expressed, purified and crystallized. The crystals belonged to the rhombohedral space group R32, with unit-cell parameters a = b = 103.97, c = 364.57 Å for the wild-type construct and a = b = 103.47, c = 362.08 Å for the SeMet-derivatized form. Although the diffraction quality of these crystals was initially very poor, dehydration of the crystals substantially improved the resolution limit from ∼ 4.0 to ∼ 2.0 Å. The initial phase was solved by the single-wavelength anomalous dispersion (SAD) method using a dehydrated SeMet CofB crystal, which resulted in an interpretable electron-density map.

Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog-Dependent Medulloblastoma Initiation and Maintenance

DTIC Science & Technology

2014-10-01

Remodeling Factor in Sonic Hedgehog -Dependent Medulloblastoma Initiation and Maintenance PRINCIPAL INVESTIGATOR: Xuanming Shi CONTRACTING...Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog -Dependent 5b. GRANT NUMBER W81XWH-12-1-0527 Medulloblastoma Initiation and Maintenance...medulloblastoma. 15. SUBJECT TERMS Medulloblastoma, Sonic Hedgehog , Chromatin remodeling, BAF complex, Brg1, mouse model of shh-subtype medulloblastoma

PTSD Trajectory, Co-morbidity, and Utilization of Mental Health Services among National Guard Forces

DTIC Science & Technology

2011-10-01

constructed a survey for initial data collection as well as subsequent waves that contains modules on (1) risk or protective factors for psychological ...morbidity over the life course (general traumas, psychological resources, life and family concerns), (2) mental health (depression, PTSD, emotional...protective factors for psychological morbidity among National Guard force members, (b) mental health, and (c) service utilization patterns among

A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

PubMed Central

2011-01-01

Background Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. Methods We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. Results TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands. Conclusion Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I. PMID:21867536

Impulse approximation in nuclear pion production reactions: Absence of a one-body operator

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

Bolton, Daniel R.; Miller, Gerald A.

2011-06-15

The impulse approximation of pion production reactions is studied by developing a relativistic formalism, consistent with that used to define the nucleon-nucleon potential. For plane wave initial states we find that the usual one-body (1B) expression O{sub 1B} is replaced by O{sub 2B}=-iK(m{sub {pi}}/2)O{sub 1B}/m{sub {pi}}, where K(m{sub {pi}}/2) is the sum of all irreducible contributions to nucleon-nucleon scattering with energy transfer of m{sub {pi}}/2. We show that O{sub 2B}{approx_equal}O{sub 1B} for plane wave initial states. For distorted waves, we find that the usual operator is replaced with a sum of two-body operators that are well approximated by the operatormore » O{sub 2B}. Our new formalism solves the (previously ignored) problem of energy transfer forbidding a one-body impulse operator. Using a purely one pion exchange deuteron, the net result is that the impulse amplitude for np{yields}d{pi}{sup 0} at threshold is enhanced by a factor of approximately two. This amplitude is added to the larger ''rescattering'' amplitude and, although experimental data remain in disagreement, the theoretical prediction of the threshold cross section is brought closer to (and in agreement with) the data.« less

Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways

PubMed Central

Mandal, Animesh; Bhatia, Deepak; Bishayee, Anupam

2017-01-01

Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2–5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-κB, inhibitory κBα (IκBα) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IκBα, hindered the translocation of NF-κB from cytosol to nucleus and increased the expression and nuclear translocation of Nrf2 during DMBA-induced mammary tumorigenesis. These findings, together with our previous results, indicate that PE-mediated prevention of DMBA-evoked mammary carcinogenesis may involve anti-inflammatory mechanisms through concurrent but differential regulation of two interrelated molecular pathways, namely NF-κB and Nrf2 signaling. PMID:28452959

Identification of Associations Between Genetic Factors and Asthma that are Modified by Obesity

DTIC Science & Technology

2016-06-01

AFRL-SA-WP-TR-2016-0010 Identification of Associations Between Genetic Factors and Asthma That Are Modified by Obesity Andrew T...Between Genetic Factors and Asthma That Are Modified by Obesity 5a. CONTRACT NUMBER FA8650-13-2-6371 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...among African American women in the Women’s Health Initiative study. 15. SUBJECT TERMS Body mass index, SNP, asthma, obesity , genome, genes 16

Clostridium difficile virulence factors: Insights into an anaerobic spore-forming pathogen.

PubMed

Awad, Milena M; Johanesen, Priscilla A; Carter, Glen P; Rose, Edward; Lyras, Dena

2014-01-01

The worldwide emergence of epidemic strains of Clostridium difficile linked to increased disease severity and mortality has resulted in greater research efforts toward determining the virulence factors and pathogenesis mechanisms used by this organism to cause disease. C. difficile is an opportunist pathogen that employs many factors to infect and damage the host, often with devastating consequences. This review will focus on the role of the 2 major virulence factors, toxin A (TcdA) and toxin B (TcdB), as well as the role of other putative virulence factors, such as binary toxin, in C. difficile-mediated infection. Consideration is given to the importance of spores in both the initiation of disease and disease recurrence and also to the role that surface proteins play in host interactions.

Clostridium difficile virulence factors: Insights into an anaerobic spore-forming pathogen

PubMed Central

Awad, Milena M; Johanesen, Priscilla A; Carter, Glen P; Rose, Edward; Lyras, Dena

2014-01-01

The worldwide emergence of epidemic strains of Clostridium difficile linked to increased disease severity and mortality has resulted in greater research efforts toward determining the virulence factors and pathogenesis mechanisms used by this organism to cause disease. C. difficile is an opportunist pathogen that employs many factors to infect and damage the host, often with devastating consequences. This review will focus on the role of the 2 major virulence factors, toxin A (TcdA) and toxin B (TcdB), as well as the role of other putative virulence factors, such as binary toxin, in C. difficile-mediated infection. Consideration is given to the importance of spores in both the initiation of disease and disease recurrence and also to the role that surface proteins play in host interactions. PMID:25483328

Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation.

PubMed

Thornton, K J; Kamange-Sollo, E; White, M E; Dayton, W R

2015-09-01

Implanting cattle with steroids significantly enhances feed efficiency, rate of gain, and muscle growth. However, the mechanisms responsible for these improvements in muscle growth have not been fully elucidated. Trenbolone acetate (TBA), a testosterone analog, has been shown to increase proliferation rate in bovine satellite cell (BSC) cultures. The classical genomic actions of testosterone have been well characterized; however, our results indicate that TBA may also initiate a quicker, nongenomic response that involves activation of G protein-coupled receptors (GPCR) resulting in activation of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) that release membrane-bound heparin-binding epidermal growth factor-like growth factor (hbEGF), which then binds to and activates the epidermal growth factor receptor (EGFR) and/or erbB2. Furthermore, the EGFR has been shown to regulate expression of the IGF-1 receptor (IGF-1R), which is well known for its role in modulating muscle growth. To determine whether this nongenomic pathway is potentially involved in TBA-stimulated BSC proliferation, we analyzed the effects of treating BSC with guanosine 5'-O-2-thiodiphosphate (GDPβS), an inhibitor of all GPCR; a MMP2 and MMP9 inhibitor (MMPI); CRM19, a specific inhibitor of hbEGF; AG1478, a specific EGFR tyrosine kinase inhibitor; AG879, a specific erbB2 kinase inhibitor; and AG1024, an IGF-1R tyrosine kinase inhibitor on TBA-stimulated proliferation rate (H-thymidine incorporation). Assays were replicated at least 9 times for each inhibitor experiment using BSC cultures obtained from at least 3 different animals. Bovine satellite cell cultures were obtained from yearling steers that had no previous exposure to androgenic or estrogenic compounds. As expected, BSC cultures treated with 10 n TBA showed ( < 0.05) increased proliferation rate when compared with control cultures. Additionally, treatment with 5 ng hbEGF/mL stimulated proliferation in BSC cultures ( < 0.05). Treatment with GDPβS, MMPI, CRM197, AG1024, AG1478, and/or AG879 all suppressed ( < 0.05) TBA-induced increases in proliferation. These data indicate that TBA likely initiates a nongenomic response involving GPCR, MMP2 and MMP9, hbEGF, EGFR, erbB2, and IGF-1R, which may play a role in TBA-mediated increases in BSC proliferation.

[Breastfeeding (part one): Frequency, benefits and drawbacks, optimal duration and factors influencing its initiation and prolongation. Clinical guidelines for practice].

PubMed

Chantry, A A; Monier, I; Marcellin, L

2015-12-01

The objectives were to on assess the frequency and the duration of breastfeeding in France. On the other hand, the objectives were to identify its benefits and drawbacks, and to study the factors influencing its initiation and its extension. Bibliographic research in Medline, Google Scholar and in the Cochrane Library. Breastfeeding concerns in France about 70% of children at birth (EL2). Its median duration is about 15 weeks and 3 weeks ½ for exclusive breastfeeding. At three months, only one third of children breastfed at birth are still being breastfed (EL2). Whether this is due to the composition of breast milk or the behavior of mothers with their children or their socio-cultural level, or even by all these components at once, breastfeeding is associated with better cognitive development children (EL2). This effect is even more reinforced that mothers breastfeed exclusively and prolonged (EL2). As part of the prevention of many diseases (ear infections, gastrointestinal infections, atopic diseases, obesity and cardiovascular diseases…), exclusive and prolonged breastfeeding (grade B) between 4 to 6 months is recommended (professional consensus). Breastfeeding is not a means of preventing postpartum depression (professional consensus). To reduce the incidence of breast cancer, prolonged breastfeeding is recommended (grade B). In order to increase the rate of initiation of breastfeeding as well as its duration, it is recommended that health professionals work closely with mothers in their project (grade A), the breastfeeding promotion messages include message to husbands (grade B), and to promote breastfeeding on demand without fixed interval between feedings (grade B). However, there is not enough data to recommend the use of a specific position during breastfeeding, or the use of one or two breast or to early start breastfeeding or not (professional consensus). Exclusive and extended breastfeeding is recommended (grade B) between 4 to 6 months (professional consensus). Copyright © 2015. Published by Elsevier Masson SAS.

Antithrombotic Therapy for VTE Disease

PubMed Central

Kearon, Clive; Comerota, Anthony J.; Prandoni, Paolo; Bounameaux, Henri; Goldhaber, Samuel Z.; Nelson, Michael E.; Wells, Philip S.; Gould, Michael K.; Dentali, Francesco; Crowther, Mark; Kahn, Susan R.

2012-01-01

Background: This article addresses the treatment of VTE disease. Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences. PMID:22315268

Simultaneous inactivation of sigma factors B and D interferes with light acclimation of the cyanobacterium Synechocystis sp. strain PCC 6803.

PubMed

Pollari, Maija; Ruotsalainen, Virpi; Rantamäki, Susanne; Tyystjärvi, Esa; Tyystjärvi, Taina

2009-06-01

In cyanobacteria, gene expression is regulated mainly at the level of transcription initiation, which is mediated by the RNA polymerase holoenzyme. The RNA polymerase core is catalytically active, while the sigma factor recognizes promoter sequences. Group 2 sigma factors are similar to the principal sigma factor but are nonessential. Group 2 sigma factors SigB and SigD are structurally the most similar sigma factors in Synechocystis sp. strain PCC 6803. Under standard growth conditions, simultaneous inactivation of sigB and sigD genes did not affect the growth, but the photosynthesis and growth of the DeltasigBD strain were slower than in the control strain at double light intensity. Light-saturated electron transfer rates and the fluorescence and thermoluminescence measurements showed that photosynthetic light reactions are fully functional in the DeltasigBD strain, but absorption and 77 K emission spectra measurements suggest that the light-harvesting system of the DeltasigBD strain does not acclimate normally to higher light intensity. Furthermore, the DeltasigBD strain is more sensitive to photoinhibition under bright light because impaired upregulation of psbA genes leads to insufficient PSII repair.

Persistent Enhancement of Ethanol Drinking Following a Monosodium Glutamate-Substitution Procedure in C57BL6/J and DBA/2J Mice

PubMed Central

McCool, Brian A.; Chappell, Ann M.

2014-01-01

Inbred mouse strains such as C57BL/6J (B6) and DBA/2J (D2) and related strains have been used extensively to help identify genetic controls for a number of ethanol-related behaviors, including acute intoxication and sensitivity to repeated exposures. The disparate ethanol drinking behaviors of B6 mice expressing high-drinking/preference and D2 mice expressing low-drinking/preference have yielded considerable insight into the heritable control of alcohol drinking. However, the B6-high and D2-low drinking phenotypes are contrasted with ethanol-conditioned reward-like behaviors, which are robustly expressed by D2 mice and considerably less expressed by B6 mice. This suggests that peripheral factors, chiefly ethanol taste, may help drive ethanol drinking by these and related strains, which complicates mouse genetic studies designed to understand the relationships between reward-related behaviors and ethanol drinking. Traditional approaches such as the sucrose/saccharin-substitution procedure that normally accentuate ethanol drinking in rodents have had limited success in low drinking/preferring mice such as the D2 line. This may be due to allelic variations of the sweet taste receptor subunit, expressed by many ethanol low-drinking/preferring strains, which would limit the utility of these types of substitution approaches. We have recently shown (McCool & Chappell, 2012) that monosodium glutamate (MSG), the primary component of umami taste, can be used in a substitution procedure to initiate ethanol drinking in both B6 and D2 mice that greatly surpasses that initiated by a more traditional sucrose-substitution procedure. In this study, we show that ethanol drinking initiated by MSG substitution in D2 mice, but not sucrose substitution, can persist for several weeks following removal of the flavor. These findings further illustrate the utility of MSG substitution to initiate ethanol drinking in distinct mouse strains. PMID:24355071

B cells as accessory cells in a Con A response of a T cell clone.

PubMed

Takeuchi, M; Kakiuchi, T; Taira, S; Nariuchi, H

1987-12-01

Accessory cell (AC) function of B cells was examined in Con A response of a cloned T cell line, 22-9D, which is Thy 1+,L3T4+,Lyt2-,H-2KbDb+ and I-Ab-.22-9D cells produced IL 2 in the presence of Con A without participation of AC. For the initiation of a proliferative response to Con A, the addition of spleen cells or spleen adherent cells was required. B cells as AC were unable to induce the proliferative response. In the presence of culture supernatant of spleen cells stimulated with Con A (CAS), 22-9D cells showed proliferative response to Con A with B cell AC. The response was inhibited by a relevant monoclonal anti-I-A antibody. Although irradiated spleen cells as AC induced IL 2 receptor expression of 22-9D cells in the presence of Con A, B cells were shown to require the addition of unknown factor(s) in CAS, which was suggested to be different from IL 1, IL 2, IL 3, or IFN-gamma, for the induction of the receptor expression on 22-9D cells.

RNF168 forms a functional complex with RAD6 during the DNA damage response

PubMed Central

Liu, Chao; Wang, Degui; Wu, Jiaxue; Keller, Jennifer; Ma, Teng; Yu, Xiaochun

2013-01-01

Summary Protein ubiquitination plays an important role in initiating the DNA damage response. Following DNA damage, E2 ubiquitin conjugating enzymes are crucial for catalyzing substrate ubiquitination that recruits downstream DNA repair factors to DNA lesions. To identify novel E2 conjugating enzymes important for initiating the DNA-damage-induced ubiquitination cascade, we screened most of the known E2 enzymes and found that RAD6A and RAD6B function together with RNF168 in the ionizing radiation (IR)-induced DNA damage response. Similarly to RNF168-deficient cells, RAD6A- or RAD6B-deficient cells exhibit a reduction in DNA-damage-induced protein ubiquitination. Correspondingly, DNA-damage-induced foci formation of DNA damage repair proteins, such as BRCA1 and 53BP1, is impaired in the absence of RAD6A or RAD6B. Moreover, the RNF168–RAD6 complex targeted histone H1.2 for ubiquitination in vitro and regulated DNA-damage-induced histone H1.2 ubiquitination in vivo. Collectively, these data demonstrate that RNF168, in complex with RAD6A or RAD6B, is activated in the DNA-damage-induced protein ubiquitination cascade. PMID:23525009

7 CFR 1427.170 - Quantity for loan.

Code of Federal Regulations, 2010 CFR

2010-01-01

... necessary to protect the interests of CCC on the basis of one or more of the following risk factors: (1... turnout factor determined under paragraph (b) of this section. (b) The lint turnout factor for any lot of... initial inspection of the lot. If a control portion of the lot is weighed and ginned, the turnout factor...

7 CFR 1427.170 - Quantity for loan.

Code of Federal Regulations, 2011 CFR

2011-01-01

... necessary to protect the interests of CCC on the basis of one or more of the following risk factors: (1... turnout factor determined under paragraph (b) of this section. (b) The lint turnout factor for any lot of... initial inspection of the lot. If a control portion of the lot is weighed and ginned, the turnout factor...

Specific Inhibition of HER-2/neu Transcription Initiation

DTIC Science & Technology

2006-07-01

normoxia due to posttranslational processing involving proline hy- droxylation and the von Hippel Lindau (VHL) protein, a multifunctional adapter...inducible factor 1 alpha; VHL, Von Hippel Lindau; HRE, hypoxia response element; VEGF, vascular endothelial growth factor; PI3K, phosphatidyl inositol...Biol. 13, 167-171. 3. Zhong, H., De Marzo, A. M., Laughner, E., Lim, M., Hilton , D. A., Zagzag, D., Buechler, P ., Isaacs, W. B., Semenza, G. L., and

eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G

PubMed Central

Sen, Neelam Dabas; Zhou, Fujun; Harris, Michael S.; Ingolia, Nicholas T.

2016-01-01

DEAD-box RNA helicases eukaryotic translation initiation factor 4A (eIF4A) and Ded1 promote translation by resolving mRNA secondary structures that impede preinitiation complex (PIC) attachment to mRNA or scanning. Eukaryotic translation initiation factor 4B (eIF4B) is a cofactor for eIF4A but also might function independently of eIF4A. Ribosome profiling of mutants lacking eIF4B or with impaired eIF4A or Ded1 activity revealed that eliminating eIF4B reduces the relative translational efficiencies of many more genes than does inactivation of eIF4A, despite comparable reductions in bulk translation, and few genes display unusually strong requirements for both factors. However, either eliminating eIF4B or inactivating eIF4A preferentially impacts mRNAs with longer, more structured 5′ untranslated regions (UTRs). These findings reveal an eIF4A-independent role for eIF4B in addition to its function as eIF4A cofactor in promoting PIC attachment or scanning on structured mRNAs. eIF4B, eIF4A, and Ded1 mutations also preferentially impair translation of longer mRNAs in a fashion mitigated by the ability to form closed-loop messenger ribonucleoprotein particles (mRNPs) via eIF4F–poly(A)-binding protein 1 (Pab1) association, suggesting cooperation between closed-loop assembly and eIF4B/helicase functions. Remarkably, depleting eukaryotic translation initiation factor 4G (eIF4G), the scaffold subunit of eukaryotic translation initiation factor 4F (eIF4F), preferentially impacts short mRNAs with strong closed-loop potential and unstructured 5′ UTRs, exactly the opposite features associated with hyperdependence on the eIF4B/helicases. We propose that short, highly efficient mRNAs preferentially depend on the stimulatory effects of eIF4G-dependent closed-loop assembly. PMID:27601676

The amino terminal extension of mammalian mitochondrial RNA polymerase ensures promoter specific transcription initiation

PubMed Central

Posse, Viktor; Hoberg, Emily; Dierckx, Anke; Shahzad, Saba; Koolmeister, Camilla; Larsson, Nils-Göran; Wilhelmsson, L. Marcus; Hällberg, B. Martin; Gustafsson, Claes M.

2014-01-01

Mammalian mitochondrial transcription is executed by a single subunit mitochondrial RNA polymerase (Polrmt) and its two accessory factors, mitochondrial transcription factors A and B2 (Tfam and Tfb2m). Polrmt is structurally related to single-subunit phage RNA polymerases, but it also contains a unique N-terminal extension (NTE) of unknown function. We here demonstrate that the NTE functions together with Tfam to ensure promoter-specific transcription. When the NTE is deleted, Polrmt can initiate transcription in the absence of Tfam, both from promoters and non-specific DNA sequences. Additionally, when in presence of Tfam and a mitochondrial promoter, the NTE-deleted mutant has an even higher transcription activity than wild-type polymerase, indicating that the NTE functions as an inhibitory domain. Our studies lead to a model according to which Tfam specifically recruits wild-type Polrmt to promoter sequences, relieving the inhibitory effect of the NTE, as a first step in transcription initiation. In the second step, Tfb2m is recruited into the complex and transcription is initiated. PMID:24445803

Demonstration of GTG as an alternative initiation codon for the serpin endopin 2B-2.

PubMed

Hwang, Shin-Rong; Garza, Christina Z; Wegrzyn, Jill L; Hook, Vivian Y H

2005-02-18

This study demonstrates GTG as a novel, alternative initiation codon for translation of bovine endopin 2B-2, a serpin protease inhibitor. Molecular cDNA cloning revealed the endopin 2B-1 and endopin 2B-2 isoforms that are predicted to inhibit papain and elastase. Notably, GTG was demonstrated as the initiation codon for endopin 2B-2, whereas endopin 2B-1 possesses ATG as its initiation codon. GTG mediated in vitro translation of 46kDa endopin 2B-2. GTG also mediated translation of EGFP by in vitro translation and by expression in mammalian cells. Notably, mutagenesis of GTG to GTC resulted in the absence of EGFP expression in cells. GTG produced a lower level of protein expression compared to ATG. The use of GTG as an initiation codon to direct translation of endopin 2B, as well as the heterologous protein EGFP, demonstrates the role of GTG in the regulation of mRNA translation in mammalian cells. Significantly, further analyses of mammalian genomes based on GTG as an alternative initiation codon may predict new candidate gene products expressed by mammalian and human genomes.

Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway.

PubMed

Bhui, Kulpreet; Prasad, Sahdeo; George, Jasmine; Shukla, Yogeshwer

2009-09-18

Chemoprevention impels the pursuit for either single targeted or cocktail of multi-targeted agents. Bromelain, potential agent in this regard, is a pharmacologically active compound, present in stems and fruits of pineapple (Ananas cosmosus), endowed with anti-inflammatory, anti-invasive and anti-metastatic properties. Herein, we report the anti tumor-initiating effects of bromelain in 2-stage mouse skin tumorigenesis model. Pre-treatment of bromelain resulted in reduction in cumulative number of tumors (CNT) and average number of tumors per mouse. Preventive effect was also comprehended in terms of reduction in tumor volume up to a tune of approximately 65%. Components of the cell signaling pathways, connecting proteins involved in cell death were targeted. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in Bcl-2. A marked inhibition in cyclooxygenase-2 (Cox-2) expression and inactivation of nuclear factor-kappa B (NF-kappaB) was recorded, as phosphorylation and consequent degradation of I kappa B alpha was blocked by bromelain. Also, bromelain treatment curtailed extracellular signal regulated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (MAPK) and Akt activity. The basis of anti tumor-initiating activity of bromelain was revealed by its time dependent reduction in DNA nick formation and increase in percentage prevention. Thus, modulation of inappropriate cell signaling cascades driven by bromelain is a coherent approach in achieving chemoprevention.

A new link between transcriptional initiation and pre-mRNA splicing: The RNA binding histone variant H2A.B

PubMed Central

Hart-Smith, Gene; Tay, Ying Jin; Tng, Wei-Quan; Wilkins, Marc; Ryan, Daniel

2017-01-01

The replacement of histone H2A with its variant forms is critical for regulating all aspects of genome organisation and function. The histone variant H2A.B appeared late in evolution and is most highly expressed in the testis followed by the brain in mammals. This raises the question of what new function(s) H2A.B might impart to chromatin in these important tissues. We have immunoprecipitated the mouse orthologue of H2A.B, H2A.B.3 (H2A.Lap1), from testis chromatin and found this variant to be associated with RNA processing factors and RNA Polymerase (Pol) II. Most interestingly, many of these interactions with H2A.B.3 (Sf3b155, Spt6, DDX39A and RNA Pol II) were inhibited by the presence of endogenous RNA. This histone variant can bind to RNA directly in vitro and in vivo, and associates with mRNA at intron—exon boundaries. This suggests that the ability of H2A.B to bind to RNA negatively regulates its capacity to bind to these factors (Sf3b155, Spt6, DDX39A and RNA Pol II). Unexpectedly, H2A.B.3 forms highly decompacted nuclear subdomains of active chromatin that co-localizes with splicing speckles in male germ cells. H2A.B.3 ChIP-Seq experiments revealed a unique chromatin organization at active genes being not only enriched at the transcription start site (TSS), but also at the beginning of the gene body (but being excluded from the +1 nucleosome) compared to the end of the gene. We also uncover a general histone variant replacement process whereby H2A.B.3 replaces H2A.Z at intron-exon boundaries in the testis and the brain, which positively correlates with expression and exon inclusion. Taken together, we propose that a special mechanism of splicing may occur in the testis and brain whereby H2A.B.3 recruits RNA processing factors from splicing speckles to active genes following its replacement of H2A.Z. PMID:28234895

Affinity of antigen encounter and other early B-cell signals determine B-cell fate

PubMed Central

Benson, Micah J; Erickson, Loren D; Gleeson, Michael W; Noelle, Randolph J

2010-01-01

Three possible effector fates await the naïve follicular B cell following antigen stimulation in thymus-dependent reactions. Short-lived plasma cells produce an initial burst of germline-encoded protective antibodies, and long-lived plasma cells and memory B cells arise from the germinal center and function to enhance and sustain the humoral immune response. The inherent B-cell receptor affinity of naïve follicular B cells and the contribution of other early B-cell signals pre-determines the pattern of transcription factor expression and the differentiation path taken by these cells. High initial B-cell receptor affinity shunts naïve follicular B-cell clones towards the short-lived plasma cell fate, whereas modest-affinity clones are skewed towards a plasma cell fate and low-affinity clones are recruited into the germinal center and are selected for both long-lived plasma cells and memory B cell pathways. In the germinal center reaction, increased levels of the transcription factor interferon regulatory factor-4 drive the molecular program that dictates differentiation into the long-lived plasma cell phenotype but has no impact on the memory B cell compartment. We hypothesize that graded interferon regulatory factor-4 levels driven by signals to B cells, including B-cell receptor signal strength, are responsible for this branch point in the B-cell terminal differentiation pathway. PMID:17433651

eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control

PubMed Central

Jennings, Martin D.; Kershaw, Christopher J.; White, Christopher; Hoyle, Danielle; Richardson, Jonathan P.; Costello, Joseph L.; Donaldson, Ian J.; Zhou, Yu; Pavitt, Graham D.

2016-01-01

In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. eIF2 GDP/GTP status is regulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2α phosphorylation in response to diverse signals is a major point of translational control. Here we characterize a growth suppressor mutation in eIF2β that prevents eIF5 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation. By monitoring the binding of fluorescent nucleotides and initiator tRNA to purified eIF2 we show that the eIF2β mutation does not affect intrinsic eIF2 affinities for these ligands, neither does it interfere with eIF2 binding to 43S pre-initiation complex components. Instead we show that the eIF2β mutation prevents eIF5 GDI stabilizing nucleotide binding to eIF2, thereby altering the off-rate of GDP from eIF2•GDP/eIF5 complexes. This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 targets in response to amino acid starvation. These findings provide support for the importance of eIF5 GDI activity in vivo and demonstrate that eIF2β acts in concert with eIF5 to prevent premature release of GDP from eIF2γ and thereby ensure tight control of protein synthesis initiation. PMID:27458202

eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control.

PubMed

Jennings, Martin D; Kershaw, Christopher J; White, Christopher; Hoyle, Danielle; Richardson, Jonathan P; Costello, Joseph L; Donaldson, Ian J; Zhou, Yu; Pavitt, Graham D

2016-11-16

In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. eIF2 GDP/GTP status is regulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2α phosphorylation in response to diverse signals is a major point of translational control. Here we characterize a growth suppressor mutation in eIF2β that prevents eIF5 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation. By monitoring the binding of fluorescent nucleotides and initiator tRNA to purified eIF2 we show that the eIF2β mutation does not affect intrinsic eIF2 affinities for these ligands, neither does it interfere with eIF2 binding to 43S pre-initiation complex components. Instead we show that the eIF2β mutation prevents eIF5 GDI stabilizing nucleotide binding to eIF2, thereby altering the off-rate of GDP from eIF2•GDP/eIF5 complexes. This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 targets in response to amino acid starvation. These findings provide support for the importance of eIF5 GDI activity in vivo and demonstrate that eIF2β acts in concert with eIF5 to prevent premature release of GDP from eIF2γ and thereby ensure tight control of protein synthesis initiation. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Increased C3 production in human monocytes after stimulation with Candida albicans is suppressed by granulocyte-macrophage colony-stimulating factor.

PubMed Central

Høgåsen, A K; Abrahamsen, T G

1993-01-01

Activation of the complement system is an important part of host resistance against fungal infections. When human monocytes, cultured for 2 days or more, were treated in vitro with Candida albicans for 24 h, an enhancement of their biosynthesis of the complement components C3 and factor B was found. However, when C. albicans was administered to freshly isolated monocytes, a consistent stimulation of factor B biosynthesis occurred, while the C3 production was increased in about 50% of the donors. C. albicans also induced the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) from the cultured cells, apparently in larger amounts in the donors in whom no stimulation of C3 production was found. An antibody to GM-CSF administered with the yeast at the initiation of the monocyte culture caused an increase in the C3 production. Furthermore, when monocytes were treated with recombinant human GM-CSF either at the same time as or 4 days prior to the addition of C. albicans, the increase in C3 production was suppressed or neutralized, while factor B biosynthesis was unaffected. Taken together, these results indicate that monocytes respond to C. albicans with an increased production of complement factors. This may be an important mechanism both for opsonization of the fungus and for initiation of an inflammatory reaction. At an inflammatory site, this complement response may be suppressed by locally produced GM-CSF. PMID:8478067

MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis

PubMed Central

Musa, Julian; Aynaud, Marie-Ming; Mirabeau, Olivier; Delattre, Olivier; Grünewald, Thomas GP

2017-01-01

Limitless cell proliferation, evasion from apoptosis, dedifferentiation, metastatic spread and therapy resistance: all these properties of a cancer cell contribute to its malignant phenotype and affect patient outcome. MYBL2 (alias B-Myb) is a transcription factor of the MYB transcription factor family and a physiological regulator of cell cycle progression, cell survival and cell differentiation. When deregulated in cancer cells, MYBL2 mediates the deregulation of these properties. In fact, MYBL2 is overexpressed and associated with poor patient outcome in numerous cancer entities. MYBL2 and players of its downstream transcriptional network can be used as prognostic and/or predictive biomarkers as well as potential therapeutic targets to offer less toxic and more specific anti-cancer therapies in future. In this review, we summarize current knowledge on the physiological roles of MYBL2 and highlight the impact of its deregulation on cancer initiation and progression. PMID:28640249

Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates Recombinase Activating Gene Expression and V(D)J Recombination

PubMed Central

Lee, Baeck-Seung; Lee, Bum-Kyu; Iyer, Vishwanath R.; Sleckman, Barry P.; Shaffer, Arthur L.; Ippolito, Gregory C.

2017-01-01

ABSTRACT Recombination activating gene 1 (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining [V(D)J] segment recombination, an essential process for antigen receptor expression and lymphocyte development. The BCL11A transcription factor is required for B cell and plasmacytoid dendritic cell (pDC) development, but its molecular function(s) in early B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds directly to the RAG1 promoter as well as directly to regulatory regions of transcription factors previously implicated in both B cell and pDC development to activate RAG1 and RAG2 gene transcription in pro- and pre-B cells. We employed BCL11A overexpression with recombination substrates to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination. PMID:29038163

Psychopathological factors that can influence academic achievement in early adolescence: a three-year prospective study.

PubMed

Voltas, Núria; Hernández-Martínez, Carmen; Aparicio, Estefania; Arija, Victoria; Canals, Josefa

2014-12-30

This three-phase prospective study investigated psychosocial factors predicting or associated with academic achievement. An initial sample of 1,514 school-age children was assessed with screening tools for emotional problems (Screen for Childhood Anxiety and Related Emotional Disorders; Leyton Obsessional Inventory-Child Version; Children's Depression Inventory). The following year, 562 subjects (risk group/without risk group) were re-assessed and attention deficit/hyperactivity disorder (ADHD) was assessed. Two years later, 242 subjects were followed, and their parents informed about their academic achievement. Results showed that early depression (phase 1 B = -.130, p = .001; phase 1 + phase 2 B = -.187, p < .001), persistent anxiety symptoms (phase 1 + phase 2 B = -1.721, p = .018), and ADHD were predictors of lower academic achievement (phase 1 + phase 2 B = -3.415, p = .005). However, some anxiety symptoms can improve academic achievement (Social phobia B = .216, p = .018; Generalized anxiety B = .313, p < .001). Socio-economic status (SES) was positively related to academic achievement. We can conclude that in the transition period to adolescence, school-health professionals and teachers need to consider the emotional issues of students to avoid unwanted academic outcomes.

A region rich in aspartic acid, arginine, tyrosine, and glycine (DRYG) mediates eukaryotic initiation factor 4B (eIF4B) self-association and interaction with eIF3.

PubMed Central

Méthot, N; Song, M S; Sonenberg, N

1996-01-01

The binding of mRNA to the ribosome is mediated by eukaryotic initiation factors eukaryotic initiation factor 4F (eIF4F), eIF4B, eIF4A, and eIF3, eIF4F binds to the mRNA cap structure and, in combination with eIF4B, is believed to unwind the secondary structure in the 5' untranslated region to facilitate ribosome binding. eIF3 associates with the 40S ribosomal subunit prior to mRNA binding. eIF4B copurifies with eIF3 and eIF4F through several purification steps, suggesting the involvement of a multisubunit complex during translation initiation. To understand the mechanism by which eIF4B promotes 40S ribosome binding to the mRNA, we studied its interactions with partner proteins by using a filter overlay (protein-protein [far Western]) assay and the two-hybrid system. In this report, we show that eIF4B self-associates and also interacts directly with the p170 subunit of eIF3. A region rich in aspartic acid, arginine, tyrosine, and glycine, termed the DRYG domain, is sufficient for self-association of eIF4B, both in vitro and in vivo, and for interaction with the p170 subunit of eIF3. These experiments suggest that eIF4B participates in mRNA-ribosome binding by acting as an intermediary between the mRNA and eIF3, via a direct interaction with the p170 subunit of eIF3. PMID:8816444

RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.

PubMed

Sirinian, Chaido; Papanastasiou, Anastasios D; Schizas, Michail; Spella, Magda; Stathopoulos, Georgios T; Repanti, Maria; Zarkadis, Ioannis K; King, Tari A; Kalofonos, Haralabos P

2018-05-29

The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, progression, and metastasis. RANK-c is a RANK receptor isoform produced through alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative regulator of RANK-induced nuclear factor-κB (NF-κB) activation. Here we report that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas breast cancer cohort evenly between ER-positive and ER-negative cases. Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in ER-negative breast cancer cell lines compared to ER-positive breast cancer cell lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell lines inhibited stimuli-induced NF-κB activation and attenuated migration, invasion, colony formation, and adhesion of cancer cells. Further, RANK-c expression in MDA-MB-231 cells inhibited lung metastasis and colonization in vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear factor-κB (NF-κB) activation in breast cancer cells seems to rely on a RANK-c/TNF receptor-associated factor-2 (TRAF2) protein interaction. This was further confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes the ability to attenuate NF-κB activation, migration, and invasion. Additional protein interaction characterization revealed epidermal growth factor receptor (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a negative effect on EGFR phosphorylation and EGF-dependent downstream signaling pathway activation. Our findings further elucidate the complex molecular biology of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c as a possible marker for disease progression and aggressiveness.

Functional equivalence of translation factor eIF5B from Candida albicans and Saccharomyces cerevisiae.

PubMed

Jun, Kyung Ok; Yang, Eun Ji; Lee, Byeong Jeong; Park, Jeong Ro; Lee, Joon H; Choi, Sang Ki

2008-04-30

Eukaryotic translation initiation factor 5B (eIF5B) plays a role in recognition of the AUG codon in conjunction with translation factor eIF2, and promotes joining of the 60S ribosomal subunit. To see whether the eIF5B proteins of other organisms function in Saccharomyces cerevisiae, we cloned the corresponding genes from Oryza sativa, Arabidopsis thaliana, Aspergillus nidulans and Candida albican and expressed them under the control of the galactose-inducible GAL promoter in the fun12Delta strain of Saccharomyces cerevisiae. Expression of Candida albicans eIF5B complemented the slow-growth phenotype of the fun12Delta strain, but that of Aspergillus nidulance did not, despite the fact that its protein was expressed better than that of Candida albicans. The Arabidopsis thaliana protein was also not functional in Saccharomyces. These results reveal that the eIF5B in Candida albicans has a close functional relationship with that of Sacharomyces cerevisiae, as also shown by a phylogenetic analysis based on the amino acid sequences of the eIF5Bs.

PCBP2 enables the cadicivirus IRES to exploit the function of a conserved GRNA tetraloop to enhance ribosomal initiation complex formation

PubMed Central

Asnani, Mukta; Pestova, Tatyana V.; Hellen, Christopher U.T.

2016-01-01

The cadicivirus IRES diverges structurally from canonical Type 1 IRESs (e.g. poliovirus) but nevertheless also contains an essential GNRA tetraloop in a subdomain (d10c) that is homologous to poliovirus dIVc. In addition to canonical initiation factors, the canonical Type 1 and divergent cadicivirus IRESs require the same IRES trans-acting factor, poly(C)-binding protein 2 (PCBP2). PCBP2 has three KH domains and binds poliovirus IRES domain dIV in the vicinity of the tetraloop. How PCBP2 binds the cadicivirus IRES, and the roles of PCBP2 and the tetraloop in Type 1 IRES function are unknown. Here, directed hydroxyl radical probing showed that KH1 also binds near the cadicivirus tetraloop. KH2 and KH3 bind adjacently to an IRES subdomain (d10b) that is unrelated to dIV, with KH3 in an inverted orientation. KH3 is critical for PCBP2's binding to this IRES whereas KH1 is essential for PCBP2's function in promoting initiation. PCBP2 enforced the wild-type structure of d10c when it contained minor destabilizing substitutions, exposing the tetraloop. Strikingly, PCBP2 enhanced initiation on mutant IRESs that retained consensus GNRA tetraloops, whereas mutants with divergent sequences did not respond to PCBP2. These studies show that PCBP2 enables the IRES to exploit the GNRA tetraloop to enhance initiation. PMID:27387282

Diphtheria, tetanus, poliomyelitis, yellow fever and hepatitis B seroprevalence among HIV1-infected migrants. Results from the ANRS VIHVO vaccine sub-study.

PubMed

Mullaert, Jimmy; Abgrall, Sophie; Lele, Nathalie; Batteux, Frederic; Slama, Lilia Ben; Meritet, Jean-Francois; Lebon, Pierre; Bouchaud, Olivier; Grabar, Sophie; Launay, Odile

2015-09-11

Few data are available on the seroprotection status of HIV1-infected patients with respect to vaccine-preventable diseases. To describe, in a population of HIV1-infected migrants on stable, effective ART therapy, the seroprevalence of diphtheria, poliomyelitis, tetanus, yellow fever antibodies and serostatus for hepatitis B, and to identify factors associated with seroprotection. Vaccine responses against diphtheria, tetanus, poliomyelitis and yellow fever were also studied. Sub-Saharan African patients participating in the ANRS-VIHVO cohort were enrolled prior to travel to their countries of origin. Serologic analyses were performed in a central laboratory before and after the trip. Univariate and multivariate logistic regression was used to identify factors associated with initial seroprotection. 250 patients (99 men and 151 women) were included in the seroprevalence study. Median age was 45 years (IQR 39-52), median CD4 cell count was 440/μL (IQR 336-571), and 237 patients (95%) had undetectable HIV1 viral load. The initial seroprevalence rates were 69.0% (95%CI 63.2-74.7) for diphtheria, 70.7% (95%CI 65.0-76.3) for tetanus, and 85.9% (95%CI 81.6-90.2) for yellow fever. Only 64.4% (95%CI 58.5-70.3) of patients had protective antibody titers against all three poliomyelitis vaccine strains before travel. No serological markers of hepatitis B were found in 18.6% of patients (95%CI 13.7-23.3). Patient declaration of prior vaccination was the only factor consistently associated with initial seroprotection. We found a low prevalence of seroprotection against diphtheria, poliomyelitis, tetanus and hepatitis B. HIV infected migrants living in France and traveling to their native countries need to have their vaccine schedule completed. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Phytochrome-Interacting VASCULAR PLANT ONE–ZINC FINGER1 and VOZ2 Redundantly Regulate Flowering in Arabidopsis[C][W

PubMed Central

Yasui, Yukiko; Mukougawa, Keiko; Uemoto, Mitsuhiro; Yokofuji, Akira; Suzuri, Ryota; Nishitani, Aiko; Kohchi, Takayuki

2012-01-01

The timing of the transition to flowering in plants is regulated by various environmental factors, including daylength and light quality. Although the red/far-red photoreceptor phytochrome B (phyB) represses flowering by indirectly regulating the expression of a key flowering regulator, FLOWERING LOCUS T (FT), the mechanism of phyB signaling for flowering is largely unknown. Here, we identified two Arabidopsis thaliana genes, VASCULAR PLANT ONE–ZINC FINGER1 (VOZ1) and VOZ2, which are highly conserved throughout land plant evolution, as phyB-interacting factors. voz1 voz2 double mutants, but neither single mutant, showed a late-flowering phenotype under long-day conditions, which indicated that VOZ1 and VOZ2 redundantly promote flowering. voz1 voz2 mutations suppressed the early-flowering phenotype of the phyB mutant, and FT expression was repressed in the voz1 voz2 mutant. Green fluorescent protein–VOZ2 signal was observed in the cytoplasm, and interaction of VOZ proteins with phyB was indicated to occur in the cytoplasm under far-red light. However, VOZ2 protein modified to localize constitutively in the nucleus promoted flowering. In addition, the stability of VOZ2 proteins in the nucleus was modulated by light quality in a phytochrome-dependent manner. We propose that partial translocation of VOZ proteins from the cytoplasm to the nucleus mediates the initial step of the phyB signal transduction pathway that regulates flowering. PMID:22904146

The Role of Complement in Cnidarian-Dinoflagellate Symbiosis and Immune Challenge in the Sea Anemone Aiptasia pallida

PubMed Central

Poole, Angela Z.; Kitchen, Sheila A.; Weis, Virginia M.

2016-01-01

The complement system is an innate immune pathway that in vertebrates, is responsible for initial recognition and ultimately phagocytosis and destruction of microbes. Several complement molecules including C3, Factor B, and mannose binding lectin associated serine proteases (MASP) have been characterized in invertebrates and while most studies have focused on their conserved role in defense against pathogens, little is known about their role in managing beneficial microbes. The purpose of this study was to (1) characterize complement pathway genes in the symbiotic sea anemone Aiptasia pallida, (2) investigate the evolution of complement genes in invertebrates, and (3) examine the potential dual role of complement genes Factor B and MASP in the onset and maintenance of cnidarian-dinoflagellate symbiosis and immune challenge using qPCR based studies. The results demonstrate that A. pallida has multiple Factor B genes (Ap_Bf-1, Ap_Bf-2a, and Ap_Bf-2b) and one MASP gene (Ap_MASP). Phylogenetic analysis indicates that the evolutionary history of complement genes is complex, and there have been many gene duplications or gene loss events, even within members of the same phylum. Gene expression analyses revealed a potential role for complement in both onset and maintenance of cnidarian-dinoflagellate symbiosis and immune challenge. Specifically, Ap_Bf-1 and Ap_MASP are significantly upregulated in the light at the onset of symbiosis and in response to challenge with the pathogen Serratia marcescens suggesting that they play a role in the initial recognition of both beneficial and harmful microbes. Ap_Bf-2b in contrast, was generally downregulated during the onset and maintenance of symbiosis and in response to challenge with S. marcescens. Therefore, the exact role of Ap_Bf-2b in response to microbes remains unclear, but the results suggest that the presence of microbes leads to repressed expression. Together, these results indicate functional divergence between Ap_Bf-1 and Ap_Bf-2b, and that Ap_Bf-1 and Ap_MASP may be functioning together in an ancestral hybrid of the lectin and alternative complement pathways. Overall, this study provides information on the role of the complement system in a basal metazoan and its role in host-microbe interactions. PMID:27148208

The Role of Complement in Cnidarian-Dinoflagellate Symbiosis and Immune Challenge in the Sea Anemone Aiptasia pallida.

PubMed

Poole, Angela Z; Kitchen, Sheila A; Weis, Virginia M

2016-01-01

The complement system is an innate immune pathway that in vertebrates, is responsible for initial recognition and ultimately phagocytosis and destruction of microbes. Several complement molecules including C3, Factor B, and mannose binding lectin associated serine proteases (MASP) have been characterized in invertebrates and while most studies have focused on their conserved role in defense against pathogens, little is known about their role in managing beneficial microbes. The purpose of this study was to (1) characterize complement pathway genes in the symbiotic sea anemone Aiptasia pallida, (2) investigate the evolution of complement genes in invertebrates, and (3) examine the potential dual role of complement genes Factor B and MASP in the onset and maintenance of cnidarian-dinoflagellate symbiosis and immune challenge using qPCR based studies. The results demonstrate that A. pallida has multiple Factor B genes (Ap_Bf-1, Ap_Bf-2a, and Ap_Bf-2b) and one MASP gene (Ap_MASP). Phylogenetic analysis indicates that the evolutionary history of complement genes is complex, and there have been many gene duplications or gene loss events, even within members of the same phylum. Gene expression analyses revealed a potential role for complement in both onset and maintenance of cnidarian-dinoflagellate symbiosis and immune challenge. Specifically, Ap_Bf-1 and Ap_MASP are significantly upregulated in the light at the onset of symbiosis and in response to challenge with the pathogen Serratia marcescens suggesting that they play a role in the initial recognition of both beneficial and harmful microbes. Ap_Bf-2b in contrast, was generally downregulated during the onset and maintenance of symbiosis and in response to challenge with S. marcescens. Therefore, the exact role of Ap_Bf-2b in response to microbes remains unclear, but the results suggest that the presence of microbes leads to repressed expression. Together, these results indicate functional divergence between Ap_Bf-1 and Ap_Bf-2b, and that Ap_Bf-1 and Ap_MASP may be functioning together in an ancestral hybrid of the lectin and alternative complement pathways. Overall, this study provides information on the role of the complement system in a basal metazoan and its role in host-microbe interactions.

Clinicopathological Factors Affecting Survival and Recurrence after Initial Hepatectomy in Non-B Non-C Hepatocellular Carcinoma Patients with Comparison to Hepatitis B or C Virus

PubMed Central

Shiraishi, Taizou; Murata, Yasuhiro; Tanemura, Akihiro; Azumi, Yoshinori; Kuriyama, Naohisa; Kishiwada, Masashi; Usui, Masanobu; Tabata, Masami; Yamada, Tomomi

2014-01-01

We evaluated clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients with comparison to hepatitis B or C virus, paying attention to relationship between alcohol consumption and histopathological findings. The medical records on the 201HCC patients who underwent initial hepatectomy between January 2000 and April 2013 were retrospectively reviewed. NBNC patients had higher prevalence of hypertension (47.4%), diabetes mellitus (35.5%), alcohol consumption (>20 g/day) (61.8%), and preserved liver function than hepatitis B or C patients. The 5-year survival rate of NBNC patients (74.1%) was significantly better than hepatitis B (49.1%) or C (65.0%) patients (NBNC versus B, P = 0.031). Among the NBNC patients, there was no relationship between alcohol consumption and clinicopathological findings including nonalcoholic fatty liver disease activity score (NAS). However, the 5-year OS and RFS rates in the alcohol-unrelated NBNC patients tend to be better than in the alcohol-related. By multivariate analysis, independent factors for OS in NBNC patients were Child-Pugh B/C, intrahepatic metastasis (im), and extrahepatic recurrence. NBNC patients, who were highly associated with lifestyle-related disease and preserved liver function, had significantly better prognosis compared to hepatitis B/C patients; however, there was no association between alcohol consumption and histopathological findings. PMID:24745029

Using SCIAMACHY and Ground-based FTS Measurements to Test the OCO X(sub CO2) Retrieval and Validation Approach

NASA Technical Reports Server (NTRS)

Boesch, Hartmut; Toon, G.; Sen, B; Li, Q. B.; Salawitch, R.; Miller, C.; Crisp, D.; Washenfelder, R.; Wennberg, P.; Natraj, V.;

Demonstration of GTG as an endogenous initiation codon for a human mRNA transcript revealed by molecular cloning of the serpin endopin 2B.

PubMed

Hwang, Shin-Rong; Garza, Christina Z; Wegrzyn, Jill; Hook, Vivian Y H

2004-08-16

This study demonstrates utilization of the novel GTG initiation codon for translation of a human mRNA transcript that encodes the serpin endopin 2B, a protease inhibitor. Molecular cloning revealed the nucleotide sequence of the human endopin 2B cDNA. Its deduced primary sequence shows high homology to bovine endopin 2A that possesses cross-class protease inhibition of elastase and papain. Notably, the human endopin 2B cDNA sequence revealed GTG as the predicted translation initiation codon; the predicted translation product of 46 kDa endopin 2B was produced by in vitro translation of 35S-endopin 2B with mammalian (rabbit) protein translation components. Importantly, bioinformatic studies demonstrated the presence of the entire human endopin 2B cDNA sequence with GTG as initiation codon within the human genome on chromosome 14. Further evidence for GTG as a functional initiation codon was illustrated by GTG-mediated in vitro translation of the heterologous protein EGFP, and by GTG-mediated expression of EGFP in mammalian PC12 cells. Mutagenesis of GTG to GTC resulted in the absence of EGFP expression in PC12 cells, indicating the function of GTG as an initiation codon. In addition, it was apparent that the GTG initiation codon produces lower levels of translated protein compared to ATG as initiation codon. Significantly, GTG-mediated translation of endopin 2B demonstrates a functional human gene product not previously predicted from initial analyses of the human genome. Further analyses based on GTG as an alternative initiation codon may predict new candidate genes of the human genome.

Staphylococcal leukotoxins trigger free intracellular Ca2+ rise in neurones, signalling through acidic stores and activation of store-operated channels

PubMed Central

Jover, Emmanuel; Tawk, Mira Y; Laventie, Benoît-Joseph; Poulain, Bernard; Prévost, Gilles

2013-01-01

Headache, muscle aches and chest pain of mild to medium intensity are among the most common clinical symptoms in moderate Staphylococcus aureus infections, with severe infections usually associated with worsening pain symptoms. These nociceptive responses of the body raise the question of how bacterial infection impinges on the nervous system. Does S. aureus, or its released virulence factors, act directly on neurones? To address this issue, we evaluated the potential effects on neurones of certain bi-component leukotoxins, which are virulent factors released by the bacterium. The activity of four different leukotoxins was verified by measuring the release of glutamate from rat cerebellar granular neurones. The bi-component γ-haemolysin HlgC/HlgB was the most potent leukotoxin, initiating transient rises in intracellular Ca2+ concentration in cerebellar neurones and in primary sensory neurones from dorsal root ganglia, as probed with the Fura-2 Ca2+ indicator dye. Using pharmacological antagonists of receptors and Ca2+ channels, the variations in intracellular Ca2+ concentration were found independent of the activation of voltage-operatedCa2+ channels or glutamate receptors. Drugs targeting Sarco-Endoplasmic Reticulum Ca2+-ATPase (SERCA) or H+-ATPase and antagonists of the store-operated Ca2+ entry complex blunted, or significantly reduced, the leukotoxin-induced elevation in intracellular Ca2+. Moreover, activation of the ADP-ribosyl cyclase CD38 was also required to initiate the release of Ca2+ from acidic stores. These findings suggest that, prior to forming a pore at the plasma membrane, leukotoxin HlgC/HlgB triggers a multistep process which initiates the release of Ca2+ from lysosomes, modifies the steady-state level of reticular Ca2+ stores and finally activates the Store-Operated Calcium Entry complex. PMID:23152983

Staphylococcal leukotoxins trigger free intracellular Ca(2+) rise in neurones, signalling through acidic stores and activation of store-operated channels.

PubMed

Jover, Emmanuel; Tawk, Mira Y; Laventie, Benoît-Joseph; Poulain, Bernard; Prévost, Gilles

2013-05-01

Headache, muscle aches and chest pain of mild to medium intensity are among the most common clinical symptoms in moderate Staphylococcus aureus infections, with severe infections usually associated with worsening pain symptoms. These nociceptive responses of the body raise the question of how bacterial infection impinges on the nervous system. Does S. aureus, or its released virulence factors, act directly on neurones? To address this issue, we evaluated the potential effects on neurones of certain bi-component leukotoxins, which are virulent factors released by the bacterium. The activity of four different leukotoxins was verified by measuring the release of glutamate from rat cerebellar granular neurones. The bi-component γ-haemolysin HlgC/HlgB was the most potent leukotoxin, initiating transient rises in intracellular Ca(2+) concentration in cerebellar neurones and in primary sensory neurones from dorsal root ganglia, as probed with the Fura-2 Ca(2+) indicator dye. Using pharmacological antagonists of receptors and Ca(2+) channels, the variations in intracellular Ca(2+) concentration were found independent of the activation of voltage-operated Ca(2+) channels or glutamate receptors. Drugs targeting Sarco-Endoplasmic Reticulum Ca(2+)-ATPase (SERCA) or H(+)-ATPase and antagonists of the store-operated Ca(2+) entry complex blunted, or significantly reduced, the leukotoxin-induced elevation in intracellular Ca(2+). Moreover, activation of the ADP-ribosyl cyclase CD38 was also required to initiate the release of Ca(2+) from acidic stores. These findings suggest that, prior to forming a pore at the plasma membrane, leukotoxin HlgC/HlgB triggers a multistep process which initiates the release of Ca(2+) from lysosomes, modifies the steady-state level of reticular Ca(2+) stores and finally activates the Store-Operated Calcium Entry complex. © 2012 Blackwell Publishing Ltd.

Characterization of feeding-delaying factors from the silkworm Bombyx mori.

PubMed

Nagata, Shinji; Morooka, Nobukatsu; Matsumoto, Sumihiro; Nagasawa, Hiromichi

2009-04-01

In several phytophagous insects, feeding behavior occurs regularly. Recently, we demonstrated that feeding behavior in larvae of the silkworm Bombyx mori had a regular frequency. To address the control of the feeding cycle in B. mori, we aimed to characterize factors influencing feeding initiation and termination. Injection of extracts of the midgut, foregut, and fat body into starved Bombyx larvae delayed the initiation of feeding. This result indicates the presence in these tissues of factors capable of decreasing the likelihood of feeding initiation.

HNF1β Is Essential for Nephron Segmentation during Nephrogenesis

PubMed Central

Naylor, Richard W.; Przepiorski, Aneta; Ren, Qun; Yu, Jing

2012-01-01

Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1β paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms’ tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1β factors are essential for normal segmentation of nephrons during kidney organogenesis. PMID:23160512

HNF1β is essential for nephron segmentation during nephrogenesis.

PubMed

Naylor, Richard W; Przepiorski, Aneta; Ren, Qun; Yu, Jing; Davidson, Alan J

2013-01-01

Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1β paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms' tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1β factors are essential for normal segmentation of nephrons during kidney organogenesis.

Co-regulation of nuclear respiratory factor-1 by NFκB and CREB links LPS-induced inflammation to mitochondrial biogenesis

PubMed Central

Suliman, Hagir B.; Sweeney, Timothy E.; Withers, Crystal M.; Piantadosi, Claude A.

2010-01-01

The nuclear respiratory factor-1 (NRF1) gene is activated by lipopolysaccharide (LPS), which might reflect TLR4-mediated mitigation of cellular inflammatory damage via initiation of mitochondrial biogenesis. To test this hypothesis, we examined NRF1 promoter regulation by NFκB, and identified interspecies-conserved κB-responsive promoter and intronic elements in the NRF1 locus. In mice, activation of Nrf1 and its downstream target, Tfam, by Escherichia coli was contingent on NFκB, and in LPS-treated hepatocytes, NFκB served as an NRF1 enhancer element in conjunction with NFκB promoter binding. Unexpectedly, optimal NRF1 promoter activity after LPS also required binding by the energy-state-dependent transcription factor CREB. EMSA and ChIP assays confirmed p65 and CREB binding to the NRF1 promoter and p65 binding to intron 1. Functionality for both transcription factors was validated by gene-knockdown studies. LPS regulation of NRF1 led to mtDNA-encoded gene expression and expansion of mtDNA copy number. In cells expressing plasmid constructs containing the NRF-1 promoter and GFP, LPS-dependent reporter activity was abolished by cis-acting κB-element mutations, and nuclear accumulation of NFκB and CREB demonstrated dependence on mitochondrial H2O2. These findings indicate that TLR4-dependent NFκB and CREB activation co-regulate the NRF1 promoter with NFκB intronic enhancement and redox-regulated nuclear translocation, leading to downstream target-gene expression, and identify NRF-1 as an early-phase component of the host antibacterial defenses. PMID:20587593

Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor.

PubMed

Witters, Lois; Scherle, Peggy; Friedman, Steven; Fridman, Jordan; Caulder, Eian; Newton, Robert; Lipton, Allan

2008-09-01

The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-alpha, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu-positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points.

A single amino acid substitution in IIIf subfamily of basic helix-loop-helix transcription factor AtMYC1 leads to trichome and root hair patterning defects by abolishing its interaction with partner proteins in Arabidopsis.

PubMed

Zhao, Hongtao; Wang, Xiaoxue; Zhu, Dandan; Cui, Sujuan; Li, Xia; Cao, Ying; Ma, Ligeng

2012-04-20

Plant trichomes and root hairs are powerful models for the study of cell fate determination. In Arabidopsis thaliana, trichome and root hair initiation requires a combination of three groups of proteins, including the WD40 repeat protein transparent TESTA GLABRA1 (TTG1), R2R3 repeat MYB protein GLABRA1 (GL1), or werewolf (WER) and the IIIf subfamily of basic helix-loop-helix (bHLH) protein GLABRA3 (GL3) or enhancer of GLABRA3 (EGL3). The bHLH component acts as a docking site for TTG1 and MYB proteins. Here, we isolated a mutant showing defects in trichome and root hair patterning that carried a point mutation (R173H) in AtMYC1 that encodes the fourth member of IIIf bHLH family protein. Genetic analysis revealed partial redundant yet distinct function between AtMYC1 and GL3/EGL3. GLABRA2 (GL2), an important transcription factor involved in trichome and root hair control, was down-regulated in Atmyc1 plants, suggesting the requirement of AtMYC1 for appropriate GL2 transcription. Like its homologs, AtMYC1 formed a complex with TTG1 and MYB proteins but did not dimerized. In addition, the interaction of AtMYC1 with MYB proteins and TTG1 was abrogated by the R173H substitution in Atmyc1-1. We found that this amino acid (Arg) is conserved in the AtMYC1 homologs GL3/EGL3 and that it is essential for their interaction with MYB proteins and for their proper functions. Our findings indicate that AtMYC1 is an important regulator of trichome and root hair initiation, and they reveal a novel amino acid necessary for protein-protein interactions and gene function in IIIf subfamily bHLH transcription factors.

A Single Amino Acid Substitution in IIIf Subfamily of Basic Helix-Loop-Helix Transcription Factor AtMYC1 Leads to Trichome and Root Hair Patterning Defects by Abolishing Its Interaction with Partner Proteins in Arabidopsis*

PubMed Central

Zhao, Hongtao; Wang, Xiaoxue; Zhu, Dandan; Cui, Sujuan; Li, Xia; Cao, Ying; Ma, Ligeng

2012-01-01

Plant trichomes and root hairs are powerful models for the study of cell fate determination. In Arabidopsis thaliana, trichome and root hair initiation requires a combination of three groups of proteins, including the WD40 repeat protein TRANSPARENT TESTA GLABRA1 (TTG1), R2R3 repeat MYB protein GLABRA1 (GL1), or WEREWOLF (WER) and the IIIf subfamily of basic helix-loop-helix (bHLH) protein GLABRA3 (GL3) or ENHANCER OF GLABRA3 (EGL3). The bHLH component acts as a docking site for TTG1 and MYB proteins. Here, we isolated a mutant showing defects in trichome and root hair patterning that carried a point mutation (R173H) in AtMYC1 that encodes the fourth member of IIIf bHLH family protein. Genetic analysis revealed partial redundant yet distinct function between AtMYC1 and GL3/EGL3. GLABRA2 (GL2), an important transcription factor involved in trichome and root hair control, was down-regulated in Atmyc1 plants, suggesting the requirement of AtMYC1 for appropriate GL2 transcription. Like its homologs, AtMYC1 formed a complex with TTG1 and MYB proteins but did not dimerized. In addition, the interaction of AtMYC1 with MYB proteins and TTG1 was abrogated by the R173H substitution in Atmyc1-1. We found that this amino acid (Arg) is conserved in the AtMYC1 homologs GL3/EGL3 and that it is essential for their interaction with MYB proteins and for their proper functions. Our findings indicate that AtMYC1 is an important regulator of trichome and root hair initiation, and they reveal a novel amino acid necessary for protein-protein interactions and gene function in IIIf subfamily bHLH transcription factors. PMID:22334670

Blocking Modification of Eukaryotic Initiation 5A2 Antagonizes Cervical Carcinoma via Inhibition of RhoA/ROCK Signal Transduction Pathway.

PubMed

Liu, Xiaojun; Chen, Dong; Liu, Jiamei; Chu, Zhangtao; Liu, Dongli

2017-10-01

Cervical carcinoma is one of the leading causes of cancer-related death for female worldwide. Eukaryotic initiation factor 5A2 belongs to the eukaryotic initiation factor 5A family and is proposed to be a key factor involved in the development of diverse cancers. In the current study, a series of in vivo and in vitro investigations were performed to characterize the role of eukaryotic initiation factor 5A2 in oncogenesis and metastasis of cervical carcinoma. The expression status of eukaryotic initiation factor 5A2 in 15 cervical carcinoma patients was quantified. Then, the effect of eukaryotic initiation factor 5A2 knockdown on in vivo tumorigenicity ability, cell proliferation, cell cycle distribution, and cell mobility of HeLa cells was measured. To uncover the mechanism driving the function of eukaryotic initiation factor 5A2 in cervical carcinoma, expression of members within RhoA/ROCK pathway was detected, and the results were further verified with an RhoA overexpression modification. The level of eukaryotic initiation factor 5A2 in cervical carcinoma samples was significantly higher than that in paired paratumor tissues ( P < .05). And the in vivo tumorigenic ability of HeLa cells was reduced by inhibition of eukaryotic initiation factor 5A2. Knockdown of eukaryotic initiation factor 5A2 in HeLa cells decreased the cell viability compared with normal cells and induced G1 phase cell cycle arrest ( P < .05). Moreover, the cell migration ability of eukaryotic initiation factor 5A2 knockdown cells was dramatically inhibited. Associated with alterations in phenotypes, RhoA, ROCK I, and ROCK II were downregulated. The above-mentioned changes in eukaryotic initiation factor 5A2 knockdown cells were alleviated by the overexpression of RhoA. The major findings outlined in the current study confirmed the potential of eukaryotic initiation factor 5A2 as a promising prognosis predictor and therapeutic target for cervical carcinoma treatment. Also, our data inferred that eukaryotic initiation factor 5A2 might function in carcinogenesis of cervical carcinoma through an RhoA/ROCK-dependent manner.

Novel characteristics of the biological properties of the yeast Saccharomyces cerevisiae eukaryotic initiation factor 2A.

PubMed

Komar, Anton A; Gross, Stephane R; Barth-Baus, Diane; Strachan, Ryan; Hensold, Jack O; Goss Kinzy, Terri; Merrick, William C

2005-04-22

Eukaryotic initiation factor 2A (eIF2A) has been shown to direct binding of the initiator methionyl-tRNA (Met-tRNA(i)) to 40 S ribosomal subunits in a codon-dependent manner, in contrast to eIF2, which requires GTP but not the AUG codon to bind initiator tRNA to 40 S subunits. We show here that yeast eIF2A genetically interacts with initiation factor eIF4E, suggesting that both proteins function in the same pathway. The double eIF2A/eIF4E-ts mutant strain displays a severe slow growth phenotype, which correlated with the accumulation of 85% of the double mutant cells arrested at the G(2)/M border. These cells also exhibited a disorganized actin cytoskeleton and elevated actin levels, suggesting that eIF2A might be involved in controlling the expression of genes involved in morphogenic processes. Further insights into eIF2A function were gained from the studies of eIF2A distribution in ribosomal fractions obtained from either an eIF5BDelta (fun12Delta) strain or a eIF3b-ts (prt1-1) strain. It was found that the binding of eIF2A to 40 and 80 S ribosomes was not impaired in either strain. We also found that eIF2A functions as a suppressor of Ure2p internal ribosome entry site-mediated translation in yeast cells. The regulation of expression from the URE2 internal ribosome entry site appears to be through the levels of eIF2A protein, which has been found to be inherently unstable with a half-life of approximately 17 min. It was hypothesized that this instability allows for translational control through the level of eIF2A protein in yeast cells.

IGF-1-Involved Negative Feedback of NR2B NMDA Subunits Protects Cultured Hippocampal Neurons Against NMDA-Induced Excitotoxicity.

PubMed

Li, Yun; Sun, Wei; Han, Song; Li, Jianing; Ding, Shu; Wang, Wei; Yin, Yanling

2017-01-01

Insulin-like growth factor 1 (IGF-1) is a multifunctional protein involved in neuronal polarity and axonal guidance. In our previous study, it was discovered that IGF-1 alleviated 50-μM NMDA-induced excitotoxicity against neuronal autophagy via depression of NR2B p-Ser1303 activation. However, it was found that NMDA at a higher dose did not cause neuronal autophagy. And, the performance of IGF-1 under severe excitotoxicity still needs to be clarified. In this study, we observed that IGF-1 can salvage the hippocampal neurons in an autophagy-independent manner after 150-μM NMDA exposure using thiazolyl blue tetrazolium bromide (MTT), lactate dehydrogenase (LDH), Western blot assay, and transmission electron microscopy. In addition, over-activation of post-synaptic NMDARs was found with the whole-cell patch clamp recording method. In order to explore whether there is a positive feedback way for post-synaptic NMDARs and the different pathway caused by 150 μM NMDA, the phosphorylation level of Fyn and the phosphorylation site of NR2B were investigated. It was observed that NR2B p-Tyr1472 was increased by the activation of Fyn after 150-μM NMDA exposure. When the neutralizing antibody against NR2B p-Ser1303 was added into the medium, both the activations of Fyn and NR2B p-Tyr1472 were blocked, suggesting NR2B p-Ser1303 may be the initial step of NMDA-induced excitotoxicity. In addition, since IGF-1 can block the initial step of NR2B activation, its effect is concluded to continue with the development of excitotoxicity. Overall, this study strongly indicates that the relationship between different phosphorylation sites of NR2B should be laid more emphasis on, which may be a vital target for the NR2B-involved excitotoxicity.

Elucidation of Altered Pathways in Tumor-Initiating Cells of Triple-Negative Breast Cancer: A Useful Cell Model System for Drug Screening.

PubMed

Christensen, Anne G; Ehmsen, Sidse; Terp, Mikkel G; Batra, Richa; Alcaraz, Nicolas; Baumbach, Jan; Noer, Julie B; Moreira, José; Leth-Larsen, Rikke; Larsen, Martin R; Ditzel, Henrik J

2017-08-01

A limited number of cancer cells within a tumor are thought to have self-renewing and tumor-initiating capabilities that produce the remaining cancer cells in a heterogeneous tumor mass. Elucidation of central pathways preferentially used by tumor-initiating cells/cancer stem cells (CSCs) may allow their exploitation as potential cancer therapy targets. We used single cell cloning to isolate and characterize four isogenic cell clones from a triple-negative breast cancer cell line; two exhibited mesenchymal-like and two epithelial-like characteristics. Within these pairs, one, but not the other, resulted in tumors in immunodeficient NOD/Shi-scid/IL-2 Rγ null mice and efficiently formed mammospheres. Quantitative proteomics and phosphoproteomics were used to map signaling pathways associated with the tumor-initiating ability. Signaling associated with apoptosis was suppressed in tumor-initiating versus nontumorigenic counterparts with pro-apoptotic proteins, such as Bcl2-associated agonist of cell death (BAD), FAS-associated death domain protein (FADD), and myeloid differentiation primary response protein (MYD88), downregulated in tumor-initiating epithelial-like cells. Functional studies confirmed significantly lower apoptosis in tumor-initiating versus nontumorigenic cells. Moreover, central pathways, including β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signaling, exhibited increased activation in the tumor-initiating cells. To evaluate the CSC model as a tool for drug screening, we assessed the effect of separately blocking NF-κB and Wnt/β-catenin signaling and found markedly reduced mammosphere formation, particularly for tumor-initiating cells. Similar reduction was also observed using patient-derived primary cancer cells. Furthermore, blocking NF-κB signaling in mice transplanted with tumor-initiating cells significantly reduced tumor outgrowth. Our study demonstrates that suppressed apoptosis, activation of pathways associated with cell viability, and CSCs are the major differences between tumor-initiating and nontumorigenic cells independent of their epithelial-like/mesenchymal-like phenotype. These altered pathways may provide targets for future drug development to eliminate CSCs, and the cell model may be a useful tool in such drug screenings. Stem Cells 2017;35:1898-1912. © 2017 AlphaMed Press.

Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects

PubMed Central

Kubitza, Dagmar; Becka, Michael; Mück, Wolfgang; Krätzschmar, Jöern

2014-01-01

Aims This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects. Methods Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0–3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0–3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured. Results An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39–6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53–2.21) in group B and 1.57-fold (CV 9.98%; range 1.37–2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin. Conclusions Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity. PMID:24528331

Initial apixaban dosing in patients with atrial fibrillation.

PubMed

Buchholz, Alexander; Ueberham, Laura; Gorczynska, Kaja; Dinov, Borislav; Hilbert, Sebastian; Dagres, Nikolaos; Husser, Daniela; Hindricks, Gerhard; Bollmann, Andreas

2018-05-01

Apixaban is a non-vitamin K oral anticoagulant approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Current labeling recommends dose reduction based on patient age, weight, and renal function. The aim of this study was to analyze adherence to current labeling instructions concerning initial apixaban dosing in clinical practice and identify factors associated with inappropriate dose reduction. Patients with AF initiated on apixaban in 2016 were identified in the Heart Center Leipzig database. Records were screened to identify patient characteristics, prescribed apixaban dose, renal function, and further dosing-relevant secondary diagnoses and co-medication. We identified 569 consecutive patients with AF initiated on apixaban. In 301 (52.9%) patients, apixaban was prescribed in standard dose (5 mg b.i.d.) and in 268 (47.1%) in a reduced dose (2.5 mg b.i.d.). Of 268 patients receiving a reduced dose, 163 (60.8%) did not meet labeling criteria for dose reduction. In univariate and multivariate regression analysis, age (OR: 0.736, 95% CI: 0.664-0.816, P < 0.0001), patient weight (OR: 1.120, 95% CI: 1.076-1.166, P < 0.0001), and serum creatinine level (OR: 0.910, 95% CI: 0.881-0.940, P < 0.0001) were independent predictors for apixaban underdosage. In clinical practice, apixaban dosing is frequently inconsistent with labeling. Factors associated with inappropriate dose reduction are age, patient weight, and serum creatinine level, the same factors used as criteria for dose adjustment. However, in underdosed patients, the 3 factors did not meet the criteria for dose reduction. © 2018 Wiley Periodicals, Inc.

Screening Active Components from Yu-Ping-Feng-San for Regulating Initiative Key Factors in Allergic Sensitization

PubMed Central

Zhu, Zhijie; Yu, Xi; Liu, Hailiang; Wang, Huizhu; Fan, Hongwei; Wang, Dawei; Jiang, Guorong; Hong, Min

2014-01-01

Yu-ping-feng-san (YPFS) is a Chinese medical formula that is used clinically for allergic diseases and characterized by reducing allergy relapse. Our previous studies demonstrated that YPFS efficiently inhibited T helper 2 cytokines in allergic inflammation. The underlying mechanisms of action of YPFS and its effective components remain unclear. In this study, it was shown that YPFS significantly inhibited production of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived initiative factor in allergic inflammation, in vitro and in vivo. A method of human bronchial epithelial cell (16HBE) binding combined with HPLC-MS (named 16HBE-HPLC-MS) was established to explore potential active components of YPFS. The following five components bound to 16HBE cells: calycosin-7-glucoside, ononin, claycosin, sec-o-glucosylhamaudol and formononetin. Serum from YPFS-treated mice was analyzed and three major components were detected claycosin, formononetin and cimifugin. Among these, claycosin and formononetin were detected by 16HBE-HPLC-MS and in the serum of YPFS-treated mice. Claycosin and formononetin decreased the level of TSLP markedly at the initial stage of allergic inflammation in vivo. Nuclear factor (NF)-κB, a key transcription factor in TSLP production, was also inhibited by claycosin and formononetin, either in terms of transcriptional activation or its nuclear translocation in vitro. Allergic inflammation was reduced by claycosin and formononetin when they are administered only at the initial stage in a murine model of atopic contact dermatitis. Thus, epithelial cell binding combined with HPLC-MS is a valid method for screening active components from complex mixtures of Chinese medicine. It was demonstrated that the compounds screened from YPFS significantly attenuated allergic inflammation probably by reducing TSLP production via regulating NF-κB activation. PMID:25198676

Regulation of p53, nuclear factor {kappa}B and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin

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

Kalra, Neetu; Bhui, Kulpreet; Roy, Preeti

2008-01-01

Bromelain is a pharmacologically active compound, present in stems and immature fruits of pineapples (Ananas cosmosus), which has been shown to have anti-edematous, anti-inflammatory, anti-thrombotic and anti-metastatic properties. In the present study, antitumorigenic activity of bromelain was recorded in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted 2-stage mouse skin model. Results showed that bromelain application delayed the onset of tumorigenesis and reduced the cumulative number of tumors, tumor volume and the average number of tumors/mouse. To establish a cause and effect relationship, we targeted the proteins involved in the cell death pathway. Bromelain treatment resulted in upregulation of p53 and Bax andmore » subsequent activation of caspase 3 and caspase 9 with concomitant decrease in antiapoptotic protein Bcl-2 in mouse skin. Since persistent induction of cyclooxygenase-2 (Cox-2) is frequently implicated in tumorigenesis and is regulated by nuclear factor-kappa B (NF-{kappa}B), we also investigated the effect of bromelain on Cox-2 and NF-{kappa}B expression. Results showed that bromelain application significantly inhibited Cox-2 and inactivated NF-{kappa}B by blocking phosphorylation and subsequent degradation of I{kappa}B{alpha}. In addition, bromelain treatment attenuated DMBA-TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), mitogen-activated protein kinase (MAPK) and Akt. Taken together, we conclude that bromelain induces apoptosis-related proteins along with inhibition of NF-{kappa}B-driven Cox-2 expression by blocking the MAPK and Akt/protein kinase B signaling in DMBA-TPA-induced mouse skin tumors, which may account for its anti-tumorigenic effects.« less

Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4.

PubMed

Sutherland, Robert L

2011-05-20

Endocrine resistance is a major limitation to the successful treatment of estrogen receptor-positive (ER(+)) breast cancer, and the EGFR (epidermal growth factor receptor) and ErbB-2 receptor tyrosine kinases are involved in this process. A recent study now implicates the other two ErbB family members, ErbB-3 and -4. Exposure of ER+ breast cancer cells to the pure antiestrogen, fulvestrant, increased levels of ErbB-3 or ErbB-4 and sensitivity to the growth-stimulatory effects of heregulin β1, a potent ligand for these receptors. Thus, the initial growth-inhibitory effects of fulvestrant appear compromised by cellular plasticity that allows rapid compensatory growth stimulation via ErbB-3/4. Further evaluation of pan-ErbB receptor inhibitors in endocrine-resistant disease appears warranted.

A Kinase Independent Role for EGF Receptor in Autophagy Initiation

PubMed Central

Tan, Xiaojun; Thapa, Narendra; Sun, Yue; Anderson, Richard A

2014-01-01

The Epidermal Growth Factor Receptor (EGFR) is upregulated in numerous human cancers. Inhibition of EGFR signaling induces autophagy in tumor cells. Here we report an unanticipated role for the inactive EGFR in autophagy initiation. Inactive EGFR interacts with the oncoprotein LAPTM4B that is required for the endosomal accumulation of EGFR upon serum starvation. Inactive EGFR and LAPTM4B stabilize each other at endosomes and recruit the exocyst subcomplex containing Sec5. We show that inactive EGFR, LAPTM4B, and the Sec5 subcomplex are required for basal and starvation induced autophagy. LAPTM4B and Sec5 promote EGFR association with the autophagy inhibitor Rubicon, which in turn disassociates Beclin 1 from Rubicon to initiate autophagy. Thus, the oncoprotein LAPTM4B facilitates the role of inactive EGFR in autophagy initiation. This pathway is positioned to control tumor metabolism and promote tumor cell survival upon serum deprivation or metabolic stress. PMID:25594178

Characteristics and outcomes of women initiating ART during pregnancy versus breastfeeding in Option B+ in Malawi.

PubMed

Landes, M; Sodhi, S; Matengeni, A; Meaney, C; van Lettow, M; Chan, A K; van Oosterhout, J J

2016-08-04

Malawi adopted the PMTCT strategy 'Option B+' in 2011, providing life-long ART for all HIV-infected pregnant and breastfeeding women. We explored differences in characteristics and outcomes of women initiating ART during pregnancy versus breastfeeding. We conducted a retrospective cohort analysis of women in Zomba District, southern Malawi, from January 2012- September 2013. Data were extracted from the Zomba District Observational Cohort Study, a surveillance project collecting data from standardized Ministry of Health ART monitoring tools. 1986 (67.2 %) women initiated ART during pregnancy and 969 (32.8 %) during breastfeeding. Women initiating ART in breastfeeding were more likely to be > 30 years (aOR = 1.33, 95 % CI1.11-1.59, p = 0.003) and have WHO Stage 3/4 (aOR = 2.74, 95 % CI1.94-3.87, p < 0.001). Eighteen (0.6 %) deaths occurred and 942 (31.9 %) women defaulted ART. 'Early' death (< 30 days) occurred in 3 (0.1 %) women and 449 (16.4 %) women defaulted early. Death/default < 30 days was more likely among women initiating ART during pregnancy (aOR 1.62, 95 % CI1.28-2.05, p < 0.001) or < 30 years old (aOR 1.27, 95 % CI 1.02-1.57, p = 0.03) and was less likely among those with WHO Stage 3/4 (aOR 0.30, 95 % CI 0.15-0.60, p < 0.001). Using Kaplan-Meier estimators to investigate time to death/default, we showed a sharp drop in death/default-free survival probability at time zero, yet survival probability decreased in a nearly linear manner after this initial period of high default. Women under 30 years had increased rates of death/default over time (log rank test: p < 0.001), however no significant differences were observed in death/default over time associated with timing of ART initiation, documented clinical stage at initiation, health clinic size or adherence rates. Many women in Malawi started ART during breastfeeding within Option B+ and were older and had more advanced WHO Clinical Staging. This represents a missed PMTCT opportunity to initiate treatment early in pregnancy. Early defaulting is identified as a challenge within Option B+, and was more likely among younger women and those initiating ART in pregnancy. Targeted research to understand factors associated with uptake of ART during pregnancy and retention in care could improve the efficacy of Option B+ in Malawi.

Differential Regulation of Mouse B Cell Development by Transforming Growth Factor β1

PubMed Central

Kaminski, Denise A.; Letterio, John J.; Burrows, Peter D.

2002-01-01

Transforming growth factor β (TGFβ) can inhibit the in vitro proliferation, survival and differentiation of B cell progenitors, mature B lymphocytes and plasma cells. Here we demonstrate unexpected, age-dependent reductions in the bone marrow (BM) B cell progenitors and immature B cells in TGFβ1-/- mice. To evaluate TGFβ responsiveness during normal B lineage development, cells were cultured in interleukin 7 (IL7)±TGFβ. Picomolar doses of TGFβ1 reduced pro-B cell recoveries at every timepoint. By contrast, the pre-B cells were initially reduced in number, but subsequently increased compared to IL7 alone, resulting in a 4-fold increase in the growth rate for the pre-B cell population. Analysis of purified BM sub-populations indicated that pro-B cells and the earliest BP1- pre-B cells were sensitive to the inhibitory effects of TGFβ1. However, the large BP1+ pre-B cells, although initially reduced, were increased in number at days 5 and 7 of culture. These results indicate that TGFβ1 is important for normal B cell development in vivo, and that B cell progenitors are differentially affected by the cytokine according to their stage of differentiation. PMID:12739785

Attrition from antiretroviral treatment services among pregnant and non-pregnant patients following adoption of Option B+ in Haiti

PubMed Central

Domercant, Jean Wysler; Puttkammer, Nancy; Young, Paul; Yuhas, Krista; François, Kesner; Grand’Pierre, Reynold; Lowrance, David; Adler, Michelle

2017-01-01

ABSTRACT Background: Access to antiretroviral therapy (ART) has expanded in Haiti because of the adoption of Option B+ and the revision of treatment guidelines. Retention in care and treatment varies greatly and few studies have examined retention rates, particularly among women enrolled in Option B+. Objective: To assess attrition among pregnant and non-pregnant patients initiating ART following adoption of Option B+ in Haiti. Methods: Longitudinal data of adult patients initiated on ART from October 2012 through August 2014 at 73 health facilities across Haiti were analyzed using a survival analysis framework to determine levels of attrition. The Kaplan–Meier method and Cox proportional hazards regression were used to examine risk factors associated with attrition. Results: Among 17,059 patients who initiated ART, 7627 (44.7%) were non-pregnant women, 5899 (34.6%) were men, and 3533 (20.7%) were Option B+ clients. Attrition from the ART program was 36.7% at 12 months (95% CI: 35.9–37.5%). Option B+ patients had the highest level of attrition at 50.4% at 12 months (95% CI: 48.6–52.3%). While early HIV disease stage at ART initiation was protective among non-pregnant women and men, it was a strong risk factor among Option B+ clients. In adjusted analyses, key protective factors were older age (p < 0.0001), living near the health facility (p = 0.04), having another known HIV-positive household member (p < 0.0001), having greater body mass index (BMI) (p < 0.0001), pre-ART counseling (p < 0.0001), and Cotrimoxazole prophylaxis during baseline (p < 0.01). Higher attrition was associated with rapidly starting ART after enrollment (p < 0.0001), anemia (p < 0.0001), and regimen tenofovir+lamivudine+nevirapine (TDF+3TC+NVP) (p < 0.001). Conclusions: ART attrition in Haiti is high among adults, especially among Option B+ patients. Identifying newly initiated patients most at risk for attrition and providing appropriate interventions could help reduce ART attrition. PMID:28640661

Attrition from antiretroviral treatment services among pregnant and non-pregnant patients following adoption of Option B+ in Haiti.

PubMed

Domercant, Jean Wysler; Puttkammer, Nancy; Young, Paul; Yuhas, Krista; François, Kesner; Grand'Pierre, Reynold; Lowrance, David; Adler, Michelle

2017-01-01

Access to antiretroviral therapy (ART) has expanded in Haiti because of the adoption of Option B+ and the revision of treatment guidelines. Retention in care and treatment varies greatly and few studies have examined retention rates, particularly among women enrolled in Option B+. To assess attrition among pregnant and non-pregnant patients initiating ART following adoption of Option B+ in Haiti. Longitudinal data of adult patients initiated on ART from October 2012 through August 2014 at 73 health facilities across Haiti were analyzed using a survival analysis framework to determine levels of attrition. The Kaplan-Meier method and Cox proportional hazards regression were used to examine risk factors associated with attrition. Among 17,059 patients who initiated ART, 7627 (44.7%) were non-pregnant women, 5899 (34.6%) were men, and 3533 (20.7%) were Option B+ clients. Attrition from the ART program was 36.7% at 12 months (95% CI: 35.9-37.5%). Option B+ patients had the highest level of attrition at 50.4% at 12 months (95% CI: 48.6-52.3%). While early HIV disease stage at ART initiation was protective among non-pregnant women and men, it was a strong risk factor among Option B+ clients. In adjusted analyses, key protective factors were older age (p < 0.0001), living near the health facility (p = 0.04), having another known HIV-positive household member (p < 0.0001), having greater body mass index (BMI) (p < 0.0001), pre-ART counseling (p < 0.0001), and Cotrimoxazole prophylaxis during baseline (p < 0.01). Higher attrition was associated with rapidly starting ART after enrollment (p < 0.0001), anemia (p < 0.0001), and regimen tenofovir+lamivudine+nevirapine (TDF+3TC+NVP) (p < 0.001). ART attrition in Haiti is high among adults, especially among Option B+ patients. Identifying newly initiated patients most at risk for attrition and providing appropriate interventions could help reduce ART attrition.

Who Gets Jobs? Initial Labour Market Experiences of York Graduates. Working Paper.

ERIC Educational Resources Information Center

Grayson, J. Paul

As part of a study which is following college graduates for 5 years, a survey of 2,264 graduates of York University (Ontario, Canada) who received B.A. degrees in 1995-96 shows that within 3 months of graduation, 54 percent of those seeking full-time employment had achieved this objective. The factors considered included background…

40 CFR 63.5890 - How do I calculate an organic HAP emissions factor to demonstrate compliance for continuous...

Code of Federal Regulations, 2010 CFR

2010-07-01

... for Hazardous Air Pollutants: Reinforced Plastic Composites Production Testing and Initial Compliance... per year Oc=controlled oven organic HAP emissions, lbs per year R=total usage of neat resin plus, tpy G=total usage of neat gel coat plus, tpy (b) Averaging option. Use Equation 2 of this section to...

Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog-Dependent Medulloblastoma Initiation and Maintenance

DTIC Science & Technology

2013-10-01

Remodeling Factor in Sonic Hedgehog -Dependent Medulloblastoma Initiation and Maintenance PRINCIPAL INVESTIGATOR: Xuanming Shi CONTRACTING...5a. CONTRACT NUMBER W81XWH-12-1-0527 Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog -Dependent 5b. GRANT NUMBER W81XWH-12-1...drug development and therapy of pediatric brain tumor and other Shh- dependent tumors. 15. SUBJECT TERMS Medulloblastoma, Sonic Hedgehog , Chromatin

Modulatory effect of phytoglycoprotein (38 kDa) on cyclin D1/CDK4 in BNL CL.2 cells induced by N-methyl-N'-nitro-N-nitrosoguanidine.

PubMed

Lee, Jin; Lim, Kye-Taek

2012-02-01

In the developmental stages of cancer, cell transformation occurs after the promotion stage and is a marker of cancer progression. This cell transformation is related to abnormal proliferation during the cancer initiation stage. The purpose of this study was to evaluate the effect of Styrax japonica Siebold et al. Zuccarin (SJSZ) glycoprotein on cell transformation in murine embryonic liver cells (BNL CL.2) following N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment. To determine abnormal proliferation during the initiation stage, intracellular reactive oxygen species (ROS), phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), activities of cell cycle-related factors [cyclin D1/cyclin dependent kinase (CDK) 4], cell cycle inhibitors (p53, p21, and p27), nuclear factor (NF)-κB, and proliferating cell nuclear antigen (PCNA) were evaluated using Western blot analysis and real-time PCR. Our study demonstrated that SJSZ glycoprotein (50 μg/ml) reduces foci formation with combined treatment [MNNG and 12-O-tetradecanoyl phorbol-13-acetate] of BNL CL.2 cells. With regard to proliferation-related signals, our finding indicated that SJSZ glycoprotein (50 μg/ml) diminished the production of intracellular ROS, activity of phosphorylated ERK, p38 MAPK, NF-κB (p50 and p65), PCNA, and cyclin D1/CDK4 in MNNG-induced BNL CL.2 cells. Taken together, these results lead us to speculate that SJSZ glycoprotein can inhibit abnormal cell proliferation at the initiation stage of hepatocarcinogenesis.

The B55α Regulatory Subunit of Protein Phosphatase 2A Mediates Fibroblast Growth Factor-Induced p107 Dephosphorylation and Growth Arrest in Chondrocytes

PubMed Central

Daempfling, Lea

2013-01-01

Fibroblast growth factor (FGF)-induced growth arrest of chondrocytes is a unique cell type-specific response which contrasts with the proliferative response of most cell types and underlies several genetic skeletal disorders caused by activating FGF receptor (FGFR) mutations. We have shown that one of the earliest key events in FGF-induced growth arrest is dephosphorylation of the retinoblastoma protein (Rb) family member p107 by protein phosphatase 2A (PP2A), a ubiquitously expressed multisubunit phosphatase. In this report, we show that the PP2A-B55α holoenzyme (PP2A containing the B55α subunit) is responsible for this phenomenon. Only the B55α (55-kDa regulatory subunit, alpha isoform) regulatory subunit of PP2A was able to bind p107, and this interaction was induced by FGF in chondrocytes but not in other cell types. Small interfering RNA (siRNA)-mediated knockdown of B55α prevented p107 dephosphorylation and FGF-induced growth arrest of RCS (rat chondrosarcoma) chondrocytes. Importantly, the B55α subunit bound with higher affinity to dephosphorylated p107. Since the p107 region interacting with B55α is also the site of cyclin-dependent kinase (CDK) binding, B55α association may also prevent p107 phosphorylation by CDKs. FGF treatment induces dephosphorylation of the B55α subunit itself on several serine residues that drastically increases the affinity of B55α for the PP2A A/C dimer and p107. Together these observations suggest a novel mechanism of p107 dephosphorylation mediated by activation of PP2A through B55α dephosphorylation. This mechanism might be a general signal transduction pathway used by PP2A to initiate cell cycle arrest when required by external signals. PMID:23716589

Molecular pathways mediating differential responses to lipopolysaccharide between human and baboon arterial endothelial cells.

PubMed

Shi, Qiang; Cox, Laura A; Glenn, Jeremy; Tejero, Maria E; Hondara, Vida; Vandeberg, John L; Wang, Xing Li

2010-02-01

1. Vascular inflammation plays a critical role in atherogenesis. Previously, we showed that baboon arterial endothelial cells (BAEC) were hyporesponsive to lipopolysaccharide (LPS) compared with human arterial endothelial cells (HAEC). 2. In the present study, we investigated mechanisms underlying differential responses between HAEC and BAEC to tumour necrosis factor (TNF)-alpha and LPS. 3. Both HAEC and BAEC responded similarly to TNF-alpha. However, BAEC showed retarded responses to LPS in expression of E-selectin, intercellular adhesion molecule-1, monocyte chemotactic protein-1 and interleukin-8 (P < 0.05). These changes were confirmed at the mRNA level. Tumour necrosis factor-alpha activated nuclear factor-kappaB members such as p50, p52, p65, c-rel and RelB in both HAEC and BAEC. In contrast, LPS activated p50 and p65 only in HAEC. Using microarray assays, we found that TNF receptor-associated factor 2 (TRAF-2), TNF receptor superfamily, member 1A-associated via death domain (TRADD) and nuclear factors such as nuclear factor of kappa in B-cells inhibitor, alpha (NFKBIA) and nuclear factor of kappa in B-cells inhibitor, beta (NFKBIB) were upregulated by LPS only in HAEC. Although the baseline expression of Toll-like receptor (TLR) 4 was low in both HAEC and BAEC, TNF-alpha activated TLR4 expression in both cell types. Although LPS increased TLR4 expression only in HAEC, human and baboon peripheral blood mononuclear cells exhibited similar TLR4 expression and response to LPS. Transfecting BAEC with TLR4/myeloid differentiation protein-2 overexpression vector conferred BAEC responsiveness to LPS. 4. The findings of the present study indicate that an altered TLR4 system may be responsible for the resistance of baboon endothelial cells to LPS. Given the importance of TLR4 in human immune responses and vascular diseases, the natural resistance of baboons to LPS/TLR4-initiated inflammation could make the baboon a valuable animal model in which to study how inflammation affects atherogenesis.

Helper signals in the plaque-forming cell response to protein-bound haptens.

PubMed

Roehm, N W; Marrack, P; Kappler, J W

1983-08-01

We have demonstrated the ability of a series of murine T cell hybridomas to deliver an antigen-specific, B cell I-region-restricted helper signal in the generation of specific PFC responses to protein-bound haptens. With some hybridomas the elicitation of optimal PFC responses required the addition of nonspecific factors provided by culture supernatants of concanavalin A-stimulated (Con A SN) spleen cells. Using hapten-primed B cells depleted of both T cells and macrophages (Mphi) we have now demonstrated a requirement for three nonspecific factor preparations to substitute for spleen Con A SN in the elicitation of optimal PFC responses. The first preparation was the interleukin 1 containing culture supernatant of the Mphi tumor cell line P388D1, the second the interleukin 2 (IL-2) and B cell growth factor containing Con A SN of the T cell hybridoma FS6-14.13, and the third, the gamma interferon containing Con A SN of the T cell hybridoma FS7-20.6.18. The P388D1 and FS6-14.13 factor preparations were most effective when added at the initiation of culture, while the FS7-20.6.18 factor preparation was most effective when added at 24 h of culture. The activity of FS6-14.13 Con A SN was depleted by incubation with the IL-2-dependent T cell line HT-2. The activity of FS7-20.6.18 Con A SN was abrogated by incubation at pH 2. The results suggest that the generation of PFC responses to protein-bound haptens require at least three nonspecific factors in addition to an antigen/Ia specific helper signal.

Association between recovery from Bell's palsy and body mass index.

PubMed

Choi, S A; Shim, H S; Jung, J Y; Kim, H J; Kim, S H; Byun, J Y; Park, M S; Yeo, S G

2017-06-01

Although many factors have been found to be involved in recovery from Bell's palsy, no study has investigated the association between recovery from Bell's palsy and obesity. This study therefore evaluated the association between recovery from Bell's palsy and body mass index (BMI). Subjects were classified into five groups based on BMI (kg/m 2 ). Demographic and clinical characteristics were compared among these groups. Assessed factors included sex, age, time from paralysis to visiting a hospital, the presence of comorbidities such as diabetes mellitus and hypertension, degree of initial facial nerve paralysis by House-Brackmann (H-B) grade and neurophysiological testing, and final recovery rate. Based on BMI, 37 subjects were classified as underweight, 169 as normal weight, 140 as overweight, 155 as obese and 42 as severely obese. Classification of the degree of initial facial nerve paralysis as moderate or severe, according to H-B grade and electroneurography, showed no difference in severity of initial facial paralysis among the five groups (P > 0.05). However, the final recovery rate was significantly higher in the normal weight than in the underweight or obese group (P < 0.05). Obesity or underweight had no effect on the severity of initial facial paralysis, but the final recovery rate was lower in the obese and underweight groups than in the normal group. © 2016 John Wiley & Sons Ltd.

Activity Dependent Signal Transduction in Skeletal Muscle

NASA Technical Reports Server (NTRS)

Hamilton, Susan L.

1999-01-01

The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

78 FR 5210 - Open Government Initiative: Implementation of the iCERT Labor Certification Registry for the H-1B...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-24

...: Implementation of the iCERT Labor Certification Registry for the H-1B, H-1B1, E-3, H-2A, H-2B and Permanent Labor... new initiative to make available to the general public appropriately redacted copies of H-1B, H-1B1, E-3, H-2A, H-2B and permanent labor certification documents through its iCERT Visa Portal System. This...

Heat shock protein 70 promotes coxsackievirus B3 translation initiation and elongation via Akt-mTORC1 pathway depending on activation of p70S6K and Cdc2.

PubMed

Wang, Fengping; Qiu, Ye; Zhang, Huifang M; Hanson, Paul; Ye, Xin; Zhao, Guangze; Xie, Ronald; Tong, Lei; Yang, Decheng

2017-07-01

We previously demonstrated that coxsackievirus B3 (CVB3) infection upregulated heat shock protein 70 (Hsp70) and promoted CVB3 multiplication. Here, we report the underlying mechanism by which Hsp70 enhances viral RNA translation. By using an Hsp70-overexpressing cell line infected with CVB3, we found that Hsp70 enhanced CVB3 VP1 translation at two stages. First, Hsp70 induced upregulation of VP1 translation at the initiation stage via upregulation of internal ribosome entry site trans-acting factor lupus autoantigen protein and activation of eIF4E binding protein 1, a cap-dependent translation suppressor. Second, we found that Hsp70 increased CVB3 VP1 translation by enhancing translation elongation. This was mediated by the Akt-mammalian target of rapamycin complex 1 signal cascade, which led to the activation of eukaryotic elongation factor 2 via p70S6K- and cell division cycle protein 2 homolog (Cdc2)-mediated phosphorylation and inactivation of eukaryotic elongation factor 2 kinase. We also determined the position of Cdc2 in this signal pathway, indicating that Cdc2 is regulated by mammalian target of rapamycin complex 1. This signal transduction pathway was validated using a number of specific pharmacological inhibitors, short interfering RNAs (siRNAs) and a dominant negative Akt plasmid. Because Hsp70 is a central component of the cellular network of molecular chaperones enhancing viral replication, these data may provide new strategies to limit this viral infection. © 2017 John Wiley & Sons Ltd.

Initial programmatic implementation of WHO option B in Botswana associated with increased projected MTCT.

PubMed

Dryden-Peterson, Scott; Lockman, Shahin; Zash, Rebecca; Lei, Quonhong; Chen, Jennifer Y; Souda, Sajini; Petlo, Chipo; Dintwa, Eldah; Lebelonyane, Refeletswe; Mmalane, Mompati; Shapiro, Roger L

2015-03-01

: Botswana was one of the first African countries to transition from WHO Option A to Option B for prevention of mother-to-child HIV transmission (MTCT). We evaluated the impact of this transition on projected MTCT risk through review of 10,681 obstetric records of HIV-infected women delivering at 6 maternity wards. Compared with Option A, women receiving antenatal care under Option B were more likely to receive combination antiretroviral therapy (ART), adjusted odds ratio (aOR): 2.59 (95% confidence interval: 2.25 to 2.98), but they were also more likely to receive no antenatal antiretrovirals, aOR: 2.10 (95% confidence interval: 1.74 to 2.53). Consequently, initial implementation of Option B was associated with increased projected MTCT at 6 months of age, 3.79% under Option A and 4.69% under Option B (P < 0.001). Successful implementation of Option B or B+ may require that ART can be initiated within antenatal clinics, and novel strategies to remove barriers to rapid ART initiation.

[A Jehovah's Witness child with hemophilia B and factor IX inhibitors undergoing scoliosis surgery].

PubMed

Chau, Anthony; Wu, John; Ansermino, Mark; Tredwell, Stephen; Purdy, Robert

2008-01-01

To describe the successful perioperative hemostatic management of a Jehovah's Witness patient with hemophilia B and anaphylactic inhibitors to factor IX, undergoing scoliosis surgery. A 14 (1/2)-yr-old boy with severe hemophilia B who had a history of anaphylactic inhibitors to factor IX was scheduled to undergo corrective scoliosis surgery. He was initially started on epoetin alfa and iron supplementation to maximize preoperative red cell mass. Additionally, he was placed on a desensitization protocol of recombinant coagulation factor IX (rFIX) and was then treated with activated recombinant coagulation factor VII (rFVIIa) during the postoperative period. Tranexamic acid was given concomitantly. The intraoperative blood loss was approximately 350 mL. The nadir hemoglobin concentration was 111 g.L(-1) on postoperative days one and two. On postoperative day 11, the patient was stable and discharged home with a hemoglobin of 138 g.L(-1). He did not require blood transfusion and no adverse events were observed. The use of rFIX, rFVIIa, erythropoetin, iron, and tranexamic acid before, during and after scoliosis surgery may be a viable and safe option for hemophilia patients with inhibitors, who refuse blood products.

State orthogonality, boson bunching parameter and bosonic enhancement factor

NASA Astrophysics Data System (ADS)

Marchewka, Avi; Granot, Er'el

2016-04-01

It is emphasized that the bunching parameter β ≡ p B / p D , i.e. the ratio between the probability to measure two bosons and two distinguishable particles at the same state, is a constant of motion and depends only on the overlap between the initial wavefunctions. This ratio is equal to β = 2 / (1 + I 2), where I is the overlap integral between the initial wavefunctions. That is, only when the initial wavefunctions are orthogonal this ratio is equal to 2, however, this bunching ratio can be reduced to 1, when the two wavefunctions are identical. This simple equation explains the experimental evidences of a beam splitter. A straightforward conclusion is that by measuring the local bunching parameter β (at any point in space and time) it is possible to evaluate a global parameter I (the overlap between the initial wavefunctions). The bunching parameter is then generalized to arbitrary number of particles, and in an analogy to the two-particles scenario, the well-known bosonic enhancement appears only when all states are orthogonal.

Effects of sex steroids on expression of genes regulating growth-related mechanisms in rainbow trout (Oncorhynchus mykiss).

PubMed

Cleveland, Beth M; Weber, Gregory M

2015-05-15

Effects of a single injection of 17β-estradiol (E2), testosterone (T), or 5β-dihydrotestosterone (DHT) on expression of genes central to the growth hormone (GH)/insulin-like growth factor (IGF) axis, muscle-regulatory factors, transforming growth factor-beta (TGFβ) superfamily signaling cascade, and estrogen receptors were determined in rainbow trout (Oncorhynchus mykiss) liver and white muscle tissue. In liver in addition to regulating GH sensitivity and IGF production, sex steroids also affected expression of IGF binding proteins, as E2, T, and DHT increased expression of igfbp2b and E2 also increased expression of igfbp2 and igfbp4. Regulation of this system also occurred in white muscle in which E2 increased expression of igf1, igf2, and igfbp5b1, suggesting anabolic capacity may be maintained in white muscle in the presence of E2. In contrast, DHT decreased expression of igfbp5b1. DHT and T decreased expression of myogenin, while other muscle regulatory factors were either not affected or responded similarly for all steroid treatments. Genes within the TGFβ superfamily signaling cascade responded to steroid treatment in both liver and muscle, suggesting a regulatory role for sex steroids in the ability to transmit signals initiated by TGFβ superfamily ligands, with a greater number of genes responding in liver than in muscle. Estrogen receptors were also regulated by sex steroids, with era1 expression increasing for all treatments in muscle, but only E2- and T-treatment in liver. E2 reduced expression of erb2 in liver. Collectively, these data identify how physiological mechanisms are regulated by sex steroids in a manner that promotes the disparate effects of androgens and estrogens on growth in salmonids. Published by Elsevier Inc.

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons.

PubMed

König, Hans-Georg; Fenner, Beau J; Byrne, Jennifer C; Schwamborn, Robert F; Bernas, Tytus; Jefferies, Caroline A; Prehn, Jochen H M

2012-12-15

Neuronal survival and plasticity critically depend on constitutive activity of the transcription factor nuclear factor-κB (NF-κB). We here describe a role for a small intracellular fibroblast growth factor homologue, the fibroblast growth factor homologous factor 1 (FHF1/FGF12), in the regulation of NF-κB activity in mature neurons. FHFs have previously been described to control neuronal excitability, and mutations in FHF isoforms give rise to a form of progressive spinocerebellar ataxia. Using a protein-array approach, we identified FHF1b as a novel interactor of the canonical NF-κB modulator IKKγ/NEMO. Co-immunoprecipitation, pull-down and GAL4-reporter experiments, as well as proximity ligation assays, confirmed the interaction of FHF1 and NEMO and demonstrated that a major site of interaction occurred within the axon initial segment. Fhf1 gene silencing strongly activated neuronal NF-κB activity and increased neurite lengths, branching patterns and spine counts in mature cortical neurons. The effects of FHF1 on neuronal NF-κB activity and morphology required the presence of NEMO. Our results imply that FHF1 negatively regulates the constitutive NF-κB activity in neurons.

Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5).

PubMed

Bousquet, J; Farrell, J; Crooks, G; Hellings, P; Bel, E H; Bewick, M; Chavannes, N H; de Sousa, J Correia; Cruz, A A; Haahtela, T; Joos, G; Khaltaev, N; Malva, J; Muraro, A; Nogues, M; Palkonen, S; Pedersen, S; Robalo-Cordeiro, C; Samolinski, B; Strandberg, T; Valiulis, A; Yorgancioglu, A; Zuberbier, T; Bedbrook, A; Aberer, W; Adachi, M; Agusti, A; Akdis, C A; Akdis, M; Ankri, J; Alonso, A; Annesi-Maesano, I; Ansotegui, I J; Anto, J M; Arnavielhe, S; Arshad, H; Bai, C; Baiardini, I; Bachert, C; Baigenzhin, A K; Barbara, C; Bateman, E D; Beghé, B; Kheder, A Ben; Bennoor, K S; Benson, M; Bergmann, K C; Bieber, T; Bindslev-Jensen, C; Bjermer, L; Blain, H; Blasi, F; Boner, A L; Bonini, M; Bonini, S; Bosnic-Anticevitch, S; Boulet, L P; Bourret, R; Bousquet, P J; Braido, F; Briggs, A H; Brightling, C E; Brozek, J; Buhl, R; Burney, P G; Bush, A; Caballero-Fonseca, F; Caimmi, D; Calderon, M A; Calverley, P M; Camargos, P A M; Canonica, G W; Camuzat, T; Carlsen, K H; Carr, W; Carriazo, A; Casale, T; Cepeda Sarabia, A M; Chatzi, L; Chen, Y Z; Chiron, R; Chkhartishvili, E; Chuchalin, A G; Chung, K F; Ciprandi, G; Cirule, I; Cox, L; Costa, D J; Custovic, A; Dahl, R; Dahlen, S E; Darsow, U; De Carlo, G; De Blay, F; Dedeu, T; Deleanu, D; De Manuel Keenoy, E; Demoly, P; Denburg, J A; Devillier, P; Didier, A; Dinh-Xuan, A T; Djukanovic, R; Dokic, D; Douagui, H; Dray, G; Dubakiene, R; Durham, S R; Dykewicz, M S; El-Gamal, Y; Emuzyte, R; Fabbri, L M; Fletcher, M; Fiocchi, A; Fink Wagner, A; Fonseca, J; Fokkens, W J; Forastiere, F; Frith, P; Gaga, M; Gamkrelidze, A; Garces, J; Garcia-Aymerich, J; Gemicioğlu, B; Gereda, J E; González Diaz, S; Gotua, M; Grisle, I; Grouse, L; Gutter, Z; Guzmán, M A; Heaney, L G; Hellquist-Dahl, B; Henderson, D; Hendry, A; Heinrich, J; Heve, D; Horak, F; Hourihane, J O' B; Howarth, P; Humbert, M; Hyland, M E; Illario, M; Ivancevich, J C; Jardim, J R; Jares, E J; Jeandel, C; Jenkins, C; Johnston, S L; Jonquet, O; Julge, K; Jung, K S; Just, J; Kaidashev, I; Kaitov, M R; Kalayci, O; Kalyoncu, A F; Keil, T; Keith, P K; Klimek, L; Koffi N'Goran, B; Kolek, V; Koppelman, G H; Kowalski, M L; Kull, I; Kuna, P; Kvedariene, V; Lambrecht, B; Lau, S; Larenas-Linnemann, D; Laune, D; Le, L T T; Lieberman, P; Lipworth, B; Li, J; Lodrup Carlsen, K; Louis, R; MacNee, W; Magard, Y; Magnan, A; Mahboub, B; Mair, A; Majer, I; Makela, M J; Manning, P; Mara, S; Marshall, G D; Masjedi, M R; Matignon, P; Maurer, M; Mavale-Manuel, S; Melén, E; Melo-Gomes, E; Meltzer, E O; Menzies-Gow, A; Merk, H; Michel, J P; Miculinic, N; Mihaltan, F; Milenkovic, B; Mohammad, G M Y; Molimard, M; Momas, I; Montilla-Santana, A; Morais-Almeida, M; Morgan, M; Mösges, R; Mullol, J; Nafti, S; Namazova-Baranova, L; Naclerio, R; Neou, A; Neffen, H; Nekam, K; Niggemann, B; Ninot, G; Nyembue, T D; O'Hehir, R E; Ohta, K; Okamoto, Y; Okubo, K; Ouedraogo, S; Paggiaro, P; Pali-Schöll, I; Panzner, P; Papadopoulos, N; Papi, A; Park, H S; Passalacqua, G; Pavord, I; Pawankar, R; Pengelly, R; Pfaar, O; Picard, R; Pigearias, B; Pin, I; Plavec, D; Poethig, D; Pohl, W; Popov, T A; Portejoie, F; Potter, P; Postma, D; Price, D; Rabe, K F; Raciborski, F; Radier Pontal, F; Repka-Ramirez, S; Reitamo, S; Rennard, S; Rodenas, F; Roberts, J; Roca, J; Rodriguez Mañas, L; Rolland, C; Roman Rodriguez, M; Romano, A; Rosado-Pinto, J; Rosario, N; Rosenwasser, L; Rottem, M; Ryan, D; Sanchez-Borges, M; Scadding, G K; Schunemann, H J; Serrano, E; Schmid-Grendelmeier, P; Schulz, H; Sheikh, A; Shields, M; Siafakas, N; Sibille, Y; Similowski, T; Simons, F E R; Sisul, J C; Skrindo, I; Smit, H A; Solé, D; Sooronbaev, T; Spranger, O; Stelmach, R; Sterk, P J; Sunyer, J; Thijs, C; To, T; Todo-Bom, A; Triggiani, M; Valenta, R; Valero, A L; Valia, E; Valovirta, E; Van Ganse, E; van Hage, M; Vandenplas, O; Vasankari, T; Vellas, B; Vestbo, J; Vezzani, G; Vichyanond, P; Viegi, G; Vogelmeier, C; Vontetsianos, T; Wagenmann, M; Wallaert, B; Walker, S; Wang, D Y; Wahn, U; Wickman, M; Williams, D M; Williams, S; Wright, J; Yawn, B P; Yiallouros, P K; Yusuf, O M; Zaidi, A; Zar, H J; Zernotti, M E; Zhang, L; Zhong, N; Zidarn, M; Mercier, J

2016-01-01

Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.

Piezomagnetic behavior of Fe-Al-B alloys

NASA Astrophysics Data System (ADS)

Bormio-Nunes, Cristina; Hubert, Olivier

2015-11-01

For the first time, the piezomagnetic behavior of polycrystalline Fe-Al-B alloys is accessed. Piezomagnetic factors of up to 4.0 kA m-1/MPa were reached for an interval of applied compressive stresses between 0 and -140 MPa. The experimental results together with a powerful multiscale and biphasic modeling allowed the general understanding of the magnetostrictive and piezomagnetic behaviors of these materials. The magnetic and mechanical localizations as well as homogeneous stresses were considered in the modeling and are associated to the intrinsic presence of the Fe2B phase. The interplay of the magnetocrystalline anisotropy, initial susceptibility, saturation magnetostriction and texture were quantified by the model and compared to the experimental results. An improvement of the piezomagnetic factor to 15 kA m-1/MPa is predicted, for an alloy containing 20% of aluminum, by getting an adequate texture near < 100 > directions.

Biodrying of sewage sludge: kinetics of volatile solids degradation under different initial moisture contents and air-flow rates.

PubMed

Villegas, Manuel; Huiliñir, Cesar

2014-12-01

This study focuses on the kinetics of the biodegradation of volatile solids (VS) of sewage sludge for biodrying under different initial moisture contents (Mc) and air-flow rates (AFR). For the study, a 3(2) factorial design, whose factors were AFR (1, 2 or 3L/minkgTS) and initial Mc (59%, 68% and 78% w.b.), was used. Using seven kinetic models and a nonlinear regression method, kinetic parameters were estimated and the models were analyzed with two statistical indicators. Initial Mc of around 68% increases the temperature matrix and VS consumption, with higher moisture removal at lower initial Mc values. Lower AFRs gave higher matrix temperatures and VS consumption, while higher AFRs increased water removal. The kinetic models proposed successfully simulate VS biodegradation, with root mean square error (RMSE) between 0.007929 and 0.02744, and they can be used as a tool for satisfactory prediction of VS in biodrying. Copyright © 2014 Elsevier Ltd. All rights reserved.

Central 300 PC of the Galaxy Probed by the Infrared Spectra of H_3^+ and Co: I. Predominance of Warm and Diffuse Gas and High H_2 Ionization Rate

NASA Astrophysics Data System (ADS)

Oka, Takeshi; Geballe, Thomas R.; Goto, Miwa; Usuda, Tomonori; Indriolo, Nick

2016-06-01

A low-resolution 2.0-2.5 μm survey of ˜500 very red point-like objects in the Central Molecular Zone (CMZ) of our Galaxy, initiated in 2008, has revealed many new bright objects with featureless spectra that are suitable for high resolution absorption spectroscopy of H_3^+ and CO. We now have altogether 48 objects mostly close to the Galactic plane located from 142 pc to the west of Sgr A* to 120 pc east allowing us to probe dense and diffuse gas by H_3^+ and dense gas by CO. Our observations demonstrate that the warm (˜250 K) and diffuse (≤100 cm-3) gas with a large column length (≥30 pc) initially observed toward the brightest star in the CMZ, GCS3-2 of the Quintuplet Cluster, exists throughout the CMZ with the surface filling factor of ˜ 100% dominating the region. The column densities of CO in the CMZ are found to be much less than those in the three foreground spiral arms except in the directions of Sgr B and Sgr E complexes and indicate that the volume filling factor of dense clouds of 10% previously estimated is a gross overestimate for the front half of the CMZ. Nevertheless the predominance of the newly found diffuse molecular gas makes the term "Central Molecular Zone" even more appropriate. The ultra-hot X-rays emitting plasma which some thought to dominate the region must be non existent except near the stars and SNRs. Recently the H_2 fraction f(H_2) in diffuse gas of the CMZ has been reported to be ˜0.6. If we use this value, the cosmic ray H_2 ionization rate ζ of a few times 10-15 s-1 reported earlier^b on the assumption of f(H_2)=1 needs to be increased by a factor of ˜3 since the value is approximately inversely proportional to f(H_2)^2. Geballe, T. R., Oka, T., Lambridges, E., Yeh, S. C. C., Schlegelmilch, B., Goto, M., Westrick, C. W., WI07 at the 70th ISMS, Urbana, IL, USA,2015 Oka, T., Geballe, T. R., Goto, M., Usuda, T., McCall, B. J. 2005, ApJ, 632, 882 Le Petit, F., Ruaud, M., Bron, E., Godard, B., Roueff, E., Languignon, D., Le Bourlot, J. 2016, A&A, 585, A105

32 CFR 989.4 - Initial considerations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... ENVIRONMENTAL IMPACT ANALYSIS PROCESS (EIAP) § 989.4 Initial considerations. Air Force personnel will: (a... CATEX from environmental impact analysis (appendix B). (c) Make environmental documents, comments, and... national security interests while at the same time considering important environmental factors. (g...

32 CFR 989.4 - Initial considerations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... ENVIRONMENTAL IMPACT ANALYSIS PROCESS (EIAP) § 989.4 Initial considerations. Air Force personnel will: (a... CATEX from environmental impact analysis (appendix B). (c) Make environmental documents, comments, and... national security interests while at the same time considering important environmental factors. (g...

32 CFR 989.4 - Initial considerations.

Code of Federal Regulations, 2014 CFR

2014-07-01

... ENVIRONMENTAL IMPACT ANALYSIS PROCESS (EIAP) § 989.4 Initial considerations. Air Force personnel will: (a... CATEX from environmental impact analysis (appendix B). (c) Make environmental documents, comments, and... national security interests while at the same time considering important environmental factors. (g...

An inhibitor of eIF2 activity in the sRNA pool of eukaryotic cells.

PubMed

Centrella, Michael; Porter, David L; McCarthy, Thomas L

2011-08-15

Eukaryotic protein synthesis is a multi-step and highly controlled process that includes an early initiation complex containing eukaryotic initiation factor 2 (eIF2), GTP, and methionine-charged initiator methionyl-tRNA (met-tRNAi). During studies to reconstruct formation of the ternary complex containing these molecules, we detected a potent inhibitor in low molecular mass RNA (sRNA) preparations of eukaryotic tRNA. The ternary complex inhibitor (TCI) was retained in the total sRNA pool after met-tRNAi was charged by aminoacyl tRNA synthetase, co-eluted with sRNA by size exclusion chromatography, but resolved from met-tRNAi by ion exchange chromatography. The adverse effect of TCI was not overcome by high GTP or magnesium omission and was independent of GTP regeneration. Rather, TCI suppressed the rate of ternary complex formation, and disrupted protein synthesis and the accumulation of heavy polymeric ribosomes in reticulocyte lysates in vitro. Lastly, a component or components in ribosome depleted cell lysate significantly reversed TCI activity. Since assembly of the met-tRNAi/eIF2/GTP ternary complex is integral to protein synthesis, awareness of TCI is important to avoid confusion in studies of translation initiation. A clear definition of TCI may also allow a better appreciation of physiologic or pathologic situations, factors, and events that control protein synthesis in vivo. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of ultraviolet light on water- and fat-soluble vitamins in cow and goat milk.

PubMed

Guneser, O; Karagul Yuceer, Y

2012-11-01

The objective of this study was to investigate and compare the effects of UV light and heat treatment on vitamins A, B(2), C, and E in cow and goat milk. Vitamins were analyzed by reverse-phase high-pressure liquid chromatography. Ultraviolet and pasteurization treatments caused loss in vitamin C in milk. Pasteurization did not have any significant effect on vitamin B(2). However, UV light treatment decreased the amount of vitamin B(2) after several passes of milk through the UV system. In addition, UV light treatment decreased the amount of vitamins A and E. Vitamins C and E are more sensitive to UV light. UV light sensitivities of vitamins were C>E>A>B(2). These results show that UV light treatment decreases the vitamin content in milk. Also, the number of passes through the UV system and the initial amount of vitamins in milk are important factors affecting vitamin levels. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Infantile onset Vanishing White Matter disease associated with a novel EIF2B5 variant, remarkably long life span, severe epilepsy, and hypopituitarism.

PubMed

Woody, April L; Hsieh, David T; McIver, Harkirtin K; Thomas, Linda P; Rohena, Luis

2015-04-01

Vanishing White Matter disease (VWM) is an inherited progressive leukoencephalopathy caused by mutations in the genes EIF2B1-5, which encode for the 5 subunits of the eukaryotic initiation factor 2B (eIF2B), a regulator of protein synthesis. VWM typically presents with acute neurological decline following febrile infections or minor head trauma, and subsequent progressive neurological and cognitive regression. There is a varied clinical spectrum of VWM, with earlier onset associated with more severe phenotypes. Brain magnetic resonance imaging is usually diagnostic with diffusely abnormal white matter, progressing over time to cystic degeneration. We are reporting on a patient with infantile onset VWM associated with three heterozygous missense variants in EIF2B5, including a novel missense variant on exon 6 of EIF2B5 (D262N), as well as an interstitial duplication at 7q21.12. In addition, our case is unusual because of a severe epilepsy course, a novel clinical finding of hypopituitarism manifested by hypothyroidism and adrenal insufficiency, and a prolonged life span with current age of survival of 4 years and 11 months. © 2015 Wiley Periodicals, Inc.

Pregnancy as a Window to Future Cardiovascular Health: Design and Implementation of the nuMoM2b Heart Health Study

PubMed Central

Haas, David M; Ehrenthal, Deborah B; Koch, Matthew A; Catov, Janet M; Barnes, Shannon E; Facco, Francesca; Parker, Corette B; Mercer, Brian M; Bairey-Merz, C Noel; Silver, Robert M; Wapner, Ronald J; Simhan, Hyagriv N; Hoffman, Matthew K; Grobman, William A; Greenland, Philip; Wing, Deborah A; Saade, George R; Parry, Samuel; Zee, Phyllis C; Reddy, Uma M; Pemberton, Victoria L; Burwen, Dale R

2016-01-01

Abstract The National Institute of Child Health and Human Development's Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study (HHS) was designed to investigate the relationships between adverse pregnancy outcomes and modifiable risk factors for cardiovascular disease. The ongoing nuMoM2b-HHS, which started in 2013, is a prospective follow-up of the nuMoM2b cohort, which included 10,038 women recruited between 2010 and 2013 from 8 centers across the United States who were initially observed over the course of their first pregnancies. In this report, we detail the design and study procedures of the nuMoM2b-HHS. Women in the pregnancy cohort who consented to be contacted for participation in future studies were approached at 6-month intervals to ascertain health information and to maintain ongoing contact. Two to 5 years after completion of the pregnancy documented in the nuMoM2b, women in the nuMoM2b-HHS were invited to an in-person study visit. During this visit, they completed psychosocial and medical history questionnaires and had clinical measurements and biological specimens obtained. A subcohort of participants who had objective assessments of sleep-disordered breathing during pregnancy were asked to repeat this investigation. This unique prospective observational study includes a large, geographically and ethnically diverse cohort, rich depth of phenotypic information about adverse pregnancy outcomes, and clinical data and biospecimens from early in the index pregnancy onward. Data obtained from this cohort will provide mechanistic and clinical insights into how data on a first pregnancy can provide information about the potential development of subsequent risk factors for cardiovascular disease. PMID:26825925

Acute molecular response of mouse hindlimb muscles to chronic stimulation.

PubMed

LaFramboise, W A; Jayaraman, R C; Bombach, K L; Ankrapp, D P; Krill-Burger, J M; Sciulli, C M; Petrosko, P; Wiseman, R W

2009-09-01

Stimulation of the mouse hindlimb via the sciatic nerve was performed for a 4-h period to investigate acute muscle gene activation in a model of muscle phenotype conversion. Initial force production (1.6 +/- 0.1 g/g body wt) declined 45% within 10 min and was maintained for the remainder of the experiment. Force returned to initial levels upon study completion. An immediate-early growth response was present in the extensor digitorum longus (EDL) muscle (FOS, JUN, activating transcription factor 3, and musculoaponeurotic fibrosarcoma oncogene) with a similar but attenuated pattern in the soleus muscle. Transcript profiles showed decreased fast fiber-specific mRNA (myosin heavy chains 2A and 2B, fast troponins T(3) and I, alpha-tropomyosin, muscle creatine kinase, and parvalbumin) and increased slow transcripts (myosin heavy chain-1beta/slow, troponin C slow, and tropomyosin 3y) in the EDL versus soleus muscles. Histological analysis of the EDL revealed glycogen depletion without inflammatory cell infiltration in stimulated versus control muscles, whereas ultrastructural analysis showed no evidence of myofiber damage after stimulation. Multiple fiber type-specific transcription factors (tea domain family member 1, nuclear factor of activated T cells 1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -beta, circadian locomotor output cycles kaput, and hypoxia-inducible factor-1alpha) increased in the EDL along with transcription factors characteristic of embryogenesis (Kruppel-like factor 4; SRY box containing 17; transcription factor 15; PBX/knotted 1 homeobox 1; and embryonic lethal, abnormal vision). No established in vivo satellite cell markers or genes activated in our parallel experiments of satellite cell proliferation in vitro (cyclins A(2), B(2), C, and E(1) and MyoD) were differentially increased in the stimulated muscles. These results indicated that the molecular onset of fast to slow phenotype conversion occurred in the EDL within 4 h of stimulation without injury or satellite cell recruitment. This conversion was associated with the expression of phenotype-specific transcription factors from resident fiber myonuclei, including the activation of nascent developmental transcriptional programs.

[Analysis of obstetric-pediatric care in the perinatal period. Are births before 31 weeks' gestation in level 2B maternity units avoidable?

PubMed

Martin, I; Roussel, A; Olieric, M-F; Feldmann, M; Wallerich, Y; Trabelsi, N; Miton, A; Zuily-Lamy, C; Valdès, V; Fresson, J

2017-12-01

Regionalization of perinatal care has been developed to improve the survival of preterm babies. The mortality rate is higher among very premature infants born outside level-3 maternity units. The objective of this study was to evaluate the preventability of these very premature births occurring outside recommendations within level-2B maternity units. The secondary objective was to describe the care of premature infants between 23 and 24 weeks. This is a single-center retrospective qualitative study of the care delivery pathways. Thirty-one deliveries in which the fetus was alive between 23 and 30 weeks+6 days occurred in a level-2B maternity unit in Thionville, France, between 1 January 2013 and 31 December 2015. After oral presentation of the cases, a level 2-3 multidisciplinary committee of experts in Lorraine evaluated the preventability criteria and reasons, and divided the deliveries into three groups: (i) birth in level-2B institutions avoidable, (ii) inevitable with factors related to the mother or the organization of care, (iii) with no inevitable factors. Out of the 31 deliveries included, the committee classified six deliveries as preventable, 14 as inevitable with factors, and 11 as inevitable with no factors. The criteria for preventability of birth in a level-2B unit were underestimation of maternal and fetal risk, an erroneous initial estimate of term or preterm labor, and two births in the upper limits of the French recommendations for in utero transfer. Nineteen of the 35 premature infants before 31 weeks' gestation died, 16 children were transferred to a level-3 maternity ward, and 16 children were allowed to go home. Analysis of the obstetrical-pediatric care course by an expert committee determined the preventability of the average birth and prematurity in level-2B maternity units in Lorraine for a small but significant number of cases. The local regionalization of neonatal care could be improved by the application of this method of analysis to other maternity wards in the Lorraine network. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Modulating Leukemia-Initiating Cell Quiescence to Improve Leukemia Treatment

DTIC Science & Technology

2015-09-01

T- cells and in innate immunity (Lacorazza et al., 2002). It controls the proliferation and homing of CD8+ T- cells via the Kruppel-like factors...Lin2Sca12IL7R2Kit1FccRII/ IIIhighCD34high), megakaryocyte-erythroid progenitor cell (MEP) (Lin2Sca12IL7R2Kit1FccRII/IIIlowCD34low), and common lymphoid ...to this model, the first wave gives rise exclusively to innate immune B cells in early embryonic life and may be derived from progenitor cells

MiR-181b targets Six2 and inhibits the proliferation of metanephric mesenchymal cells in vitro

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

Lyu, Zhongshi; Mao, Zhaomin; Wang, Honglian

2013-11-01

Highlights: •We do bio-informatics websites to analysis of Six2 3′UTR. •MiR181b is a putative miRNA which can targets Six2 3′UTR. •MiR-181b binding site in the 3′UTR of Six2 is functional. •MiR-181b suppresses MK3 cells cell proliferation by targeting Six2. -- Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that down-regulate gene expression by binding to target mRNA for cleavage or translational repression, and play important regulatory roles in renal development. Despite increasing genes have been predicted to be miRNA targets by bioinformatic analysis during kidney development, few of them have been verified by experiment. The objective of our study is tomore » identify the miRNAs targeting Six2, a critical transcription factor that maintains the mesenchymal progenitor pool via self-renewal (proliferation) during renal development. We initially analyzed the 3′UTR of Six2 and found 37 binding sites targeted by 50 putative miRNAs in the 3′UTR of Six2. Among the 50 miRNAs, miR-181b is the miRNAs predicted by the three used websites. In our study, the results of luciferase reporter assay, realtime-PCR and Western blot demonstrated that miR-181b directly targeted on the 3′UTR of Six2 and down-regulate the expression of Six2 at mRNA and protein levels. Furthermore, EdU proliferation assay along with the Six2 rescue strategy showed that miR-181b suppresses the proliferation of metanephric mesenchymal by targeting Six2 in part. In our research, we concluded that by targeting the transcription factor gene Six2, miR-181b inhibits the proliferation of metanephric mesenchymal cells in vitro and might play an important role in the formation of nephrons.« less

Eukaryotic translation initiation factor 3 plays distinct roles at the mRNA entry and exit channels of the ribosomal preinitiation complex

PubMed Central

Aitken, Colin Echeverría; Beznosková, Petra; Vlčkova, Vladislava; Chiu, Wen-Ling; Zhou, Fujun; Valášek, Leoš Shivaya; Hinnebusch, Alan G; Lorsch, Jon R

2016-01-01

Eukaryotic translation initiation factor 3 (eIF3) is a central player in recruitment of the pre-initiation complex (PIC) to mRNA. We probed the effects on mRNA recruitment of a library of S. cerevisiae eIF3 functional variants spanning its 5 essential subunits using an in vitro-reconstituted system. Mutations throughout eIF3 disrupt its interaction with the PIC and diminish its ability to accelerate recruitment to a native yeast mRNA. Alterations to the eIF3a CTD and eIF3b/i/g significantly slow mRNA recruitment, and mutations within eIF3b/i/g destabilize eIF2•GTP•Met-tRNAi binding to the PIC. Using model mRNAs lacking contacts with the 40S entry or exit channels, we uncovered a critical role for eIF3 requiring the eIF3a NTD, in stabilizing mRNA interactions at the exit channel, and an ancillary role at the entry channel requiring residues of the eIF3a CTD. These functions are redundant: defects at each channel can be rescued by filling the other channel with mRNA. DOI: http://dx.doi.org/10.7554/eLife.20934.001 PMID:27782884

The roles of SSU processome components and surveillance factors in the initial processing of human ribosomal RNA

PubMed Central

Sloan, Katherine E.; Bohnsack, Markus T.; Schneider, Claudia; Watkins, Nicholas J.

2014-01-01

During eukaryotic ribosome biogenesis, three of the mature ribosomal (r)RNAs are released from a single precursor transcript (pre-rRNA) by an ordered series of endonucleolytic cleavages and exonucleolytic processing steps. Production of the 18S rRNA requires the removal of the 5′ external transcribed spacer (5′ETS) by endonucleolytic cleavages at sites A0 and A1/site 1. In metazoans, an additional cleavage in the 5′ETS, at site A′, upstream of A0, has also been reported. Here, we have investigated how A′ processing is coordinated with assembly of the early preribosomal complex. We find that only the tUTP (UTP-A) complex is critical for A′ cleavage, while components of the bUTP (UTP-B) and U3 snoRNP are important, but not essential, for efficient processing at this site. All other factors involved in the early stages of 18S rRNA processing that were tested here function downstream from this processing step. Interestingly, we show that the RNA surveillance factors XRN2 and MTR4 are also involved in A′ cleavage in humans. A′ cleavage is largely bypassed when XRN2 is depleted, and we also discover that A′ cleavage is not always the initial processing event in all cell types. Together, our data suggest that A′ cleavage is not a prerequisite for downstream pre-rRNA processing steps and may, in fact, represent a quality control step for initial pre-rRNA transcripts. Furthermore, we show that components of the RNA surveillance machinery, including the exosome and TRAMP complexes, also play key roles in the recycling of excised spacer fragments and degradation of aberrant pre-rRNAs in human cells. PMID:24550520

Simultaneous effect of initial moisture content and airflow rate on biodrying of sewage sludge.

PubMed

Huiliñir, Cesar; Villegas, Manuel

2015-10-01

The simultaneous effect of initial moisture content (initial Mc) and air-flow rate (AFR) on biodrying performance was evaluated. For the study, a 3(2) factorial design, whose factors were AFR (1, 2 and 3 L/min kg(TS)) and initial Mc (59, 68 and 78% w.b.), was used. Using energy and water mass balance the main routes of water removal, energy use and efficiencies were determined. The results show that initial Mc has a stronger effect on the biodrying than the AFR, affecting the air outlet temperature and improving the water removal, with higher maximum temperatures obtained around 68% and the lowest maximum matrix temperature obtained at initial Mc = 78%.Through the water mass balance it was found that the main mechanism for water removal was the aeration, with higher water removal at intermediate initial Mc (68%) and high AFR (3 L/min kg(TS)). The energy balance indicated that bioreaction is the main energy source for water evaporation, with higher energy produced at intermediate initial Mc (68%). Finally, it was found that low values of initial Mc (59%) improve biodrying efficiency. Copyright © 2015 Elsevier Ltd. All rights reserved.

TRAF1 knockdown alleviates palmitate-induced insulin resistance in HepG2 cells through NF-κB pathway

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

Zhang, Wanlu; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province; Tang, Zhuqi

High-fat diet (HFD) and inflammation are key contributors to insulin resistance (IR) and Type 2 diabetes mellitus (T2DM). With HFD, plasma free fatty acids (FFAs) can activate the nuclear factor-κB (NF-κB) in target tissues, then initiate negative crosstalk between FFAs and insulin signaling. However, the molecular link between IR and inflammation remains to be identified. We here reported that tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, was involved in the onset of IR in hepatocytes. TRAF1 was significantly up-regulated in insulin-resistant liver tissues and palmitate (PA)-treated HepG2 cells. In addition, we showed that depletion ofmore » TRAF1 led to inhibition of the activity of NF-κB. Given the fact that the activation of NF-κB played a facilitating role in IR, the phosphorylation of Akt and GSK3β was also analyzed. We found that depletion of TRAF1 markedly reversed PA-induced attenuation of the phosphorylation of Akt and GSK3β in the cells. The accumulation of lipid droplets in hepatocyte and expression of two key gluconeogenic enzymes, PEPCK and G6Pase, were also determined and found to display a similar tendency with the phosphorylation of Akt and GSK3β. Glucose uptake assay indicated that knocking down TRAF1 blocked the effect of PA on the suppression of glucose uptake. These data implicated that TRAF1 knockdown might alleviate PA-induced IR in HepG2 cells through NF-κB pathway. - Highlights: • TRAF1 accelerated PA-induced IR in HepG2 cells mediated through NF-κB signaling. • Knockdown of TRAF1 alleviated PA-induced IR in HepG2 cells. • Knockdown of TRAF1 alleviated PA-induced lipid accumulation in HepG2 cells. • Knockdown of TRAF1 reversed PA-induced suppression of glucose uptake in HepG2 cells. • Knockdown of TRAF1 reversed PA-induced gluconeogenesis in HepG2 cells.« less

Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma.

PubMed

Kaseb, Ahmed O; Shindoh, Junichi; Patt, Yehuda Z; Roses, Robert E; Zimmitti, Giuseppe; Lozano, Richard D; Hassan, Manal M; Hassabo, Hesham M; Curley, Steven A; Aloia, Thomas A; Abbruzzese, James L; Vauthey, Jean-Nicolas

2013-09-15

The purpose of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma. The study included 2 groups of patients treated with conventional high-dose PIAF (n = 84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n = 33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the 2 groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival. The modified PIAF group had a higher median number of PIAF cycles (4 versus 2, P = .049), higher objective response rate (36% versus 15%, P = .013), higher rate of conversion to curative surgery (33% versus 10%, P = .004), and longer median overall survival (21.3 versus 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR] = 1.68; 95% confidence interval [CI] = 1.08-2.59) and Eastern Cooperative Oncology Group performance status ≥ 2 (HR = 1.75; 95% CI = 1.04-2.93) were associated with worse survival whereas curative surgical resection after PIAF treatment (HR = 0.15; 95% CI = 0.07-0.35) was associated with improved survival. In patients with initially unresectable hepatocellular carcinoma, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival. © 2013 American Cancer Society.

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

PubMed Central

Watanabe, Akira; Ogiwara, Hideki; Ehata, Shogo; Mukasa, Akitake; Ishikawa, Shumpei; Maeda, Daichi; Ueki, Keisuke; Ino, Yasushi; Todo, Tomoki; Yamada, Yasuhiro; Fukayama, Masashi; Saito, Nobuhito; Miyazono, Kohei; Aburatani, Hiroyuki

2011-01-01

Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells. PMID:21750150

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

PubMed Central

Kanzaki, Hirotaka; Mukhopadhya, Nishit K.; Cui, Xiaojiang; Ramanujan, V. Krishnan

2016-01-01

A major clinical problem in the treatment of breast cancer is mortality due to metastasis. Understanding the molecular mechanisms associated with metastasis should aid in designing new therapeutic approaches for breast cancer. Trastuzumab is the main therapeutic option for HER2+ breast cancer patients; however, the molecular basis for trastuzumab resistance (TZR) and subsequent metastasis is not known. Earlier, we found expression of basal-like molecular markers in TZR tissues from patients with invasive breast cancer.(1) The basal-like phenotype is a particularly aggressive form of breast cancer. This observation suggests that TZR might contribute to an aggressive phenotype. To understand if resistance to TZR can lead to basal-like phenotype, we generated a trastuzumab-resistant human breast cancer cell line (BT-474-R) that maintained human epidermal growth factor receptor 2 (HER2) overexpression and HER2 mediated signaling. Analysis showed that nuclear factor-kappa B (NF-κB) was constitutively activated in the BT-474-R cells, a feature similar to the basal-like tumor phenotype. Pharmacologic inhibition of NF-κB improved sensitivity of BT-474-R cells to trastuzumab. Interestingly, activation of HER2 independent NF-κB is not shown in luminal B breast cancer cells. Our study suggests that by activating the NF-κB pathway, luminal B cells may acquire a HER2+ basal-like phenotype in which NF-κB is constitutively activated; this notion is consistent with the recently proposed “progression through grade” or “evolution of resistance” hypothesis. Furthermore, we identified IKK-α/IKK-β and nuclear accumulation of RelA/p65 as the major determinants in the resistant cells. Thus our study additionally suggests that the nuclear accumulation of p65 may be a useful marker for identifying metastasis-initiating tumor cells and targeting RelA/p65 may limit metastasis of breast and other cancers associated with NF-κB activation. PMID:26871511

Paraplegia-quadriplegia Independently Increases All Percutaneous Nephrolithotomy Complications: A Comparative Study Using the Modified Clavien System.

PubMed

Danawala, Zeeshan A; Singh, Dinesh

2015-05-01

To investigate the perioperative complication rates for paraplegic-quadriplegic patients (PQPs) undergoing percutaneous nephrolithotomy (PCNL) as compared with non-PQPs using a standardized method of complication reporting via the Clavien system. Two hundred thirteen consecutive PCNLs performed by a single surgeon were analyzed. There were 31 and 115 patients separated into PQP and non-PQP groups, respectively. Data collection included demographic and clinical factors, as well as perioperative and delayed complications. Complications were organized by the Clavien grade. All- and initial-procedure complications were analyzed. The rate of adverse events for each Clavien grade was calculated, and statistical comparisons were made. The relationship between PQP and complication severity was investigated using univariate and multivariate analyses. There were 38 and 43 initial-procedure complications in the PQP and non-PQP groups, respectively. The rate of adverse events was higher across the spectrum of Clavien grades for the PQP group, specifically grade 1 (48.4% vs 20.2%; P = .002), grade 2 (22.6% vs 5.3%; P = .004), grade 3b (12.9% vs 2.6%; P = .038), grade 4a (6.5% vs 0%), and grade 4b (9.7% vs 1.8%; P = .066). Approximately 51.6% and 31.5% of PQPs and non-PQPs experienced ≥ 1 complications, respectively (odds ratio = 2.34; P = .05). Multivariate analysis demonstrated paraplegia or quadriplegia status to be an independent risk factor for the development of perioperative complications after adjusting for confounding factors (odds ratio = 2.91; P = .040). PCNL complication rates are higher in PQPs compared with non-PQPs. This study is one of the first in PCNL to use a standardized reporting system to highlight high-risk individuals within the stone population. Copyright © 2015 Elsevier Inc. All rights reserved.

S100a8/a9 released by CD11b+Gr1+ neutrophils activates cardiac fibroblasts to initiate angiotensin II-Induced cardiac inflammation and injury.

PubMed

Wu, Yina; Li, Yulin; Zhang, Congcong; A, Xi; Wang, Yueli; Cui, Wei; Li, Huihua; Du, Jie

2014-06-01

Angiotensin II induces cardiovascular injury, in part, by activating inflammatory response; however, the initial factors that trigger the inflammatory cascade remain unclear. Microarray analysis of cardiac tissue exposed to systemic angiotensin II infusion revealed that extracellular heterodimeric proteins S100a8/a9 were highly upregulated. The increase in S100a8/a9 mRNA of CD11b(+)Gr1(+) neutrophils isolated from both the peripheral blood and heart was highest on day 1 of angiotensin II infusion and decreased to baseline at day 7. Immunostaining showed that S100a8/a9 was primarily present in infiltrating CD11b(+)Gr1(+) neutrophils in the heart. The receptor for advanced glycation end products, an S100a8/a9 receptor, was expressed in cardiac fibroblasts (CFs). Microarray analysis and Bio-Plex protein array showed that treatment of CFs with recombinant S100a8/a9 activated multiple chemokine and cytokines released. Luciferase reporter assay indicated S100a8/a9-activated nuclear factor-κ B pathway in CFs. Consequently, recombinant S100a8/a9-treated CFs promoted migration of monocytes and CFs, whereas neutralizing S100a9 antibody blocked S100a9 or receptor for advanced glycation end products-suppressed cellular migration. Finally, administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, subsequent perivascular and interstitial fibrosis, and hypertrophy in heart. Our findings identify neutrophil-produced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute hypertension.

Baclofen and naltrexone effects on alcohol self-administration: Comparison of treatment initiated during abstinence or ongoing alcohol access in baboons.

PubMed

Holtyn, August F; Kaminski, Barbara J; Weerts, Elise M

2017-10-01

Baclofen, a GABA B receptor agonist, is under investigation as a pharmacotherapy for alcohol use disorder. Treatment with a pharmacotherapeutic can be initiated during alcohol abstinence or active drinking, which may influence treatment outcomes. This study examined whether baclofen treatment initiated and maintained during alcohol abstinence would reduce alcohol seeking and self-administration upon return to alcohol access, and whether effects differed from treatment initiated and maintained during ongoing alcohol access. Naltrexone was tested under similar conditions for comparison. Five baboons self-administered alcohol under a three-component chained schedule of reinforcement that modeled periods of anticipation (Component 1), seeking (Component 2), and consumption (Component 3). Alcohol was only available in Component 3. In Experiment 1, baclofen (0.1-1.8mg/kg) or naltrexone (1.0-5.6mg/kg) was administered daily beginning on the first day of a 5-day abstinence period and treatment was continued for 5days of alcohol access. In Experiment 2, selected doses of both drugs were administered during ongoing alcohol access. When treatment was initiated during alcohol abstinence, baclofen and naltrexone did not significantly reduce total alcohol intake (g/kg) or alcohol seeking. In comparison, when treatment was initiated during ongoing alcohol access, both baclofen (1.8mg/kg) and naltrexone (3.2 and 5.6mg/kg) significantly reduced total alcohol intake (g/kg). Naltrexone (5.6mg/kg), but not baclofen, significantly reduced alcohol seeking. Initiation of baclofen treatment (or other alcohol use disorder treatments) during abstinence or active drinking may be an important factor in influencing efficacy and appropriate dose selection. Copyright © 2017 Elsevier B.V. All rights reserved.

DEREGULATION OF DUX4 AND ERG IN ACUTE LYMPHOBLASTIC LEUKEMIA

PubMed Central

Zhang, Jinghui; McCastlain, Kelly; Yoshihara, Hiroki; Xu, Beisi; Chang, Yunchao; Churchman, Michelle L.; Wu, Gang; Li, Yongjin; Wei, Lei; Iacobucci, Ilaria; Liu, Yu; Qu, Chunxu; Wen, Ji; Edmonson, Michael; Payne-Turner, Debbie; Kaufmann, Kerstin B.; Takayanagi, Shin-ichiro; Wienholds, Erno; Waanders, Esmé; Ntziachristos, Panagiotis; Bakogianni, Sofia; Wang, Jingjing; Aifantis, Iannis; Roberts, Kathryn G.; Ma, Jing; Song, Guangchun; Easton, John; Mulder, Heather L.; Chen, Xiang; Newman, Scott; Ma, Xiaotu; Rusch, Michael; Gupta, Pankaj; Boggs, Kristy; Vadodaria, Bhavin; Dalton, James; Liu, Yanling; Valentine, Marcus L; Ding, Li; Lu, Charles; Fulton, Robert S.; Fulton, Lucinda; Tabib, Yashodhan; Ochoa, Kerri; Devidas, Meenakshi; Pei, Deqing; Cheng, Cheng; Yang, Jun; Evans, William E.; Relling, Mary V.; Pui, Ching-Hon; Jeha, Sima; Harvey, Richard C.; Chen, I-Ming L; Willman, Cheryl L.; Marcucci, Guido; Bloomfield, Clara D.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Paietta, Elisabeth; Tallman, Martin S.; Stock, Wendy; Foster, Matthew C.; Racevskis, Janis; Rowe, Jacob M.; Luger, Selina; Kornblau, Steven M.; Shurtleff, Sheila A; Raimondi, Susana C.; Mardis, Elaine R.; Wilson, Richard K.; Dick, John E.; Hunger, Stephen P; Loh, Mignon L.; Downing, James R.; Mullighan, Charles G.

2016-01-01

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL).1,2 Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases, and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt utilizes a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivating domains of ERG, but inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia, in which DUX4 deregulation results in loss-of-function of ERG, either by deletion or induction of expression of an isoform that is a dominant negative inhibitor of wild type ERG function. PMID:27776115

Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis.

PubMed

Brozek, Wolfgang; Manhardt, Teresa; Kállay, Enikö; Peterlik, Meinrad; Cross, Heide S

2012-07-26

Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1a-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.

Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis

PubMed Central

Brozek, Wolfgang; Manhardt, Teresa; Kállay, Enikö; Peterlik, Meinrad; Cross, Heide S.

2012-01-01

Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1α-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression. PMID:24213465

Human Factors Engineering Program for Intercontinental Ballistic Missile Systems, (MIL-STD-1794(USAF))

DTIC Science & Technology

1986-10-01

opeational test and evaluation (OT&R). The OT&B Is comprised of Initial operational test and evaluation ( IOT &R) and follow-on test and evaluation (FOT&R). OT&I...BP HYL FVAC beating, ventilation and air conditioning am. ICBM Intercntinental ballistic missile an. IOT &R Initial operational test and *valuation so...and maintenance vehicles (stop- B pod, engine idle-exterior), facility equipment utility rooms, heating, ventilation and air conditioning ( HVAC

The factors associated with longitudinal changes in liver stiffness in patients with chronic hepatitis B

PubMed Central

Yo, In Ku; Park, Jin Woong; Lee, Jong Joon; Lee, Jung Hyun; Won, In Sik; Na, Sun Young; Jang, Pil Kyu; Park, Pyung Hwa; Choi, Duck Joo; Kim, Yun Soo; Kim, Ju Hyun

2015-01-01

Background/Aims Liver stiffness (LS) as assessed by transient elastography (TE) can change longitudinally in patients with chronic hepatitis B (CHB). The aim of this study was to identify the factors that improve LS. Methods Between April 2007 and December 2012, 151 patients with CHB who underwent two TE procedures with an interval of about 2 years were enrolled. Ninety-six of the 151 patients were treated with nucleos(t)ide analogues [the antiviral therapy (+) group], while the remaining 55 patients were not [the antiviral therapy (-) group]. The two groups of patients were stratified according to whether they exhibited an improvement or a deterioration in LS during the study period (defined as an LS change of ≤0 or >0 kPa, respectively, over a 1-year period), and their data were compared. Results No differences were observed between the antiviral therapy (+) and (-) groups with respect to either their clinical characteristics or their initial LS. The observed LS improvement was significantly greater in the antiviral therapy (+) group than in the antiviral therapy (-) group (-3.0 vs. 0.98 kPa, P=0.011). In the antiviral therapy (+) group, the initial LS was higher in the LS improvement group (n=63) than in the LS deterioration group (n=33; 7.9 vs. 4.8 kPa, P<0.001). However, there were no differences in any other clinical characteristic. In the antiviral therapy (-) group, the initial LS was also higher in the LS improvement group (n=29) than in the LS deterioration group (n=26; 8.3 vs. 6.5 kPa, P=0.021), with no differences in any other clinical characteristic. Conclusions A higher initial LS was the only factor associated with LS improvement in patients with CHB in this study. PMID:25834800

The factors associated with longitudinal changes in liver stiffness in patients with chronic hepatitis B.

PubMed

Yo, In Ku; Kwon, Oh Sang; Park, Jin Woong; Lee, Jong Joon; Lee, Jung Hyun; Won, In Sik; Na, Sun Young; Jang, Pil Kyu; Park, Pyung Hwa; Choi, Duck Joo; Kim, Yun Soo; Kim, Ju Hyun

2015-03-01

Liver stiffness (LS) as assessed by transient elastography (TE) can change longitudinally in patients with chronic hepatitis B (CHB). The aim of this study was to identify the factors that improve LS. Between April 2007 and December 2012, 151 patients with CHB who underwent two TE procedures with an interval of about 2 years were enrolled. Ninety-six of the 151 patients were treated with nucleos(t)ide analogues [the antiviral therapy (+) group], while the remaining 55 patients were not [the antiviral therapy (-) group]. The two groups of patients were stratified according to whether they exhibited an improvement or a deterioration in LS during the study period (defined as an LS change of ≤0 or >0 kPa, respectively, over a 1-year period), and their data were compared. No differences were observed between the antiviral therapy (+) and (-) groups with respect to either their clinical characteristics or their initial LS. The observed LS improvement was significantly greater in the antiviral therapy (+) group than in the antiviral therapy (-) group (-3.0 vs. 0.98 kPa, P=0.011). In the antiviral therapy (+) group, the initial LS was higher in the LS improvement group (n=63) than in the LS deterioration group (n=33; 7.9 vs. 4.8 kPa, P<0.001). However, there were no differences in any other clinical characteristic. In the antiviral therapy (-) group, the initial LS was also higher in the LS improvement group (n=29) than in the LS deterioration group (n=26; 8.3 vs. 6.5 kPa, P=0.021), with no differences in any other clinical characteristic. A higher initial LS was the only factor associated with LS improvement in patients with CHB in this study.

Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B

PubMed Central

Nathwani, A.C.; Reiss, U.M.; Tuddenham, E.G.D.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y.-M.; Halka, K.G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K.A.; Allay, J.; Kay, M.A.; Ng, C.Y.C.; Zhou, J.; Cancio, M.; Morton, C.L.; Gray, J.T.; Srivastava, D.; Nienhuis, A.W.; Davidoff, A.M.

2014-01-01

BACKGROUND In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity. METHODS We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.) PMID:25409372

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

Chen, De-Ju; Xu, Yan-Ming; Du, Ji-Ying

Highlights: • Normal human bronchial epithelial cells (BEAS-2B) were dosed with cadmium (Cd). • A low level (2 μM) of Cd treatment for 36 h elicited negligible cytotoxicity. • High levels (20 or 30 μM) of Cd treatment for 36 h induced cell death. • High levels of Cd can upregulate the protein levels of eIF5A1 and NF-κB p65. • We suggest that eIF5A1 level is possibly modulated by NF-κB. - Abstract: Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well-known carcinogens. Here, we report that in CdCl{sub 2}-exposed human bronchial epithelial cells (BEAS-2B), the level ofmore » p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 μM) of Cd can significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-κB p65. Moreover, there is an enhanced NF-κB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF5A1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF5A1 in Cd cytotoxicity. As eIF5A1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-κB might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB binding on eIF5A1 promoter region of Cd-treated BEAS-2B cells. Taken together, our findings suggest for the first time a regulatory mechanism for the pro-apoptotic protein eIF5A1 in which its level is possibly modulated by NF-κB in human lung cells.« less

Combination of ALDH2 and ADH1B polymorphisms is associated with smoking initiation: A large-scale cross-sectional study in a Japanese population.

PubMed

Masaoka, Hiroyuki; Ito, Hidemi; Gallus, Silvano; Watanabe, Miki; Yokomizo, Akira; Eto, Masatoshi; Matsuo, Keitaro

2017-04-01

Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms are known to strongly influence alcohol　drinking behavior. Given evidence of an association between smoking and drinking behaviors, we hypothesized that ALDH2/ADH1B polymorphisms might also be associated with smoking initiation, and conducted a cross-sectional study to examine this hypothesis. Study subjects were first-visit outpatients diagnosed not to have cancer at Aichi Cancer Center Hospital between 2001 and 2005, including 4141 never smokers and 2912 ever smokers. Unconditional logistic regression models were applied to estimate odds ratios (OR) and 95% confidence intervals (CI) for smoking initiation by comparing ever smokers with never smokers. Excessive alcohol drinking was associated with a higher likelihood of ever smoking. After adjustment for drinking behaviors, compared to individuals with ALDH2 Glu/Glu, the ORs of ever smoking were 1.71 (95% CI, 1.49-1.95) and 2.28 (1.81-2.87) among those with ALDH2 Glu/Lys and Lys/Lys, respectively. Combination of ALDH2 Lys/Lys and ADH1B His/His (i.e., the most alcohol-intolerant subpopulation) showed the highest OR [2.44 (1.84-3.23)], whereas combination of ALDH2 Glu/Glu and ADH1B Arg/Arg (i.e., the most alcohol-tolerant subpopulation) showed the lowest OR [0.83 (0.57-1.21)] compared with ALDH2 Glu/Glu and ADH1B His/His. Besides the amount and frequency of alcohol drinking, the combination of ALDH2 and ADH1B polymorphisms predicts smoking initiation. This study suggests that alcohol tolerance regulated by ALDH2 and ADH1B polymorphisms is associated with smoking initiation, and facilitates the development of targeted interventions to reduce smoking prevalence. Copyright © 2017 Elsevier B.V. All rights reserved.

Biological Effects of Activating Distinct ErbB Receptor Dimers in Polarized Growth Arrested Epithelia

DTIC Science & Technology

2006-09-01

deregulating the function of Par protein complex, we made the unexpected observation that overexpression of Par6 induced growth- factor independent...predisposition factors for human cancer [8] and the human papillomavirus protein E6, targets scribble for degradation[9]. It has also been shown that Par6...vivo and thus is an excellent model to study the important factors in the initiation of the oncogenic process. However, activation of ErbB1 does not

Characterizing executive functioning in older special populations: from cognitively elite to cognitively impaired.

PubMed

de Frias, Cindy M; Dixon, Roger A; Strauss, Esther

2009-11-01

The authors examined the structure and invariance of executive functions (EF) across (a) a continuum of cognitive status in 3 groups of older adults (cognitively elite [CE], cognitively normal [CN], and cognitively impaired [CI]) and (b) a 3-year longitudinal interval. Using latent variable analyses (LISREL 8.80), the authors tested 3-factor models ("Inhibition": Hayling [Burgess & Shallice, 1997], Stroop [Regard, 1981]; "Shifting": Brixton [Burgess & Shallice, 1997], Color Trails [D'Elia et al., 1996]; and "Updating": Reading and Computational Span [Salthouse & Babcock, 1991]) and 1-factor models within each group. Participants (initial N = 570; 53-90 years) were from the Victoria Longitudinal Study (Sample 3, Waves 1 and 2). Cross-sectionally, the authors observed a 3-factor EF structure especially for the CE group and 1-factor solutions for all 3 groups. Longitudinally, temporal invariance was supported for the 3-factor model (CE and CN groups) and the 1-factor model (CI and CN groups). Subgroups with higher cognitive status and greater 3-year stability performed better on EF factors than corresponding groups with lower cognitive status and less stability. Studies of EF structure, performance, dedifferentiation, and dysfunction will benefit from considering initial cognitive status and longitudinal stability.

Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke.

PubMed

Baker, R I; Eikelboom, J; Lofthouse, E; Staples, N; Afshar-Kharghan, V; López, J A; Shen, Y; Berndt, M C; Hankey, G

2001-07-01

Platelets are pivotal to the process of arterial thrombosis resulting in ischemic stroke. Occlusive thrombosis is initiated by the interaction of von Willebrand factor (vWf) and platelet glycoprotein (GP) Ibalpha. Three polymorphisms have been described in GP Ibalpha (Kozak T/C polymorphism, variable number of tandem repeats [VNTR], and the human platelet antigen 2a [HPA-2a] [Thr] or HPA-2b [Met] at position 145), each of which may enhance the vWf and GP Ibalpha interaction. This study investigated whether these polymorphisms are candidate genes for first-ever ischemic stroke. A hospital-based case-control study was conducted of 219 cases of first-ever ischemic stroke and 205 community controls randomly selected from the electoral roll and stratified by age, sex, and postal code. The subtypes of stroke were classified, the prevalence of conventional risk factors was recorded, and blood was collected to perform genotyping analysis for Kozak C or T alleles, VNTR, and HPA-2a/b. It was found that the Kozak T/C genotype was over-represented in the stroke group (32.2%) compared with controls (22.8%) (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.03-2.54; P <.03), and the association was still present even after adjusting for conventional risk factors. There was a trend in the increased prevalence of HPA-2a/b in stroke patients (15%) compared with controls (9.9%) (adjusted OR, 1.8; 95% CI, 0.94-3.4; P =.07). No associations were seen with the VNTR polymorphism or with any of the polymorphisms with stroke subtype. It was concluded that the Kozak T/C polymorphism, which is associated with an increase in platelet GP Ibalpha surface expression, is an independent risk factor for first-ever ischemic stroke.

Phenotypic and familial associations between childhood maltreatment and cannabis initiation and problems in young adult European-American and African-American women.

PubMed

Grant, Julia D; Agrawal, Arpana; Werner, Kimberly B; McCutcheon, Vivia V; Nelson, Elliot C; Madden, Pamela A F; Bucholz, Kathleen K; Heath, Andrew C; Sartor, Carolyn E

2017-10-01

Childhood maltreatment is a known risk factor for cannabis initiation and problem use, but the extent to which this association is attributable to shared familial influences is unknown. We estimate the magnitude of associations between childhood maltreatment, timing of cannabis initiation, and cannabis-related problems, in European-American (EA) and African-American (AA) women, and parse the relative influence of additive genetic (A), shared environmental (C), and individual-specific environmental (E) factors on these constructs and their covariation. Data were from diagnostic telephone interviews conducted with 3786 participants (14.6% AA) in a population-based study of female twins. Logistic regression analyses and twin modeling were used to test for associations, and estimate the relative contributions of genetic and environmental influences to childhood maltreatment and cannabis outcomes and their covariation. Maltreatment was significantly associated with increased likelihood of cannabis initiation before age 15 among EAs (OR=6.33) and AAs (OR=3.93), but with increased likelihood of later initiation among EAs only (OR=1.68). Maltreatment was associated with cannabis problems among both groups (EA OR=2.32; AA OR=2.03). Among EA women, the covariation between maltreatment and cannabis outcomes was primarily attributable to familial environment (rC=0.67-0.70); among AAs, only individual-specific environment contributed (rE=0.37-0.40). Childhood maltreatment is a major contributor to early initiation of cannabis as well as progression to cannabis problems in both AA and EA women. Distinctions by race/ethnicity are not in the relative contribution of genetic factors, but rather in the type of environmental influences that contribute to stages of cannabis involvement. Copyright © 2017 Elsevier B.V. All rights reserved.

Indications for Vitamin B12 Therapy

PubMed Central

Delva, M. Dianne; Anderson, J.E.

1992-01-01

A retrospective chart audit was undertaken to determine the clinical reasons for vitamin B12 therapy in family practice. Abnormal laboratory tests and symptoms were the most common reasons for initiating therapy. The high proportion of cases with little supporting evidence of B12 deficiency suggests that other factors influence treatment decisions. PMID:20469527

Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway.

PubMed

Ohtsu, Naoki; Nakatani, Yuka; Yamashita, Daisuke; Ohue, Shiro; Ohnishi, Takanori; Kondo, Toru

2016-01-01

Glioblastoma (GBM)-initiating cells (GIC) are a tumorigenic subpopulation that are resistant to radio- and chemotherapies and are the source of disease recurrence. Therefore, the identification and characterization of GIC-specific factors is critical toward the generation of effective GBM therapeutics. In this study, we investigated the role of epithelial V-like antigen 1 (Eva1, also known as myelin protein zero-like 2) in stemness and GBM tumorigenesis. Eva1 was prominently expressed in GICs in vitro and in stem cell marker (Sox2, CD15, CD49f)-expressing cells derived from human GBM tissues. Eva1 knockdown in GICs reduced their self-renewal and tumor-forming capabilities, whereas Eva1 overexpression enhanced these properties. Eva1 deficiency was also associated with decreased expression of stemness-related genes, indicating a requirement for Eva1 in maintaining GIC pluripotency. We further demonstrate that Eva1 induced GIC proliferation through the activation of the RelB-dependent noncanonical NF-κB pathway by recruiting TRAF2 to the cytoplasmic tail. Taken together, our findings highlight Eva1 as a novel regulator of GIC function and also provide new mechanistic insight into the role of noncanonical NF-κB activation in GIC, thus offering multiple potential therapeutic targets for preclinical investigation in GBM. ©2015 American Association for Cancer Research.

Factors associated with retention in Option B+ in Malawi: a case control study.

PubMed

Hoffman, Risa M; Phiri, Khumbo; Parent, Julie; Grotts, Jonathan; Elashoff, David; Kawale, Paul; Yeatman, Sara; Currier, Judith S; Schooley, Alan

2017-04-27

There are limited data on factors associated with retention in Option B+. We sought to explore the characteristics of women retained in Option B+ in Malawi, with a focus on the role of HIV disclosure, awareness of partner HIV status, and knowledge around the importance of Option B+ for maternal-child health. Methods We performed a case-control study of HIV-infected women in Malawi initiated on antiretroviral therapy (ART) under Option B+. Cases were enrolled if they met criteria for default from Option B+ (out of ART for >60 days), and controls were enrolled in approximately 3:1 ratio if they were retained in care for at least 12 months. We surveyed socio-demographic characteristics, HIV disclosure and awareness of partner HIV status, self-report about receiving pre-ART education, and knowledge of Option B+. Univariate logistic regression was performed to determine factors associated with retention. Multivariate logistic regression model was used to evaluate the relationship between HIV disclosure, Option B+ knowledge, and retention after adjusting for age, schooling, and travel time to clinic. We enrolled 50 cases and 153 controls. Median age was 30 years (interquartile range (IQR) 25-34), and the majority (82%) initiated ART during pregnancy at a median gestational age of 24 weeks (IQR 16-28). Ninety-one per cent of the cases (39/43) who started ART during pregnancy defaulted by three months postpartum. HIV disclosure to the primary sex partner was more common among women retained in care (100% versus 78%, p  < 0.001). Odds of retention were significantly higher among women with: age >25 years (odds ratio (OR) 2.44), completion of primary school (OR 3.06), awareness of partner HIV status (OR 5.20), pre-ART education (OR 6.17), higher number of correct answers to Option B+ knowledge questions (OR 1.82), and support while taking ART (OR 3.65). Pre-ART education and knowledge were significantly correlated ( r  = 0.43, p  < 0.001). In multivariate analysis, awareness of partner HIV status (OR 4.07, 95% confidence interval (CI) 1.51-10.94, p  = 0.02) and Option B+ knowledge (OR 1.60, 95% CI 1.15-2.23, p  = 0.004) remained associated with retention. Interventions that address partner disclosure and strengthen pre-ART education around the benefits of ART for maternal and child health should be evaluated to improve retention in Malawi's Option B+ programme.

Factors associated with retention in Option B+ in Malawi: a case control study

PubMed Central

Hoffman, Risa M; Phiri, Khumbo; Parent, Julie; Grotts, Jonathan; Elashoff, David; Kawale, Paul; Yeatman, Sara; Currier, Judith S; Schooley, Alan

2017-01-01

Abstract Introduction: There are limited data on factors associated with retention in Option B+. We sought to explore the characteristics of women retained in Option B+ in Malawi, with a focus on the role of HIV disclosure, awareness of partner HIV status, and knowledge around the importance of Option B+ for maternal–child health. Methods: We performed a case-control study of HIV-infected women in Malawi initiated on antiretroviral therapy (ART) under Option B+. Cases were enrolled if they met criteria for default from Option B+ (out of ART for >60 days), and controls were enrolled in approximately 3:1 ratio if they were retained in care for at least 12 months. We surveyed socio-demographic characteristics, HIV disclosure and awareness of partner HIV status, self-report about receiving pre-ART education, and knowledge of Option B+. Univariate logistic regression was performed to determine factors associated with retention. Multivariate logistic regression model was used to evaluate the relationship between HIV disclosure, Option B+ knowledge, and retention after adjusting for age, schooling, and travel time to clinic. Results: We enrolled 50 cases and 153 controls. Median age was 30 years (interquartile range (IQR) 25–34), and the majority (82%) initiated ART during pregnancy at a median gestational age of 24 weeks (IQR 16–28). Ninety-one per cent of the cases (39/43) who started ART during pregnancy defaulted by three months postpartum. HIV disclosure to the primary sex partner was more common among women retained in care (100% versus 78%, p < 0.001). Odds of retention were significantly higher among women with: age >25 years (odds ratio (OR) 2.44), completion of primary school (OR 3.06), awareness of partner HIV status (OR 5.20), pre-ART education (OR 6.17), higher number of correct answers to Option B+ knowledge questions (OR 1.82), and support while taking ART (OR 3.65). Pre-ART education and knowledge were significantly correlated (r = 0.43, p < 0.001). In multivariate analysis, awareness of partner HIV status (OR 4.07, 95% confidence interval (CI) 1.51–10.94, p = 0.02) and Option B+ knowledge (OR 1.60, 95% CI 1.15–2.23, p = 0.004) remained associated with retention. Conclusions: Interventions that address partner disclosure and strengthen pre-ART education around the benefits of ART for maternal and child health should be evaluated to improve retention in Malawi’s Option B+ programme. PMID:28453243

Identification of Flaws Responsible for Crack Initiation and Micromechanisms of Slow Crack Growth in the Delayed Fracture of Alumina.

DTIC Science & Technology

1982-02-01

ntsitycrOtained Alumina in 50 % Relative Humidity . 123 (1) the material constants under a certain environment, A, B, and n in eq. (2-14) and eq. (2-15), evalu... Fatigue Crack Growth," Int. Jour. Fract., 17 (1981) 235-247. 3. S.M. Wiederhorn, " Effects of Environment on the Fracture of Glass," Environment-Sensitive...Distribution of Alumina 4 1 34 2-11 Schematic Drawing of Variation in Effective Critical Stress Intensity Factor, KC ff with Crack Length Relative to Grain

Does the cerebellum initiate movement?

PubMed

Thach, W T

2014-02-01

Opinion is divided on what the exact function of the cerebellum is. Experiments are summarized that support the following views: (1) the cerebellum is a combiner of multiple movement factors; (2) it contains anatomically fixed permanent focal representation of individual body parts (muscles and segments) and movement modes (e.g., vestibular driven vs. cognitive driven); (3) it contains flexible changing representations/memory of physical properties of the body parts including muscle strength, segment inertia, joint viscosity, and segmental interaction torques (dynamics); (4) it contains mechanisms for learning and storage of the properties in item no. 3 through trial-and-error practice; (5) it provides for linkage of body parts, motor modes, and motordynamics via the parallel fiber system; (6) it combines and integrates the many factors so as to initiate coordinated movements of the many body parts; (7) it is thus enabled to play the unique role of initiating coordinated movements; and (8) this unique causative role is evidenced by the fact that: (a) electrical stimulation of the cerebellum can initiate compound coordinated movements; (b) in naturally initiated compound movements, cerebellar discharge precedes that in downstream target structures such as motor cerebral cortex; and (c) cerebellar ablation abolishes the natural production of compound movements in the awake alert individuals.

Sensor kinase KinB and its pathway-associated key factors sense the signal of nutrition starvation in sporulation of Bacillus subtilis.

PubMed

Liu, Weipeng; He, Zeying; Gao, Feng; Yan, Jinyuan; Huang, Xiaowei

2018-01-03

Bacillus subtilis responds to environmental stress cues and develops endospores for survival. In the process of endospore formation, sporulation initiation is a vital stage and this stage is governed by autophosphorylation of the sensor histidine kinases. The second major sensor kinase KinB perceives the intracellular changes of GTP and ATP during sporulation. However, determination of the environmental signals as well as its related signaling pathway of KinB requires further elucidation. Our current study found that, contrary to the sporulation failure induced by ΔkinA in the nutrient-rich 2× SG medium, the sensor kinase KinB sensed the environmental cues in the nutrient-poor MM medium. Two other membrane proteins, KapB and KbaA, also responded similarly to the same external signal as KinB. Both KapB and KbaA acted upstream of KinB, but they exerted their regulation upon KinB independently. Furthermore, we demonstrated that both the SH3 domain and the α-helix structure in KapB are required for sensing or transducing the signal of sporulation initiation. Collectively, our work here supplied the direct evidences that KinB and its pathway sense the external signal of nutrient starvation in MM medium, and further analyzes the interrelationship among KinB, KbaA, and KapB. © 2018 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

Copper binding affinity of the C2B domain of synaptotagmin-1 and its potential role in the nonclassical secretion of Acidic Fibroblast Growth Factor

PubMed Central

Jayanthi, Srinivas; Kathir, Karuppanan Muthusamy; Rajalingam, Dakshinamurthy; Furr, Mercede; Daily, Anna; Thurman, Ryan; Rutherford, Lindsay; Chandrashekar, Reena; Adams, Paul; Prudovsky, Igor; Suresh Kumar, Thallapuranam Krishnaswamy

2014-01-01

Fibroblast growth factor 1 (FGF1) is a heparin-binding proangiogenic protein. FGF1 lacks the conventional N-terminal signal peptide required for secretion through the endoplasmic reticulum (ER) -Golgi secretory pathway. FGF1 is released through a Cu2+ - mediated nonclassical secretion pathway. The secretion of FGF1 involves the formation of a Cu2+- mediated multiprotein release complex (MRC) including FGF1, S100A13 (a calcium-binding protein) and p40 synaptotagmin (Syt1). It is believed that binding of Cu2+ to the C2B domain is important for the release of FGF1 in to the extracellular medium. In this study, using a variety of biophysical studies, Cu2+ and lipid interactions of the C2B domain of Syt1were characterized. Isothermal titration calorimetry (ITC) experiments reveal that C2B domain binds to Cu2+ in a biphasic manner involving an initial endothermic and a subsequent exothermic phase. Fluorescence energy transfer experiments using Tb3+ show that there are two Cu2+- binding pockets on the C2B domain, and one of these is also a Ca2+- binding site. Lipid-binding studies using ITC demonstrate that the C2B domain preferentially binds to small unilamellar vesicles of phosphatidyl serine (PS). Results of the differential scanning calorimetry and limited trypsin digestion experiments suggest that C2B domain is marginally destabilized upon binding to PS vesicles. These results, for the first time, suggest that the main role of the C2B domain of Syt1 is to serve as an anchor for the FGF1 MRC on the membrane bilayer. In addition, binding of the C2B domain to the lipid bilayer is shown to significantly decrease the binding affinity of the protein to Cu2+. The study provides valuable insights on the sequence of structural events that occur in the nonclassical secretion of FGF1. PMID:25224745

Breast cancers with EGFR and HER2 co-amplification favor distant metastasis and poor clinical outcome

PubMed Central

Guo, Peng; Pu, Tianjie; Chen, Shinan; Qiu, Yan; Zhong, Xiaorong; Zheng, Hong; Chen, Lina; Bu, Hong; Ye, Feng

2017-01-01

ErbB signaling serves essential roles in invasive ductal carcinoma (IDC). The aim of the present study was to assess gene amplification in ErbB family members in IDC with clinical implications. Quantitative polymerase chain reaction and fluorescence in situ hybridization were performed on formalin-fixed paraffin-embedded tumor samples for gene amplification detection. The clinical and histopathological characteristics, as well as the prognostic significance, were analyzed. Among the 119 IDC patients evaluated, epidermal growth factor receptor [EGFR; also known as human epidermal growth factor receptor (HER)1], HER2, HER3 and HER4 gene amplification was observed in 30 (25.2%), 44 (36.9%), 0 (0.0%) and 1 (0.8%) patients, respectively. EGFR amplification was associated with estrogen receptor status (P=0.028) and higher possibilities of recurrence (P=0.015) and distant metastasis (following initial surgery) (P=0.011). In survival analysis, EGFR amplification was also associated with disease-free survival (DFS) (P=0.001) and overall survival (OS) (P=0.003). HER2 amplification was associated with larger tumor size (P=0.006), later clinical stage (P=0.003) and distant metastasis (following initial surgery) (P=0.006). In survival analysis, HER2 amplification was also associated with DFS (P=0.011). Notably, the present study identified a group of patients in whom EGFR and HER2 were co-amplified. This group of patients appeared to have a higher possibility of metastasis (when diagnosed) (P=0.014) and distant metastasis (following initial surgery) (P<0.001). In survival analysis, these patients were noticed to be associated with DFS (P<0.001) and OS (P=0.002). With respect to treatment regimen, this was also true for the DFS association with chemotherapy (P<0.001), radiotherapy (P<0.001) and hormonal therapy (P=0.001). The present results suggest that EGFR and HER2 amplification favor distant metastasis following initial surgery and are significantly associated with poor clinical outcome in breast cancer patients. PMID:29181099

Modified Cisplatin/Interferon α-2b/Doxorubicin/Fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability and survival of initially unresectable hepatocellular carcinoma

PubMed Central

Kaseb, Ahmed O.; Shindoh, Junichi; Patt, Yehuda Z.; Roses, Robert E.; Zimmitti, Giuseppe; Lozano, Richard D.; Hassan, Manal M.; Hassabo, Hesham M.; Curley, Steven A.; Aloia, Thomas A.; Abbruzzese, James L.; Vauthey, Jean-Nicolas

2013-01-01

Purpose The purposes of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-flurouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma (HCC). Patients and Methods The study included two groups of patients treated with conventional high-dose PIAF (n=84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n=33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the two groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival. Results The modified PIAF group had a higher median number of PIAF cycles (4 vs. 2, P = .049), higher objective response rate (36% vs. 15%, P = .013), higher rate of conversion to curative surgery (33% vs. 10%, P = .004), and longer median overall survival (21.3 vs. 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR], 1.68; 95% CI, 1.08 to 2.59) and Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.75; 95% CI 1.04 to 2.93) were associated with worse survival while curative surgical resection after PIAF treatment (HR, 0.15; 95% CI, 0.07 to 0.35) was associated with improved survival. Conclusions In patients with initially unresectable HCC, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival. PMID:23821538

Divergent Functions of orthologous NAC Transcription Factors in Wheat and Rice

PubMed Central

Distelfeld, Assaf; Pearce, Stephen P.; Avni, Raz; Scherer, Beatrice; Uauy, Cristobal; Piston, Fernando; Slade, Ann; Zhao, Rongrong; Dubcovsky, Jorge

2016-01-01

The wheat GPC-B1 gene located on chromosome 6B is an early regulator of senescence and affects remobilization of protein and minerals to the grain. GPC-B1 is a NAC transcription factor and has a paralogous copy on chromosome 2B in tetraploid wheat, GPC-B2. The closest rice homolog to both wheat GPC genes is Os07g37920 which is located on rice chromosome 2 and is colinear with GPC-B2. Since rice is a diploid species with a sequenced genome, we initiated the study of Os07g37920 to develop a simpler model to study senescence and mineral remobilization in cereals. We developed eleven independent RNA interference transgenic rice lines (Os07g37920-RNAi) and 10 over-expressing transgenic lines (Os07g37920-OE), but none of them showed differences in senescence. Transgenic Os07g37920-RNAi rice plants had reduced proportions of viable pollen grains and were male-sterile, but were able to produce seeds by cross pollination. Analysis of the flower morphology of the transgenic rice plants showed that anthers failed to dehisce. Transgenic Os07g37920-OE lines showed no sterility or anther dehiscence problems. Os07g37920 transcript levels were higher in stamens compared to leaves and significantly reduced in the transgenic Os07g37920-RNAi plants. Wheat GPC genes showed the opposite transcription profile (higher transcript levels in leaves than in flowers) and plants carrying knock-out mutations of all GPC-1 and GPC-2 genes exhibited delayed senescence but normal anther dehiscence and fertility. These results indicate a functional divergence of the homologous wheat and rice NAC genes and suggest the need for separate studies of the function and targets of these transcription factors in wheat and rice. PMID:22278768

Optimization of photocatalytic degradation of palm oil mill effluent in UV/ZnO system based on response surface methodology.

PubMed

Ng, Kim Hoong; Cheng, Yoke Wang; Khan, Maksudur R; Cheng, Chin Kui

2016-12-15

This paper reports on the optimization of palm oil mill effluent (POME) degradation in a UV-activated-ZnO system based on central composite design (CCD) in response surface methodology (RSM). Three potential factors, viz. O 2 flowrate (A), ZnO loading (B) and initial concentration of POME (C) were evaluated for the significance analysis using a 2 3 full factorial design before the optimization process. It is found that all the three main factors were significant, with contributions of 58.27% (A), 15.96% (B) and 13.85% (C), respectively, to the POME degradation. In addition, the interactions between the factors AB, AC and BC also have contributed 4.02%, 3.12% and 1.01% to the POME degradation. Subsequently, all the three factors were subjected to statistical central composite design (CCD) analysis. Quadratic models were developed and rigorously checked. A 3D-response surface was subsequently generated. Two successive validation experiments were carried out and the degradation achieved were 55.25 and 55.33%, contrasted with 52.45% for predicted degradation value. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hybrid Silver Mesh Electrode for ITO-Free Flexible Polymer Solar Cells with Good Mechanical Stability.

PubMed

Kim, Wanjung; Kim, Soyeon; Kang, Iljoong; Jung, Myung Sun; Kim, Sung June; Kim, Jung Kyu; Cho, Sung Min; Kim, Jung-Hyun; Park, Jong Hyeok

2016-05-10

Herein, we report a tailored Ag mesh electrode coated with poly(3,4-ethylenedioxythiophene) (PEDOT) polymer on a flexible polyethylene terephthalate (PET) substrate. The introduction of this highly conductive polymer solves the existing problems of Ag mesh-type transparent conductive electrodes, such as high pitch, roughness, current inhomogeneity, and adhesion problems between the Ag mesh grid and PEDOT polymer or PET substrate, to result in excellent electron spreading from the discrete Ag mesh onto the entire surface without sacrificing sheet conductivity and optical transparency. Based on this hybrid anode, we demonstrate highly efficient flexible polymer solar cells (PSCs) with a high fill factor of 67.11 %, which results in a power conversion efficiency (PCE) of 6.9 % based on a poly({4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b'] dithiophene-2,6-diyl}{3-fluoro-2-[(2-ethylhexyl) carbonyl]thieno[3,4-b]thiophenediyl}):[6,6]-phenyl-C71 -butyric acid methyl ester bulk heterojunction device. Furthermore, the PSC device with the Ag mesh electrode also exhibits a good mechanical bending stability, as indicated by a 70 % retention of the initial PCE after 500 bending cycles compared with the PSC device with a PET/indium tin oxide electrode, which retained 0 % of the initial PCE after 300 bending cycles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Burkholderia gladioli sepsis in newborns.

PubMed

Dursun, Arzu; Zenciroglu, Aysegul; Karagol, Belma Saygili; Hakan, Nilay; Okumus, Nurullah; Gol, Nese; Tanir, Gonul

2012-10-01

Burkholderia gladioli is a rare cause of bacteremia and sepsis in the absence of such predisposing factors as chronic granulomatous disease, cystic fibrosis, and immunosuppression. Little is known about B. gladioli infection in newborns. The aim of this study was to present the features of B. gladioli infection in newborns. Clinicopathological characteristics, patterns of antimicrobial susceptibility, predisposing factors, and outcomes of B. gladioli bloodstream infection were retrospectively analyzed in newborns treated between 2008 and 2011. During the 3-year study period, B. gladioli was isolated from the blood cultures of 14 patients (3.7 per 1,000 admissions). In all, 5 (35.7 %) of the 14 cases had a positive blood culture at the time of initial admission. Primary diagnoses in the neonates were severe major congenital anomalies, congenital leukemia, prematurity with respiratory distress syndrome, pneumonia, and parapneumonic pleural effusion. In total, 10 (71.4 %) of the patients underwent ≥2 invasive procedures. The overall in-hospital mortality rate was 21.4 %, whereas the mortality rate due to B. gladioli infection was 7 %. B. gladioli might be a causative microorganism of both early neonatal and nosocomial sepsis in newborns. To the best of our knowledge, this is the first study on B. gladioli infection in newborns. Invasive procedures and severe major congenital anomalies may be predisposing factors for B. gladioli bloodstream infection in neonates. Although it appears to have low pathogenic potential and an insidious clinical course in newborns, resistance to antibiotics may be a potential problem. Mortality was primarily associated with underlying diseases.

Optimization of Maillard Reaction in Model System of Glucosamine and Cysteine Using Response Surface Methodology

PubMed Central

Arachchi, Shanika Jeewantha Thewarapperuma; Kim, Ye-Joo; Kim, Dae-Wook; Oh, Sang-Chul; Lee, Yang-Bong

2017-01-01

Sulfur-containing amino acids play important roles in good flavor generation in Maillard reaction of non-enzymatic browning, so aqueous model systems of glucosamine and cysteine were studied to investigate the effects of reaction temperature, initial pH, reaction time, and concentration ratio of glucosamine and cysteine. Response surface methodology was applied to optimize the independent reaction parameters of cysteine and glucosamine in Maillard reaction. Box-Behnken factorial design was used with 30 runs of 16 factorial levels, 8 axial levels and 6 central levels. The degree of Maillard reaction was determined by reading absorption at 425 nm in a spectrophotometer and Hunter’s L, a, and b values. ΔE was consequently set as the fifth response factor. In the statistical analyses, determination coefficients (R2) for their absorbance, Hunter’s L, a, b values, and ΔE were 0.94, 0.79, 0.73, 0.96, and 0.79, respectively, showing that the absorbance and Hunter’s b value were good dependent variables for this model system. The optimum processing parameters were determined to yield glucosamine-cysteine Maillard reaction product with higher absorbance and higher colour change. The optimum estimated absorbance was achieved at the condition of initial pH 8.0, 111°C reaction temperature, 2.47 h reaction time, and 1.30 concentration ratio. The optimum condition for colour change measured by Hunter’s b value was 2.41 h reaction time, 114°C reaction temperature, initial pH 8.3, and 1.26 concentration ratio. These results can provide the basic information for Maillard reaction of aqueous model system between glucosamine and cysteine. PMID:28401086

Optimization of Maillard Reaction in Model System of Glucosamine and Cysteine Using Response Surface Methodology.

PubMed

Arachchi, Shanika Jeewantha Thewarapperuma; Kim, Ye-Joo; Kim, Dae-Wook; Oh, Sang-Chul; Lee, Yang-Bong

2017-03-01

Sulfur-containing amino acids play important roles in good flavor generation in Maillard reaction of non-enzymatic browning, so aqueous model systems of glucosamine and cysteine were studied to investigate the effects of reaction temperature, initial pH, reaction time, and concentration ratio of glucosamine and cysteine. Response surface methodology was applied to optimize the independent reaction parameters of cysteine and glucosamine in Maillard reaction. Box-Behnken factorial design was used with 30 runs of 16 factorial levels, 8 axial levels and 6 central levels. The degree of Maillard reaction was determined by reading absorption at 425 nm in a spectrophotometer and Hunter's L, a, and b values. ΔE was consequently set as the fifth response factor. In the statistical analyses, determination coefficients (R 2 ) for their absorbance, Hunter's L, a, b values, and ΔE were 0.94, 0.79, 0.73, 0.96, and 0.79, respectively, showing that the absorbance and Hunter's b value were good dependent variables for this model system. The optimum processing parameters were determined to yield glucosamine-cysteine Maillard reaction product with higher absorbance and higher colour change. The optimum estimated absorbance was achieved at the condition of initial pH 8.0, 111°C reaction temperature, 2.47 h reaction time, and 1.30 concentration ratio. The optimum condition for colour change measured by Hunter's b value was 2.41 h reaction time, 114°C reaction temperature, initial pH 8.3, and 1.26 concentration ratio. These results can provide the basic information for Maillard reaction of aqueous model system between glucosamine and cysteine.

Patterns of growth factor usage and febrile neutropenia among older patients with diffuse large B-cell non-Hodgkin lymphoma treated with CHOP or R-CHOP: the Intergroup experience (CALGB 9793; ECOG-SWOG 4494).

PubMed

Morrison, Vicki A; Weller, Edie A; Habermann, Thomas M; Li, Shuli; Fisher, Richard I; Cheson, Bruce D; Peterson, Bruce A

2017-08-01

Patterns of myeloid growth factor (GF) usage and febrile neutropenia (FN) were examined in patients >60 years of age with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) enrolled on CALGB 9793/ECOG-SWOG 4494, receiving initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab + CHOP (R-CHOP). Myeloid GFs were administered to 256/520 (49%) patients. Indications for use were: prevent dose reduction/dose delay (81%, 207/256); treat FN or non-febrile neutropenia (NFN) (19%, 48/256). One or more FN episodes occurred in 41% (212/520) of patients, with FN most often in cycle 1 (38% of episodes). In multivariate analysis, risk factors for FN included age >65 years (odds ratio (OR) = 2.6, 95% CI: [1.4, 4.9]) and anemia (hemoglobin <12 g/dl) (OR =2.2, 95% confidence intervals (CI): [1.4, 3.5]. Myeloid GF use was common in this older DLBCL population receiving CHOP-based therapy, as was FN, especially during cycle one. Risk factors predictive for FN should be used prospectively to identify patients for whom myeloid GFs are best utilized.

Appropriate insulin initiation dosage for insulin-naive type 2 diabetes outpatients receiving insulin monotherapy or in combination with metformin and/or pioglitazone.

PubMed

Liao, Lin; Yang, Ming; Qiu, Lu-Lu; Mou, Ya-Ru; Zhao, Jia-Jun; Dong, Jian-Jun

2010-12-01

Few studies have given suggestions on appropriate initiation insulin dosage when combined with oral antidiabetic drugs (OADs). This research was to investigate appropriate initiation insulin doses for insulin-naive type 2 diabetes patients with different combinations and the relationship between insulin dosage and relevant factors. This was a randomized, open-label, treat to target study. The target was 20% decrease of both fasting plasma glucose (FPG) and 2 hours post-breakfast blood glucose (P2hBG). One hundred and forty-seven insulin-naive Chinese patients recruited were randomly assigned to 3 groups: group A, patients received insulin monotherapy; group B, received insulin plus metformin (0.5 g, tid) and group C, received insulin plus metformin (0.5 g, tid) and pioglitazone (15 mg, qd). Insulin doses were initiated with a dose of 0.3 U×kg(-1)×d(-1) and titrated according to FPG and P2hBG till reached the targets. Both the time of getting 20% reduction of FPG and P2hBG showed significant differences among the three groups. The time was shortest in Group C. The insulin doses needed to achieve glucose reduction of 20% in three treatment groups were (0.40 ± 0.04) U×kg(-1)×d(-1) for Group A, (0.37 ± 0.04) U×kg(-1)×d(-1) for Group B, and (0.35 ± 0.03) U×kg(-1)×d(-1) for Group C, respectively. Multiple linear stepwise regression analysis showed that insulin doses correlated with body weight, FPG, diabetes duration, age and history of sulfonylurea treatment. The standardized regression coefficients were 0.871, 0.322, 0.089, 0.067 and 0.063 (with all P < 0.05). To achieve blood glucose's reduction of 20% within safety context, initial insulin doses were recommended as the following: 0.40 U×kg(-1)×d(-1) for insulin mono-therapy, 0.37 U×kg(-1)×d(-1) for insulin plus metformin treatment, and 0.35 U×kg(-1)×d(-1) for insulin plus metformin and pioglitazone treatment in Chinese type 2 diabetes outpatients. Body weight is found the most closely related factor to the insulin dosage.

Impedimetric aptasensor for nuclear factor kappa B with peroxidase-like mimic coupled DNA nanoladders as enhancer.

PubMed

Peng, Kanfu; Zhao, Hongwen; Xie, Pan; Hu, Shuang; Yuan, Yali; Yuan, Ruo; Wu, Xiongfei

2016-07-15

In this work, we developed a sensitive and universal aptasensor for nuclear factor kappa B (NF-κB) detection based on peroxidase-like mimic coupled DNA nanoladders for signal amplification. The dsDNA formed by capture DNA S1 and NF-κB binding aptamer (NBA) was firstly assembled on electrode surface. The presence of target NF-κB then led to the leave of NBA from electrode surface and thus provided the binding sites for immobilizing initiator to trigger in situ formation of DNA nanoladders on electrode surface. Since the peroxidase-like mimic manganese (III) meso-tetrakis (4-Nmethylpyridyl)-porphyrin (MnTMPyP) interacts with DNA nanoladders via groove binding, the insoluble benzo-4-chlorohexadienone (4-CD) precipitation derived from the oxidation of 4-chloro-1-naphthol (4-CN) could be formed on electrode surface in the presence of H2O2, resulting in a significantly amplified EIS signal output for quantitative target analysis. As a result, the developed aptasensor showed a low detection limit of 7pM and a wide linear range of 0.01-20nM. Featured with high sensitivity and label-free capability, the proposed sensing scheme can thus offer new opportunities for achieving sensitive, selective and stable detection of different types of target proteins. Copyright © 2016 Elsevier B.V. All rights reserved.

Sensory polyneuropathy in human immunodeficiency virus-infected patients receiving tuberculosis treatment.

PubMed

Centner, C M; Carrara, H; Harrison, T B; Benatar, M; Heckmann, J M

2014-01-01

Human immunodeficiency virus (HIV) infection and treatments for HIV infection and tuberculosis (TB) are associated with the risk of developing sensory polyneuropathy (SPN). Vitamin B6 and genetically determined slow isoniazid (INH) acetylation are believed to play key roles in the development of SPN in a TB treatment setting. To investigate slow acetylation and risk factors for SPN in HIV-infected patients receiving TB treatment, and establish vitamin B6 status and its association with SPN. HIV-infected in-patients were prospectively assessed after initiating TB treatment and vitamin B6 supplementation, and monthly during hospitalisation. SPN was defined as ≥1 symptom plus ≥1 sign. NAT2 genotyping predicted acetylation status, and plasma high performance liquid chromatography estimated vitamin B6 status. A survival analysis estimated hazard ratios (HRs) for SPN during TB treatment. Of 116 participants, 56% had SPN at study entry. Participants developed SPN at a rate of 26/100 person-months (95%CI 18-35) during TB treatment, which was independently associated with slow acetylation (HR 2.5; 95%CI 1.1-5.9), as well as black race, previous TB and extra-pulmonary/disseminated TB. Vitamin B6 status was normal, irrespective of SPN. Risk factors for SPN suggest a multi-factorial pathogenesis related to INH and other potential nervous system insults. SPN developed despite normal vitamin B6 status, suggesting other mechanisms of injury.

Characterization of Transcription from TATA-Less Promoters: Identification of a New Core Promoter Element XCPE2 and Analysis of Factor Requirements

PubMed Central

Anish, Ramakrishnan; Hossain, Mohammad B.; Jacobson, Raymond H.; Takada, Shinako

2009-01-01

Background More than 80% of mammalian protein-coding genes are driven by TATA-less promoters which often show multiple transcriptional start sites (TSSs). However, little is known about the core promoter DNA sequences or mechanisms of transcriptional initiation for this class of promoters. Methodology/Principal Findings Here we identify a new core promoter element XCPE2 (X core promoter element 2) (consensus sequence: A/C/G-C-C/T-C-G/A-T-T-G/A-C-C/A+1-C/T) that can direct specific transcription from the second TSS of hepatitis B virus X gene mRNA. XCPE2 sequences can also be found in human promoter regions and typically appear to drive one of the start sites within multiple TSS-containing TATA-less promoters. To gain insight into mechanisms of transcriptional initiation from this class of promoters, we examined requirements of several general transcription factors by in vitro transcription experiments using immunodepleted nuclear extracts and purified factors. Our results show that XCPE2-driven transcription uses at least TFIIB, either TFIID or free TBP, RNA polymerase II (RNA pol II) and the MED26-containing mediator complex but not Gcn5. Therefore, XCPE2-driven transcription can be carried out by a mechanism which differs from previously described TAF-dependent mechanisms for initiator (Inr)- or downstream promoter element (DPE)-containing promoters, the TBP- and SAGA (Spt-Ada-Gcn5-acetyltransferase)-dependent mechanism for yeast TATA-containing promoters, or the TFTC (TBP-free-TAF-containing complex)-dependent mechanism for certain Inr-containing TATA-less promoters. EMSA assays using XCPE2 promoter and purified factors further suggest that XCPE2 promoter recognition requires a set of factors different from those for TATA box, Inr, or DPE promoter recognition. Conclusions/Significance We identified a new core promoter element XCPE2 that are found in multiple TSS-containing TATA-less promoters. Mechanisms of promoter recognition and transcriptional initiation for XCPE2-driven promoters appear different from previously shown mechanisms for classical promoters that show single “focused” TSSs. Our studies provide insight into novel mechanisms of RNA Pol II transcription from multiple TSS-containing TATA-less promoters. PMID:19337366

Factors Related to Breastfeeding Discontinuation Between Hospital Discharge and 2 Weeks Postpartum

PubMed Central

Brand, Elizabeth; Kothari, Catherine; Stark, Mary Ann

2011-01-01

Although breastfeeding is known to be beneficial to both mother and infant, many women encounter barriers to breastfeeding, even after successful breastfeeding initiation, which may put them at greater risk for early cessation of breastfeeding. The objectives of this study were to conduct a secondary analysis of data from a longitudinal study of postpartum depression to (a) examine factors related to very early discontinuation of breastfeeding (at 2 weeks postpartum) following hospital discharge and (b) identify women’s reasons for very early cessation of breastfeeding. The results of this study support findings from previous research. Having a perceived support system, whether it is personal or professional, may have an effect on both the initiation and duration of breastfeeding. Educating expectant and new mothers, especially women who encounter multiple barriers and are at risk for very early cessation of breastfeeding, of the benefits of breastfeeding and supporting them in developing efficient techniques and problem-solving skills can help increase the duration of breastfeeding. PMID:22211058

Can Non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes?

PubMed

Steck, Andrea K; Xu, Ping; Geyer, Susan; Redondo, Maria J; Antinozzi, Peter; Wentworth, John M; Sosenko, Jay; Onengut-Gumuscu, Suna; Chen, Wei-Min; Rich, Stephen S; Pugliese, Alberto

2017-08-01

Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-human leukocyte antigens (non-HLA) loci. The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression. The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Abs) and T1D. Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1016 Ab-positive, at-risk non-Hispanic white relatives. Effect of SNPs on the development of multiple Abs and T1D. Cox proportional analyses included all substantial non-HLA SNPs, HLA genotypes, relationship to proband, sex, age at initial screening, initial Ab type, and number. Factors involved in progression from single to multiple Abs included age at screening, relationship to proband, HLA genotypes, and rs3087243 (cytotoxic T lymphocyte antigen-4). Significant factors for diabetes progression included age at screening, Ab number, HLA genotypes, rs6476839 [GLIS family zinc finger 3 (GLIS3)], and rs3184504 [SH2B adaptor protein 3 (SH2B3)]. When glucose area under the curve (AUC) was included, factors involved in disease progression included glucose AUC, age at screening, Ab number, relationship to proband, HLA genotypes, rs6476839 (GLIS3), and rs7221109 (CCR7). In stratified analyses by age, glucose AUC, age at screening, sibling, HLA genotypes, rs6476839 (GLIS3), and rs4900384 (C14orf64) were significantly associated with progression to diabetes in participants <12 years old, whereas glucose AUC, sibling, rs3184504 (SH2B3), and rs4900384 (C14orf64) were significant in those ≥12. In conclusion, we identified five non-HLA SNPs associated with increased risk of progression from Ab positivity to disease that may improve risk stratification for prevention trials. Copyright © 2017 by the Endocrine Society

Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology

PubMed Central

Dey, Aditi; Castleton, Anna Z.; Schwab, Claire; Samuel, Edward; Sivakumaran, Janani; Beaton, Brendan; Zareian, Nahid; Zhang, Christie Yu; Rai, Lena; Enver, Tariq; Moorman, Anthony V.; Fielding, Adele K.

2014-01-01

The distinct nature of acute lymphoblastic leukemia (ALL) in adults, evidenced by inferior treatment outcome and different genetic landscape, mandates specific studies of disease-initiating mechanisms. In this study, we used NOD/LtSz-scid IL2Rγ nullc (NSG) mouse xenotransplantation approaches to elucidate leukemia-initiating cell (LIC) biology in primary adult precursor B (pre-B) ALL to optimize disease modeling. In contrast with xenografting studies of pediatric ALL, we found that modification of the NSG host environment using preconditioning total body irradiation (TBI) was indispensable for efficient engraftment of adult non-t(4;11) pre-B ALL, whereas t(4;11) pre-B ALL was successfully reconstituted without this adaptation. Furthermore, TBI-based xenotransplantation of non-t(4;11) pre-B ALL enabled detection of a high frequency of LICs (<1:6900) and permitted frank leukemic engraftment from a remission sample containing drug-resistant minimal residual disease. Investigation of TBI-sensitive stromal-derived factor-1/chemokine receptor type 4 signaling revealed greater functional dependence of non-t(4;11) pre-B ALL on this niche-based interaction, providing a possible basis for the differential engraftment behavior. Thus, our studies establish the optimal conditions for experimental modeling of human adult pre-B ALL and demonstrate the critical protumorogenic role of microenvironment-derived SDF-1 in regulating adult pre-B LIC activity that may present a therapeutic opportunity. PMID:24825861

Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling

PubMed Central

Tan, Xiang-Lin; Bhattacharyya, Kalyan K.; Dutta, Shamit K.; Bamlet, William R.; Rabe, Kari G.; Wang, Enfeng; Smyrk, Thomas C.; Oberg, Ann L.; Petersen, Gloria M.; Mukhopadhyay, Debabrata

2015-01-01

Objectives To further elucidate anti-cancer mechanisms of metformin again pancreatic cancer, we evaluated inhibitory effects of metformin on pancreatic tumorigenesis in a genetically-engineered mouse model, and investigated its possible anti-inflammatory and anti-angiogenesis effects. Methods Six-week old LSL-KrasG12D/+;Trp53F2-10 mice (10 per group) were administered once daily intraperitoneally with saline (control) for one week or metformin (125 mg/kg) for one week (Met_1wk) or three weeks (Met_3wk) prior to tumor initiation. All mice continued with their respective injections for six weeks post-tumor initiation. Molecular changes were evaluated by quantitative polymerase chain reaction (PCR), immunohistochemistry, and Western blotting. Results At euthanasia, pancreatic tumor volume in Met_1wk (median, 181.8 mm3) and Met_3wk (median, 137.9 mm3) groups was significantly lower than the control group (median, 481.1 mm3) (P = 0.001 and 0.0009, respectively). No significant difference was observed between Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB (NFκB) and signal transducer and activator of transcription 3 (STAT3) as well as the expression of Sp1 transcription factor and several NFκB-regulated genes. Conclusions Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways. PMID:25875801

Strong minor groove base conservation in sequence logos implies DNA distortion or base flipping during replication and transcription initiation.

PubMed

Schneider, T D

2001-12-01

The sequence logo for DNA binding sites of the bacteriophage P1 replication protein RepA shows unusually high sequence conservation ( approximately 2 bits) at a minor groove that faces RepA. However, B-form DNA can support only 1 bit of sequence conservation via contacts into the minor groove. The high conservation in RepA sites therefore implies a distorted DNA helix with direct or indirect contacts to the protein. Here I show that a high minor groove conservation signature also appears in sequence logos of sites for other replication origin binding proteins (Rts1, DnaA, P4 alpha, EBNA1, ORC) and promoter binding proteins (sigma(70), sigma(D) factors). This finding implies that DNA binding proteins generally use non-B-form DNA distortion such as base flipping to initiate replication and transcription.

Applying Central Composite Design and Response Surface Methodology to Optimize Growth and Biomass Production of Haemophilus influenzae Type b.

PubMed

Momen, Seyed Bahman; Siadat, Seyed Davar; Akbari, Neda; Ranjbar, Bijan; Khajeh, Khosro

2016-06-01

Haemophilus influenzae type b (Hib) is the leading cause of bacterial meningitis, otitis media, pneumonia, cellulitis, bacteremia, and septic arthritis in infants and young children. The Hib capsule contains the major virulence factor, and is composed of polyribosyl ribitol phosphate (PRP) that can induce immune system response. Vaccines consisting of Hib capsular polysaccharide (PRP) conjugated to a carrier protein are effective in the prevention of the infections. However, due to costly processes in PRP production, these vaccines are too expensive. To enhance biomass, in this research we focused on optimizing Hib growth with respect to physical factors such as pH, temperature, and agitation by using a response surface methodology (RSM). We employed a central composite design (CCD) and a response surface methodology to determine the optimum cultivation conditions for growth and biomass production of H. influenzae type b. The treatment factors investigated were initial pH, agitation, and temperature, using shaking flasks. After Hib cultivation and determination of dry biomass, analysis of experimental data was performed by the RSM-CCD. The model showed that temperature and pH had an interactive effect on Hib biomass production. The dry biomass produced in shaking flasks was about 5470 mg/L, which was under an initial pH of 8.5, at 250 rpm and 35° C. We found CCD and RSM very effective in optimizing Hib culture conditions, and Hib biomass production was greatly influenced by pH and incubation temperature. Therefore, optimization of the growth factors to maximize Hib production can lead to 1) an increase in bacterial biomass and PRP productions, 2) lower vaccine prices, 3) vaccination of more susceptible populations, and 4) lower risk of Hib infections.

Surface association and the MreB cytoskeleton regulate pilus production, localization and function in Pseudomonas aeruginosa.

PubMed

Cowles, Kimberly N; Gitai, Zemer

2010-06-01

Spatial organization of bacterial proteins influences many cellular processes, including division, chromosome segregation and motility. Virulence-associated proteins also localize to specific destinations within bacterial cells. However, the functions and mechanisms of virulence factor localization remain largely unknown. In this work, we demonstrate that polar assembly of the Pseudomonas aeruginosa PAO1 type IV pilus is regulated by surface association in a manner that affects gene transcription, protein levels and protein localization. We also uncover one mechanism for this regulation that acts through the actin homologue MreB. Inactivation of MreB leads to mislocalization of the pilus retraction ATPase PilT, mislocalization of the pili themselves and a reduction in motility. Furthermore, the role of MreB in polar localization of PilT is modulated by surface association, corroborating our results that environmental factors influence the regulation of pilus production. Specifically, MreB mediates both the initiation and maintenance of PilT localization when cells are grown in suspension but only affects the initiation of localization when cells are grown on a surface. Together, these results suggest that the bacterial cytoskeleton provides a mechanism for the polar localization of P. aeruginosa pili and demonstrate that protein localization may represent an important aspect of virulence factor regulation in bacterial pathogens.

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

PubMed Central

Gu, Zhaohui; Churchman, Michelle; Roberts, Kathryn; Li, Yongjin; Liu, Yu; Harvey, Richard C.; McCastlain, Kelly; Reshmi, Shalini C.; Payne-Turner, Debbie; Iacobucci, Ilaria; Shao, Ying; Chen, I-Ming; Valentine, Marcus; Pei, Deqing; Mungall, Karen L.; Mungall, Andrew J.; Ma, Yussanne; Moore, Richard; Marra, Marco; Stonerock, Eileen; Gastier-Foster, Julie M.; Devidas, Meenakshi; Dai, Yunfeng; Wood, Brent; Borowitz, Michael; Larsen, Eric E.; Maloney, Kelly; Mattano Jr, Leonard A.; Angiolillo, Anne; Salzer, Wanda L.; Burke, Michael J.; Gianni, Francesca; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Moorman, Anthony V.; Patel, Bella; Fielding, Adele K.; Rowe, Jacob M.; Luger, Selina M.; Bhatia, Ravi; Aldoss, Ibrahim; Forman, Stephen J.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M.; Konopleva, Marina; Paietta, Elisabeth; Willman, Cheryl L.; L. Loh, Mignon; P. Hunger, Stephen; Mullighan, Charles G.

2016-01-01

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. PMID:27824051

Mouse model for acute Epstein-Barr virus infection.

PubMed

Wirtz, Tristan; Weber, Timm; Kracker, Sven; Sommermann, Thomas; Rajewsky, Klaus; Yasuda, Tomoharu

2016-11-29

Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.

High Power Microwave Tube Reliability Study

DTIC Science & Technology

1976-08-01

Factors . . . . . ................ 67 1. Environmental Factors . . . . . . . . . a. Ground Fixed ...... .......... 67 b. Ground Mobile ...including cube structure and operating parameters as factors in the models but also environment and aplication . Initially, the tubes to be included in...instLllations. Mobile ground based and seagoing systems have minimum restrictions, spacecraft systems the maximum and airborne system Y 6 .*.. restrictionts

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

PubMed Central

Gao, Lu; Rabbitt, Elizabeth H.; Condon, Jennifer C.; Renthal, Nora E.; Johnston, John M.; Mitsche, Matthew A.; Chambon, Pierre; Xu, Jianming; O’Malley, Bert W.; Mendelson, Carole R.

2015-01-01

The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A–deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2–deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2–deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2–deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2–dependent production of SP-A and PAF is crucial for this process. PMID:26098214

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition.

PubMed

Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C; Renthal, Nora E; Johnston, John M; Mitsche, Matthew A; Chambon, Pierre; Xu, Jianming; O'Malley, Bert W; Mendelson, Carole R

2015-07-01

The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A-deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2-deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2-deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2-deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2-dependent production of SP-A and PAF is crucial for this process.

Prediction of hearing outcomes by multiple regression analysis in patients with idiopathic sudden sensorineural hearing loss.

PubMed

Suzuki, Hideaki; Tabata, Takahisa; Koizumi, Hiroki; Hohchi, Nobusuke; Takeuchi, Shoko; Kitamura, Takuro; Fujino, Yoshihisa; Ohbuchi, Toyoaki

2014-12-01

This study aimed to create a multiple regression model for predicting hearing outcomes of idiopathic sudden sensorineural hearing loss (ISSNHL). The participants were 205 consecutive patients (205 ears) with ISSNHL (hearing level ≥ 40 dB, interval between onset and treatment ≤ 30 days). They received systemic steroid administration combined with intratympanic steroid injection. Data were examined by simple and multiple regression analyses. Three hearing indices (percentage hearing improvement, hearing gain, and posttreatment hearing level [HLpost]) and 7 prognostic factors (age, days from onset to treatment, initial hearing level, initial hearing level at low frequencies, initial hearing level at high frequencies, presence of vertigo, and contralateral hearing level) were included in the multiple regression analysis as dependent and explanatory variables, respectively. In the simple regression analysis, the percentage hearing improvement, hearing gain, and HLpost showed significant correlation with 2, 5, and 6 of the 7 prognostic factors, respectively. The multiple correlation coefficients were 0.396, 0.503, and 0.714 for the percentage hearing improvement, hearing gain, and HLpost, respectively. Predicted values of HLpost calculated by the multiple regression equation were reliable with 70% probability with a 40-dB-width prediction interval. Prediction of HLpost by the multiple regression model may be useful to estimate the hearing prognosis of ISSNHL. © The Author(s) 2014.

Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

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

Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira

Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcriptionmore » elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. - Highlights: • Cocaine induces the initiation phase of HIV transcription by activating NF-ĸB. • Cocaine induced NF-ĸB phosphorylation promotes its interaction with P300. • Cocaine enhances the elongation phase of HIV transcription by stimulating MSK1. • Cocaine activated MSK1 catalyzes the phosphorylation of histone H3 at its Ser10. • Cocaine induced H3S10 phosphorylation facilitates the recruitment of P-TEFb at LTR.« less

Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review

PubMed Central

Canestaro, William J.; Austin, Melissa A.; Thummel, Kenneth E.

2015-01-01

Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1. PMID:24810685

Correlates of adherence to a telephone-based multiple health behavior change cancer preventive intervention for teens: the Healthy for Life Program (HELP).

PubMed

Mays, Darren; Peshkin, Beth N; Sharff, McKane E; Walker, Leslie R; Abraham, Anisha A; Hawkins, Kirsten B; Tercyak, Kenneth P

2012-02-01

This study examined factors associated with teens' adherence to a multiple health behavior cancer preventive intervention. Analyses identified predictors of trial enrollment, run-in completion, and adherence (intervention initiation, number of sessions completed). Of 104 teens screened, 73% (n = 76) were trial eligible. White teens were more likely to enroll than non-Whites (χ(2)[1] df = 4.49, p = .04). Among enrolled teens, 76% (n = 50) completed the run-in; there were no differences between run-in completers and noncompleters. A majority of run-in completers (70%, n = 35) initiated the intervention, though teens who initiated the intervention were significantly younger than those who did not (p < .05). The mean number of sessions completed was 5.7 (SD = 2.6; maximum = 8). After adjusting for age, teens with poorer session engagement (e.g., less cooperative) completed fewer sessions (B = -1.97, p = .003, R (2) = .24). Implications for adolescent cancer prevention research are discussed.

Mining heart disease risk factors in clinical text with named entity recognition and distributional semantic models.

PubMed

Urbain, Jay

2015-12-01

We present the design, and analyze the performance of a multi-stage natural language processing system employing named entity recognition, Bayesian statistics, and rule logic to identify and characterize heart disease risk factor events in diabetic patients over time. The system was originally developed for the 2014 i2b2 Challenges in Natural Language in Clinical Data. The system's strengths included a high level of accuracy for identifying named entities associated with heart disease risk factor events. The system's primary weakness was due to inaccuracies when characterizing the attributes of some events. For example, determining the relative time of an event with respect to the record date, whether an event is attributable to the patient's history or the patient's family history, and differentiating between current and prior smoking status. We believe these inaccuracies were due in large part to the lack of an effective approach for integrating context into our event detection model. To address these inaccuracies, we explore the addition of a distributional semantic model for characterizing contextual evidence of heart disease risk factor events. Using this semantic model, we raise our initial 2014 i2b2 Challenges in Natural Language of Clinical data F1 score of 0.838 to 0.890 and increased precision by 10.3% without use of any lexicons that might bias our results. Copyright © 2015 Elsevier Inc. All rights reserved.

A-B-C-1-2-3 Healthy Kids in Tennessee - Let's Eat Well, Play, and Be Aware Every Day: a preliminary report.

PubMed

Chafin, Cynthia; Edwards, M Jo; Morgan, Debbie; Isom, Pam; Morgan, Don

2012-01-01

The "A-B-C-1-2-3 Healthy Kids in Tennessee - Let's Eat Well, Play, and Be Aware Every Day" project is a hands-on educational program emphasizing healthy living that targets childcare providers, the children they care for, and their families. The program was initially implemented as a pilot project in 6 middle Tennessee childcare centers. Materials were organized and developed by the Middle Tennessee Cancer Coalition's childhood action team in conjunction with staff from Middle Tennessee State University (MTSU) Center for Health and Human Services and the MTSU Center for Physical Activity and Health in Youth. The A-B-C-1-2-3 initiative served as a feasibility project to inform the conduct of field operations. Through the MTSU Center for Physical Activity and Health in Youth, an expanded 12-week pilot program took place during 2010 in 2 childcare centers. The purpose of the program is to educate childcare providers who, in turn, educate children and their parents and promote healthy lifestyles and decrease the risk of developing cancer, obesity, and other lifestyle-associated diseases and health conditions. The overall goal of the project is to decrease lifestyle and environmental cancer risk factors among Tennesseans by 2012 as detailed in the 2009-2012 Tennessee Comprehensive Cancer Control Plan and to provide educational opportunities in healthy eating and healthy weight to childcare providers detailed in the 2010-2015 Tennessee Statewide Nutrition and Physical Activity Plan using a "train the trainer approach" along with classroom and family education. In 2012, the project will partner with a statewide Tennessee Department of Health initiative, Gold Sneakers, which provides a policy piece to the A-B-C-1-2-3 Healthy Kids in Tennessee's approach to disseminate nutritional and physical activity education to childcare providers, children, and their families, offering a full-circle approach to health promotion in a childcare setting.

Comparative evaluation of zinc oxide eugenol versus gelatin sponge soaked in plasma rich in growth factor in the treatment of dry socket: An initial study

PubMed Central

Pal, U. S.; Singh, Balendra Pratap; Verma, Vikas

2013-01-01

Purpose: The aim of this study was to report a comparison between the zinc oxide eugenol dressing and plasma rich in growth factor (PRGF) with gelatin sponge in the treatment of dry socket. Materials and Methods: This study comprised of 45 patients of dry socket in the span of one year. The patients were randomly divided into three groups on the basis of treatments: Group A (PRGF with gelatin sponge), group B (zinc oxide eugenol group), and group C (irrigation with sterile saline only). The clinical progress was noted at 1st, 2nd, 3rd, 7th, and 15th day after the treatment. Results: Patient's healing was better in group A than in group B but symptomatic pain relief was faster in group B. Group C fared worst in both aspects. Conclusion: We conclude that PRGF with gelatin sponge might be a treatment of choice in the management of dry socket. PMID:23853450

Involvement of Alpha-PAK-Interacting Exchange Factor in the PAK1–c-Jun NH2-Terminal Kinase 1 Activation and Apoptosis Induced by Benzo[a]pyrene

PubMed Central

Yoshii, Shigeto; Tanaka, Masamitsu; Otsuki, Yoshiro; Fujiyama, Toshiharu; Kataoka, Hideki; Arai, Hajime; Hanai, Hiroyuki; Sugimura, Haruhiko

2001-01-01

Benzo[a]pyrene [B(a)P], a potent procarcinogen found in combustion products such as diesel exhaust and cigarette smoke, has been recently shown to activate the c-Jun NH2-terminal kinase 1 (JNK1) and induce caspase-3-mediated apoptosis in Hepa1c1c7 cells. However, the molecules of the signaling pathway that control the mitogen-activated protein kinase cascades induced by B(a)P and the interaction between those and apoptosis by B(a)P have not been well defined. We report here that B(a)P promoted Cdc42/Rac1, p21-activated kinase 1 (PAK1), and JNK1 activities in 293T and HeLa cells. Moreover, alpha-PAK-interacting exchange factor (α PIX) mRNA and its protein expression were upregulated by B(a)P. While overexpression of an active mutant of α PIX (ΔCH) facilitated B(a)P-induced activation of Cdc42/Rac1, PAK1, and JNK1, overexpression of mutated αPIX (L383R, L384S), which lacks guanine nucleotide exchange factor activity, SH3 domain-deleted αPIX (Δ SH3), which lacks the ability to bind PAK, kinase-negative PAK1 (K299R), and kinase-negative SEK1 (K220A, K224L) inhibited B(a)P-triggered JNK1 activation. Interestingly, overexpression of αPIX (Δ CH) and a catalytically active mutant PAK1 (T423E) accelerated B(a)P-induced apoptosis in HeLa cells, whereas αPIX (Δ SH3), PAK1 (K299R), and SEK 1 (K220A, K224L) inhibited B(a)P-initiated apoptosis. Finally, a preferential caspase inhibitor, Z-Asp-CH2-DCB, strongly blocked the αPIX (Δ CH)-enhanced apoptosis in cells treated with B(a)P but did not block PAK1/JNK1 activation. Taken together, these results indicate that αPIX plays a crucial role in B(a)P-induced apoptosis through activation of the JNK1 pathway kinases. PMID:11564864

Fear Avoidance and Clinical Outcomes from Mild Traumatic Brain Injury.

PubMed

Silverberg, Noah D; Panenka, William; Iverson, Grant L

2018-04-18

Characterizing psychological factors that contribute to persistent symptoms after mild traumatic brain injury (MTBI) can inform early intervention. To determine whether fear avoidance, a known risk factor for chronic disability after musculoskeletal injury, is associated with worse clinical outcomes from MTBI, adults were recruited from four outpatient MTBI clinics and assessed at their first clinic visit (M=2.7, SD=1.5 weeks post-injury) and again 4-5 months later. Of 273 patients screened, 102 completed the initial assessment and 87 returned for the outcome assessment. The initial assessment included a battery of questionnaires that measure activity avoidance and associated fears. Endurance, an opposite behavior pattern, was measured with the Behavioral Response to Illness Questionnaire. The multidimensional outcome assessment included measures of post-concussion symptoms (British Columbia Postconcussion Symptom Inventory), functional disability (World Health Organization Disability Assessment Schedule-12 2.0), return to work status, and psychiatric complications (MINI Neuropsychiatric Interview). A single component was retained from principal components analysis of the six avoidance subscales. In generalized linear modeling, the avoidance composite score predicted symptom severity (95% confidence interval [CI] for B= 1.22-6.33) and disability (95% CI for B=2.16-5.48), but not return to work (95% CI for B=-0.68-0.24). The avoidance composite was also associated with an increased risk for depression (OR=1.76, 95% CI=1.02-3.02) and anxiety disorders (OR=1.89, 95% CI=1.16-3.19). Endurance behavior predicted the same outcomes, except for depression. In summary, avoidance and endurance behavior were associated with a range of adverse clinical outcomes from MTBI. These may represent early intervention targets.

Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B

PubMed Central

Özeş, Ali R.; Feoktistova, Kateryna; Avanzino, Brian C.; Fraser, Christopher S.

2011-01-01

Eukaryotic initiation factor 4A (eIF4A) is a DEAD-box helicase that stimulates translation initiation by unwinding mRNA secondary structure. The accessory proteins, eIF4G, eIF4B, and eIF4H enhance the duplex unwinding activity of eIF4A, but the extent to which they modulate eIF4A activity is poorly understood. Here, we use real time fluorescence assays to determine the kinetic parameters of duplex unwinding and ATP hydrolysis by these initiation factors. To ensure efficient duplex unwinding, eIF4B and eIF4G cooperatively activate the duplex unwinding activity of eIF4A. Our data reveal that eIF4H is much less efficient at stimulating eIF4A unwinding activity than eIF4B, implying that eIF4H is not able to completely substitute for eIF4B in duplex unwinding. By monitoring unwinding and ATPase assays using identical conditions, we demonstrate that eIF4B couples the ATP hydrolysis cycle of eIF4A with strand separation, thereby minimizing non-productive unwinding events. Using duplex substrates with altered GC contents, but with similar predicted thermal stabilities, we further show that the rate of formation of productive unwinding complexes is strongly influenced by the local stability per base pair in addition to the stability of the entire duplex. This finding explains how a change in the GC content of a hairpin while maintaining overall predicted thermal stability is able to influence translation initiation. PMID:21840318

A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly

PubMed Central

Abdulkarim, Baroj; Igoillo-Esteve, Mariana; Daures, Mathilde; Romero, Sophie; Philippi, Anne; Senée, Valérie; Lopes, Miguel; Cunha, Daniel A.; Harding, Heather P.; Derbois, Céline; Bendelac, Nathalie; Hattersley, Andrew T.; Eizirik, Décio L.; Ron, David

2015-01-01

Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic β-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2α phosphorylation [CReP]) encoding the regulatory subunit of an eIF2α-specific phosphatase in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. The R658C mutation in PPP1R15B affects a conserved amino acid within the domain important for protein phosphatase 1 (PP1) binding. The R658C mutation decreases PP1 binding and eIF2α dephosphorylation and results in β-cell apoptosis. Our findings support the concept that dysregulated eIF2α phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to β-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities. PMID:26159176

NFκB signaling regulates embryonic and adult neurogenesis

PubMed Central

ZHANG, Yonggang; HU, Wenhui

2013-01-01

Both embryonic and adult neurogenesis involves the self-renewal/proliferation, survival, migration and lineage differentiation of neural stem/progenitor cells. Such dynamic process is tightly regulated by intrinsic and extrinsic factors and complex signaling pathways. Misregulated neurogenesis contributes much to a large range of neurodevelopmental defects and neurodegenerative diseases. The signaling of NFκB regulates many genes important in inflammation, immunity, cell survival and neural plasticity. During neurogenesis, NFκB signaling mediates the effect of numerous niche factors such as cytokines, chemokines, growth factors, extracellular matrix molecules, but also crosstalks with other signaling pathways such as Notch, Shh, Wnt/β-catenin. This review summarizes current progress on the NFκB signaling in all aspects of neurogenesis, focusing on the novel role of NFκB signaling in initiating early neural differentiation of neural stem cells and embryonic stem cells. PMID:24324484

Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.

PubMed

Nomura, Alice; Majumder, Kaustav; Giri, Bhuwan; Dauer, Patricia; Dudeja, Vikas; Roy, Sabita; Banerjee, Sulagna; Saluja, Ashok K

2016-12-01

NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

Geniposide promotes autophagy to inhibit insulin resistance in HepG2 cells via P62/NF-κB/GLUT-4

PubMed Central

Jiang, Hongwei; Ma, Yujin; Yan, Junqiang; Liu, Jie; Li, Liping

2017-01-01

Insulin resistance (IR) is known to be an important factor, which can lead to the onset of type 2 diabetes. Autophagy is a cellular process, which sequesters senescent or damaged proteins in autophagosomes for recycling of their products. Insulin and intracellular molecules, including mammalian target of rapamycin (mTOR), are well-known inhibitors of autophagy. In patients with type 2 diabetes, the expression levels of glucose transporter 4 (GLUT-4) in skeletal muscles are significantly decreased, indicating decreased glucose-processing ability. Geniposide is an iridoid compound isolated from Gardenia jasminoides Ellis. Previously, it was reported that geniposide significantly promoted glucose uptake. In the present study, a HepG2 cell model of IR was constructed to determine whether geniposide can promote autophagy to inhibit insulin resistance in HepG2 cells via P62/nuclear factor (NF)-κB/GLUT-4. Cell proliferation was analyzed by performing an MTT assay, and the mRNA expression levels of NF-κB and GLUT-4 were assessed using semi-quantitative polymerase chain reaction and immunohistochemical staining. In addition, the protein levels of GLUT-4, P62 and phosphorylated-P65 were assessed by western blotting. The expression of GLUT-4 was initially increased following geniposide treatment, decreasing in time to its lowest level at 8 h. The expression levels of NF-κB and GLUT-4 in the IR cells treated with and without geniposide were significantly different, compared with those in the control group. Geniposide promoted autophagy in the IR HepG2 cells and significantly improved IR in the HepG2 cells, which may be associated with the dynamic regulation of the P62/NF-κB/GLUT-4 pathway. PMID:28944847

The free growth criterion for grain initiation in TiB 2 inoculated γ-titanium aluminide based alloys

NASA Astrophysics Data System (ADS)

Gosslar, D.; Günther, R.

2014-02-01

γ-titanium aluminide (γ-TiAl) based alloys enable for the design of light-weight and high-temperature resistant engine components. This work centers on a numerical study of the condition for grain initiation during solidification of TiB2 inoculated γ-TiAl based alloys. Grain initiation is treated according to the so-called free growth criterion. This means that the free growth barrier for grain initiation is determined by the maximum interfacial mean curvature between a nucleus and the melt. The strategy presented in this paper relies on iteratively increasing the volume of a nucleus, which partially wets a hexagonal TiB2 crystal, minimizing the interfacial energy and calculating the corresponding interfacial curvature. The hereby obtained maximum curvature yields a scaling relation between the size of TiB2 crystals and the free growth barrier. Comparison to a prototypical TiB2 crystal in an as cast γ-TiAl based alloy allowed then to predict the free growth barrier prevailing under experimental conditions. The validity of the free growth criterion is discussed by an interfacial energy criterion.

Hygroscopic growth of particles nebulized from water-soluble extracts of PM2.5 aerosols over the Bay of Bengal: Influence of heterogeneity in air masses and formation pathways.

PubMed

Boreddy, S K R; Kawamura, Kimitaka; Bikkina, Srinivas; Sarin, M M

2016-02-15

Hygroscopic properties of water-soluble matter (WSM) extracted from fine-mode aerosols (PM2.5) in the marine atmospheric boundary layer of the Bay of Bengal (BoB) have been investigated during a cruise from 27th December 2008 to 30th January 2009. Hygroscopic growth factors were measured on particles generated from the WSM using an H-TDMA system with an initial dry size of 100 nm in the range of 5-95% relative humidity (RH). The measured hygroscopic growth of WSM at 90% RH, g(90%)WSM, were ranged from 1.11 to 1.74 (mean: 1.43 ± 0.19) over the northern BoB and 1.12 to 1.38 (mean: 1.25 ± 0.09) over the southern BoB. A key finding is that distinct hygroscopic growth factors are associated with the air masses from the Indo-Gangetic plains (IGP), which are clearly distinguishable from those associated with air masses from Southeast Asia (SEA). We found higher (lower) g(90%)WSM over the northern (southern) BoB, which were associated with an IGP (SEA) air masses, probably due the formation of high hygroscopic salts such as (NH4)2SO4. On the other hand, biomass burning influenced SEA air masses confer the low hygroscopic salts such as K2SO4, MgSO4, and organic salts over the southern BoB. Interestingly, mass fractions of water-soluble organic matter (WSOM) showed negative and positive correlations with g(90%)WSM over the northern and southern BoB, respectively, suggesting that the mixing state of organic and inorganic fractions could play a major role on the g(90%)WSM over the BoB. Further, WSOM/SO4(2-) mass ratios suggest that SO4(2-) dominates the g(90%)WSM over the northern BoB whereas WSOM fractions were important over the southern BoB. The present study also suggests that aging process could significantly alter the hygroscopic growth of aerosol particles over the BoB, especially over the southern BoB. Copyright © 2015 Elsevier B.V. All rights reserved.

Serum apolipoprotein B-100 concentration predicts the virological response to pegylated interferon plus ribavirin combination therapy in patients infected with chronic hepatitis C virus genotype 1b.

PubMed

Yoshizawa, Kai; Abe, Hiroshi; Aida, Yuta; Ishiguro, Haruya; Ika, Makiko; Shimada, Noritomo; Tsubota, Akihito; Aizawa, Yoshio

2013-07-01

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity-determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg-IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b-infected patients to investigate whether the response to Peg-IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B-100 (apoB-100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB-100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046-2.456), alpha-fetoprotein (OR, 0.764; 95% CI, 0.610-0.958), non-wild-type ISDR (OR, 5.617; 95% CI, 1.274-24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225-114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3-log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB-100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB-100 concentrations could predict virological response to Peg-IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype. Copyright © 2013 Wiley Periodicals, Inc.

The effect of ultraviolet radiation on choroidal melanocytes and melanoma cell lines: cell survival and matrix metalloproteinase production.

PubMed

Lai, Kenneth; Di Girolamo, Nick; Conway, Robert M; Jager, Martine J; Madigan, Michele C

2007-05-01

Ultraviolet radiation (UVR) can induce DNA damage and regulate the expression of factors important for tumour growth and metastasis, including matrix metalloproteinases (MMPs). Epidemiological studies suggest that chronic UVR exposure, especially during early adulthood, may be a risk factor in patients with choroidal melanoma. However, the effects of UV(R)-B on human choroidal melanocyte survival and growth are unknown. In this study, we investigated if UV(R)-B affected the in vitro survival, growth and MMP production of choroidal melanocytes and melanoma cells. Cultures of primary choroidal melanocytes and melanoma cell lines (OCM-1 and OCM-8) were exposed to UV(R)-B (0-30 mJ/cm(2)). The cell morphology and growth were examined, and cell viability was assessed using an MTT assay. Gelatin zymography was used to assess the enzymatic activity for MMP-2 and -9 in conditioned media following UV(R)-B treatment. UV(R)-B > or =20 mJ/cm(2) was cytotoxic for choroidal melanocytes. Cytotoxic doses of 5 to 10 mJ/cm(2) were found for OCM-8 and OCM-1 melanoma cell lines. Low levels of UV(R)-B (2.5 and 3.5 mJ/cm(2)) significantly reduced melanoma cell viability after 48 h, although melanocyte viability was not affected by doses of UV(R)-B <10 mJ/cm(2). Conditioned media from melanoma cells and melanocytes displayed pro-MMP-2 activity independent of UV(R)-B. Control and UV(R)-B-treated OCM-1 cells secreted active MMP-2 up to 72 h. Pro-MMP-9 activity was seen from 36 h for control and UV(R)-B-treated OCM-1 and OCM-8 cells. Melanocytes appeared more resistant to physiological doses of UV(R)-B than melanoma cells; the potential of melanocytes to initially survive DNA damage following UV(R)-B exposure may be relevant to the subsequent transformation of melanocytes to melanomas. Although UV(R)-B did not induce the production and/or activation of MMP-2 and -9 in melanocytes or melanoma cells, we are currently investigating whether DNA damage-response genes such as p53 and p21 can be regulated following UVR exposure, and whether they are important for choroidal melanoma development.

The optimization of fermentation conditions for producing cellulase of Bacillus amyloliquefaciens and its application to goose feed

PubMed Central

Ye, Miao; Sun, Linghong; Yang, Ru; Qi, KeZong

2017-01-01

The proper culture conditions for producing cellulase of Bacillus amyloliquefaciens S1, isolated from the cecum of goose was optimized by single-factor experiment combined with orthogonal test. The properties of the cellulase were investigated by DNS method. The appropriate doses of B. amyloliquefaciens S1 were obtained by adding them to goose feed. It indicated that the suitable culture conditions of producing cellulase were the culture temperature of 37°C, the initial pH of 7.0, the incubation time of 72 h and the loaded liquid volume of 75 ml per 250 ml. The effects of each factor on producing cellulase by B. amyloliquefaciens S1 were as follows: initial pH > incubation time = culture temperature > loaded liquid volume. The optimum reaction temperature and pH were 50°C and 7.0, respectively. This enzyme is a kind of neutral cellulase that possesses resistance to heat and acidity. It showed high activity to absorbent cotton, soya bean meal and filter paper. By adding different doses of B. amyloliquefaciens S1 to the goose feed, it was found that the egg production, average egg weight, fertilization rate and the hatching rate were promoted both in experiment 1 (1.5 g kg−1) and experiment 2 (3 g kg−1). Also the difference of egg production, fertilization rate and hatching rate between experiment 1 and control group was obvious (p < 0.05), and the average egg weight was significantly increased in experiment 2 (p < 0.05). PMID:29134097

Mitochondrial translational-initiation and elongation factors in Saccharomyces cerevisiae.

PubMed

Vambutas, A; Ackerman, S H; Tzagoloff, A

1991-11-01

C155 and E252 are respiratory-defective mutants of Saccharomyces cerevisiae, previously assigned to complementation groups G37 and G142, respectively. The following evidence suggested that both mutants were likely to have lesions in components of the mitochondrial translational machinery: C155 and E252 display a pleiotropic deficiency in cytochromes a, a3 and b; both strains are severly limited in their ability to incorporate radioactive methionine into the mitochondrial translation products and, in addition, display a tendency to loose wild-type mitochondrial DNA. This set of characteristics is commonly found in strains affected in mitochondrial protein synthesis. To identify the biochemical lesions, each mutant was transformed with a wild-type yeast genomic library and clones complemented for the respiratory defect were selected for growth on a non-fermentable substrate. Analysis of the cloned genes revealed that C155 has a mutation in a protein which has high sequence similarity to bacterial elongation factor G and that E252 has a mutation in a protein homologous to bacterial initiation factor 2. Disruption of the chromosomal copy of each gene in a wild-type haploid yeast induced a phenotype analogous to that of the original mutants, but does not affect cell viability. These results indicate that both gene products function exclusively in mitochondrial protein synthesis. Subcloning of the IFM1 gene, coding for the mitochondrial initiation factor, indicates that the amino-terminal 423 residues of the protein are sufficient to promote peptide-chain initiation in vivo.

Visualization of the entire differentiation process of murine M cells: suppression of their maturation in cecal patches.

PubMed

Kimura, S; Yamakami-Kimura, M; Obata, Y; Hase, K; Kitamura, H; Ohno, H; Iwanaga, T

2015-05-01

The microfold (M) cell residing in the follicle-associated epithelium is a specialized epithelial cell that initiates mucosal immune responses by sampling luminal antigens. The differentiation process of M cells remains unclear due to limitations of analytical methods. Here we found that M cells were classified into two functionally different subtypes based on the expression of Glycoprotein 2 (GP2) by newly developed image cytometric analysis. GP2-high M cells actively took up luminal microbeads, whereas GP2-negative or low cells scarcely ingested them, even though both subsets equally expressed the other M-cell signature genes, suggesting that GP2-high M cells represent functionally mature M cells. Further, the GP2-high mature M cells were abundant in Peyer's patch but sparse in the cecal patch: this was most likely due to a decrease in the nuclear translocation of RelB, a downstream transcription factor for the receptor activator of nuclear factor-κB signaling. Given that murine cecum contains a protrusion of beneficial commensals, the restriction of M-cell activity might contribute to preventing the onset of any excessive immune response to the commensals through decelerating the M-cell-dependent uptake of microorganisms.

Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR.

PubMed

Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira; Aiamkitsumrit, Benjamas; Fassnacht, Ryan; Kashanchi, Fatah; Ochem, Alex; Simon, Gary L; Karn, Jonathan; Hauser, Kurt F; Tyagi, Mudit

2015-09-01

Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. Copyright © 2015 Elsevier Inc. All rights reserved.

Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

PubMed Central

Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira; Aiamkitsumrit, Benjamas; Fassnacht, Ryan; Kashanchi, Fatah; Ochem, Alex; Simon, Gary L.; Karn, Jonathan; Hauser, Kurt F.; Tyagi, Mudit

2015-01-01

Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-κB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-κB at 276th serine residue. These modifications enhance the interaction of NF-κB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. PMID:25980739

Pregnancy as a Window to Future Cardiovascular Health: Design and Implementation of the nuMoM2b Heart Health Study.

PubMed

Haas, David M; Ehrenthal, Deborah B; Koch, Matthew A; Catov, Janet M; Barnes, Shannon E; Facco, Francesca; Parker, Corette B; Mercer, Brian M; Bairey-Merz, C Noel; Silver, Robert M; Wapner, Ronald J; Simhan, Hyagriv N; Hoffman, Matthew K; Grobman, William A; Greenland, Philip; Wing, Deborah A; Saade, George R; Parry, Samuel; Zee, Phyllis C; Reddy, Uma M; Pemberton, Victoria L; Burwen, Dale R

2016-03-15

The National Institute of Child Health and Human Development's Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study (HHS) was designed to investigate the relationships between adverse pregnancy outcomes and modifiable risk factors for cardiovascular disease. The ongoing nuMoM2b-HHS, which started in 2013, is a prospective follow-up of the nuMoM2b cohort, which included 10,038 women recruited between 2010 and 2013 from 8 centers across the United States who were initially observed over the course of their first pregnancies. In this report, we detail the design and study procedures of the nuMoM2b-HHS. Women in the pregnancy cohort who consented to be contacted for participation in future studies were approached at 6-month intervals to ascertain health information and to maintain ongoing contact. Two to 5 years after completion of the pregnancy documented in the nuMoM2b, women in the nuMoM2b-HHS were invited to an in-person study visit. During this visit, they completed psychosocial and medical history questionnaires and had clinical measurements and biological specimens obtained. A subcohort of participants who had objective assessments of sleep-disordered breathing during pregnancy were asked to repeat this investigation. This unique prospective observational study includes a large, geographically and ethnically diverse cohort, rich depth of phenotypic information about adverse pregnancy outcomes, and clinical data and biospecimens from early in the index pregnancy onward. Data obtained from this cohort will provide mechanistic and clinical insights into how data on a first pregnancy can provide information about the potential development of subsequent risk factors for cardiovascular disease. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Central nervous system involvement in AIDS-related lymphomas.

PubMed

Barta, Stefan K; Joshi, Jitesh; Mounier, Nicolas; Xue, Xiaonan; Wang, Dan; Ribera, Josep-Maria; Navarro, Jose-Tomas; Hoffmann, Christian; Dunleavy, Kieron; Little, Richard F; Wilson, Wyndham H; Spina, Michele; Galicier, Lionel; Noy, Ariela; Sparano, Joseph A

2016-06-01

Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNS(B) ) and relapse (CNS(R) ) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNS(B) or IT prophylaxis. CNS(B) was found in 13%. CNS(B) was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNS(B) between the pre-combination antiretroviral therapy (cART) and cART eras. 5·3% of patients experienced CNS(R) at a median of 4·2 months after diagnosis (12% if CNS(B) ; 4% if not). Median OS after CNS(R) was 1·6 months. On multivariate analysis, only CNS(B) [hazard ratio (HR) 3·68, P = 0·005] and complete response to initial therapy (HR 0·14, P < 0·0001) were significantly associated with CNS(R) . When restricted to patients without CNS(B) , IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNS(R) . Despite IT CNS prophylaxis, 5% of patients experienced CNS(R) . Our data confirms that CNS(R) in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNS(R) . Although CNS(B) conferred an increased risk for CNS(R) , it did not impact OS. © 2016 John Wiley & Sons Ltd.

Purification and characterization of nattokinase from Bacillus subtilis natto B-12.

PubMed

Wang, Cong; Du, Ming; Zheng, Dongmei; Kong, Fandong; Zu, Guoren; Feng, Yibing

2009-10-28

Bacillus subtilis natto B-12 was isolated from natto, a traditional fermented soybean food in Japan. A fibrinolytic enzyme (B-12 nattokinase) was purified from the supernatant of B. subtilis natto B-12 culture broth and showed strong fibrinolytic activity. The enzyme was homogenously purified to 56.1-fold, with a recovery of 43.2% of the initial activity. B-12 nattokinase was demonstrated to be homogeneous by SDS-PAGE and was identified as a monomer of 29000 +/- 300 Da in its native state by SDS-PAGE and size exclusion methods. The optimal pH value and temperature were 8.0 and 40 degrees C, respectively. Purified nattokinase showed high thermostability at temperatures from 30 to 50 degrees C and alkaline stability within the range of pH 6.0-9.0. The enzyme activity was activated by Zn(2+) and obviously inhibited by Fe(3+) and Al(3+). This study provides some important information for the effect factors of fibrinolytic activity, the purification methods, and characterization of nattokinase from B. subtilis natto B-12, which enriches the theoretical information of nattokinase for the research and development of nattokinase as a functional additive of food.

Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

PubMed Central

Satriotomo, Irawan; Dale, Erica A.; Dahlberg, Jenny M.; Mitchell, Gordon S.

2015-01-01

Acute intermittent hypoxia (AIH) initiates plasticity in respiratory motor control, including phrenic long term facilitation (pLTF). Since pLTF is enhanced by preconditioning with repetitive exposure to AIH (rAIH), we hypothesized that a rAIH protocol consisting of 3 AIH exposures per week for 10 weeks (3×wAIH; AIH: 10, 5-min episodes of 10.5% O2; 5-min normoxic intervals) would enhance expression of molecules that play key roles in pLTF within the phrenic motor nucleus. Immunohistochemical analyses revealed that 3×wAIH for 10 weeks increased serotonin terminal density in the C4 phrenic motor nucleus and serotonin 2A (5-HT2A) receptor expression in presumptive phrenic motor neurons. Immunoreactive brain derived neurotrophic factor (BDNF) and its high affinity receptor (TrkB) also increased following 3×wAIH. 3×wAIH also increased expression of another hypoxia-sensitive growth factor known to elicit phrenic motor facilitation, vascular endothelial growth factor (VEGF), and its receptor (VEGFR-2). Kinases “downstream” from TrkB and VEGFR-2 were up-regulated in or near presumptive phrenic motor neurons, including phosphorylated extracellular-signal regulated kinase (p-ERK) and protein kinase B (p-AKT). Thus, 3×wAIH up-regulates neurochemicals known to be associated with phrenic motor plasticity. Since 3×wAIH upregulates pro-plasticity molecules without evidence for CNS pathology, it may be a useful therapeutic tool in treating disorders that cause respiratory insufficiency, such as spinal injury or motor neuron disease. PMID:22704858

Λ b→pl⁻ν¯ l form factors from lattice QCD with static b quarks

DOE PAGES

Detmold, William; Lin, C.-J. David; Meinel, Stefan; ...

2013-07-23

We present a lattice QCD calculation of form factors for the decay Λ b→pμ⁻ν¯ μ, which is a promising channel for determining the Cabibbo-Kobayashi-Maskawa matrix element |V ub| at the Large Hadron Collider. In this initial study we work in the limit of static b quarks, where the number of independent form factors reduces to two. We use dynamical domain-wall fermions for the light quarks, and perform the calculation at two different lattice spacings and at multiple values of the light-quark masses in a single large volume. Using our form factor results, we calculate the Λ b→pμ⁻ν¯ μ differential decaymore » rate in the range 14 GeV²≤q²≤q² max, and obtain the integral ∫ q²max 14 GeV²[dΓ/dq²]dq²/|V ub|²=15.3±4.2 ps⁻¹. Combined with future experimental data, this will give a novel determination of |V ub| with about 15% theoretical uncertainty. The uncertainty is dominated by the use of the static approximation for the b quark, and can be reduced further by performing the lattice calculation with a more sophisticated heavy-quark action.« less

Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways

PubMed Central

Calzas, Cynthia; Goyette-Desjardins, Guillaume; Lemire, Paul; Gagnon, Fleur; Lachance, Claude; Van Calsteren, Marie-Rose

2013-01-01

Streptococcus agalactiae (also known as group B Streptococcus [GBS]) and Streptococcus suis are encapsulated streptococci causing severe septicemia and meningitis. Bacterial capsular polysaccharides (CPSs) are poorly immunogenic, but anti-CPS antibodies are essential to the host defense against encapsulated bacteria. The mechanisms underlying anti-CPS antibody responses are not fully elucidated, but the biochemistry of CPSs, particularly the presence of sialic acid, may have an immunosuppressive effect. We investigated the ability of highly purified S. suis and GBS native (sialylated) CPSs to activate dendritic cells (DCs), which are crucial actors in the initiation of humoral immunity. The influence of CPS biochemistry was studied using CPSs extracted from different serotypes within these two streptococcal species, as well as desialylated CPSs. No interleukin-1β (IL-1β), IL-6, IL-12p70, tumor necrosis factor alpha (TNF-α), or IL-10 production was observed in S. suis or GBS CPS-stimulated DCs. Moreover, these CPSs exerted immunosuppressive effects on DC activation, as a diminution of gamma interferon (IFN-γ)-induced B cell-activating factor of the tumor necrosis factor family (BAFF) expression was observed in CPS-pretreated cells. However, S. suis and GBS CPSs induced significant production of CCL3, via partially Toll-like receptor 2 (TLR2)- and myeloid differentiation factor 88 (MyD88)-dependent pathways, and CCL2, via TLR-independent mechanisms. No major influence of CPS biochemistry was observed on the capacity to induce chemokine production by DCs, indicating that DCs respond to these CPSs in a patterned way rather than a structure-dedicated manner. PMID:23774593

Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IκBα.

PubMed

Bao, Yan; Wu, Xuewei; Chen, Jinjing; Hu, Xiangming; Zeng, Fuxing; Cheng, Jianjun; Jin, Hong; Lin, Xin; Chen, Lin-Feng

2017-05-16

Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/threonine-protein kinase 2 ( Mknk2 ). Brd4 -deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.

Connective Tissue Growth Factor (CTGF) as a Regulator of Lactogenic Differentiation

DTIC Science & Technology

2009-06-09

1 1.62 Myeloid leukemia factor 1, Mlf1 1.57 ADAMTS-l4 1.55 E2F transcription factor, E2F2 1.44 Tensin 4 -1.5 BCL2/adenovirus E1B interacting... Mlf1 1.57 ADAMTS-l4 1.55 Ras homolog gene family, member B, RhoB 1.48 Cell Differentiation-associated Wingless-type MMTV integration site family...B, relB 1.92 Myeloid leukemia factor 1, Mlf1 1.57 Growth Factor, Catalytic Activity-associated Dual specificity protein phosphatase 8, Dusp8

Effects of basic fibroblast growth factor and insulin-like growth factor on cultured cartilage cells from skate Raja porasa

NASA Astrophysics Data System (ADS)

Fan, Tingjun; Jin, Lingyun; Wang, Xiaofeng

2003-12-01

Effects of basic fibroblast growth factor (bFGF) and insulin-like growth factor II (IGF-II) on cartilage cells from proboscis of skate, Raja porasa Günther, were investigated in this study. The cartilage cells were cultured in 20% FBS-supplemented MEM medium at 24°C. Twelve hours after culture initiation, the cartilage cells were treated with bFGF and IGF-II at different concentration combinations. It was found that 20 ng/ml of bFGF or 80 ng/ml of IGF-II was enough to have obvious stimulating effect on the growth and division of skate cartilage cells. Test of bFGF and IGF-II together, revealed that 20 ng/ml of bFGF and 80 ng/ml of IGF-II together had the best stimulating effect on the growth and division of skate cartilage cells. The cartilage cells cultured could form a monolayer at day 7.

Attenuating homologous recombination stimulates an AID-induced antileukemic effect

PubMed Central

Lamont, Kristin R.; Hasham, Muneer G.; Donghia, Nina M.; Branca, Jane; Chavaree, Margaret; Chase, Betsy; Breggia, Anne; Hedlund, Jacquelyn; Emery, Ivette; Cavallo, Francesca; Jasin, Maria; Rüter, Jens

2013-01-01

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4′-diisothiocyanatostilbene-2-2′-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population. PMID:23589568

40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 6 2014-07-01 2014-07-01 false Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures 2B Table 2B to Subpart E of Part 59 Protection of Environment ENVIRONMENTAL... Coatings Pt. 59, Subpt. E, Table 2B Table 2B to Subpart E of Part 59—Reactivity Factors for Aliphatic...

40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 6 2013-07-01 2013-07-01 false Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures 2B Table 2B to Subpart E of Part 59 Protection of Environment ENVIRONMENTAL... Coatings Pt. 59, Subpt. E, Table 2B Table 2B to Subpart E of Part 59—Reactivity Factors for Aliphatic...

40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 6 2012-07-01 2012-07-01 false Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures 2B Table 2B to Subpart E of Part 59 Protection of Environment ENVIRONMENTAL... Coatings Pt. 59, Subpt. E, Table 2B Table 2B to Subpart E of Part 59—Reactivity Factors for Aliphatic...

A Possible Role of the Full-Length Nascent Protein in Post-Translational Ribosome Recycling.

PubMed

Das, Debasis; Samanta, Dibyendu; Bhattacharya, Arpita; Basu, Arunima; Das, Anindita; Ghosh, Jaydip; Chakrabarti, Abhijit; Das Gupta, Chanchal

2017-01-01

Each cycle of translation initiation in bacterial cell requires free 50S and 30S ribosomal subunits originating from the post-translational dissociation of 70S ribosome from the previous cycle. Literature shows stable dissociation of 70S from model post-termination complexes by the concerted action of Ribosome Recycling Factor (RRF) and Elongation Factor G (EF-G) that interact with the rRNA bridge B2a/B2b joining 50S to 30S. In such experimental models, the role of full-length nascent protein was never considered seriously. We observed relatively slow release of full-length nascent protein from 50Sof post translation ribosome, and in that process, its toe prints on the rRNA in vivo and in in vitro translation with E.coli S30 extract. We reported earlier that a number of chemically unfolded proteins like bovine carbonic anhydrase (BCA), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), lysozyme, ovalbumin etc., when added to free 70Sin lieu of the full length nascent proteins, also interact with identical RNA regions of the 23S rRNA. Interestingly the rRNA nucleotides that slow down release of the C-terminus of full-length unfolded protein were found in close proximity to the B2a/B2b bridge. It indicated a potentially important chemical reaction conserved throughout the evolution. Here we set out to probe that conserved role of unfolded protein conformation in splitting the free or post-termination 70S. How both the RRF-EFG dependent and the plausible nascent protein-EFG dependent ribosome recycling pathways might be relevant in bacteria is discussed here.

A Possible Role of the Full-Length Nascent Protein in Post-Translational Ribosome Recycling

PubMed Central

Das, Debasis; Samanta, Dibyendu; Bhattacharya, Arpita; Basu, Arunima; Das, Anindita; Ghosh, Jaydip; Chakrabarti, Abhijit; Das Gupta, Chanchal

2017-01-01

Each cycle of translation initiation in bacterial cell requires free 50S and 30S ribosomal subunits originating from the post-translational dissociation of 70S ribosome from the previous cycle. Literature shows stable dissociation of 70S from model post-termination complexes by the concerted action of Ribosome Recycling Factor (RRF) and Elongation Factor G (EF-G) that interact with the rRNA bridge B2a/B2b joining 50S to 30S. In such experimental models, the role of full-length nascent protein was never considered seriously. We observed relatively slow release of full-length nascent protein from 50Sof post translation ribosome, and in that process, its toe prints on the rRNA in vivo and in in vitro translation with E.coli S30 extract. We reported earlier that a number of chemically unfolded proteins like bovine carbonic anhydrase (BCA), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), lysozyme, ovalbumin etc., when added to free 70Sin lieu of the full length nascent proteins, also interact with identical RNA regions of the 23S rRNA. Interestingly the rRNA nucleotides that slow down release of the C-terminus of full-length unfolded protein were found in close proximity to the B2a/B2b bridge. It indicated a potentially important chemical reaction conserved throughout the evolution. Here we set out to probe that conserved role of unfolded protein conformation in splitting the free or post-termination 70S. How both the RRF-EFG dependent and the plausible nascent protein–EFG dependent ribosome recycling pathways might be relevant in bacteria is discussed here. PMID:28099529

Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression

PubMed Central

Fahey, Ciara; Kenny, Elaine M; Terenin, Ilya M; Dmitriev, Sergey E; Cormican, Paul; Morris, Derek W; Shatsky, Ivan N; Baranov, Pavel V

2015-01-01

Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eukaryotic initiation factor 2 (eIF2). However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. Although this led to a 5.4-fold general translational repression, the protein coding open reading frames (ORFs) of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated upstream open reading frame (uORF) that represses translation of the main coding ORF under normal conditions. Site-specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Phylogenetic analysis suggests that at least two regulatory uORFs (namely, in SLC35A4 and MIEF1) encode functional protein products. DOI: http://dx.doi.org/10.7554/eLife.03971.001 PMID:25621764

Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

PubMed Central

Kueffer, Peter J.; Maitz, Charles A.; Khan, Aslam A.; Schuster, Seth A.; Shlyakhtina, Natalia I.; Jalisatgi, Satish S.; Brockman, John D.; Nigg, David W.; Hawthorne, M. Frederick

2013-01-01

The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2′-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 1012 neutrons per cm2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study. PMID:23536304

Blindness and Glaucoma: A Multicenter Data Review from 7 Academic Eye Clinics.

PubMed

Rossetti, Luca; Digiuni, Maurizio; Montesano, Giovanni; Giovanni, Montesano; Centofanti, Marco; Fea, Antonio M; Iester, Michele; Frezzotti, Paolo; Figus, Michele; Ferreras, Antonio; Oddone, Francesco; Tanga, Lucia; Rolle, Teresa; Battaglino, Valentina; Posarelli, Chiara; Motolese, Ilaria; Mittica, Pietro; Bagaglia, Simone Alex; Menicacci, Cristina; De Cilla', Stefano; Autelitano, Alessandro; Fogagnolo, Paolo

2015-01-01

To evaluate frequency, conversion rate, and risk factors for blindness in glaucoma patients treated in European Universities. This multicenter retrospective study included 2402 consecutive patients with glaucoma in at least one eye. Medical charts were inspected and patients were divided into those blind and the remainder ('controls'). Blindness was defined as visual acuity≤0.05 and/or visual field loss to less than 10°. Unilateral and bilateral blindness were respectively 11.0% and 1.6% at the beginning, and 15.5% and 3.6% at the end of the observation period (7.5±5.5 years, range:1-25 years); conversion to blindness (at least unilateral) was 1.1%/year. 134 eyes (97 patients) developed blindness by POAG during the study. At the first access to study centre, they had mean deviation (MD) of -17.1±8.3 dB and treated intraocular pressure (IOP) of 17.1±6.6 mmHg. During follow-up the IOP decreased by 14% in these eyes but MD deteriorated by 1.1±3.5 dB/year, which was 5-fold higher than controls (0.2±1.6 dB/year). In a multivariate model, the best predictors for blindness by glaucoma were initial MD (p<0.001), initial IOP (p<0.001), older age at the beginning of follow-up (p<0.001), whereas final IOP was found to be protective (p<0.05). In this series of patients, blindness occurred in about 20%. Blindness by glaucoma had 2 characteristics: late diagnosis and/or late referral, and progression of the disease despite in most cases IOP was within the range of normality and target IOP was achieved; it could be predicted by high initial MD, high initial IOP, and old age.

Calcium-Mediated Apoptosis and Apoptotic Sensitization in Prostate Cancer

DTIC Science & Technology

2004-06-01

calcium- sensitive protease calpain, stimulating two distinct pathways that regulate phosphotyrosine-initiated cell signaling ( PTP1B ) or directly...trigger apoptosis (caspase 7). The role of caspase 7 and PTP1B in PC cell death and survival signaling was investigated using dominant negatives, siRNA...of a calpain-proteolyzed variant of PTP1B (tPTP1B) had minimal impact on growth-factor or cytokine-mediated tyrosine phosphorylation or cell

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

Lee, Jeong Eun; Hanyang Biomedical Research Institute, Seoul; Park, Jae Hyeon

Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-κB) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, against CPF-induced neuronalmore » cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-α. CPF also induced nuclear translocation of NF-κB and inhibitors of NF-κB abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-κB-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-κB. - Highlights: • CPF induces apoptotic cell death in SH-SY5Y cells • ROS involved in CPF-mediated apoptotic cell death • Inflammation involved in CPF-mediated apoptotic cell death • Rosiglitazone modulates ROS and inflammatory response in CPF-treated cells.« less

The DnaK Chaperone Uses Different Mechanisms To Promote and Inhibit Replication of Vibrio cholerae Chromosome 2

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

Jha, Jyoti K.; Li, Mi; Ghirlando, Rodolfo

Replication of Vibrio cholerae chromosome 2 (Chr2) depends on molecular chaperone DnaK to facilitate binding of the initiator (RctB) to the replication origin. The binding occurs at two kinds of site, 12-mers and 39-mers, which promote and inhibit replication, respectively. Here we show that DnaK employs different mechanisms to enhance the two kinds of binding. We found that mutations inrctBthat reduce DnaK binding also reduce 12-mer binding and initiation. The initiation defect is suppressed by second-site mutations that increase 12-mer binding only marginally. Instead, they reduce replication inhibitory mechanisms: RctB dimerization and 39-mer binding. One suppressing change was in amore » dimerization domain which is folded similarly to the initiator of an iteron plasmid—the presumed progenitor of Chr2. In plasmids, DnaK promotes initiation by reducing dimerization. A different mutation was in the 39-mer binding domain of RctB and inactivated it, indicating an alternative suppression mechanism. Paradoxically, although DnaK increases 39-mer binding, the increase was also achieved by inactivating the DnaK binding site of RctB. This result suggests that the site inhibits the 39-mer binding domain (via autoinhibition) when prevented from binding DnaK. Taken together, our results reveal an important feature of the transition from plasmid to chromosome: the Chr2 initiator retains the plasmid-like dimerization domain and its control by chaperones but uses the chaperones in an unprecedented way to control the inhibitory 39-mer binding. IMPORTANCE The capacity of proteins to undergo remodeling provides opportunities to control their function. However, remodeling remains a poorly understood aspect of the structure-function paradigm due to its dynamic nature. Here we have studied remodeling of the initiator of replication ofVibrio choleraeChr2 by the molecular chaperone, DnaK. We show that DnaK binds to a site on the Chr2 initiator (RctB) that promotes initiation by reducing the initiator’s propensity to dimerize. Dimerization of the initiator of the putative plasmid progenitor of Chr2 is also reduced by DnaK, which promotes initiation. Paradoxically, the DnaK binding also promotes replication inhibition by reducing an autoinhibitory activity of RctB. In the plasmid-to-chromosome transition, it appears that the initiator has acquired an autoinhibitory activity and along with it a new chaperone activity that apparently helps to control replication inhibition independently of replication promotion.« less

Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-κB activity.

PubMed

Wu, Mei-Yao; Hung, Shih-Kai; Fu, Shu-Ling

2011-10-12

Fisetin, a flavonoid compound commonly present in fruits and vegetables, can exert anti-inflammation activities via inhibition of the NF-κB-signaling pathway. This study aims to evaluate the antiasthma activity of fisetin and investigate its possible molecular mechanisms. We found that fisetin attenuated lung inflammation, goblet cell hyperplasia, and airway hyperresponsiveness in ovalbumin-induced asthma and decreased eosinophils and lymphocytes in bronchoalveolar lavage fluid. Fisetin treatment reduced expression of the key initiators of allergic airway inflammation (eotaxin-1 and TSLP), Th2-associated cytokines (IL-4, IL-5, and IL-13) in lungs, and Th2-predominant transcription factor GATA-3 and cytokines in thoracic lymph node cells and splenocytes. Notably, fisetin treatment impaired NF-κB activation in OVA-stimulated lung tissues and TNF-α-stimulated bronchial epithelial cells. Collectively, this study demonstrated the beneficial effect of fisetin in the amelioration of asthmatic phenotypes. The antiasthma activity of fisetin is associated with reduction of Th2 responses as well as suppression of NF-κB and its downstream chemokines.

The effects of pre-natal-, early-life- and indirectly-initiated exposures to maximum adversities on the course of schizophrenia.

PubMed

Levine, Stephen Z; Levav, Itzhak; Yoffe, Rinat; Pugachova, Inna

2014-09-01

The effects of pre-natal-, early-life- and indirectly-initiated exposures to protracted maximum adversity on the course of schizophrenia are unknown. To compare the aforementioned Holocaust directly exposed subgroups with an indirectly exposed subgroup on the course of schizophrenia. The study population were: Israeli Jews in-uterus or born in Nazi-occupied or dominated European nations by the end of the persecution of the Jews, who were alive in 1950, and who had a last discharge diagnosis of schizophrenia in the Israel National Psychiatric Case Registry by 2013 (N=4933). The population was disaggregated into subgroups who (1) migrated after WWII and who had (1a) pre-natal (n=584, 11.8%) and (1b) early-life (n=3709, 75.2%) initiated exposures to the maximum adversities of the Holocaust, and (2) indirectly exposed individuals to the Holocaust who migrated before the Nazi-era persecution begun (n=640, 13%). Recurrent event survival analyses were computed to examine the psychiatric re-hospitalization risk of the study subgroups, unadjusted and adjusted for age of onset of the disorder and sex. The pre-natal initiated exposure subgroup had a significantly (p<0.05) greater risk of psychiatric re-hospitalizations for schizophrenia than the other subgroups (unadjusted: HR=3.39, 95% CI 2.95, 3.90; adjusted: HR=2.28, 2.00, 2.60). This result replicated in sensitivity analyses for: Poland-born individuals, the years 1922 and 1935; and followed at least 10 years and to the year 2000. Pre-natal initiated exposure to the maximal adversity of the holocaust constitutes a consistent risk factor for a worse course of schizophrenia, a possible byproduct of neurodevelopment disruptions induced by maternal stress and/or famine and/or infections. Copyright © 2014 Elsevier B.V. All rights reserved.

Early growth response 2 and Egr3 are unique regulators in immune system.

PubMed

Taefehshokr, Sina; Key, Yashar Azari; Khakpour, Mansour; Dadebighlu, Pourya; Oveisi, Amin

2017-01-01

The immune system is evolved to defend the body against pathogens and is composed of thousands of complicated and intertwined pathways, which are highly controlled by processes such as transcription and repression of cellular genes. Sometimes the immune system malfunctions and a break down in self-tolerance occurs. This lead to the inability to distinguish between self and non-self and cause attacks on host tissues, a condition also known as autoimmunity, which can result in chronic debilitating diseases. Early growth response genes are family of transcription factors comprising of four members, Egr1, Egr2, Egr3 and Egr4. All of which contain three cyc2-His2 zinc fingers. Initially, Egr2 function was identified in the regulation of peripheral nerve myelination, hindbrain segmentation. Egr3, on the other hand, is highly expressed in muscle spindle development. Egr2 and Egr3 are induced due to the antigen stimulation and this signaling is implemented through the B and T cell receptors in the adaptive immunity. T cell receptor signaling plays a key role in Egr 2 and 3 expressions via their interaction with NFAT molecules. Egr 2 and 3 play a crucial role in regulation of the immune system and their involvement in B and T cell activation, anergy induction and preventing the autoimmune disease has been investigated. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expression of effector and activated T cells.

Hepatitis B virus in Pakistan: a systematic review of prevalence, risk factors, awareness status and genotypes.

PubMed

Ali, Muhammad; Idrees, Muhammad; Ali, Liaqat; Hussain, Abrar; Ur Rehman, Irshad; Saleem, Sana; Afzal, Samia; Butt, Sadia

2011-03-06

In Pakistan, there are estimated 7-9 million carriers of hepatitis B virus (HBV) with a carrier rate of 3-5%. This article reviews the available literature about the prevalence, risk factors, awareness status and genotypes of the HBV in Pakistan by using key words; HBV prevalence, risk factors, awareness status and genotypes in Pakistani population in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. One hundred and six different studies published from 1998 to 2010 were included in this study. Weighted mean and standard deviation were determined for each population group. The percentage of hepatitis B virus infection in general population was 4.3318% ± 1.644%, healthy blood donors (3.93% ± 1.58%), military recruits (4.276% ± 1.646%), healthcare persons (3.25% ± 1.202%), pregnant women (5.872% ± 4.984), prisoners (5.75% ± 0.212%), surgical patients (7.397% ± 2.012%), patients with cirrhosis (28.87% ± 11.90%), patients with HCC (22% ± 2.645%), patients with hepatitis (15.896% ± 14.824%), patients with liver diseases (27.54% ± 6.385%), multiple transfused patients (6.223% ± 2.121%), opthalmic patients (3.89% ± 1.004%) and users of injectable drugs (14.95% ± 10.536%). Genotype D (63.71%) is the most prevalent genotype in Pakistani population. Mass vaccination and awareness programs should be initiated on urgent basis especially in populations with HBV infection rates of more than 5%.

Geraniol attenuates 4NQO-induced tongue carcinogenesis through downregulating the activation of NF-κB in rats.

PubMed

Madankumar, Arumugam; Tamilarasi, Sasivarnam; Premkumar, Thandavamoorthy; Gopikrishnan, Mani; Nagabhishek, Natesh; Devaki, Thiruvengadam

2017-10-01

Geraniol, an acyclic monoterpene found in lemon grass and aromatic herb oil, has been shown to exert antitumor and antioxidant activities against various cancer types. The objective of this study was to investigate the potential chemoprotective role of geraniol against 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis in male Wistar rats and furthermore to study anti-inflammatory mechanisms of action through possible NF-κB signaling. 4NQO was administered to rats at the dose of 50 ppm through drinking water to induce tongue cancer in 20 weeks. 4NQO provoked inflammation by upregulating the expressions of the p65 subunit nuclear factor kappa-β (NF-κB) in the nucleus, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Additionally, staining for immature and mature mast cells in cancer niche by toluidine blue staining and alcian blue-safranin staining showed more accumulation. Co-treatment of geraniol 200 mg/kg b.w. showed a significant decrease in the level of p65 NF-κB in the nucleus, and this might be due to the inhibition of NF-κB activation/translocation into nucleus, which was further confirmed by decreased immature and mature mast cell density and the expression of inflammatory downstream mediators such as TNF-α, IL-1β, COX-2, and iNOS. Collectively, our results suggested that geraniol as a potential anti-inflammatory agent having the capability to obstruct 4NQO initiated NF-κB activation and modulated the expression of inflammatory mediators.

75 FR 27411 - Airworthiness Directives; Turbomeca Arriel 1B, 1D, 1D1, and 1S1 Turboshaft Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-17

.... That AD requires initial and repetitive relative position checks of the gas generator 2nd stage turbine... repetitive replacements of 2nd stage turbines on Arriel 1B, 1D, and 1D1 engines. This AD requires lowering the initial and repetitive thresholds for replacement of 2nd stage turbines on Arriel 1B, 1D, and 1D1...

Re-Evaluation of the Lower San Fernando Dam. Report 2. Examination of the Post-Earthquake Slide of February 9, 1971

DTIC Science & Technology

1989-09-01

the initial shear driving shear stress stress Initial {Failure occurs when strength drops below the initial shear idriving shear stressstress Steady...back pressure saturation (to a "B-value" o iot less than B = 0.98) most of the samples were isotropically co:,solidated to 0𔃽, i = 2.0 ksc. Some of the

Factors associated with loss to follow-up among women in Option B+ PMTCT programme in northeast Ethiopia: a retrospective cohort study.

PubMed

Mitiku, Israel; Arefayne, Mastewal; Mesfin, Yonatal; Gizaw, Muluken

2016-01-01

Ethiopia has recently adopted lifelong antiretroviral therapy (ART) for all HIV-positive pregnant and breastfeeding women (Option B+ strategy), regardless of CD4 count or clinical stage. However, the exact timing and predictors of loss to follow-up (LFU) are unknown. Thus, we examined the levels and determinants of LFU under Option B+ among pregnant and breastfeeding women initiated on lifelong ART for prevention of mother-to-child transmission (PMTCT) in Ethiopia. We conducted a retrospective cohort study among 346 pregnant and breastfeeding women who started ART at 14 public health facilities in northeast Ethiopia from March 2013 to April 2015. We defined LFU as 90 days since the last clinic visit among those not known to have died or transferred out. We used Kaplan-Meier and Cox proportional hazards regression to estimate cumulative LFU and identify the predictors of LFU, respectively. Of the 346 women included, 88.4% were pregnant and the median follow-up was 13.7 months. Overall, 57 (16.5%) women were LFU. The cumulative proportions of LFU at 6, 12 and 24 months were 11.9, 15.7 and 22.6%, respectively. The risk of LFU was higher in younger women (adjusted hazard ratio (aHR) 18 to 24 years/30 to 40 years: 2.3; 95% confidence interval (CI): 1.2 to 4.5), in those attending hospitals compared to those attending health centres (aHR: 1.8; 95% CI: 1.1 to 3.2), in patients starting ART on the same day of diagnosis (aHR: 1.85; 95% CI: 1.1 to 3.2) and missing CD4 cell counts at ART initiation (aHR: 2.3; 95% CI: 1.2 to 4.4). The level of LFU we found in this study is comparable with previous findings from other resource-limited settings. However, high early LFU shortly after ART initiation is still a major problem. LFU was high among younger women, those initiating ART on the day of HIV diagnosis, those missing baseline CD4 count and those attending hospitals. Thus, targeted HIV care and treatment programmes for these patients should be part of future interventions to improve retention in care under the Option B+ PMTCT programme.

NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming

PubMed Central

Hawkins, Kate E.; Joy, Shona; Delhove, Juliette M.K.M.; Kotiadis, Vassilios N.; Fernandez, Emilio; Fitzpatrick, Lorna M.; Whiteford, James R.; King, Peter J.; Bolanos, Juan P.; Duchen, Michael R.; Waddington, Simon N.; McKay, Tristan R.

2016-01-01

Summary The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα) activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation. PMID:26904936

[Research in high frequency ultrasonic for degradation of azo dye wastewater containing MX-5B].

PubMed

Xie, Wei-Ping; Qin, Yan; Zou, Yuan; He, De-Wen; Song, Dan

2010-09-01

The degradation of azo dye wastewater, containing MX-5B, was investigated by using high frequency ultrasonic irradiation. The effect of different factors like the initial pH of solution, sonolysis parameters, air-blowing, Fe2+ concentration were studied, the synergistic action of complex frequency and the mechanism of degradation was explored primarily. The results show that MX-5B in aqueous solution can be degraded efficiently by ultrasonic irradiation, when the pH 3.5, ultrasonic frequency 418.3 kHz, ultrasonic power 69 W, color removal rate up to 100% in 180 min. Adding of Fe2+ and blowing air had some effects. The results also indicated that radical-oxidation controlled the ultrasonic decompose of MX-5B and MX-5B ultrasonic removal was observed to behave as pseudo-first-order kinetics under different experimental conditions tested in the present work. Comparison of UV-Vis absorption spectrums before and after treatment showed that all of the conjugate structure and part of aromatic structure were destroyed after being ultrasonic irradiation.

The Red Light Receptor Phytochrome B Directly Enhances Substrate-E3 Ligase Interactions to Attenuate Ethylene Responses.

PubMed

Shi, Hui; Shen, Xing; Liu, Renlu; Xue, Chang; Wei, Ning; Deng, Xing Wang; Zhong, Shangwei

2016-12-05

Plants germinating under subterranean darkness assume skotomorphogenesis, a developmental program strengthened by ethylene in response to mechanical pressure of soil. Upon reaching the surface, light triggers a dramatic developmental transition termed de-etiolation that requires immediate termination of ethylene responses. Here, we report that light activation of photoreceptor phyB results in rapid degradation of EIN3, the master transcription factor in the ethylene signaling pathway. As a result, light rapidly and efficiently represses ethylene actions. Specifically, phyB directly interacts with EIN3 in a light-dependent manner and also physically associates with F box protein EBFs. The light-activated association of phyB, EIN3, and EBF1/EBF2 proteins stimulates robust EIN3 degradation by SCF EBF1/EBF2 E3 ligases. We reveal that phyB manipulates substrate-E3 ligase interactions in a light-dependent manner, thus directly controlling the stability of EIN3. Our findings illustrate a mechanistic model of how plants transduce light information to immediately turn off ethylene signaling for de-etiolation initiation. Copyright © 2016 Elsevier Inc. All rights reserved.

Discretely Self-Similar Solutions to the Navier-Stokes Equations with Besov Space Data

NASA Astrophysics Data System (ADS)

Bradshaw, Zachary; Tsai, Tai-Peng

2018-07-01

We construct self-similar solutions to the three dimensional Navier-Stokes equations for divergence free, self-similar initial data that can be large in the critical Besov space \\dot{B}_{p,∞}^{3/p-1} where 3 < p < 6. We also construct discretely self-similar solutions for divergence free initial data in \\dot{B}_{p,∞}^{3/p-1} for 3 < p < 6 that is discretely self-similar for some scaling factor λ > 1. These results extend those of Bradshaw and Tsai (Ann Henri Poincaré 2016. https://doi.org/10.1007/s00023-016-0519-0) which dealt with initial data in L 3 w since {L^3_w\\subsetneq \\dot{B}_{p,∞}^{3/p-1}} for p > 3. We also provide several concrete examples of vector fields in the relevant function spaces.

Drosophila nuclear factor DREF regulates the expression of the mitochondrial DNA helicase and mitochondrial transcription factor B2 but not the mitochondrial translation factor B1

PubMed Central

Fernández-Moreno, Miguel A.; Hernández, Rosana; Adán, Cristina; Roberti, Marina; Bruni, Francesco; Polosa, Paola Loguercio; Cantatore, Palmiro; Matsushima, Yuichi; Kaguni, Laurie S.; Garesse, Rafael

2016-01-01

DREF [DRE (DNA replication-related element)-binding factor] controls the transcription of numerous genes in Drosophila, many involved in nuclear DNA (nDNA) replication and cell proliferation, three in mitochondrial DNA (mtDNA) replication and two in mtDNA transcription termination. In this work, we have analysed the involvement of DREF in the expression of the known remaining genes engaged in the minimal mtDNA replication (d-mtDNA helicase) and transcription (the activator d-mtTFB2) machineries and of a gene involved in mitochondrial mRNA translation (d-mtTFB1). We have identified their transcriptional initiation sites and DRE sequences in their promoter regions. Gel-shift and chromatin immunoprecipitation assays demonstrate that DREF interacts in vitro and in vivo with the d-mtDNA helicase and d-mtTFB2, but not with the d-mtTFB1 promoters. Transient transfection assays in Drosophila S2 cells with mutated DRE motifs and truncated promoter regions show that DREF controls the transcription of d-mtDNA helicase and d-mtTFB2, but not that of d-mtTFB1. RNA interference of DREF in S2 cells reinforces these results showing a decrease in the mRNA levels of d-mtDNA helicase and d-mtTFB2 and no changes in those of the d-mtTFB1. These results link the genetic regulation of nuclear DNA replication with the genetic control of mtDNA replication and transcriptional activation in Drosophila. PMID:23916463

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

PubMed Central

Lisak, D; Schacht, T; Gawlitza, A; Albrecht, P; Aktas, O; Koop, B; Gliem, M; Hofstetter, H H; Zanger, K; Bultynck, G; Parys, J B; De Smedt, H; Kindler, T; Adams-Quack, P; Hahn, M; Waisman, A; Reed, J C; Hövelmeyer, N; Methner, A

2016-01-01

The endoplasmic reticulum (ER) serves as the major intracellular Ca2+ store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca2+ leak channel also implicated in the response against protein misfolding, thereby connecting the Ca2+ store and protein-folding functions of the ER. We found that BI-1-deficient mice suffer from leukopenia and erythrocytosis, have an increased number of splenic marginal zone B cells and higher abundance and nuclear translocation of NF-κB (nuclear factor-κ light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca2+ levels. When put into culture, purified knockout T cells and even more so B cells die spontaneously. This is preceded by increased activity of the mitochondrial initiator caspase-9 and correlated with a significant surge in mitochondrial Ca2+ levels, suggesting an exhausted mitochondrial Ca2+ buffer capacity as the underlying cause for cell death in vitro. In vivo, T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production are attenuated, corroborating the ex vivo results. These results suggest that BI-1 has a major role in the functioning of the adaptive immune system by regulating intracellular Ca2+ homeostasis in lymphocytes. PMID:26470731

Morris Water Maze Training in Mice Elevates Hippocampal Levels of Transcription Factors Nuclear Factor (Erythroid-derived 2)-like 2 and Nuclear Factor Kappa B p65

PubMed Central

Snow, Wanda M.; Pahlavan, Payam S.; Djordjevic, Jelena; McAllister, Danielle; Platt, Eric E.; Alashmali, Shoug; Bernstein, Michael J.; Suh, Miyoung; Albensi, Benedict C.

2015-01-01

Research has identified several transcription factors that regulate activity-dependent plasticity and memory, with cAMP-response element binding protein (CREB) being the most well-studied. In neurons, CREB activation is influenced by the transcription factor nuclear factor kappa B (NF-κB), considered central to immunity but more recently implicated in memory. The transcription factor early growth response-2 (Egr-2), an NF-κB gene target, is also associated with learning and memory. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcription factor linked to NF-κB in pathological conditions, has not been studied in normal memory. Given that numerous transcription factors implicated in activity-dependent plasticity demonstrate connections to NF-κB, this study simultaneously evaluated protein levels of NF-κB, CREB, Egr-2, Nrf2, and actin in hippocampi from young (1 month-old) weanling CD1 mice after training in the Morris water maze, a hippocampal-dependent spatial memory task. After a 6-day acquisition period, time to locate the hidden platform decreased in the Morris water maze. Mice spent more time in the target vs. non-target quadrants of the maze, suggestive of recall of the platform location. Western blot data revealed a decrease in NF-κB p50 protein after training relative to controls, whereas NF-κB p65, Nrf2 and actin increased. Nrf2 levels were correlated with platform crosses in nearly all tested animals. These data demonstrate that training in a spatial memory task results in alterations in and associations with particular transcription factors in the hippocampus, including upregulation of NF-κB p65 and Nrf2. Training-induced increases in actin protein levels caution against its use as a loading control in immunoblot studies examining activity-dependent plasticity, learning, and memory. PMID:26635523

Formation of polycrystalline MgB2 synthesized by powder in sealed tube method with different initial boron phase

NASA Astrophysics Data System (ADS)

Yudanto, Sigit Dwi; Imaduddin, Agung; Kurniawan, Budhy; Manaf, Azwar

2018-04-01

Magnesium diboride, MgB2 is a new high critical temperature superconductor that discovered in the beginning of the 21st century. The MgB2 has a simple crystal structure and a high critical temperature, which can be manufactured in several forms like thin films, tapes, wires including bulk in the large scale. For that reason, the MgB2 has good prospects for various applications in the field of electronic devices. In the current work, we have explored the synthesis of MgB2 polycrystalline using powder in a sealed tube method. Different initial boron phase for the synthesized of MgB2 polycrystalline were used. These were, in addition to magnesium powders, crystalline boron, amorphous boron and combination both of them were respectively fitted in the synthesis. The raw materials were mixed in a stoichiometric ratio of Mg: B=1:2, ground using agate mortar, packed into stainless steel SS304. The pack was then sintered at temperature of 800°C for 2 hours in air atmosphere. Phase formation of MgB2 polycrystalline in difference of initial boron phase was characterized using XRD and SEM. Referring to the diffraction pattern and microstructure observation, MgB2 polycrystalline was formed, and the formation was effective when using the crystalline Mg and fully amorphous B as the raw materials. The critical temperature of the specimen was evaluated by the cryogenic magnet. The transition temperature of the MgB2 specimen synthesized using crystalline magnesium and full amorphous boron is 42.678 K (ΔTc = 0.877 K).

Use of the i2b2 research query tool to conduct a matched case-control clinical research study: advantages, disadvantages and methodological considerations.

PubMed

Johnson, Emilie K; Broder-Fingert, Sarabeth; Tanpowpong, Pornthep; Bickel, Jonathan; Lightdale, Jenifer R; Nelson, Caleb P

2014-01-30

A major aim of the i2b2 (informatics for integrating biology and the bedside) clinical data informatics framework aims to create an efficient structure within which patients can be identified for clinical and translational research projects.Our objective was to describe the respective roles of the i2b2 research query tool and the electronic medical record (EMR) in conducting a case-controlled clinical study at our institution. We analyzed the process of using i2b2 and the EMR together to generate a complete research database for a case-control study that sought to examine risk factors for kidney stones among gastrostomy tube (G-tube) fed children. Our final case cohort consisted of 41/177 (23%) of potential cases initially identified by i2b2, who were matched with 80/486 (17%) of potential controls. Cases were 10 times more likely to be excluded for inaccurate coding regarding stones vs. inaccurate coding regarding G-tubes. A majority (67%) of cases were excluded due to not meeting clinical inclusion criteria, whereas a majority of control exclusions (72%) occurred due to inadequate clinical data necessary for study completion. Full dataset assembly required complementary information from i2b2 and the EMR. i2b2 was critical as a query analysis tool for patient identification in our case-control study. Patient identification via procedural coding appeared more accurate compared with diagnosis coding. Completion of our investigation required iterative interplay of i2b2 and the EMR to assemble the study cohort.

Chalepin: A Compound from Ruta angustifolia L. Pers Exhibits Cell Cycle Arrest at S phase, Suppresses Nuclear Factor-Kappa B (NF-κB) Pathway, Signal Transducer and Activation of Transcription 3 (STAT3) Phosphorylation and Extrinsic Apoptotic Pathway in Non-small Cell Lung Cancer Carcinoma (A549).

PubMed

Richardson, Jaime Stella Moses; Aminudin, Norhaniza; Abd Malek, Sri Nurestri

2017-10-01

Plants have been a major source of inspiration in developing novel drug compounds in the treatment of various diseases that afflict human beings worldwide. Ruta angustifolia L. Pers known locally as Garuda has been conventionally used for various medicinal purposes such as in the treatment of cancer. A dihydrofuranocoumarin named chalepin, which was isolated from the chloroform extract of the plant, was tested on its ability to inhibit molecular pathways of human lung carcinoma (A549) cells. Cell cycle analysis and caspase 8 activation were conducted using a flow cytometer, and protein expressions in molecular pathways were determined using Western blot technique. Cell cycle analysis showed that cell cycle was arrested at the S phase. Further studies using Western blotting technique showed that cell cycle-related proteins such as cyclins, cyclin-dependent kinases (CDKs), and inhibitors of CDKs correspond to a cell cycle arrest at the S phase. Chalepin also showed inhibition in the expression of inhibitors of apoptosis proteins. Nuclear factor-kappa B (NF-κB) pathway, signal transducer and activation of transcription 3 (STAT-3), cyclooxygenase-2, and c-myc were also downregulated upon treatment with chalepin. Chalepin was found to induce extrinsic apoptotic pathway. Death receptors 4 and 5 showed a dramatic upregulation at 24 h. Analysis of activation of caspase 8 with the flow cytometer showed an increase in activity in a dose- and time-dependent manner. Activation of caspase 8 induced cleavage of BH3-interacting domain death agonist, which initiated a mitochondrial-dependent or -independent apoptosis. Chalepin causes S phase cell cycle arrest, NF-κB pathway inhibition, and STAT-3 inhibition, induces extrinsic apoptotic pathway, and could be an excellent chemotherapeutic agent. This study reports the capacity of an isolated bioactive compound known as chalepin to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, signal transducer and activation of transcription 3, and extrinsic apoptotic pathway and also its ability to arrest cell cycle in S phase. This compound was from the leaves of Ruta angustifolia L. Pers. It provides new insight on the ability of this plant in suppressing certain cancers, especially the nonsmall cell lung carcinoma according to this study. Abbreviations used: °C: Degree Celsius, ANOVA: Analysis of variance, ATCC: American Type Culture Collection, BCL-2: B-Cell CLL/Lymphoma 2, Bcl-xL: B-cell lymphoma extra-large, BH3: Bcl-2 homology 3, BID: BH3-interacting domain death agonist, BIR: Baculovirus inhibitor of apoptosis protein repeat, Caspases: Cysteinyl aspartate-specific proteases, CDK: Cyclin-dependent kinase, CO 2 : Carbon dioxide, CST: Cell signaling technologies, DISC: Death-inducing signaling complex, DMSO: Dimethyl sulfoxide, DNA: Deoxyribonucleic acid, DR4: Death receptor 4, DR5: Death receptor 5, E1a: Adenovirus early region 1A, ECL: Enhanced chemiluminescence, EDTA: Ethylenediaminetetraacetic acid, ELISA: Enzyme-linked immunosorbent assay, etc.: Etcetera, FADD: Fas-associated protein with death domain, FBS: Fetal bovine serum, FITC: Fluorescein isothiocyanate, G1: Gap 1, G2: Gap 2, HPLC: High-performance liquid chromatography, HRP: Horseradish peroxidase, IAPs: Inhibitor of apoptosis proteins, IC50: Inhibitory concentration at half maximal inhibitory, IKK-α: Inhibitor of nuclear factor kappa-B kinase subunit alpha, IKK-β: Inhibitor of nuclear factor kappa-B kinase subunit beta, IKK-γ: Inhibitor of nuclear factor kappa-B kinase subunit gamma, IKK: IκB kinase, IkBα: Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, m: Meter, M: Mitotic, mm: Millimeter, mRNA: Messenger ribonucleic acid, NaCl: Sodium chloride, NaVO4: Sodium orthovanadate, NEMO: NF-Kappa-B essential modulator, NF-κB: Nuclear factor kappa-light chain-enhancer of activated B cells, NSCLC: Nonsmall cell lung carcinoma, PBS: Phosphate buffered saline, PGE2: Prostaglandin E2, PI: Propidium iodide, PMSF: Phenylmethylsulfonyl fluoride, pRB: Phosphorylated retinoblastoma, R. angustifolia : Ruta angustifolia L. Pers, Rb: Retinoblastoma, rpm: Rotation per minute, RPMI: Roswell Park Memorial Institute, S phase: Synthesis phase, SD: Standard deviation, SDS-PAGE: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Smac: Second mitochondria-derived activator of caspase, SPSS: Statistical Package for the Social Sciences, STAT3: Signal transducer and activation of transcription 3, tBID: Truncated BID, TNF: Tumor necrosis factor, TRADD: Tumor necrosis factor receptor type-1 associated death domain, TRAIL: TNF-related apoptosis- inducing ligand, USA: United States of America, v/v: Volume over volume.

Photocatalytic pretreatment of oily wastewater from the restaurant by a vacuum ultraviolet/TiO2 system.

PubMed

Kang, Jian-xiong; Lu, Lu; Zhan, Wei; Li, Bo; Li, Dao-sheng; Ren, Yong-zheng; Liu, Dong-qi

2011-02-15

The present study aims at investigating the performance of a vacuum ultraviolet (VUV, 185 nm) and TiO(2) oxidation system for the pretreatment of oily wastewater from restaurant. The influence of irradiation time, pH, dissolved oxygen (DO), the dosage of TiO(2) and the initial chemical oxygen demand (COD) concentration on COD removal efficiency was ascertained and optimum process conditions for stable and effective operation were determined. Under the optimum conditions of irradiation 10 min, initial COD 3981 mg/L, TiO(2) 150 mg/L, pH 7.0 and flow rate of air 40 L/h, the process of VUV and TiO(2)/VUV achieved removal efficiencies of COD, BOD(5) and oil as 50±3%, 37±2%, 86±3%, and 63±3%, 43±2%, 70±3%, respectively. The biodegradability factor f(B) of the wastewater was determined as 1.56 which indicated that the VUV/TiO(2) process improved the biodegradability of the oily wastewater significantly. Results clearly indicate that VUV/TiO(2) photolysis tends to destruct parts of COD, BOD(5), and ammonia, as well as enhances the biodegradability of the oily wastewater simultaneously. Thus, this technique could be used as a pretreatment step for conventional biological treatment of oily wastewater. Copyright © 2010 Elsevier B.V. All rights reserved.

Comparison of Cox's Regression Model and Parametric Models in Evaluating the Prognostic Factors for Survival after Liver Transplantation in Shiraz during 2000-2012.

PubMed

Adelian, R; Jamali, J; Zare, N; Ayatollahi, S M T; Pooladfar, G R; Roustaei, N

2015-01-01

Identification of the prognostic factors for survival in patients with liver transplantation is challengeable. Various methods of survival analysis have provided different, sometimes contradictory, results from the same data. To compare Cox's regression model with parametric models for determining the independent factors for predicting adults' and pediatrics' survival after liver transplantation. This study was conducted on 183 pediatric patients and 346 adults underwent liver transplantation in Namazi Hospital, Shiraz, southern Iran. The study population included all patients undergoing liver transplantation from 2000 to 2012. The prognostic factors sex, age, Child class, initial diagnosis of the liver disease, PELD/MELD score, and pre-operative laboratory markers were selected for survival analysis. Among 529 patients, 346 (64.5%) were adult and 183 (34.6%) were pediatric cases. Overall, the lognormal distribution was the best-fitting model for adult and pediatric patients. Age in adults (HR=1.16, p<0.05) and weight (HR=2.68, p<0.01) and Child class B (HR=2.12, p<0.05) in pediatric patients were the most important factors for prediction of survival after liver transplantation. Adult patients younger than the mean age and pediatric patients weighing above the mean and Child class A (compared to those with classes B or C) had better survival. Parametric regression model is a good alternative for the Cox's regression model.

Engineering of a highly efficient Xe₂*-excilamp (xenon excimer lamp, λmax=172 nm, η=40%) and qualitative comparison to a low-pressure mercury lamp (LP-Hg, λ=185/254 nm) for water purification.

PubMed

Al-Gharabli, Samer; Engeßer, Patrick; Gera, Diana; Klein, Sandra; Oppenländer, Thomas

2016-02-01

Excilamps are mercury-free gas-discharge sources of non-coherent VUV or UV radiation with high radiant power and a long lifetime. The most efficient excilamp that is currently available on the market is a VUV xenon excilamp system (Xe2(*)-excimer lamp, λ(max) = 172 nm) with a stated radiant efficiency η of 40% at an electrical input power P(el) of 20 W, 50 W or 100 W. In this paper, the use of this highly efficient Xe2(*)-excilamp (P(el) = 20 W) for water treatment is demonstrated using a recirculating laboratory photoreactor system with negative radiation geometry. The efficiency in the 172 nm initiated bleaching of aqueous solutions of Rhodamine B is compared to that initiated by a common low-pressure mercury (LP-Hg) lamp (185 nm, TNN 15/32). The dependence of the pseudo zero order rate constant k´ of decolorization of RhB on the flow rate and on the initial concentration of RhB was investigated. Both lamps exhibited dependences of k´ on the initial concentration of RhB, which represents a typical saturation kinetical behavior. The saturation kinetics was very prominent in the case of the Xe2(*)-excilamp. Also, the Xe2(*)-excilamp treatment exhibited a significant influence on the flow rate of the RhB aqueous solution, which was not the case during the LP-Hg lamp initiated bleaching of RhB. The results of this paper demonstrate that Xe2(*)-excilamps can be used for VUV-initiated water purification. However, to reach the maximum efficacy of the Xe2(*)-excilamp for photo-initiated water purification further engineering optimization of the photoreactor concept is necessary. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Cross-Industry Review of B2B Critical Success Factors.

ERIC Educational Resources Information Center

Eid, Riyad; Trueman, Myfanwy; Ahmed, Abdel Moneim

2002-01-01

Presents a comprehensive review of B2B (business-to- business) international Internet marketing and identifies 21 critical success factors in five categories: marketing strategy, including management support, strategic goals, and collaboration; Web site factors, including Web site design; global factors, including multilanguage sites and cultural…

Methanolic extract of Boswellia serrata exhibits anti-cancer activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells.

PubMed

Ranjbarnejad, Tayebeh; Saidijam, Massoud; Moradkhani, Shirin; Najafi, Rezvan

2017-07-01

Colorectal cancer (CRC) is the most common cancer. A proper method to reduce mortality of CRC is chemoprevention to prevent initiation and promotion of intestinal tumorgenesis. One of the promising and developing chemopreventive agents is natural compounds found in plants. Frankincense, the resin extract from the Boswellia specious, has been used in traditional and modern medicine for treating various diseases with very minimal side effects. In the current study, we investigated the anti-cancer activity of methanolic extract of Boswellia serrata (B. serrata) on HT-29 human colon cancer cells. HT-29 cells were treated with different concentrations of B. serrata and cell viability was assessed by MTT assay. mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1 (HIF-1) were examined by quantitative real-time PCR. Apoptosis was evaluated by the proportion of sub-G1 cells. Prostaglandin E2 (PGE2) level and caspase 3 activity were determined by ELISA assay. Tube formation potential and HT-29 cells migration were assessed using three-dimensional vessel formation assay and scratch test. B. serrata extract considerably decreased the expression of mPGES-1, VEGF, CXCR4, MMP-2, MMP-9 and HIF-1. The caspase 3 activity and percent of cells in sub-G1 phase were increased by B. serrata extract. Cell viability, PGE2 generation, in vitro tube formation and cell migration were decreased significantly in B. serrata-treated HT-29 compared to the control group. Our findings suggest that B. serrata extract inhibits proliferation, angiogenesis and migration and induces apoptosis in HT-29 cells by inhibiting of mPGES-1 and decreasing the PGE2 level and its downstream targets. Copyright © 2017 Elsevier Inc. All rights reserved.

CD11b regulates antibody class switching via induction of AID.

PubMed

Park, Seohyun; Sim, Hyunsub; Kim, Hye-In; Jeong, Daecheol; Wu, Guang; Cho, Soo Young; Lee, Young Seek; Kwon, Hyung-Joo; Lee, Keunwook

2017-07-01

The integrin CD11b, which is encoded by the integrin subunit alpha M (ITGAM), is primarily expressed on the surface of innate immune cells. Genetic variations in ITGAM are among the strongest risk factors for systemic lupus erythematosus, an autoimmune disease characterized by the presence of autoantibodies. However, the regulatory function of CD11b in the antibody responses remains unclear. Here, we report the induction of CD11b in activated B2 B cells and define its unexpected role in immunoglobulin heavy chain class switch recombination (CSR). LPS-activated B cells lacking CD11b yielded fewer IgG subtypes such as IgG1 and IgG2a in vitro, and immunization-dependent CSR and affinity maturation of antibodies were severely impaired in CD11b-deficient mice. Notably, we observed the reduced expression of activation-induced cytidine deaminase (AID), an enzyme that initiates CSR and somatic hypermutation, and ectopic expression of AID was sufficient to rescue the defective CSR of CD11b-deficient B cells. LPS-induced phosphorylation of NF-κB p65 and IκBα was attenuated in CD11b-deficient B cells, and hyperactivation of IκB kinase 2 restored the defective AID expression and CSR, which implied that CD11b regulates the NF-κB-dependent induction of AID. Overall, our experimental evidence emphasized the function of CD11b in antibody responses and the role of CD11b as a vital regulator of CSR. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Therapeutic Efficacy of VICP+L-ASP/TKI on Adult Patients with B-ALL].

PubMed

Shen, Ming-Fang; Wei, Ju-Ying; Yu, Wen-Juan; Wang, Jing-Han; Tong, Hong-Yan; Meng, Hai-Tao; Mai, Wen-Yuan; Qian, Wen-Bin; Jin, Jie

2016-12-01

To evaluate the therapeutic efficacy of VICP+L-ASP/TKI on adult patients with B-ALL and to explore the influence factors. Forty-one adult B-ALL patients treated with VICP+L-ASP/TKI from August 2008 to June 2014 were following-up. The complete remission(CR) rate, toxicity, overall survival(OS) and event free survival(EFS) after induction treatment were analyzed, the therapeutic outcome of patients between different risk stratification subgroups was compared, the influence of standardized consolidatory and maintaining treatment as well as allogeneic hematopoietic stem cell transplantation(allo-HSCT) on survival time was analyzed. The early death not occurred in 41 patients with B-ALL including 37 cases with CR; the CR rate of 1 course treatment was 90.2%. The follow-up time lasted to March 17, 2015, the median follow-up time was 25(9-79) months; the 1 year OS rate was 75.3%, the EFS rate was 58.3%. Analysis of risk factors showed that the initial WBC count over 30×10 9 /L, LDH over 250 U/L and minimal residual disease(MRD) over 10 -4 after treatment were poor prognostic factors. After remission, the standardized consolidatory treatment or allo-HSCT according to the "2012 China adult ALL diagnosis and treatment expert consensus" could improve long-term survival, 3 years OS rate was 73.8% and 61.5% respectively, 3 years EFS were 63.5% and 65.7% respectively. The main toxic and side effects were hematologic reactions, the hematologic adverse reaction of IV grade was observed in 97.6%(40/41) during induction treatment. Induction chemotherapy based on VICP+L-ASP/TKI and standardized consolidatory after remission according to the "2012 China adult acute lymphoblastic leukemia diagnosis and treatment expert consensus" can improve the therapeutic efficacy. The allo-HSCT should be actively performed for B-ALL paients with high risk(elevated initial WBC count and LDH level); at some time, the regularly monitoring MRD and adjusting therapeutic protocol according to monitoring result can promote the prognosis of adult B-ALL patients.

Genetic Variant in ACVR2B Is Associated with Lean Mass.

PubMed

Klimentidis, Yann C; Bea, Jennifer W; Thompson, Patricia; Klimecki, Walter T; Hu, Chengcheng; Wu, Guanglin; Nicholas, J Skye; Ryckman, Kelli K; Chen, Zhao

2016-07-01

Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait. In this study, we selected 1493 single-nucleotide polymorphisms (SNP) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways and examined their association with LM, assessed by dual-energy x-ray absorptiometry, in a sample of 2760 non-Hispanic and Hispanic white postmenopausal women from the Women's Health Initiative (WHI) Observational Study. We assessed the replication of our top findings in a meta-analysis of 20 genome-wide association studies (n = 38,292) conducted by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Musculoskeletal Working Group. We identified 32 SNPs that had nominally significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B), was significantly associated with LM (β = 0.15, P = 2.17 × 10). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass. Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men and women. Additional large-scale studies will be needed to confirm our findings in different populations.

NF-kappaB Activity in Macrophages Determines Metastatic Potential of Breast Tumor Cells

DTIC Science & Technology

2011-08-01

Cheng DS, Chodosh LA, Blackwell TS, Yull FE: Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary... microbial products (15, 16). To date, the potential role of macrophages in the fetal lung innate immune response has not been closely examined. Studies...In this model, microbial products initially activate NF-kB in lung macrophages. The release of inflammatory mediators, particularly IL-1b and/or TNF-a

Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase.

PubMed Central

Hu, J; Seeger, C

1996-01-01

The heat shock protein Hsp90 is known as an essential component of several signal transduction pathways and has now been identified as an essential host factor for hepatitis B virus replication. Hsp90 interacts with the viral reverse transcriptase to facilitate the formation of a ribonucleoprotein (RNP) complex between the polymerase and an RNA ligand. This RNP complex is required early in replication for viral assembly and initiation of DNA synthesis through a protein-priming mechanism. These results thus invoke a role for the Hsp90 pathway in the formation of an RNP. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:8577714

Conformational plasticity of RepB, the replication initiator protein of promiscuous streptococcal plasmid pMV158

PubMed Central

Boer, D. Roeland; Ruiz-Masó, José Angel; Rueda, Manuel; Petoukhov, Maxim V.; Machón, Cristina; Svergun, Dmitri I.; Orozco, Modesto; del Solar, Gloria; Coll, Miquel

2016-01-01

DNA replication initiation is a vital and tightly regulated step in all replicons and requires an initiator factor that specifically recognizes the DNA replication origin and starts replication. RepB from the promiscuous streptococcal plasmid pMV158 is a hexameric ring protein evolutionary related to viral initiators. Here we explore the conformational plasticity of the RepB hexamer by i) SAXS, ii) sedimentation experiments, iii) molecular simulations and iv) X-ray crystallography. Combining these techniques, we derive an estimate of the conformational ensemble in solution showing that the C-terminal oligomerisation domains of the protein form a rigid cylindrical scaffold to which the N-terminal DNA-binding/catalytic domains are attached as highly flexible appendages, featuring multiple orientations. In addition, we show that the hinge region connecting both domains plays a pivotal role in the observed plasticity. Sequence comparisons and a literature survey show that this hinge region could exists in other initiators, suggesting that it is a common, crucial structural element for DNA binding and manipulation. PMID:26875695

Conserved Sequences at the Origin of Adenovirus DNA Replication

PubMed Central

Stillman, Bruce W.; Topp, William C.; Engler, Jeffrey A.

1982-01-01

The origin of adenovirus DNA replication lies within an inverted sequence repetition at either end of the linear, double-stranded viral DNA. Initiation of DNA replication is primed by a deoxynucleoside that is covalently linked to a protein, which remains bound to the newly synthesized DNA. We demonstrate that virion-derived DNA-protein complexes from five human adenovirus serological subgroups (A to E) can act as a template for both the initiation and the elongation of DNA replication in vitro, using nuclear extracts from adenovirus type 2 (Ad2)-infected HeLa cells. The heterologous template DNA-protein complexes were not as active as the homologous Ad2 DNA, most probably due to inefficient initiation by Ad2 replication factors. In an attempt to identify common features which may permit this replication, we have also sequenced the inverted terminal repeated DNA from human adenovirus serotypes Ad4 (group E), Ad9 and Ad10 (group D), and Ad31 (group A), and we have compared these to previously determined sequences from Ad2 and Ad5 (group C), Ad7 (group B), and Ad12 and Ad18 (group A) DNA. In all cases, the sequence around the origin of DNA replication can be divided into two structural domains: a proximal A · T-rich region which is partially conserved among these serotypes, and a distal G · C-rich region which is less well conserved. The G · C-rich region contains sequences similar to sequences present in papovavirus replication origins. The two domains may reflect a dual mechanism for initiation of DNA replication: adenovirus-specific protein priming of replication, and subsequent utilization of this primer by host replication factors for completion of DNA synthesis. Images PMID:7143575

Analysis of tandem E-box motifs within human Complement receptor 2 (CR2/CD21) promoter reveals cell specific roles for RP58, E2A, USF and localized chromatin accessibility.

PubMed

Cruickshank, Mark N; Dods, James; Taylor, Rhonda L; Karimi, Mahdad; Fenwick, Emily J; Quail, Elizabeth A; Rea, Alexander J; Holers, V Michael; Abraham, Lawrence J; Ulgiati, Daniela

2015-07-01

Complement receptor 2 (CR2/CD21) plays an important role in the generation of normal B cell immune responses. As transcription appears to be the prime mechanism via which surface CR2/CD21 expression is controlled, understanding transcriptional regulation of this gene will have broader implications to B cell biology. Here we report opposing, cell-context specific control of CR2/CD21 promoter activity by tandem E-box elements, spaced 22 bp apart and within 70 bp of the transcription initiation site. We have identified E2A and USF transcription factors as binding to the distal and proximal E-box sites respectively in CR2-positive B-cells, at a site that is hypersensitive to restriction enzyme digestion compared to non-expressing K562 cells. However, additional unidentified proteins have also been found to bind these functionally important elements. By utilizing a proteomics approach we have identified a repressor protein, RP58, binding the distal E-box motif. Co-transfection experiments using RP58 overexpression constructs demonstrated a specific 10-fold repression of CR2/CD21 transcriptional activity mediated through the distal E-box repressor element. Taken together, our results indicate that repression of the CR2/CD21 promoter can occur through one of the E-box motifs via recruitment of RP58 and other factors to bring about a silenced chromatin context within CR2/CD21 non-expressing cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immune response of Staphylococcus aureus strains in a mouse mastitis model is linked to adaptive capacity and genotypic profiles.

PubMed

Pereyra, Elizabet A L; Sacco, Sofía C; Duré, Andrea; Baravalle, Celina; Renna, María S; Andreotti, Carolina S; Monecke, Stefan; Calvinho, Luis F; Dallard, Bibiana E

2017-05-01

Staphylococcus aureus is one of the most frequently isolated major pathogens from intramammary infections (IMI) worldwide. The mechanisms by which S. aureus IMI are established and maintained in dairy cows involve both bacterial escape strategies and modulation of the host immune response. Moreover, it was shown that different S. aureus strains have varying effects on the immune response. The aim of this study was to investigate the immune response in a mouse mastitis model of two S. aureus strains isolated from bovine IMI with different clinical manifestation (persistent-P or non-persistent-NP), phenotypic and genotypic profile. Both strains were capable of establishing an IMI after 264h post inoculation (pi). Strain A (NP) showed a more aggressive behaviour than strain B (P) at early stages of IMI, while strain B multiplied initially at a lower rate but increased its replication capacity from 120h pi to the end of the study (264h pi). Strain A triggered a stronger initial inflammatory response compared with strain B inducing higher gene and protein expression of TLR2, NF-κB activation and higher gene expression of IL-1α at initial stage of IMI (6-12h pi) but inducing extensive mammary tissue damage. Immune cells response was different for each S. aureus strain throughout the course of infection, showing mammary glands inoculated with strain A greater initial immune cells stimulation compared with strain B and then a second immune cells stimulation (from 120 to 264h pi) represented by monocytes-macrophages, T and B lymphocytes, mainly stimulated by strain B, consistent with inflammatory process becoming chronic. Strain-specific pathogenicity observed underscores the importance of pathogen factors in the progression of the infectious process. These results contribute to increase the available information on host-pathogen interaction and point out for the need of further research to expand the knowledge about these interactions for developing new strategies to intervene in the IMI progress. Copyright © 2017 Elsevier B.V. All rights reserved.

A seven-year review of measured hearing levels in male manual steelworkers with high initial thresholds

PubMed Central

Howell, R. W.

1978-01-01

ABSTRACT Audiometric records of 449 male manual steelworkers were reviewed to see whether the hearing of men with high initial threshold levels deteriorated more rapidly than that of those men with more normal thresholds when exposed to similar noise levels. Subjects were between 15 and 54 years old at the time of initial examination, and had a repeat audiogram 6-8 years later. They were classified into three occupational noise exposure groups: below 90 dB(A), 90-99 dB(A), and 100 dB(A) or over, without knowledge of their audiometric threshold levels, age, or aural history. Measurements at 0·5, 1, 2, 3, 4 and 6 kHz for the right ear were considered, first as the mean for all six frequencies, then for 0·5, 1 and 2 kHz only, and finally for 6 kHz only. After standardisation for age, it was found that those in the high initial threshold groups deteriorated no faster than the remainder of the series. At the 90-99 dB(A) noise exposure level, χ2 tests showed that the differences between the groups, in terms of mean measured hearing loss, were not significant at the 0·05 probability level. The age-standardised mean threshold shifts for the 0·5-6 kHz range of frequencies over the seven-year review period were 7·5, 8·7 and 7·1 dB at a noise exposure level of 100 dB(A) or more, for workers with an initial threshold level of <12 dB, 12-26 dB and > 26 dB respectively; for those exposed to noise of 90-99 dB(A) the corresponding mean shifts were 7·8, 6·8 and 7·3 dB respectively; while for those exposed to noise of less than 90 dB(A) the mean shifts were 6·2, 5·0 and 5·2 dB respectively. PMID:629886

ABA signaling is necessary but not sufficient for RD29B transcriptional memory during successive dehydration stresses in Arabidopsis thaliana.

PubMed

Virlouvet, Laetitia; Ding, Yong; Fujii, Hiroaki; Avramova, Zoya; Fromm, Michael

2014-07-01

Plants subjected to a prior dehydration stress were seen to have altered transcriptional responses during a subsequent dehydration stress for up to 5 days after the initial stress. The abscisic acid (ABA) inducible RD29B gene of Arabidopsis thaliana was strongly induced after the first stress and displayed transcriptional memory with transcript levels nine-fold higher during the second dehydration stress. These increased transcript levels were due to an increased rate of transcription and are associated with an altered chromatin template during the recovery interval between the dehydration stresses. Here we use a combination of promoter deletion/substitutions, mutants in the trans-acting transcription factors and their upstream protein kinases, and treatments with exogenous ABA or dehydration stress to advance our understanding of the features required for transcriptional memory of RD29B. ABA Response Elements (ABREs) are sufficient to confer transcriptional memory on a minimal promoter, although there is a context effect from flanking sequences. Different mutations in Snf1 Related Protein Kinase 2 (SnRK2) genes positively and negatively affected the response, suggesting that this effect is important for transcriptional memory. Although exogenous ABA treatments could prime transcriptional memory, a second ABA treatment was not sufficient to activate transcriptional memory. Therefore, we concluded that transcriptional memory requires ABA and an ABA-independent factor that is induced or activated by a subsequent dehydration stress and directly or indirectly results in a more active RD29B chromatin template. These results advance our knowledge of the cis- and trans-acting factors that are required for transcriptional memory of RD29B. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Free factor XIII activation peptide (fAP-FXIII) is a regulator of factor XIII activity via factor XIII-B.

PubMed

Dodt, Johannes; Pasternack, Ralf; Seitz, Rainer; Volkers, Peter

2016-02-01

In a factor XIIIa (FXIIIa) generation assay with recombinant FXIII-A2 (rFXIII-A2 ) free FXIII activation peptide (fAP-FXII) prolonged the time to peak (TTP) but did not affect the area under the curve (AUC) or concentration at peak (CP). Addition of recombinant factorXIII-B2 (rFXIII-B2 ) restored the characteristics of the FXIIIa generation parameters (AUC, TTP and CP) to those observed for plasma FXIII (FXIII-A2 B2 ). FXIII-A2 B2 reconstituted from rFXIII-A2 and rFXIII-B2 showed a similar effect on AUC, TTP and CP in the presence of fAP-FXII as observed for plasma FXIII-A2 B2 , indicating a role for FXIII-B in this observation. An effect of fAP-FXIII on thrombin, the proteolytic activator of FXIII, was excluded by thrombin generation assays and clotting experiments. In a purified system, fAP-FXIII did not interfere with the FXIIIa activity development of thrombin-cleaved rFXIII-A2 (rFXIII-A2 ') also excluding direct inhibition of FXIIIa. However, FXIIIa activity development of FXIII-A2 'B2 was inhibited in a concentration-dependent manner by fAP-FXIII, indicating that an interaction between AP-FXIII and FXIII-B2 contributes to the overall stability of FXIII-A2 'B2 . In addition to its well-known role, FXIII-B also contributes to FXIII-A2 B2 stability or dissociation depending on fAP-FXIII and calcium concentrations. © 2015 John Wiley & Sons Ltd.

Initiators and promoters for the occurrence of screen-detected breast cancer and the progression to clinically-detected interval breast cancer.

PubMed

Yen, Amy Ming-Fang; Wu, Wendy Yi-Ying; Tabar, Laszlo; Duffy, Stephen W; Smith, Robert A; Chen, Hsiu-Hsi

2017-03-01

The risk factors responsible for breast cancer have been well documented, but the roles of risk factors as initiators, causing the occurrence of screen-detected breast cancer, or promoters, responsible for the progression of the screen-detected to the clinically-detected breast cancer, have been scarcely evaluated. We used data from women in a cohort in Kopparberg (Dalarna), Sweden between 1977 and 2010. Conventional risk factors, breast density, and tumor-specific biomarkers are superimposed to the temporal course of the natural history of the disease. The results show that older age at first full-term pregnancy, dense breast, and a family history of breast cancer increased the risk of entering the preclinical screen-detectable phase of breast cancer by 23%, 41%, and 89%, respectively. Overweight/obesity (body mass index ≥25 kg/m 2 ) was a significant initiator (adjusted relative risk [aRR] 1.15; 95% confidence interval [CI], 0.99-1.33), but was inversely associated with the role of promoter (aRR 0.65; 95% CI, 0.51-0.82). Dense breast (aRR 1.46; 95% CI, 1.12-1.91), triple-negative (aRR 2.07; 95% CI, 1.37-3.15), and Ki-67 positivity (aRR 1.66; 95% CI, 1.19-2.30) were statistically significant promoters. When the molecular biomarkers were considered collectively as one classification, the basal-like subtype was the most influential subtype on promoters (aRR 4.24; 95% CI, 2.56-7.02) compared with the Luminal A subtype. We ascertained state-dependent covariates of initiators and promoters to classify the risk of the two-step progression of breast cancer. The results of the current study are useful for individually-tailored screening and personalized clinical surveillance of patients with breast cancer that was detected at an early stage. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Eukaryotic initiation factor 2B epsilon induces cap-dependent translation and skeletal muscle hypertrophy

PubMed Central

Mayhew, David L; Hornberger, Troy A; Lincoln, Hannah C; Bamman, Marcas M

2011-01-01

Abstract The purpose of this study was to identify signalling components known to control mRNA translation initiation in skeletal muscle that are responsive to mechanical load and may be partly responsible for myofibre hypertrophy. To accomplish this, we first utilized a human cluster model in which skeletal muscle samples from subjects with widely divergent hypertrophic responses to resistance training were used for the identification of signalling proteins associated with the degree myofibre hypertrophy. We found that of 11 translational signalling molecules examined, the response of p(T421/S424)-p70S6K phosphorylation and total eukaryotic initiation factor 2Bɛ (eIF2Bɛ) protein abundance after a single bout of unaccustomed resistance exercise was associated with myofibre hypertrophy following 16 weeks of training. Follow up studies revealed that overexpression of eIF2Bɛ alone was sufficient to induce an 87% increase in cap-dependent translation in L6 myoblasts in vitro and 21% hypertrophy of myofibres in mouse skeletal muscle in vivo (P < 0.05). However, genetically altering p70S6K activity had no impact on eIF2Bɛ protein abundance in mouse skeletal muscle in vivo or multiple cell lines in vitro (P > 0.05), suggesting that the two phenomena were not directly related. These are the first data that mechanistically link eIF2Bɛ abundance to skeletal myofibre hypertrophy, and indicate that eIF2Bɛ abundance may at least partially underlie the widely divergent hypertrophic phenotypes in human skeletal muscle exposed to mechanical stimuli. PMID:21486778

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

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

Chen, Yu; Wang, Chengxiao; Liu, Ying

2013-08-16

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

Regulation of Deoxycholate Induction of CXCL8 by the Adenomatous Polyposis Coli Gene in Colorectal Cancer

PubMed Central

Rial, Nathaniel S; Lazennec, Gwendal; Prasad, Anil R; Krouse, Robert S; Lance, Peter; Gerner, Eugene W

2009-01-01

Elevated deoxycholic acid (DCA), mutations in the adenomatous polyposis coli (APC) gene and chronic inflammation are associated with increased risk of colorectal cancer (CRC). APC status was manipulated to determine whether DCA mediates inflammatory molecules in normal or initiated colonic mucosa. DCA increased steady state mRNA and protein levels of CXCL8 in cells which do not express wild type APC. Steady state CXCL8 mRNA and protein were suppressed when cells with conditional expression of wild type APC were exposed to DCA. Immunostaining did not detect CXCL8 in normal human colonic mucosa. CXCL8 was expressed in adenomatous polyps and adenocarcinomas. CXCL8 expression correlated with nuclear β-catenin localization in epithelial cells of adenomas, but was associated with endothelial cells and neutrophils in the adenocarcinomas. DCA-mediated CXCL8 promoter-reporter activity was elevated in a mutant APC background. Wild type APC suppressed this effect. Mutation of activator protein-1 (AP-1) or nuclear factor kappa B (NF-κB) sites suppressed the activation of the CXCL8 promoter-reporter by DCA. Chromatin immunoprecipitation (ChIP) revealed that AP-1 and NF-κB binding to the 5′-promoter of CXCL8 was induced by DCA. The β-catenin transcription factor was bound to the 5′-promoter of CXCL8 in the absence or presence of DCA. Phenotypic assays determined that DCA-mediated invasion was blocked by antibody directed against CXCL8 or wild type-APC. CXCL8 exposure lead to matrix metalloproteinase-2 (MMP-2) production and increased invasion on laminin coated filters. These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors. PMID:19173296

Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models

PubMed Central

Nguyen, Liem H.; Robinton, Daisy A.; Seligson, Marc; Wu, Linwei; Li, Lin; Rakheja, Dinesh; Comerford, Sarah; Ramezani, Saleh; Sun, Xiankai; Parikh, Monisha; Yang, Erin; Powers, John T.; Shinoda, Gen; Shah, Samar; Hammer, Robert; Daley, George Q.; Zhu, Hao

2014-01-01

SUMMARY Lin28a/b are RNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorly differentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenance has not been definitively addressed. We report that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpression in MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumor burden, extended latency, and prolonged survival. Both intravenous siRNA against Lin28b and conditional Lin28b deletion reduced tumor burden and prolonged survival. Igf2bp proteins are upregulated and Igf2bp3 is required in the context of LIN28B overexpression to promote growth. Thus, multiple murine models demonstrate that Lin28b is both sufficient to initiate liver cancer and necessary for its maintenance. PMID:25117712

Melatonin reverses H2 O2 -induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB.

PubMed

Nopparat, Chutikorn; Sinjanakhom, Puritat; Govitrapong, Piyarat

2017-08-01

Autophagy, a degradation mechanism that plays a major role in maintaining cellular homeostasis and diminishes in aging, is considered an aging characteristic. Melatonin is an important hormone that plays a wide range of physiological functions, including the anti-aging effect, potentially via the regulation of the Sirtuin1 (SIRT1) pathway. The deacetylation ability of SIRT1 is important for controlling the function of several transcription factors, including nuclear factor kappa B (NF-ĸB). Apart from inflammation, NF-ĸB can regulate autophagy by inhibiting Beclin1, an initiator of autophagy. Although numerous studies have revealed the role of melatonin in regulating autophagy, very limited experiments have shown that melatonin can increase autophagic activity via SIRT1 in a senescent model. This study focuses on the effect of melatonin on autophagy via the deacetylation activity of SIRT1 on RelA/p65, a subunit of NF-ĸB, to determine whether melatonin can attenuate the aging condition. SH-SY5Y cells were treated with H 2 O 2 to induce the senescent state. These results demonstrated that melatonin reduced a number of beta-galactosidase (SA-βgal)-positive cells, a senescent marker. In addition, melatonin increased the protein levels of SIRT1, Beclin1, and LC3-II, a hallmark protein of autophagy, and reduced the levels of acetylated-Lys310 in the p65 subunit of NF-ĸB in SH-SY5Y cells treated with H 2 O 2 . Furthermore, in the presence of SIRT1 inhibitor, melatonin failed to increase autophagic markers. The present data indicate that melatonin enhances autophagic activity via the SIRT1 signaling pathway. Taken together, we propose that in modulating autophagy, melatonin may provide a therapeutically beneficial role in the anti-aging processes. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of bovine somatotropin (500 mg) administered at ten-day intervals on ovulatory responses, expression of estrus, and fertility in dairy cows.

PubMed

Rivera, F; Narciso, C; Oliveira, R; Cerri, R L A; Correa-Calderón, A; Chebel, R C; Santos, J E P

2010-04-01

The objectives of this study were to evaluate the effect of administering 500 mg of recombinant bovine somatotropin (bST) every 10 d on ovulatory responses, estrous behavior, and fertility of lactating Holstein cows. Lactating dairy cows were assigned to 1 of 2 treatments: a control with no administration of bST (73 primiparous and 120 multiparous cows) or 6 consecutive administrations of 500 mg of bST (83 primiparous and 123 multiparous cows) given subcutaneously at 10-d intervals starting 61+/-3 d postpartum (study d 0), concurrent with the initiation of the timed artificial insemination (AI). Blood samples were collected thrice weekly from 61+/-3 to 124+/-3 d in milk (DIM), and plasma samples were analyzed for concentrations of estradiol, glucose, insulin, insulin-like growth factor 1, and progesterone. The estrous cycle of cows was presynchronized with 2 injections of PGF(2alpha) at 37+/-3 and 51+/-3 DIM, and the Ovsynch timed AI protocol was initiated at 61+/-3 DIM. Ovaries were scanned to determine ovulatory responses during the Ovsynch protocol. Pregnancy was diagnosed at 33 and 66 d after AI. Body condition was scored on study d 0, 10, 42, and 76. Sixty-four cows were fitted with a pressure mounting sensor with radiotelemetric transmitters to monitor estrous behavior. Treatment of lactating dairy cows with 500 mg of bST at 10-d intervals increased yields of milk and milk components in the first 2 mo after treatment. Body condition of bST-treated cows remained unaltered, whereas control cows gained BCS. Treatment with bST increased concentrations of insulin-like growth factor 1 chronically, but concentrations of insulin and glucose increased only transiently in the first 7 d after the first injection of bST. Concentrations of progesterone during and after the Ovsynch protocol remained unaltered after treatment with bST; likewise, ovulatory responses during the Ovsynch protocol were mostly unaltered by treatment. Concentration of estradiol tended to be greater for bST cows than for control cows immediately before induction of ovulation in the Ovsynch protocol. Similarly, the mean and the peak concentrations of estradiol were greater for bST cows than for control cows when monitored during spontaneous estrus. Nevertheless, duration of estrus and the median number of standing events were less for bST cows than for control cows. Pregnancies per AI after the first and second postpartum inseminations were not affected by bST treatment. Treatment of lactating dairy cows with 500 mg of bST every 10 d improved lactation performance, but it did not affect pregnancies per AI and it reduced expression of estrus. Copyright (c) 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

The Individual and Group Loyalty Scales (IGLS): construction and preliminary validation.

PubMed

Beer, Andrew; Watson, David

2009-05-01

Trait loyalty has received virtually no attention from researchers; consequently, the basic goal of this research was to create a measure of interpersonal loyalty. Principal factor analyses of an initial pool of items revealed 2 factors: Individual Loyalty (e.g., "I stand by my friends, even when they make mistakes") and Group Loyalty (e.g., "I am loyal to my country"). Analyses of a revised item pool identified the same 2 factors in a second sample. Scales based on these factors were internally consistent and only moderately related to one another. Additional analyses indicated that both scales (a) were stable over time; (b) showed moderate to strong self-peer agreement; (c) positively correlated with conscientiousness, agreeableness, altruism, and positive emotionality; and (d) negatively related to an avoidant attachment style. However, these associations all were moderate in magnitude (in fact, none was as high as |.40|), indicating that the Individual and Group Loyalty Scales tap unique variance that is not captured by existing instruments.

HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone

PubMed Central

Day, Kathleen C.; Hiles, Guadalupe Lorenzatti; Kozminsky, Molly; Dawsey, Scott J.; Paul, Alyssa; Broses, Luke J.; Shah, Rajal; Kunja, Lakshmi P.; Hall, Christopher; Palanisamy, Nallasivam; Daignault-Newton, Stephanie; El-Sawy, Layla; Wilson, Steven James; Chou, Andrew; Ignatoski, Kathleen Woods; Keller, Evan; Thomas, Dafydd; Nagrath, Sunitha; Morgan, Todd; Day, Mark L.

2016-01-01

Activation of the epidermal growth factor receptors EGFR (ErbB1) and HER2 (ErbB2) drive the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites. PMID:27793843

RNA polymerase I transcription in a Brassica interspecific hybrid and its progenitors: Tests of transcription factor involvement in nucleolar dominance.

PubMed Central

Frieman, M; Chen, Z J; Saez-Vasquez, J; Shen, L A; Pikaard, C S

1999-01-01

In interspecific hybrids or allopolyploids, often one parental set of ribosomal RNA genes is transcribed and the other is silent, an epigenetic phenomenon known as nucleolar dominance. Silencing is enforced by cytosine methylation and histone deacetylation, but the initial discrimination mechanism is unknown. One hypothesis is that a species-specific transcription factor is inactivated, thereby silencing one set of rRNA genes. Another is that dominant rRNA genes have higher binding affinities for limiting transcription factors. A third suggests that selective methylation of underdominant rRNA genes blocks transcription factor binding. We tested these hypotheses using Brassica napus (canola), an allotetraploid derived from B. rapa and B. oleracea in which only B. rapa rRNA genes are transcribed. B. oleracea and B. rapa rRNA genes were active when transfected into protoplasts of the other species, which argues against the species-specific transcription factor model. B. oleracea and B. rapa rRNA genes also competed equally for the pol I transcription machinery in vitro and in vivo. Cytosine methylation had no effect on rRNA gene transcription in vitro, which suggests that transcription factor binding was unimpaired. These data are inconsistent with the prevailing models and point to discrimination mechanisms that are likely to act at a chromosomal level. PMID:10224274

Detrimental effects of adenosine signaling in sickle cell disease.

PubMed

Zhang, Yujin; Dai, Yingbo; Wen, Jiaming; Zhang, Weiru; Grenz, Almut; Sun, Hong; Tao, Lijian; Lu, Guangxiu; Alexander, Danny C; Milburn, Michael V; Carter-Dawson, Louvenia; Lewis, Dorothy E; Zhang, Wenzheng; Eltzschig, Holger K; Kellems, Rodney E; Blackburn, Michael R; Juneja, Harinder S; Xia, Yang

2011-01-01

Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.

Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin.

PubMed

Wilson, Fiona A; Orellana, Renán A; Suryawan, Agus; Nguyen, Hanh V; Jeyapalan, Asumthia S; Frank, Jason; Davis, Teresa A

2008-07-01

Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7-10 days of pST (150 microg x kg(-1) x day(-1)) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 microU/ml), 2) fed control (25 microU/ml), and 3) fed pST-treated (50 microU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1.eIF4E complex association and increased active eIF4E.eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation.

Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin

PubMed Central

Wilson, Fiona A.; Orellana, Renán A.; Suryawan, Agus; Nguyen, Hanh V.; Jeyapalan, Asumthia S.; Frank, Jason; Davis, Teresa A.

2008-01-01

Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7–10 days of pST (150 μg·kg−1·day−1) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 μU/ml), 2) fed control (25 μU/ml), and 3) fed pST-treated (50 μU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1·eIF4E complex association and increased active eIF4E·eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation. PMID:18460595

40 CFR 86.117-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2014 CFR

2014-07-01

...), as measured in paragraph (b)(1) of this section. (v) r=FID response factor to methanol. (vi) PB = Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi) MHC, out = mass of...

New genetic associations detected in a host response study to hepatitis B vaccine.

PubMed

Davila, S; Froeling, F E M; Tan, A; Bonnard, C; Boland, G J; Snippe, H; Hibberd, M L; Seielstad, M

2010-04-01

The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.

How and Why Do Smokers Start Using E-Cigarettes? Qualitative Study of Vapers in London, UK

PubMed Central

Wadsworth, Elle; Neale, Joanne; McNeill, Ann; Hitchman, Sara C.

2016-01-01

The aims of the study were to (1) describe how and why smokers start to vape and what products they use; (2) relate findings to the COM-B theory of behaviour change (three conditions are necessary for behaviour change (B): capability (C), opportunity (O), and motivation (M)); and (3) to consider implications for e-cigarette policy research. Semi-structured interviews (n = 30) were conducted in London, UK, with smokers or ex-smokers who were currently using or had used e-cigarettes. E-cigarette initiation (behaviour) was facilitated by: capability (physical capability to use an e-cigarette and psychological capability to understand that using e-cigarettes was less harmful than smoking); opportunity (physical opportunity to access e-cigarettes in shops, at a lower cost than cigarettes, and to vape in “smoke-free” environments, as well as social opportunity to vape with friends and family); and motivation (automatic motivation including curiosity, and reflective motivation, including self-conscious decision-making processes related to perceived health benefits). The application of the COM-B model identified multiple factors that may lead to e-cigarette initiation, including those that could be influenced by policy, such as price relative to cigarettes and use in smoke-free environments. The effects of these policies on initiation should be further investigated along with the possible moderating/mediating effects of social support. PMID:27376312

Influence of Salmonella enterica Serovar Typhimurium ssrB on Colonization of Eastern Oysters (Crassostrea virginica) as Revealed by a Promoter Probe Screen

PubMed Central

Cox, Clayton E.; Wright, Anita C.; McClelland, Michael

2015-01-01

Although Salmonella has been isolated from 7.4 to 8.6% of domestic raw oysters, representing a significant risk for food-borne illness, little is known about the factors that influence their initial colonization by Salmonella. This study tested the hypothesis that specific regulatory changes enable a portion of the invading Salmonella population to colonize oysters. An in vivo promoter probe library screen identified 19 unique regions as regulated during colonization. The mutants in the nearest corresponding downstream genes were tested for colonization defects in oysters. Only one mutation, in ssrB, resulted in a significantly reduced ability to colonize oysters compared to that of wild-type Salmonella. Because ssrB regulates Salmonella pathogenicity island 2 (SPI-2)-dependent infections in vertebrate macrophages, the possibility that ssrB mediated colonization of oyster hemocytes in a similar manner was examined. However, no difference in hemocyte colonization was observed. The complementary hypothesis that signal exchange between Salmonella and the oyster's native microbial community aids colonization was also tested. Signals that triggered responses in quorum sensing (QS) reporters were shown to be produced by oyster-associated bacteria and present in oyster tissue. However, no evidence for signal exchange was observed in vivo. The sdiA reporter responded to salinity, suggesting that SdiA may also have a role in environmental sensing. Overall, this study suggests the initial colonization of live oysters by Salmonella is controlled by a limited number of regulators, including ssrB. PMID:26497459

HFR1 Sequesters PIF1 to Govern the Transcriptional Network Underlying Light-Initiated Seed Germination in Arabidopsis[C][W][OPEN

PubMed Central

Shi, Hui; Zhong, Shangwei; Mo, Xiaorong; Liu, Na; Nezames, Cynthia D.; Deng, Xing Wang

2013-01-01

Seed germination is the first step for seed plants to initiate a new life cycle. Light plays a predominant role in promoting seed germination, where the initial phase is mediated by photoreceptor phytochrome B (phyB). Previous studies showed that PHYTOCHROME-INTERACTING FACTOR1 (PIF1) represses seed germination downstream of phyB. Here, we identify a positive regulator of phyB-dependent seed germination, LONG HYPOCOTYL IN FAR-RED1 (HFR1). HFR1 blocks PIF1 transcriptional activity by forming a heterodimer with PIF1 that prevents PIF1 from binding to DNA. Our whole-genomic analysis shows that HFR1 and PIF1 oppositely mediate the light-regulated transcriptome in imbibed seeds. Through the HFR1–PIF1 module, light regulates expression of numerous genes involved in cell wall loosening, cell division, and hormone pathways to initiate seed germination. The functionally antagonistic HFR1–PIF1 pair constructs a fail-safe mechanism for fine-tuning seed germination during low-level illumination, ensuring a rapid response to favorable environmental changes. This study identifies the HFR1–PIF1 pair as a central module directing the whole genomic transcriptional network to rapidly initiate light-induced seed germination. PMID:24179122

Development of the Expert System Domain Advisor and Analysis Tool

DTIC Science & Technology

1991-09-01

analysis. Typical of the current methods in use at this time is the " tarot metric". This method defines a decision rule whose output is whether to go...B - TAROT METRIC B. ::TTRODUCTION The system chart of ESEM, Figure 1, shows the following three risk-based decision points: i. At prolect initiation...34 decisions. B-I 201 PRELIMINARY T" B-I. Evaluais Factan for ES Deyelopsineg FACTORS POSSIBLE VALUE RATINGS TAROT metric (overall suitability) Poor, Fair

The initiation and development of small peat-forming ecosystems adjacent to lakes in the north central Canadian low arctic during the Holocene

NASA Astrophysics Data System (ADS)

Camill, Philip; Umbanhowar, Charles E.; Geiss, Christoph; Edlund, Mark B.; Hobbs, Will O.; Dupont, Allison; Doyle-Capitman, Catherine; Ramos, Matthew

2017-07-01

Small peat-forming ecosystems in arctic landscapes may play a significant role in the regional biogeochemistry of high-latitude systems, yet they are understudied compared to arctic uplands and other major peat-forming regions of the North. We present a new data set of 25 radiocarbon-dated permafrost peat cores sampled around eight low arctic lake sites in northern Manitoba (Canada) to examine the timing of peat initiation and controls on peat accumulation throughout the Holocene. We used macrofossils and charcoal to characterize changes in the plant community and fire, and we explored potential impacts of these local factors, as well as regional climatic change, on rates of C accumulation and C stocks. Peat initiation was variable across and within sites, suggesting the influence of local topography, but 56% of the cores initiated after 3000 B.P. Most cores initiated and remained as drier bog hummock communities, with few vegetation transitions in this landscape. C accumulation was relatively slow and did not appear to be correlated with Holocene-scale climatic variability, but C stocks in this landscape were substantial (mean = 45.4 kg C m-2), potentially accounting for 13.2 Pg C in the Taiga Shield ecozone. To the extent that small peat-forming systems are underrepresented in peatland mapping, soil organic carbon (SOC) stocks may be underestimated in arctic regions. Mean fire severity appeared to be negatively correlated with C accumulation rates. Initiation and accumulation of soil C may respond to both regional and local factors, and substantial lowland soil C stocks have the potential for biogeochemical impacts on adjacent aquatic ecosystems.

A Translation System Reconstituted with Human Factors Proves That Processing of Encephalomyocarditis Virus Proteins 2A and 2B Occurs in the Elongation Phase of Translation without Eukaryotic Release Factors*

PubMed Central

Machida, Kodai; Mikami, Satoshi; Masutani, Mamiko; Mishima, Kurumi; Kobayashi, Tominari; Imataka, Hiroaki

2014-01-01

The genomic RNA of encephalomyocarditis virus (EMCV) encodes a single polyprotein, and the primary scission of the polyprotein occurs between nonstructural proteins 2A and 2B by an unknown mechanism. To gain insight into the mechanism of 2A-2B processing, we first translated the 2A-2B region in vitro with eukaryotic and prokaryotic translation systems. The 2A-2B processing occurred only in the eukaryotic systems, not in the prokaryotic systems, and the unprocessed 2A-2B protein synthesized by a prokaryotic system remained uncleaved when incubated with a eukaryotic cell extract. These results suggest that 2A-2B processing is a eukaryote-specific, co-translational event. To define the translation factors required for 2A-2B processing, we constituted a protein synthesis system with eukaryotic elongation factors 1 and 2, eukaryotic release factors 1 and 3 (eRF1 and eRF3), aminoacyl-tRNA synthetases, tRNAs, ribosome subunits, and a plasmid template that included the hepatitis C virus internal ribosome entry site. We successfully reproduced 2A-2B processing in the reconstituted system even without eRFs. Our results indicate that this unusual event occurs in the elongation phase of translation. PMID:25258322

New insights into the interplay between the translation machinery and nonsense-mediated mRNA decay factors.

PubMed

Raimondeau, Etienne; Bufton, Joshua C; Schaffitzel, Christiane

2018-06-19

Faulty mRNAs with a premature stop codon (PTC) are recognized and degraded by nonsense-mediated mRNA decay (NMD). Recognition of a nonsense mRNA depends on translation and on the presence of NMD-enhancing or the absence of NMD-inhibiting factors in the 3'-untranslated region. Our review summarizes our current understanding of the molecular function of the conserved NMD factors UPF3B and UPF1, and of the anti-NMD factor Poly(A)-binding protein, and their interactions with ribosomes translating PTC-containing mRNAs. Our recent discovery that UPF3B interferes with human translation termination and enhances ribosome dissociation in vitro , whereas UPF1 is inactive in these assays, suggests a re-interpretation of previous experiments and modification of prevalent NMD models. Moreover, we discuss recent work suggesting new functions of the key NMD factor UPF1 in ribosome recycling, inhibition of translation re-initiation and nascent chain ubiquitylation. These new findings suggest that the interplay of UPF proteins with the translation machinery is more intricate than previously appreciated, and that this interplay quality-controls the efficiency of termination, ribosome recycling and translation re-initiation. © 2018 The Author(s).

Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells.

PubMed

Choudhury, Sreetama; Ghosh, Sayan; Mukherjee, Sudeshna; Gupta, Payal; Bhattacharya, Saurav; Adhikary, Arghya; Chattopadhyay, Sreya

2016-12-01

Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53-miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols. Copyright © 2016 Elsevier Inc. All rights reserved.

Emerging insights into the biology of typhoid toxin

PubMed Central

Fowler, Casey C.; Chang, Shu-Jung; Gao, Xiang; Geiger, Tobias; Stack, Gabrielle; Galán, Jorge E.

2017-01-01

Typhoid toxin is a unique A2B5 exotoxin and an important virulence factor for Salmonella Typhi, the cause of typhoid fever. In the decade since its initial discovery, great strides have been made in deciphering the unusual biological program of this toxin, which is fundamentally different from related toxins in many ways. Purified typhoid toxin administered to laboratory animals causes many of the symptoms of typhoid fever, suggesting that typhoid toxin is a central factor in this disease. Further advances in understanding the biology of this toxin will help guide the development of badly needed diagnostics and therapeutic interventions that target this toxin to detect, prevent or treat typhoid fever. PMID:28213043

Etsrp/etv2 is directly regulated by foxc1a/b in the zebrafish angioblast

PubMed Central

Veldman, Matthew B.; Lin, Shuo

2012-01-01

Rationale Endothelial cells are developmentally derived from angioblasts specified in the mesodermal germ cell layer. The transcription factor etsrp/etv2 is at the top of the known genetic hierarchy for angioblast development. The transcriptional events that induce etsrp expression and angioblast specification are not well understood. Objective We generated etsrp:gfp transgenic zebrafish and used them to identify regulatory regions and transcription factors critical for etsrp expression and angioblast specification from mesoderm. Methods and Results To investigate the mechanisms that initiate angioblast cell transcription during embryogenesis, we have performed promoter analysis of the etsrp locus in zebrafish. We describe three enhancer elements sufficient for endothelial gene expression when place in front of a heterologous promoter. The deletion of all three regulatory regions led to a near complete loss of endothelial expression from the etsrp promoter. One of the enhancers, located 2.3 kb upstream of etsrp contains a consensus FOX binding site that binds Foxc1a and Foxc1b in vitro by EMSA and in vivo using ChIP. Combined knockdown of foxc1a/b, using morpholinos, led to a significant decrease in etsrp expression at early developmental stages as measured by quantitative RT-PCR and in situ hybridization. Decreased expression of primitive erythrocyte genes scl and gata1 was also observed while pronephric gene pax2a was relatively normal in expression level and pattern. Conclusions These findings identify mesodermal foxc1a/b as a direct upstream regulator of etsrp in angioblasts. This establishes a new molecular link in the process of mesoderm specification into angioblast. PMID:22135404

Etsrp/Etv2 is directly regulated by Foxc1a/b in the zebrafish angioblast.

PubMed

Veldman, Matthew B; Lin, Shuo

2012-01-20

Endothelial cells are developmentally derived from angioblasts specified in the mesodermal germ cell layer. The transcription factor etsrp/etv2 is at the top of the known genetic hierarchy for angioblast development. The transcriptional events that induce etsrp expression and angioblast specification are not well understood. We generated etsrp:gfp transgenic zebrafish and used them to identify regulatory regions and transcription factors critical for etsrp expression and angioblast specification from mesoderm. To investigate the mechanisms that initiate angioblast cell transcription during embryogenesis, we have performed promoter analysis of the etsrp locus in zebrafish. We describe three enhancer elements sufficient for endothelial gene expression when place in front of a heterologous promoter. The deletion of all 3 regulatory regions led to a near complete loss of endothelial expression from the etsrp promoter. One of the enhancers, located 2.3 kb upstream of etsrp contains a consensus FOX binding site that binds Foxc1a and Foxc1b in vitro by EMSA and in vivo using ChIP. Combined knockdown of foxc1a/b, using morpholinos, led to a significant decrease in etsrp expression at early developmental stages as measured by quantitative reverse transcriptase-polymerase chain reaction and in situ hybridization. Decreased expression of primitive erythrocyte genes scl and gata1 was also observed, whereas pronephric gene pax2a was relatively normal in expression level and pattern. These findings identify mesodermal foxc1a/b as a direct upstream regulator of etsrp in angioblasts. This establishes a new molecular link in the process of mesoderm specification into angioblast.

Structure and genomic organization of the human B1 receptor gene for kinins (BDKRB1).

PubMed

Bachvarov, D R; Hess, J F; Menke, J G; Larrivée, J F; Marceau, F

1996-05-01

Two subtypes of mammalian bradykinin receptors, B1 and B2 (BDKRB1 and BDKRB2), have been defined based on their pharmacological properties. The B1 type kinin receptors have weak affinity for intact BK or Lys-BK but strong affinity for kinin metabolites without the C-terminal arginine (e.g., des-Arg9-BK and Lys-des-Arg9-BK, also called des-Arg10-kallidin), which are generated by kininase I. The B1 receptor expression is up-regulated following tissue injury and inflammation (hyperemia, exudation, hyperalgesia, etc.). In the present study, we have cloned and sequenced the gene encoding human B1 receptor from a human genomic library. The human B1 receptor gene contains three exons separated by two introns. The first and the second exon are noncoding, while the coding region and the 3'-flanking region are located entirely on the third exon. The exon-intron arrangement of the human B1 receptor gene shows significant similarity with the genes encoding the B2 receptor subtype in human, mouse, and rat. Sequence analysis of the 5'-flanking region revealed the presence of a consensus TATA box and of numerous candidate transcription factor binding sequences. Primer extension experiments have shown the existence of multiple transcription initiation sites situated downstream and upstream from the consensus TATA box. Genomic Southern blot analysis indicated that the human B1 receptor is encoded by a single-copy gene.

Hyphopodium-Specific VdNoxB/VdPls1-Dependent ROS-Ca2+ Signaling Is Required for Plant Infection by Verticillium dahliae.

PubMed

Zhao, Yun-Long; Zhou, Ting-Ting; Guo, Hui-Shan

2016-07-01

Verticillium dahliae is a phytopathogenic fungus obligate in root infection. A few hyphopodia differentiate from large numbers of hyphae after conidia germination on the root surface for further infection. However, the molecular features and role of hyphopodia in the pathogenicity of V. dahliae remain elusive. In this study, we found that the VdPls1, a tetraspanin, and the VdNoxB, a catalytic subunit of membrane-bound NADPH oxidases for reactive oxygen species (ROS) production, were specifically expressed in hyphopodia. VdPls1 and VdNoxB highly co-localize with the plasma membrane at the base of hyphopodia, where ROS and penetration pegs are generated. Mutant strains, VdΔnoxb and VdΔpls1, in which VdPls1 and VdNoxB were deleted, respectively, developed defective hyphpodia incapable of producing ROS and penetration pegs. Defective plasma membrane localization of VdNoxB in VdΔpls1 demonstrates that VdPls1 functions as an adaptor protein for the recruitment and activation of the VdNoxB. Furthermore, in VdΔnoxb and VdΔpls1, tip-high Ca2+ accumulation was impaired in hyphopodia, but not in vegetative hyphal tips. Moreover, nuclear targeting of VdCrz1 and activation of calcineurin-Crz1 signaling upon hyphopodium induction in wild-type V. dahliae was impaired in both knockout mutants, indicating that VdPls1/VdNoxB-dependent ROS was specifically required for tip-high Ca2+ elevation in hyphopodia to activate the transcription factor VdCrz1 in the regulation of penetration peg formation. Together with the loss of virulence of VdΔnoxb and VdΔpls1, which are unable to initiate colonization in cotton plants, our data demonstrate that VdNoxB/VdPls1-mediated ROS production activates VdCrz1 signaling through Ca2+ elevation in hyphopodia, infectious structures of V. dahliae, to regulate penetration peg formation during the initial colonization of cotton roots.

An ErbB2-Muc4 complex in rat ocular surface epithelia.

PubMed

Swan, Jeremy S; Arango, Maria E; Carothers Carraway, Coralie A; Carraway, Kermit L

2002-05-01

To show the presence and localization of type 1 growth factor receptors (ErbB2, ErbB3 and ErbB4) in rat corneal and conjunctival epithelia and investigate the association of ErbB2 with its intramembrane ligand Muc4. Methacarn-fixed, paraffin-embedded sections of corneas and eyelids from female adult rats were immunocytochemically stained using antibodies against the ErbB receptors and Muc4. Sequential immunoprecipitation and immunoblot analyses were performed on epithelial lysates to investigate the presence of a complex of Muc4 and ErbB2 in corneal and conjunctival epithelia. Immunocytochemical staining demonstrated the presence of ErbB2, ErbB3 and ErbB4 growth factor receptors throughout the rat corneal and conjunctival epithelia. Co-immunoprecipitation of the epithelial lysates demonstrated that Muc4 and ErbB2 are present as a complex. The three type 1 growth factor receptors (ErbB2, ErbB3 and ErbB4) are present in the rat corneal and conjunctival epithelia, and ErbB2 is at least partly associated with Muc4. This demonstration of the presence and localization of these three type 1 growth factor receptors may help in understanding how these receptors contribute to ocular epithelial behavior and functions.

Risk factors for late-onset neutropenia after rituximab treatment of B-cell lymphoma.

PubMed

Arai, Yasuyuki; Yamashita, Kouhei; Mizugishi, Kiyomi; Nishikori, Momoko; Hishizawa, Masakatsu; Kondo, Tadakazu; Kitano, Toshiyuki; Kawabata, Hiroshi; Kadowaki, Norimitsu; Takaori-Kondo, Akifumi

2015-05-01

Late-onset neutropenia after rituximab (RTX) therapy (R-LON) has been widely reported, but clinical studies on a large number of cases are limited. In this study, we aimed to investigate the incidence and risk factors of R-LON. In this study, we retrospectively analyzed data of 213 enrolled B-cell lymphoma patients (male 114; female 99) treated with RTX at a single institution. R-LON was defined as otherwise unexplained grade III-IV neutropenia after RTX. The median age of the patients was 62 years, and 129 of them were initially diagnosed at advanced stages (stage III-IV). R-LON occurred in 19 patients within a median of 121 (range, 49-474) days after the last RTX administration. The 1-year cumulative incidence was 9.0%. On univariate analysis, older age (>60 years), advanced stage, and purine analog or methotrexate administration were significant or borderline significant risk factors for R-LON, whereas sex, disease type, bone marrow invasion, combination with cytotoxic chemotherapeutic drugs, intensified therapy (compared with R-CHOP), prior autologous transplantation, and repeated RTX administration were not. On multivariate analysis, older age (hazard ratio (HR), 2.95) and advanced stage (HR, 3.56) were significant risk factors. Treatment with granulocyte colony-stimulating factor was feasible in grade IV R-LON patients with high risk of infection. Careful follow-up is therefore necessary after B-cell lymphoma treatment, especially in high-risk patients with advanced disease or of older age.

Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression

PubMed Central

2013-01-01

Background Recurrent respiratory infections are one of the most important causes of morbidity in childhood. When immune functions are still largely immature, the airway epithelium plays a primary defensive role since, besides providing a physical barrier, it is also involved in the innate and the adaptive immune responses. A study was therefore designed to evaluate in vitro whether pidotimod, a synthetic dipeptide able to stimulate the inflammatory and immune effector cells, could activate bronchial epithelial cell functions involved in response to infections. Methods BEAS-2B cell line (human bronchial epithelial cells infected with a replication-defective Adenovirus 12-SV40 virus hybrid) were cultured in the presence of pidotimod, with or without tumor necrosis factor (TNF)-α or zymosan to assess: a) intercellular adhesion molecule (ICAM)-1 expression, by flow cytometry; b) toll-like receptor (TLR)-2 expression and production, by immunofluorescence flow cytometry and western blotting; d) interleukin (IL)-8 release, by enzyme-linked immunosorbent assay (ELISA); e) activated extracellular-signal-regulated kinase (ERK1/2) phosphorylation and nuclear factor-kappa B (NF-kB) activation, by western blotting. Results The constitutive expression of ICAM-1 and IL-8 release were significant up-regulated by TNF-α (ICAM-1) and by TNF-α and zymosan (IL-8), but not by pidotimod. In contrast, an increased TLR-2 expression was found after exposure to pidotimod 10 and 100 μg/ml (p < 0.05) and to the association pidotimod 100 μg/ml + TNF-α (p < 0.05). Western blot analysis substantiated that the constitutive TLR-2 expression was significantly increased after exposure to all the stimuli. Finally, while a remarkable inhibition of TNF-α -induced ERK1/2 phosphorylation was observed in the presence of pidotimod, both TNF-α and pidotimod were effective in inducing NF-kB protein expression in the cytoplasm and its nuclear translocation. Conclusion Through different effects on ERK1/2 and NF-kB, pidotimod was able to increase the expression of TLR-2 proteins, surface molecules involved in the initiation of the innate response to infectious stimuli. The lack of effect on ICAM-1 expression, the receptor for rhinovirus, and on IL-8 release, the potent chemotactic factor for neutrophils (that are already present in sites of infection), may represent protective functions. If confirmed in vivo, these activities may, at least in part, clarify the mechanism of action of this molecule at airway level. PMID:23663325

Hepatitis B virus in Pakistan: A systematic review of prevalence, risk factors, awareness status and genotypes

PubMed Central

2011-01-01

In Pakistan, there are estimated 7-9 million carriers of hepatitis B virus (HBV) with a carrier rate of 3-5%. This article reviews the available literature about the prevalence, risk factors, awareness status and genotypes of the HBV in Pakistan by using key words; HBV prevalence, risk factors, awareness status and genotypes in Pakistani population in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. One hundred and six different studies published from 1998 to 2010 were included in this study. Weighted mean and standard deviation were determined for each population group. The percentage of hepatitis B virus infection in general population was 4.3318% ± 1.644%, healthy blood donors (3.93% ± 1.58%), military recruits (4.276% ± 1.646%), healthcare persons (3.25% ± 1.202%), pregnant women (5.872% ± 4.984), prisoners (5.75% ± 0.212%), surgical patients (7.397% ± 2.012%), patients with cirrhosis (28.87% ± 11.90%), patients with HCC (22% ± 2.645%), patients with hepatitis (15.896% ± 14.824%), patients with liver diseases (27.54% ± 6.385%), multiple transfused patients (6.223% ± 2.121%), opthalmic patients (3.89% ± 1.004%) and users of injectable drugs (14.95% ± 10.536%). Genotype D (63.71%) is the most prevalent genotype in Pakistani population. Mass vaccination and awareness programs should be initiated on urgent basis especially in populations with HBV infection rates of more than 5%. PMID:21375760

Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice

PubMed Central

Ip, Blanche C.; Liu, Chun; Ausman, Lynne M.; von Lintig, Johannes; Wang, Xiang-Dong

2014-01-01

Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10’-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9’,10’-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether the lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 is important in BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs 20%) and multiplicity (58% vs 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic pro-inflammatory signaling (phosphorylation of nuclear factor-κB p65 and signal transducer and activator of transcription 3; interleukin-6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ERUPR), through decreasing ERUPR-mediated protein kinase RNA-activated like kinase– eukaryotic initiation factor 2α activation, and inositol requiring 1α–X-box binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals including Met mRNA, β-catenin protein, and mammalian target of rapamycin (mTOR) complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR-214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. PMID:25293877

Phosphoproteomic Analysis of Signaling Pathways in Head and Neck Squamous Cell Carcinoma Patient Samples

PubMed Central

Frederick, Mitchell J.; VanMeter, Amy J.; Gadhikar, Mayur A.; Henderson, Ying C.; Yao, Hui; Pickering, Curtis C.; Williams, Michelle D.; El-Naggar, Adel K.; Sandulache, Vlad; Tarco, Emily; Myers, Jeffrey N.; Clayman, Gary L.; Liotta, Lance A.; Petricoin, Emanuel F.; Calvert, Valerie S.; Fodale, Valentina; Wang, Jing; Weber, Randal S.

2011-01-01

Molecular targeted therapy represents a promising new strategy for treating cancers because many small-molecule inhibitors targeting protein kinases have recently become available. Reverse-phase protein microarrays (RPPAs) are a useful platform for identifying dysregulated signaling pathways in tumors and can provide insight into patient-specific differences. In the present study, RPPAs were used to examine 60 protein end points (predominantly phosphoproteins) in matched tumor and nonmalignant biopsy specimens from 23 patients with head and neck squamous cell carcinoma to characterize the cancer phosphoproteome. RPPA identified 18 of 60 analytes globally elevated in tumors versus healthy tissue and 17 of 60 analytes that were decreased. The most significantly elevated analytes in tumor were checkpoint kinase (Chk) 1 serine 345 (S345), Chk 2 S33/35, eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) S65, protein kinase C (PKC) ζ/ι threonine 410/412 (T410/T412), LKB1 S334, inhibitor of kappaB alpha (IκB-α) S32, eukaryotic translation initiation factor 4E (eIF4E) S209, Smad2 S465/67, insulin receptor substrate 1 (IRS-1) S612, mitogen-activated ERK kinase 1/2 (MEK1/2) S217/221, and total PKC ι. To our knowledge, this is the first report of elevated PKC ι in head and neck squamous cell carcinoma that may have significance because PKC ι is an oncogene in several other tumor types, including lung cancer. The feasibility of using RPPA for developing theranostic tests to guide personalized therapy is discussed in the context of these data. PMID:21281788

TEM study on the initial oxidation of Zircaloy-4 thin foil specimens heated in a low vacuum air condition at 280-300 °C

NASA Astrophysics Data System (ADS)

Wang, Zhen; Zhou, Bang-xin; Zhu, Wei; Wen, Bang; Yao, Mei-yi; Li, Qiang; Wu, Lu; Zhang, Jin-long; Fang, Zhong-qiang

2017-04-01

As one of the important structural materials in nuclear industry, the corrosion resistance of zirconium alloy limits their in-pile application. Therefore, it is necessary to investigate the corrosion mechanism of zirconium alloys. The zirconium-oxygen reaction at the O/M interface is one of the factors that affect the oxidation process. There are few reports in this regard. Ideally, the reaction process at the O/M interface has certain relevance with the initiation oxidation of zirconium, which provided a new way to investigate the reaction process by observing the initiation oxidation behaviours. To investigate the oxidation behaviours of zirconium alloy at the initial stage, in this paper, zircaloy-4 TEM thin foil specimens in 3 mm diameter were studied by TEM observation after heating in air condition with a vacuum of 3 Pa at 280 °C, 290 °C and 300 °C for 30 min exposures. The results show that, ZrO2 begin to nucleate at a size of 3-5 nm at a high Zr/O ratio of 10.4 and oxide layer formed while Zr/O was 4.6. As a result of stress caused by the P.B ratio of Zr, slip bands formed and a bcc structure sub-oxide b-ZrOx (a = 0.51 nm) grew up along with the slip bands was observed. At both sides of b-ZrOx, two hcp structure sub-oxides having the same a-axis lattice parameter and different c-axis lattice parameter were detected.

Insights into dechlorination of PCE and TCE from carbon isotope fractionation by vitamin B12

NASA Astrophysics Data System (ADS)

Slater, G.; Sherwood Lollar, B.; Lesage, S.; Brown, S.

2003-04-01

Reductive dechlorination of perchloroethylene (PCE) and trichloroethylene (TCE) by vitamin B12 is both a potential remediation technique and an analogue of the microbial reductive dechlorination reaction. Stable carbon isotopic analysis, an effective and powerful tool for the investigation and monitoring of contaminant remediation, was used to characterize the isotopic effects of reductive dechlorination of PCE and TCE by vitamin B12 in laboratory microcosms. 10 mg/L vitamin B12 degraded greater than 90% of an initial concentration of PCE of 20 mg/L. TCE, the primary product of PCE degradation, accounted for between 64 - 72% of the PCE degraded. In experiments with TCE, 147 mg/L vitamin B12 degraded greater than 90% of an initial concentration of TCE of 20 mg/L. Cis-dichloroethene (cDCE), the primary product of TCE degradation, accounted for between 30 - 35% of the TCE degraded. Degradation of both PCE and TCE exhibited first order kinetics. Strong isotopic fractionation of the reactant PCE and of the reactant TCE was observed over the course of degradation. This fractionation could be described by a Rayleigh model with enrichment factors between -16.5 ppm and -15.8 ppm for PCE, and -17.2 ppm and -16.6 ppm for TCE. Fractionation was similar in all four experiments, with a mean enrichment factor of -16.5 +/- 0.6 ppm. These large enrichment factors indicate that isotopic analysis can be used to assess the occurrence of dechlorination of PCE and TCE by vitamin B12 in remediation situations. Significantly, the Rayleigh model could be used to predict the isotopic compositions of the major products of the reaction as well as the reactant, notwithstanding the lack of complete mass balance observed between product and reactant. This evidence suggests that isotopic fractionation is taking place during complexation of the chlorinated ethenes to vitamin B12, as has been suggested for reductive dechlorination by zero valent iron. The differences between e for this reaction and those observed for microbial biodegradation of the chlorinated ethenes suggest that there may be differences in the rate determining step for these two processes. Determining which steps are rate determining during degradation may allow optimization of contaminant remediation.

12 CFR 327.10 - Assessment rate schedules.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) The risk factors and other factors taken into account pursuant to 12 U.S.C. 1817(b)(1); and (v) Any... prescribed in the following schedule: Initial Base Assessment Rate Schedule Risk category I * Minimum Maximum II III IV Annual rates (in basis points) 12 16 22 32 45 * All amounts for all risk categories are in...

12 CFR 327.10 - Assessment rate schedules.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) The risk factors and other factors taken into account pursuant to 12 U.S.C. 1817(b)(1); and (v) Any... prescribed in the following schedule: Initial Base Assessment Rate Schedule Risk category I * Minimum Maximum II III IV Annual rates (in basis points) 12 16 22 32 45 * All amounts for all risk categories are in...

Alternative translation initiation of Caveolin-2 desensitizes insulin signaling through dephosphorylation of insulin receptor by PTP1B and causes insulin resistance.

PubMed

Kwon, Hayeong; Jang, Donghwan; Choi, Moonjeong; Lee, Jaewoong; Jeong, Kyuho; Pak, Yunbae

2018-06-01

Insulin resistance, defined as attenuated sensitivity responding to insulin, impairs insulin action. Direct causes and molecular mechanisms of insulin resistance have thus far remained elusive. Here we show that alternative translation initiation (ATI) of Caveolin-2 (Cav-2) regulates insulin sensitivity. Cav-2β isoform yielded by ATI desensitizes insulin receptor (IR) via dephosphorylation by protein-tyrosine phosphatase 1B (PTP1B), and subsequent endocytosis and lysosomal degradation of IR, causing insulin resistance. Blockage of Cav-2 ATI protects against insulin resistance by preventing Cav-2β-PTP1B-directed IR desensitization, thereby normalizing insulin sensitivity and glucose uptake. Our findings show that Cav-2β is a negative regulator of IR signaling, and identify a mechanism causing insulin resistance through control of insulin sensitivity via Cav-2 ATI. Copyright © 2018 Elsevier B.V. All rights reserved.

Removal of azo dye using Fenton and Fenton-like processes: Evaluation of process factors by Box-Behnken design and ecotoxicity tests.

PubMed

Fernandes, Neemias Cintra; Brito, Lara Barroso; Costa, Gessyca Gonçalves; Taveira, Stephânia Fleury; Cunha-Filho, Marcílio Sérgio Soares; Oliveira, Gisele Augusto Rodrigues; Marreto, Ricardo Neves

2018-06-06

The conventional treatment of textile effluents is usually inefficient in removing azo dyes and can even generate more toxic products than the original dyes. The aim of the present study was to optimize the process factors in the degradation of Disperse Red 343 by Fenton and Fenton-like processes, as well as to investigate the ecotoxicity of the samples treated under optimized conditions. A Box-Behnken design integrated with the desirability function was used to optimize dye degradation, the amount of residual H 2 O 2 [H 2 O 2residual ], and the ecotoxicity of the treated samples (lettuce seed, Artemia salina, and zebrafish in their early-life stages). Dye degradation was affected only by catalyst concentration [Fe] in both the Fenton and Fenton-like processes. In the Fenton reaction, [H 2 O 2residual ] was significantly affected by initial [H 2 O 2 ] and its interaction with [Fe]; however, in the Fenton-like reaction, it was affected by initial [H 2 O 2 ] only. A. salina mortality was affected by different process factors in both processes, which suggests the formation of different toxic products in each process. The desirability function was applied to determine the best process parameters and predict the responses, which were confirmed experimentally. Optimal conditions facilitated the complete degradation of the dye without [H 2 O 2residual ] or toxicity for samples treated with the Fenton-like process, whereas the Fenton process induced significant mortality for A. salina. Results indicate that the Fenton-like process is superior to the Fenton reaction to degrade Disperse Red 343. Copyright © 2018 Elsevier B.V. All rights reserved.

Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

PubMed Central

Fatima, Ayesha; Abdul, Ahmad Bustamam Hj.; Abdullah, Rasedee; Karjiban, Roghayeh Abedi; Lee, Vannajan Sanghiran

2015-01-01

Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis. PMID:25629232

Positive feedback of NR2B-containing NMDA receptor activity is the initial step toward visual imprinting: a model for juvenile learning.

PubMed

Nakamori, Tomoharu; Sato, Katsushige; Kinoshita, Masae; Kanamatsu, Tomoyuki; Sakagami, Hiroyuki; Tanaka, Kohichi; Ohki-Hamazaki, Hiroko

2015-01-01

Imprinting in chicks is a good model for elucidating the processes underlying neural plasticity changes during juvenile learning. We recently reported that neural activation of a telencephalic region, the core region of the hyperpallium densocellulare (HDCo), was critical for success of visual imprinting, and that N-Methyl-D-aspartic (NMDA) receptors containing the NR2B subunit (NR2B/NR1) in this region were essential for imprinting. Using electrophysiological and multiple-site optical imaging techniques with acute brain slices, we found that long-term potentiation (LTP) and enhancement of NR2B/NR1 currents in HDCo neurons were induced in imprinted chicks. Enhancement of NR2B/NR1 currents as well as an increase in surface NR2B expression occurred even following a brief training that was too weak to induce LTP or imprinting behavior. This means that NR2B/NR1 activation is the initial step of learning, well before the activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors which induces LTP. We also showed that knockdown of NR2B/NR1 inhibited imprinting, and inversely, increasing the surface NR2B expression by treatment with a casein kinase 2 inhibitor successfully reduced training time required for imprinting. These results suggest that imprinting stimuli activate post-synaptic NR2B/NR1 in HDCo cells, increase NR2B/NR1 signaling through up-regulation of its expression, and induce LTP and memory acquisition. The study investigated the neural mechanism underlying juvenile learning. In the initial stage of chick imprinting, NMDA receptors containing the NMDA receptor subunit 2B (NR2B) are activated, surface expression of NR2B/NR1 (NMDA receptor subunit 1) is up-regulated, and consequently long-term potentiation is induced in the telencephalic neurons. We suggest that the positive feedback in the NR2B/NR1 activation is a unique process of juvenile learning, exhibiting rapid memory acquisition. © 2014 International Society for Neurochemistry.

Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH).

PubMed Central

van Vuuren, A J; Vermeulen, W; Ma, L; Weeda, G; Appeldoorn, E; Jaspers, N G; van der Eb, A J; Bootsma, D; Hoeijmakers, J H; Humbert, S

1994-01-01

ERCC3 was initially identified as a gene correcting the nucleotide excision repair (NER) defect of xeroderma pigmentosum complementation group B (XP-B). The recent finding that its gene product is identical to the p89 subunit of basal transcription factor BTF2(TFIIH), opened the possibility that it is not directly involved in NER but that it regulates the transcription of one or more NER genes. Using an in vivo microinjection repair assay and an in vitro NER system based on cell-free extracts we demonstrate that ERCC3 in BTF2 is directly implicated in excision repair. Antibody depletion experiments support the idea that the p62 BTF2 subunit and perhaps the entire transcription factor function in NER. Microinjection experiments suggest that exogenous ERCC3 can exchange with ERCC3 subunits in the complex. Expression of a dominant negative K436-->R ERCC3 mutant, expected to have lost all helicase activity, completely abrogates NER and transcription and concomitantly induces a dramatic chromatin collapse. These findings establish the role of ERCC3 and probably the entire BTF2 complex in transcription in vivo which was hitherto only demonstrated in vitro. The results strongly suggest that transcription itself is a critical component for maintenance of chromatin structure. The remarkable dual role of ERCC3 in NER and transcription provides a clue in understanding the complex clinical features of some inherited repair syndromes. Images PMID:8157004

Bacterial translation elongation factor EF-Tu interacts and colocalizes with actin-like MreB protein.

PubMed

Defeu Soufo, Hervé Joël; Reimold, Christian; Linne, Uwe; Knust, Tobias; Gescher, Johannes; Graumann, Peter L

2010-02-16

We show that translation initiation factor EF-Tu plays a second important role in cell shape maintenance in the bacterium Bacillus subtilis. EF-Tu localizes in a helical pattern underneath the cell membrane and colocalizes with MreB, an actin-like cytoskeletal element setting up rod cell shape. The localization of MreB and of EF-Tu is interdependent, but in contrast to the dynamic MreB filaments, EF-Tu structures are more static and may serve as tracks for MreB filaments. In agreement with this idea, EF-Tu and MreB interact in vivo and in vitro. Lowering of the EF-Tu levels had a minor effect on translation but a strong effect on cell shape and on the localization of MreB, and blocking of the function of EF-Tu in translation did not interfere with the localization of MreB, showing that, directly or indirectly, EF-Tu affects the cytoskeletal MreB structure and thus serves two important functions in a bacterium.

Short pulse duration shock initiation experiments plus ignition and growth modeling on Composition B

NASA Astrophysics Data System (ADS)

May, Chadd M.; Tarver, Craig M.

2014-05-01

Composition B (63% RDX, 36% TNT, 1% wax) is still a widely used energetic material whose shock initiation characteristics are necessary to understand. It is now possible to shock initiate Composition B and other secondary explosives at diameters well below their characteristic failure diameters for unconfined self-sustaining detonation. This is done using very high velocity, very thin, small diameter flyer plates accelerated by electric or laser power sources. Recently experimental detonation versus failure to detonate threshold flyer velocity curves for Composition B using several KaptonTM flyer thicknesses and diameters were measured. Flyer plates with diameters of 2 mm successfully detonated Composition B, which has a nominal failure diameter of 4.3 mm. The shock pressures required for these initiations are greater than the Chapman-Jouguet (C-J) pressure in self-sustaining Composition B detonation waves. The initiation process is two-dimensional, because both rear and side rarefactions can affect the shocked Composition B reaction rates. The Ignition and Growth reactive flow model for Composition B is extended to yield accurate simulations of this new threshold velocity data for various flyer thicknesses.

A network model of correlated growth of tissue stiffening in pulmonary fibrosis

NASA Astrophysics Data System (ADS)

Oliveira, Cláudio L. N.; Bates, Jason H. T.; Suki, Béla

2014-06-01

During the progression of pulmonary fibrosis, initially isolated regions of high stiffness form and grow in the lung tissue due to collagen deposition by fibroblast cells. We have previously shown that ongoing collagen deposition may not lead to significant increases in the bulk modulus of the lung until these local remodeled regions have become sufficiently numerous and extensive to percolate in a continuous path across the entire tissue (Bates et al 2007 Am. J. Respir. Crit. Care Med. 176 617). This model, however, did not include the possibility of spatially correlated deposition of collagen. In the present study, we investigate whether spatial correlations influence the bulk modulus in a two-dimensional elastic network model of lung tissue. Random collagen deposition at a single site is modeled by increasing the elastic constant of the spring at that site by a factor of 100. By contrast, correlated collagen deposition is represented by stiffening the springs encountered along a random walk starting from some initial spring, the rationale being that excess collagen deposition is more likely in the vicinity of an already stiff region. A combination of random and correlated deposition is modeled by performing random walks of length N from randomly selected initial sites, the balance between the two processes being determined by N. We found that the dependence of bulk modulus, B(N,c), on both N and the fraction of stiff springs, c, can be described by a strikingly simple set of empirical equations. For c<0.3, B(N,c) exhibits exponential growth from its initial value according to B(N,c)\\approx {{B}_{0}}exp (2c)\\left[ 1+{{c}^{\\beta }}ln \\left( {{N}^{{{a}_{I}}}} \\right) \\right], where \\beta =0.994+/- 0.024 and {{a}_{I}}=0.54+/- 0.026. For intermediate concentrations of stiffening, 0.3\\leqslant c\\leqslant 0.8, another exponential rule describes the bulk modulus as B(N,c)=4{{B}_{0}}exp \\left[ {{a}_{II}}\\left( c-{{c}_{c}} \\right) \\right], where {{a}_{II}} and {{c}_{c}} are parameters that depend on N. For c>0.8, B(N,c) is linear in c and independent of N, such that B(N,c)=100\\;{{B}_{0}}-100{{a}_{III}}(1-c){{B}_{0}}, where {{a}_{III}}=2.857. For small concentrations, the physiologically most relevant regime, the forces in the network springs are distributed according to a power law. When c = 0.3, the exponent of this power law increases from -4.5, when N = 1, and saturates to about -2, as N increases above 40. These results suggest that the spatial correlation of collagen deposition in the fibrotic lung has a strong effect on the rate of lung function decline and on the mechanical environment in which the cells responsible for remodeling find themselves.

Initial Development of a Measure of Emotional Dysregulation for Individuals with Cluster B Personality Disorders

ERIC Educational Resources Information Center

Newhill, Christina E.; Mulvey, Edward P.; Pilkonis, Paul A.

2004-01-01

Individuals with DSM-IV Cluster B personality disorders are at particular risk of violence toward self or others. Emotional dysregulation is likely to be a factor in such incidents and is a central issue addressed in therapies with personality-disordered individuals. This article reports findings from a study that developed an original 18-item…

40 CFR 86.1217-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... volume ft3 (m3), as measured in paragraph (b)(1) of this section. (v) r=FID response factor to methanol. (vi) PB=Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi...

40 CFR 86.1217-96 - Evaporative emission enclosure calibrations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... volume ft3 (m3), as measured in paragraph (b)(1) of this section. (v) r=FID response factor to methanol. (vi) PB=Barometric pressure, in. Hg. (kPa). (vii) T=Enclosure ambient temperature, R(K). (viii) i=Indicates initial reading. (ix) f=Indicates final reading. (x)(A) k=3.05. (B) For SI units, k=17.60. (xi...

Identification of a novel A20-binding inhibitor of nuclear factor-kappa B activation termed ABIN-2.

PubMed

Van Huffel, S; Delaei, F; Heyninck, K; De Valck, D; Beyaert, R

2001-08-10

The nuclear factor kappaB (NF-kappaB) plays a central role in the regulation of genes implicated in immune responses, inflammatory processes, and apoptotic cell death. The zinc finger protein A20 is a cellular inhibitor of NF-kappaB activation by various stimuli and plays a critical role in terminating NF-kappaB responses. The underlying mechanism for NF-kappaB inhibition by A20 is still unknown. A20 has been shown to interact with several proteins including tumor necrosis factor (TNF) receptor-associated factors 2 and 6, as well as the inhibitory protein of kappaB kinase (IKK) gamma protein. Here we report the cloning and characterization of ABIN-2, a previously unknown protein that binds to the COOH-terminal zinc finger domain of A20. NF-kappaB activation induced by TNF and interleukin-1 is inhibited by overexpression of ABIN-2. The latter also inhibits NF-kappaB activation induced by overexpression of receptor-interacting protein or TNF receptor-associated factor 2. In contrast, NF-kappaB activation by overexpression of IKKbeta or direct activators of the IKK complex, such as Tax, cannot be inhibited by ABIN-2. These results indicate that ABIN-2 interferes with NF-kappaB activation upstream of the IKK complex and that it might contribute to the NF-kappaB-inhibitory function of A20.

WIG1 is crucial for AGO2-mediated ACOT7 mRNA silencing via miRNA-dependent and -independent mechanisms.

PubMed

Lee, Hyung Chul; Jung, Seung Hee; Hwang, Hyun Jung; Kang, Donghee; De, Supriyo; Dudekula, Dawood B; Martindale, Jennifer L; Park, Byungkyu; Park, Seung Kuk; Lee, Eun Kyung; Lee, Jeong-Hwa; Jeong, Sunjoo; Han, Kyungsook; Park, Heon Joo; Ko, Young-Gyu; Gorospe, Myriam; Lee, Jae-Seon

2017-06-20

RNA-binding proteins (RBPs) are involved in mRNA splicing, maturation, transport, translation, storage and turnover. Here, we identified ACOT7 mRNA as a novel target of human WIG1. ACOT7 mRNA decay was triggered by the microRNA miR-9 in a WIG1-dependent manner via classic recruitment of Argonaute 2 (AGO2). Interestingly, AGO2 was also recruited to ACOT7 mRNA in a WIG1-dependent manner in the absence of miR-9, which indicates an alternative model whereby WIG1 controls AGO2-mediated gene silencing. The WIG1-AGO2 complex attenuated translation initiation via an interaction with translation initiation factor 5B (eIF5B). These results were confirmed using a WIG1 tethering system based on the MS2 bacteriophage coat protein and a reporter construct containing an MS2-binding site, and by immunoprecipitation of WIG1 and detection of WIG1-associated proteins using liquid chromatography-tandem mass spectrometry. We also identified WIG1-binding motifs using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation analyses. Altogether, our data indicate that WIG1 governs the miRNA-dependent and the miRNA-independent recruitment of AGO2 to lower the stability of and suppress the translation of ACOT7 mRNA. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Effects of Hematopoietic Growth Factors on Neurite Outgrowth

PubMed Central

Su, Ye; Cui, Lili; Piao, Chunshu; Li, Bin; Zhao, Li-Ru

2013-01-01

Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are initially discovered as the essential hematopoietic growth factors regulating bone marrow stem cell proliferation and differentiation, and SCF in combination with G-CSF (SCF+G-CSF) has synergistic effects on bone marrow stem cell mobilization. In this study we have determined the effect of SCF and G-CSF on neurite outgrowth in rat cortical neurons. Using molecular and cellular biology and live cell imaging approaches, we have revealed that receptors for SCF and G-CSF are expressed on the growth core of cortical neurons, and that SCF+G-CSF synergistically enhances neurite extension through PI3K/AKT and NFκB signaling pathways. Moreover, SCF+G-CSF induces much greater NFκB activation, NFκB transcriptional binding and brain-derived neurotrophic factor (BDNF) production than SCF or G-CSF alone. In addition, we have also observed that BDNF, the target gene of NFκB, is required for SCF+G-CSF-induced neurite outgrowth. These data suggest that SCF+G-CSF has synergistic effects to promote neurite growth. This study provides new insights into the contribution of hematopoietic growth factors in neuronal plasticity. PMID:24116056

Evidence-based guidelines for the use of tracheostomy in critically ill patients.

PubMed

Raimondi, Néstor; Vial, Macarena R; Calleja, José; Quintero, Agamenón; Cortés, Albán; Celis, Edgar; Pacheco, Clara; Ugarte, Sebastián; Añón, José M; Hernández, Gonzalo; Vidal, Erick; Chiappero, Guillermo; Ríos, Fernando; Castilleja, Fernando; Matos, Alfredo; Rodriguez, Enith; Antoniazzi, Paulo; Teles, José Mario; Dueñas, Carmelo; Sinclair, Jorge; Martínez, Lorenzo; von der Osten, Ingrid; Vergara, José; Jiménez, Edgar; Arroyo, Max; Rodríguez, Camilo; Torres, Javier; Fernandez-Bussy, Sebastián; Nates, Joseph L

2017-04-01

To provide evidence-based guidelines for tracheostomy in critically ill adult patients and identify areas needing further research. A taskforce composed of representatives of 10 member countries of the Pan-American and Iberic Federation of Societies of Critical and Intensive Therapy Medicine and of the Latin American Critical Care Trial Investigators Network developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation system. The group identified 23 relevant questions among 87 issues that were initially identified. In the initial search, 333 relevant publications were identified, of which 226 publications were chosen. The taskforce generated a total of 19 recommendations, 10 positive (1B, 3; 2C, 3; 2D, 4) and 9 negative (1B, 8; 2C, 1). A recommendation was not possible in 6 questions. Percutaneous techniques are associated with a lower risk of infections compared with surgical tracheostomy. Early tracheostomy only seems to reduce the duration of ventilator use but not the incidence of pneumonia, the length of stay, or the long-term mortality rate. The evidence does not support the use of routine bronchoscopy guidance or laryngeal masks during the procedure. Finally, proper prior training is as important or even a more significant factor in reducing complications than the technique used. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of Cox’s Regression Model and Parametric Models in Evaluating the Prognostic Factors for Survival after Liver Transplantation in Shiraz during 2000–2012

PubMed Central

Adelian, R.; Jamali, J.; Zare, N.; Ayatollahi, S. M. T.; Pooladfar, G. R.; Roustaei, N.

2015-01-01

Background: Identification of the prognostic factors for survival in patients with liver transplantation is challengeable. Various methods of survival analysis have provided different, sometimes contradictory, results from the same data. Objective: To compare Cox’s regression model with parametric models for determining the independent factors for predicting adults’ and pediatrics’ survival after liver transplantation. Method: This study was conducted on 183 pediatric patients and 346 adults underwent liver transplantation in Namazi Hospital, Shiraz, southern Iran. The study population included all patients undergoing liver transplantation from 2000 to 2012. The prognostic factors sex, age, Child class, initial diagnosis of the liver disease, PELD/MELD score, and pre-operative laboratory markers were selected for survival analysis. Result: Among 529 patients, 346 (64.5%) were adult and 183 (34.6%) were pediatric cases. Overall, the lognormal distribution was the best-fitting model for adult and pediatric patients. Age in adults (HR=1.16, p<0.05) and weight (HR=2.68, p<0.01) and Child class B (HR=2.12, p<0.05) in pediatric patients were the most important factors for prediction of survival after liver transplantation. Adult patients younger than the mean age and pediatric patients weighing above the mean and Child class A (compared to those with classes B or C) had better survival. Conclusion: Parametric regression model is a good alternative for the Cox’s regression model. PMID:26306158

MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

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

Uematsu, Yasuaki, E-mail: yasuaki-uematsu@ds-pharm

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantlymore » increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.« less

Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

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

Ge, Yuqing; Zhou, Fengbiao; Chen, Hong

2010-07-09

Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was amore » positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.« less

NF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise

PubMed Central

Wong, Victor C.; Bass, Victor L.; Bullock, M. Elise; Chavali, Arvind K.; Lee, Robin E.C.; Mothes, Walther; Gaudet, Suzanne; Miller-Jensen, Kathryn

2018-01-01

SUMMARY Noisy gene expression generates diverse phenotypes, but little is known about mechanisms that modulate noise. Combining experiments and modeling, we studied how tumor necrosis factor (TNF) initiates noisy expression of latent HIV via the transcription factor nuclear factor κB (NF-κB) and how the HIV genomic integration site modulates noise to generate divergent (low-versus-high) phenotypes of viral activation. We show that TNF-induced transcriptional noise varies more than mean transcript number and that amplification of this noise explains low-versus-high viral activation. For a given integration site, live-cell imaging shows that NF-κB activation correlates with viral activation, but across integration sites, NF-κB activation cannot account for differences in transcriptional noise and phenotypes. Instead, differences in transcriptional noise are associated with differences in chromatin state and RNA polymerase II regulation. We conclude that, whereas NF-κB regulates transcript abundance in each cell, the chromatin environment modulates noise in the population to support diverse HIV activation in response to TNF. PMID:29346759

Early age of e-cigarette use onset mediates the association between impulsivity and e-cigarette use frequency in youth.

PubMed

Bold, Krysten W; Morean, Meghan E; Kong, Grace; Simon, Patricia; Camenga, Deepa R; Cavallo, Dana A; Krishnan-Sarin, Suchitra

2017-12-01

Identifying risk factors for youth e-cigarette use is critical, given high rates of e-cigarette use and unknown health effects of long-term use. The current study examined whether an early age of onset of e-cigarette use mediates the association between impulsivity and e-cigarette frequency. Cross-sectional survey data of e-cigarette users (n=927) were collected from 8 high schools in southeastern Connecticut. The sample was 44.7% female (mean age 16.2 [SD=1.2], mean age of e-cigarette onset 14.7 [SD=1.6]). Two domains of self-reported, trait impulsivity were assessed using the abbreviated Barratt Impulsiveness Scale: impaired self-regulation (e.g., problems with concentration or self-control) and behavioral impulsivity (e.g., doing things without thinking). Mediation was tested with Mplus, and the model included school as a cluster variable and controlled for covariates related to e-cigarette use (i.e., sex, age, race, peer use, and other tobacco products ever tried). The hypothesized mediation was supported for both domains of impulsivity (impaired self-regulation a 1 b=0.09, SE=0.02, 95%CI [0.03-0.14], p=.002; behavioral impulsivity a 2 b=0.07, SE=0.03, 95%CI [.01-.14], p=0.03). Specifically, impaired self-regulation (B=-0.33, SE=0.06, p<0.001) and behavioral impulsivity (B=-0.26, SE=0.11, p=0.02) predicted trying e-cigarettes at an earlier age, and earlier initiation was associated with more days of e-cigarette use in the past month (B=-0.28, SE=0.08, p<0.001). Adolescents who endorse aspects of impulsivity, such as acting without thinking, are at greater risk for more frequent e-cigarette use through an early age of e-cigarette initiation. Further research is needed to evaluate these relationships longitudinally and to develop targeted e-cigarette interventions for impulsive youth. Copyright © 2017 Elsevier B.V. All rights reserved.

Eaf1p Is Required for Recruitment of NuA4 in Targeting TFIID to the Promoters of the Ribosomal Protein Genes for Transcriptional Initiation In Vivo

PubMed Central

Uprety, Bhawana; Sen, Rwik

2015-01-01

NuA4 (nucleosome acetyltransferase of H4) promotes transcriptional initiation of TFIID (a complex of TBP and TBP-associated factors [TAFs])-dependent ribosomal protein genes involved in ribosome biogenesis. However, it is not clearly understood how NuA4 regulates the transcription of ribosomal protein genes. Here, we show that NuA4 is recruited to the promoters of ribosomal protein genes, such as RPS5, RPL2B, and RPS11B, for TFIID recruitment to initiate transcription, and the recruitment of NuA4 to these promoters is impaired in the absence of its Eaf1p component. Intriguingly, impaired NuA4 recruitment in a Δeaf1 strain depletes recruitment of TFIID (a TAF-dependent form of TBP) but not the TAF-independent form of TBP to the promoters of ribosomal protein genes. However, in the absence of NuA4, SAGA (Spt-Ada-Gcn5-acetyltransferase) is involved in targeting the TAF-independent form of TBP to the promoters of ribosomal protein genes for transcriptional initiation. Thus, NuA4 plays an important role in targeting TFIID to the promoters of ribosomal protein genes for transcriptional initiation in vivo. Such a function is mediated via its targeted histone acetyltransferase activity. In the absence of NuA4, ribosomal protein genes lose TFIID dependency and become SAGA dependent for transcriptional initiation. Collectively, these results provide significant insights into the regulation of ribosomal protein gene expression and, hence, ribosome biogenesis and functions. PMID:26100014

Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5.

PubMed

Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

2014-01-01

Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2(-⧸-)) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2(-⧸-) mouse livers were lower than that in wild-type mouse livers. Nrf2(-⧸-) mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression.

Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5☆

PubMed Central

Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

2014-01-01

Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)–deficient (Nrf2−⧸−) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2−⧸− mouse livers were lower than that in wild-type mouse livers. Nrf2−⧸− mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression. PMID:24494203

Factors Affecting Business-to-Business Electronic Commerce Success: An Empirical Investigation

ERIC Educational Resources Information Center

Chen, Chun-I Philip

2010-01-01

It is generally believed that Business to Business (B2B) e-commerce has a great impact on business performance improvement. Considerable research also shows that another dependent variable, B2B e-commerce success, can be a good overall measure of B2B systems. This paper investigated and examined the impact of several factors, which are either…

Factors Affecting the Initial Adhesion and Retention of the Plant Pathogen Xylella fastidiosa in the Foregut of an Insect Vector

PubMed Central

Almeida, Rodrigo P. P.

2014-01-01

Vector transmission of bacterial plant pathogens involves three steps: pathogen acquisition from an infected host, retention within the vector, and inoculation of cells into susceptible tissue of an uninfected plant. In this study, a combination of plant and artificial diet systems were used to determine the importance of several genes on the initial adhesion and retention of the bacterium Xylella fastidiosa to an efficient insect vector. Mutant strains included fimbrial (fimA and pilB) and afimbrial (hxfA and hxfB) adhesins and three loci involved in regulatory systems (rpfF, rpfC, and cgsA). Transmission assays with variable retention time indicated that HxfA and HxfB were primarily important for early adhesion to vectors, while FimA was necessary for both adhesion and retention. The long pilus protein PilB was not deficient in initial adhesion but may be important for retention. Genes upregulated under the control of rpfF are important for both initial adhesion and retention, as transmission rates of this mutant strain were initially low and decreased over time, while disruption of rpfC and cgsA yielded trends similar to that shown by the wild-type control. Because induction of an X. fastidiosa transmissible state requires pectin, a series of experiments were used to test the roles of a polygalacturonase (pglA) and the pectin and galacturonic acid carbohydrates on the transmission of X. fastidiosa. Results show that galacturonic acid, or PglA activity breaking pectin into its major subunit (galacturonic acid), is required for X. fastidiosa vector transmission using an artificial diet system. This study shows that early adhesion and retention of X. fastidiosa are mediated by different factors. It also illustrates that the interpretation of results of vector transmission experiments, in the context of vector-pathogen interaction studies, is highly dependent on experimental design. PMID:24185853

Factors affecting the initial adhesion and retention of the plant pathogen Xylella fastidiosa in the foregut of an insect vector.

PubMed

Killiny, Nabil; Almeida, Rodrigo P P

2014-01-01

Vector transmission of bacterial plant pathogens involves three steps: pathogen acquisition from an infected host, retention within the vector, and inoculation of cells into susceptible tissue of an uninfected plant. In this study, a combination of plant and artificial diet systems were used to determine the importance of several genes on the initial adhesion and retention of the bacterium Xylella fastidiosa to an efficient insect vector. Mutant strains included fimbrial (fimA and pilB) and afimbrial (hxfA and hxfB) adhesins and three loci involved in regulatory systems (rpfF, rpfC, and cgsA). Transmission assays with variable retention time indicated that HxfA and HxfB were primarily important for early adhesion to vectors, while FimA was necessary for both adhesion and retention. The long pilus protein PilB was not deficient in initial adhesion but may be important for retention. Genes upregulated under the control of rpfF are important for both initial adhesion and retention, as transmission rates of this mutant strain were initially low and decreased over time, while disruption of rpfC and cgsA yielded trends similar to that shown by the wild-type control. Because induction of an X. fastidiosa transmissible state requires pectin, a series of experiments were used to test the roles of a polygalacturonase (pglA) and the pectin and galacturonic acid carbohydrates on the transmission of X. fastidiosa. Results show that galacturonic acid, or PglA activity breaking pectin into its major subunit (galacturonic acid), is required for X. fastidiosa vector transmission using an artificial diet system. This study shows that early adhesion and retention of X. fastidiosa are mediated by different factors. It also illustrates that the interpretation of results of vector transmission experiments, in the context of vector-pathogen interaction studies, is highly dependent on experimental design.

A systematic review of p53 regulation of oxidative stress in skeletal muscle.

PubMed

Beyfuss, Kaitlyn; Hood, David A

2018-12-01

p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases. Articles published in the English language between January 1, 1990 and March 1, 2017 were identified and isolated based on the analysis of p53 in skeletal muscle in both animal and cell culture models. Literature was categorized according to the modality of imposed oxidative stress including exercise, diet modification, exogenous oxidizing agents, tissue manipulation, irradiation, and hypoxia. With low to moderate levels of oxidative stress, p53 is involved in activating pathways that increase time for cell repair, such as cell cycle arrest and autophagy, to enhance cell survival. However, with greater levels of stress intensity and duration, such as with irradiation, hypoxia, and oxidizing agents, the role of p53 switches to facilitate increased cellular stress levels by initiating DNA fragmentation to induce apoptosis, thereby preventing aberrant cell proliferation. Current evidence confirms that p53 acts as a threshold regulator of cellular homeostasis. Therefore, within each modality, the intensity and duration are parameters of the oxidative stressor that must be analyzed to determine the role p53 plays in regulating signaling pathways to maintain cellular health and function in skeletal muscle. Acadl: acyl-CoA dehydrogenase, long chain; Acadm: acyl-CoA dehydrogenase, C-4 to C-12 straight chain; AIF: apoptosis-inducing factor; Akt: protein kinase B (PKB); AMPK: AMP-activated protein kinase; ATF-4: activating transcription factor 4; ATM: ATM serine/threonine kinase; Bax: BCL2 associated X, apoptosis regulator; Bcl-2: B cell Leukemia/Lymphoma 2 apoptosis regulator; Bhlhe40: basic helix-loop-helix family member e40; BH3: Borane; Bim: bcl-2 interacting mediator of cell death; Bok: Bcl-2 related ovarian killer; COX-IV: cytochrome c oxidase IV; cGMP: Cyclic guanosine monophosphate; c-myc: proto-oncogene protein; Cpt1b: carnitine palmitoyltransferase 1B; Dr5: death receptor 5; eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated MAP kinase; Fas: Fas Cell surface death receptor; FDXR: Ferredoxin Reductase; FOXO3a: forkhead box O3; Gadd45a: growth arrest and DNA damage-inducible 45 alpha; GLS2: glutaminase 2; GLUT 1 and 4: glucose transporter 1(endothelial) and 4 (skeletal muscle); GSH: Glutathione; Hes1: hes family bHLH transcription factor 1; Hey1: hes related family bHLH transcription factor with YRPW motif 1; HIFI-α: hypoxia-inducible factor 1, α-subunit; HK2: Hexokinase 2; HSP70: Heat Shock Protein 70; H 2 O 2 : Hydrogen Peroxide; Id2: inhibitor of DNA-binding 2; IGF-1-BP3: Insulin-like growth factor binding protein 3; IL-1β: Interleukin 1 beta; iNOS: inducible nitric oxide synthase; IRS-1: Insulin receptor substrate 1; JNK: c-Jun N-terminal kinases; LY-83583: 6-anilino-5,8-quinolinedione; inhibitor of soluble guanylate cyclase and of cGMP production; Mdm 2/ 4: Mouse double minute 2 homolog (mouse) Mdm4 (humans); mtDNA: mitochondrial DNA; MURF1: Muscle RING-finger protein-1; MyoD: Myogenic differentiation 1; MyoG: myogenin; Nanog: Nanog homeobox; NF-kB: Nuclear factor-κB; NO: nitric oxide; NoxA: phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1); NRF-1: nuclear respiratory factor 1; Nrf2: Nuclear factor erythroid 2-related factor 2; P21: Cdkn1a cyclin-dependent kinase inhibitor 1A (P21); P38 MAPK: mitogen-activated protein kinases; p53R2: p53 inducible ribonucleotide reductase gene; P66Shc: src homology 2 domain-containing transforming protein C1; PERP: p53 apoptosis effector related to PMP-22; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGM: phosphoglucomutase; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKCβ: protein kinase c beta; PTEN: phosphatase and tensin homolog; PTIO: 2-phenyl-4, 4, 5, 5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) has been used as a nitric oxide (NO) scavenger; Puma: The p53 upregulated modulator of apoptosis; PW1: paternally expressed 3 (Peg3); RNS: Reactive nitrogen species; SIRT1: sirtuin 1; SCO2: cytochrome c oxidase assembly protein; SOD2: superoxide dismutase 2; Tfam: transcription factor A mitochondrial; TIGAR: Trp53 induced glycolysis repulatory phosphatase; TNF-a: tumor necrosis factor a; TRAF2: TNF receptor associated factor 2; TRAIL: type II transmembrane protein.

Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PubMed Central

Romond, Edward H.; Jeong, Jong-Hyeon; Rastogi, Priya; Swain, Sandra M.; Geyer, Charles E.; Ewer, Michael S.; Rathi, Vikas; Fehrenbacher, Louis; Brufsky, Adam; Azar, Catherine A.; Flynn, Patrick J.; Zapas, John L.; Polikoff, Jonathan; Gross, Howard M.; Biggs, David D.; Atkins, James N.; Tan-Chiu, Elizabeth; Zheng, Ping; Yothers, Greg; Mamounas, Eleftherios P.; Wolmark, Norman

2012-01-01

Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab. PMID:22987084

Emodin inhibits coxsackievirus B3 replication via multiple signalling cascades leading to suppression of translation.

PubMed

Zhang, Huifang M; Wang, Fengping; Qiu, Ye; Ye, Xin; Hanson, Paul; Shen, Hongxing; Yang, Decheng

2016-02-15

CVB3 (coxsackievirus 3) is a primary causal agent of viral myocarditis. Emodin is a natural compound isolated from certain plant roots. In the present study, we found that emodin inhibited CVB3 replication in vitro and in mice, and now we report an unrecognized mechanism by which emodin inhibits CVB3 replication through suppression of viral protein translation via multiple pathways. On one hand, emodin treatment inhibited Akt/mTOR (mammalian target of rapamycin) signalling and activated 4EBP1 (eukaryotic initiation factor 4R-binding protein 1), leading to suppression of translation initiation of ribosomal protein L32 encoded by a 5'-TOP (terminal oligopyrimidine) mRNA. On the other hand, emodin treatment differentially regulated multiple signal cascades, including Akt/mTORC1/p70(S6K) (p70 S6 kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2)/p90(RSK) (p90 ribosomal S6 kinase) and Ca(2+)/calmodulin, leading to activation of eEF2K (eukaryotic elongation factor 2 kinase) and subsequent inactivation of eEF2 (eukaryotic elongation factor 2), resulting in inhibition of CVB3 VP1 (viral protein 1) synthesis. These data imply that eEF2K is a major factor mediating cross-talk of different arms of signalling cascades in this signal network. This notion was verified by either overexpressing eEF2K or treating the cells with siRNAs or eEF2K inhibitor A484954. We showed further that the emodin-induced decrease in p70(S6K) phosphorylation plays a dominant positive role in activation of eEF2K and in turn in conferring the antiviral effect of emodin. This finding was further solidified by expressing constitutively active and dominant-negative Akt. Collectively, our data reveal that emodin inhibits viral replication through impairing translational machinery and suppression of viral translation elongation. © 2016 Authors; published by Portland Press Limited.

Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer.

PubMed

Adam, Liana; Black, Peter C; Kassouf, Wassim; Eve, Beryl; McConkey, David; Munsell, Mark F; Benedict, William F; Dinney, Colin P N

2007-05-01

Intravesical adenovirus mediated interferon-alpha gene transfer has a potent therapeutic effect against superficial human bladder carcinoma xenografts growing in the bladder of athymic nude mice. We determined whether the inhibition of angiogenesis might contribute to the antitumor effect. We treated several human urothelial carcinoma cells with adenovirus mediated interferon-alpha 2b and monitored its effects on the production of angiogenic factors using real-time reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemical analysis and a gel shift based transcription factor array. To assess the role of adenovirus mediated interferon 2b in angiogenic activity we used in vitro invasion assays and evaluated the anti-angiogenic effects of adenovirus mediated interferon gene therapy in an orthotopic murine model of human superficial bladder cancer. In adenovirus mediated interferon-alpha infected 253J B-V cells vascular endothelial growth factor was decreased and anti-angiogenic interferon-gamma inducible protein 10 was up-regulated. In contrast, the addition of as much as 100,000 IU recombinant interferon had no apparent effect on vascular endothelial growth factor production. Conditioned medium derived from adenovirus mediated interferon 2b infected 253J B-V cells greatly decreased the invasive potential of human endothelial cells and down-regulated their matrix metalloproteinase 2 expression compared to controls. Furthermore, adenovirus mediated interferon 2b blocked pro-angiogenic nuclear signals, such as the transcription factors activating protein-1 and 2, stimulating protein-1, nuclear factor kappaB and c-myb. In vivo experiments revealed significant vascular endothelial growth factor down-regulation and decreased tumor vessel density in the adenovirus mediated interferon 2b treated group compared to controls. Treatment with adenovirus mediated interferon 2b increases the angiostatic activity of the bladder cancer microenvironment. This inhibition may prove beneficial for treating superficial bladder cancer with adenovirus mediated interferon-alpha and hopefully contribute to a decreased recurrence rate of this neoplasm.

BCL-2 Modifying Factor (BMF) Is a Central Regulator of Anoikis in Human Intestinal Epithelial Cells*

PubMed Central

Hausmann, Martin; Leucht, Katharina; Ploner, Christian; Kiessling, Stephan; Villunger, Andreas; Becker, Helen; Hofmann, Claudia; Falk, Werner; Krebs, Michaela; Kellermeier, Silvia; Fried, Michael; Schölmerich, Jürgen; Obermeier, Florian; Rogler, Gerhard

2011-01-01

BCL-2 modifying factor (BMF) is a sentinel considered to register damage at the cytoskeleton and to convey a death signal to B-cell lymphoma 2. B-cell lymphoma 2 is neutralized by BMF and thereby facilitates cytochrome C release from mitochondria. We investigated the role of BMF for intestinal epithelial cell (IEC) homeostasis. Acute colitis was induced in Bmf-deficient mice (Bmf−/−) with dextran sulfate sodium. Colonic crypt length in Bmf−/− mice was significantly increased as compared with WT mice. Dextran sulfate sodium induced less signs of colitis in Bmf−/− mice, as weight loss was reduced compared with the WT. Primary human IEC exhibited increased BMF in the extrusion zone. Quantitative PCR showed a significant up-regulation of BMF expression after initiation of anoikis in primary human IEC. BMF was found on mitochondria during anoikis, as demonstrated by Western blot analysis. RNAi mediated knockdown of BMF reduced the number of apoptotic cells and led to reduced caspase 3 activity. A significant increase in phospho-AKT was determined after RNAi treatment. BMF knockdown supports survival of IEC. BMF is induced in human IEC by the loss of cell attachment and is likely to play an important role in the regulation of IEC survival. PMID:21673109

Gene Expression Profile of NF-κB, Nrf2, Glycolytic, and p53 Pathways During the SH-SY5Y Neuronal Differentiation Mediated by Retinoic Acid.

PubMed

de Bittencourt Pasquali, Matheus Augusto; de Ramos, Vitor Miranda; Albanus, Ricardo D Oliveira; Kunzler, Alice; de Souza, Luis Henrinque Trentin; Dalmolin, Rodrigo Juliani Siqueira; Gelain, Daniel Pens; Ribeiro, Leila; Carro, Luigi; Moreira, José Cláudio Fonseca

2016-01-01

SH-SY5Y cells, a neuroblastoma cell line that is a well-established model system to study the initial phases of neuronal differentiation, have been used in studies to elucidate the mechanisms of neuronal differentiation. In the present study, we investigated alterations of gene expression in SH-SY5Y cells during neuronal differentiation mediated by retinoic acid (RA) treatment. We evaluated important pathways involving nuclear factor kappa B (NF-κB), nuclear E2-related factor 2 (Nrf2), glycolytic, and p53 during neuronal differentiation. We also investigated the involvement of reactive oxygen species (ROS) in modulating the gene expression profile of those pathways by antioxidant co-treatment with Trolox®, a hydrophilic analogue of α-tocopherol. We found that RA treatment increases levels of gene expression of NF-κB, glycolytic, and antioxidant pathway genes during neuronal differentiation of SH-SY5Y cells. We also found that ROS production induced by RA treatment in SH-SY5Y cells is involved in gene expression profile alterations, chiefly in NF-κB, and glycolytic pathways. Antioxidant co-treatment with Trolox® reversed the effects mediated by RA NF-κB, and glycolytic pathways gene expression. Interestingly, co-treatment with Trolox® did not reverse the effects in antioxidant gene expression mediated by RA in SH-SY5Y. To confirm neuronal differentiation, we quantified endogenous levels of tyrosine hydroxylase, a recognized marker of neuronal differentiation. Our data suggest that during neuronal differentiation mediated by RA, changes in profile gene expression of important pathways occur. These alterations are in part mediated by ROS production. Therefore, our results reinforce the importance in understanding the mechanism by which RA induces neuronal differentiation in SH-SY5Y cells, principally due this model being commonly used as a neuronal cell model in studies of neuronal pathologies.

Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

PubMed Central

Galinato, Melissa H.; Orio, Laura; Mandyam, Chitra D.

2014-01-01

Methamphetamine exposure reduces hippocampal long-term potentiation (LTP) and neurogenesis and these alterations partially contribute to hippocampal maladaptive plasticity. The potential mechanisms underlying methamphetamine-induced maladaptive plasticity were identified in the present study. Expression of brain-derived neurotrophic factor (BDNF; a regulator of LTP and neurogenesis), and its receptor tropomyosin-related kinase B (TrkB) were studied in the dorsal and ventral hippocampal tissue lysates in rats that intravenously self-administered methamphetamine in a limited access (1 h/day) or extended access (6 h/day) paradigm for 17 days post baseline sessions. Extended access methamphetamine enhanced expression of BDNF with significant effects observed in the dorsal and ventral hippocampus. Methamphetamine-induced enhancements in BDNF expression were not associated with TrkB receptor activation as indicated by phospho (p)-TrkB-706 levels. Conversely, methamphetamine produced hypophosphorylation of NMDA receptor subunit 2B (GluN2B) at Tyr-1472 in the ventral hippocampus, indicating reduced receptor activation. In addition, methamphetamine enhanced expression of anti-apoptotic protein Bcl-2 and reduced pro-apoptotic protein Bax levels in the ventral hippocampus, suggesting a mechanism for reducing cell death. Analysis of Akt, a pro-survival kinase that suppresses apoptotic pathways and pAkt at Ser-473 demonstrated that extended access methamphetamine reduces Akt expression in the ventral hippocampus. These data reveal that alterations in Bcl-2 and Bax levels by methamphetamine were not associated with enhanced Akt expression. Given that hippocampal function and neurogenesis vary in a subregion-specific fashion, where dorsal hippocampus regulates spatial processing and has higher levels of neurogenesis, whereas ventral hippocampus regulates anxiety-related behaviors, these data suggest that methamphetamine self-administration initiates distinct allostatic changes in hippocampal subregions that may contribute to the altered synaptic activity in the hippocampus, which may underlie enhanced negative affective symptoms and perpetuation of the addiction cycle. PMID:25463524

47 CFR 1.1107 - Schedule of charges for applications and other filings for the international services.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) (per system) 312 & 159 180.00 CGV 7. Mobile Satellite Earth Stations: a. Initial Applications of.../Receive Earth Stations: a. Initial Application (per station) 312 Main & Schedule B & 159 2,615.00 BAX b... 180.00 CGX 4. Fixed Satellite transmit/receive Earth Stations (2 meters or less operating in the 4/6...

Mercury Distribution, Methylation and Volatilization in Microcosms with and without the Sea Anemone Bunodosoma caissarum

NASA Astrophysics Data System (ADS)

Ansari, N. R.; Correia, R. R. S.; Fernandez, M. A. S.; Cordeiro, R. C.; Guimarães, J. R. D.

2014-12-01

Mercury (Hg) can be a dangerous contaminant and has a complex biogeochemical cycling in aquatic environments. The sea anemone Bunodosoma caissarum is an endemic species in Brazil capable of bioaccumulating Hg from the ambient seawater. The radiotracer 203Hg was used in order to investigate mechanisms of Hg uptake and depuration of B. caissarum and the distribution of Hg in laboratory model systems, with and without B. caissarum. A single initial spike of 203Hg was added to each microcosm. Microcosms had continuous air renovation and trapping of Hg volatile forms. Total Hg in different compartments was measured by gamma spectrometry. In the uptake experiment 203Hg activity was determined periodically in seawater and specimens for 6 days. At the end, specimens had an average bioconcentration factor of 70. After the uptake experiment, methylmercury (MeHg) in seawater was extracted and measured by liquid scintillation. In microcosms with and without B. caissarum, respectively 0.05% and 0.32% of the initial spike was found as MeHg. Hg was probably less available for methylation in the first because of bioaccumulation and higher concentrations of suspended particulate matter that could form complexes with Hg. After that, specimens were transferred to unspiked microcosms. After a 48 day depuration specimens still retained 35 - 70% of the previously bioaccumulated Hg and 0.2 - 2.4% of the total Hg was MeHg. The presence of B. caissarum resulted in an unexpected higher volatilization of Hg (58%) compared to controls (17%). This increased volatilization is possibly a result of Hg2+ reduction mediated by microorganisms associated with its tissues and mucus secretions and/or an unknown defense mechanism of this species.

Factors associated with self-reported need for treatment of sleeping difficulties: a survey of the general Swedish population.

PubMed

Sandlund, Christina; Westman, Jeanette; Hetta, Jerker

2016-06-01

This study aims to investigate factors associated with the self-reported need for treatment of sleeping difficulties in the general population. This study consisted of a cross-sectional telephone survey of 1550 people randomly selected from the total population of Sweden. The survey, conducted by the Swedish national statistics agency, Statistics Sweden, was completed by 1115 people aged 18-85 years. Participants were asked about sleep patterns, daytime symptoms, physical and mental health disorders, use of prescribed hypnotics, help-seeking behaviors, and sociodemographic characteristics. They were also asked whether they thought they needed treatment for sleeping difficulties. A total of 12.5% of the participants reported a need for treatment because of sleeping difficulties. Significantly more women than men reported such a need (OR 1.46, 95% CI 1.02-2.10). Additionally, in univariate analyses, older age (age 60-69), sick leave, retirement, and unemployment were associated with a self-reported need for treatment, as were several sleep complaints, daytime symptoms, and physical and mental health disorders. A logistic regression model showed that difficulty initiating sleep (OR 6.29, 95% CI 3.67-10.78) was the factor most strongly associated with a self-reported need for treatment for sleeping difficulties. Other important factors were nonrestorative sleep (OR 3.70, 95% CI 2.05-6.69), mental health disorders (OR 3.01, 95% CI 1.59-5.67), and fatigue (OR 2.95, 95% CI 1.53-5.68). There was considerable self-reported need for treatment for sleeping difficulties in the population. Difficulty initiating sleep was the factor most strongly associated with this need, followed by nonrestorative sleep, mental health disorders, and fatigue. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

A Business-to-Business Interoperability Testbed: An Overview

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

Kulvatunyou, Boonserm; Ivezic, Nenad; Monica, Martin

In this paper, we describe a business-to-business (B2B) testbed co-sponsored by the Open Applications Group, Inc. (OAGI) and the National Institute of Standard and Technology (NIST) to advance enterprise e-commerce standards. We describe the business and technical objectives and initial activities within the B2B Testbed. We summarize our initial lessons learned to form the requirements that drive the next generation testbed development. We also give an overview of a promising testing framework architecture in which to drive the testbed developments. We outline the future plans for the testbed development.

Distinct signaling pathways leading to the induction of human β-defensin 2 by stimulating an electrolyticaly-generated acid functional water and double strand RNA in oral epithelial cells.

PubMed

Gojoubori, Takahiro; Nishio, Yukina; Asano, Masatake; Nishida, Tetsuya; Komiyama, Kazuo; Ito, Koichi

2014-04-01

Defensins, a major family of cationic antimicrobial peptides, play important roles in innate immunity. In the present study, we investigated whether double-stranded RNA (dsRNA), a by-product of RNA virus replication, can induce human β-defensins-2 (hBD-2) expression in oral epithelial cells (OECs). We also examined the hBD-2-inducible activity of acid-electrolyzed functional water (FW). The results indicated that both dsRNA- and FW-induced hBD-2 expression in OECs. The induction efficiency was much higher for FW than for dsRNA. FW-induced production of hBD-2 was clearly observed by immunofluorescence staining. A luciferase assay was performed with 1.2 kb of the 5'-untranslated region (5'-UTR) of the hBD-2 gene. The results indicated that the nuclear factor-kappa B (NF-κB)-binding site proximal to the translation initiation site was indispensable for dsRNA-stimulated hBD-2 expression, but not in the case of FW. Moreover, FW-stimulated hBD-2 expression did not depend on NF-κB activity; instead, FW inhibited NF-κB activity. Pretreatment of the cells with specific inhibitors against NF-κB further confirmed NF-κB-independent hBD-2 induction by FW. In analogy to the results for intestinal epithelial cells (IECs), the dsRNA signal, but not FW, was sensed by toll-like receptor 3 (TLR3) in OECs. These results suggested that hBD-2 expression induced by dsRNA and FW is regulated by distinct mechanisms in OECs.

Human colonic myocytes are involved in postischemic inflammation through ADAM17-dependent TNFα production

PubMed Central

Jarry, Anne; Bach-Ngohou, Kalyane; Masson, Damien; Dejoie, Thomas; Lehur, Paul-Antoine; Mosnier, Jean-François; Denis, Marc G; Laboisse, Christian L

2005-01-01

The aim of this study was to identify human colonic resident cells able to initiate an inflammatory response in postischemic injury. Postischemic colonic injury, a condition relevant to various clinical settings, involves an inflammatory cascade in intestinal tissues through the recruitment of circulating inflammatory cells. However, there is no information on the nature of resident cells of the different intestinal layers able to initiate a postischemic inflammatory response. It is however an important issue in the context of a pharmacological approach of the early phase of intestinal ischemia. We reasoned that maintaining the different colonic layers as explant cultures in an oxygenated medium immediately after colonic resection, that is, after an ischemic period, would allow one to identify the resident cells able to initiate an inflammatory cascade, without interference of recruited inflammatory/immune cells. To this end, we designed an explant culture system that operationally defines three compartments in surgical specimens of the human colon, based on the microdissected layers, that is, mucosa, submucosa (containing muscularis mucosae) and muscularis propria. To validate the results obtained in explant cultures in the clinical setting of ischemic colitis, eight cases of sigmoid volvulus were examined. Only the myocytes-containing explants produced tumor necrosis factor alpha (TNFα), via an ADAM17 (a disintegrin and metalloproteinase-17)-dependent pathway, as shown by the abrogation of TNFα production by the inhibitor Tapi-2. Immunofluorescence studies identified nonvascular and vascular myocytes as resident cells coexpressing TNFα and ADAM17, both in our postischemic explant system and in surgical specimens from ischemic colitis patients. Finally, time-course experiments on explanted tissues showed that TNFα production by myocytes was an early event triggered by a postischemic oxidative stress involving nuclear factor kappa B (NF-κB). In conclusion, this study identifies human intestinal myocytes as resident cells able to initiate an inflammatory reaction through TNFα production in postischemic conditions, and delineates two points of control in TNFα production, NF-κB and ADAM17, which can be targeted by pharmacological manipulation. PMID:16273118

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

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

Heber, Elisa M.; Hawthorne, M. Frederick; Kueffer, Peter J.

2014-11-11

Unilamellar liposomes formulated with an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH 3(CH 2)15-7,8-C 2B 9H 11] in the lipid bilayer, and encapsulating Na 3[1-(2’-B 10-H 9)-2-NH 3B 10H 8] were prepared by probe sonication and investigated in vivo. Microwave assisted digestion followed by inductively coupled plasma-optical emission spectroscopy was utilized to determine the biodistribution of boron in various tissues following either a single tail vein injection or two identical injections (separated by 24 hours) of the liposomal suspension in BALB/c mice bearing EMT6 mammary adenocarcinomas in their right flank. Double-injection protocols resulted in a boron content in themore » tumor exceeding 50 µg of boron per gram of tissue for 48 to 72 hours subsequent to the initial injection while tumor:blood boron ratios were more ideal from 54 hours (1.9:1) to 96 hours (5.7:1) subsequent to the initial injection. Tumor bearing mice were given a double-injection of liposomes containing the 10B-enriched analogs of the aforementioned agents and subjected to a 30 minute irradiation by thermal neutrons with a flux of 8.8 x 10 8 (±7%) neutrons/cm 2 s integrated over the energy range of 0.0 – 0.414 eV. Significant tumor response for a single BNCT treatment was demonstrated by growth curves versus a control group. Vastly diminished tumor growth was witnessed at 14 days (186% increase versus 1551% in controls) in mice that were given a second injection/radiation treatment 7 days after the first. Mice given a one hour neutron irradiation following the double-injection of liposomes had a similar response (169% increase at 14 days) suggesting that neutron fluence is the limiting factor towards BNCT efficacy in this study.« less

Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice.

PubMed

Nikonorova, Inna A; Al-Baghdadi, Rana J T; Mirek, Emily T; Wang, Yongping; Goudie, Michael P; Wetstein, Berish B; Dixon, Joseph L; Hine, Christopher; Mitchell, James R; Adams, Christopher M; Wek, Ronald C; Anthony, Tracy G

2017-04-21

Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), a major ISR transducer to ER stress. Genetic loss of Gcn2 intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such as Atf5 and Trib3 failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed, and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 (ApoB100) expression. In contrast, obese mice lacking hepatic activating transcription factor 4 ( Atf4 ) showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of ApoB100 during asparaginase exposure. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of Atf4 expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective "Lymphomes Malins B" protocols. A Société Française des Cancers de l'Enfant study.

PubMed

Jourdain, Anne; Auperin, Anne; Minard-Colin, Véronique; Aladjidi, Nathalie; Zsiros, Josef; Coze, Carole; Gandemer, Virginie; Bertrand, Yves; Leverger, Guy; Bergeron, Christophe; Michon, Jean; Patte, Catherine

2015-06-01

To describe relapsed B-cell lymphoma or leukemia in children/adolescents treated with a "Lymphomes Malins B" regimen and their outcome and to identify prognostic factors for survival, we studied relapses in the LMB89, 96 and 2001 studies of the Société Française d'Oncologie Pédiatrique (Société Française des Cancers de l'Enfant). Therapeutic guidelines at relapse were to obtain a second complete remission and to consolidate the remission with high-dose chemotherapy followed by autologous stem-cell transplantation. Between July 1989 and March 2007, 67 patients of 1322 (5%) relapsed: 57 had Burkitt lymphoma and 10 had large-cell histology. Three patients were initially treated in risk group A, 41 in group B and 23 in group C. Thirty-three patients had a relapse in one site (15 in the central nervous system) and 34 at multiple sites. Sixty-five patients received salvage chemotherapy and 33 achieved complete remission. Forty-one patients also received high-dose chemotherapy followed by autologous (n=33) or allogeneic (n=8) transplantation. With a median follow-up of 6.4 years, the 5-year survival rate was 29.9%. Nineteen patients were still alive, all but one (group A) received consolidation treatment. Multivariate analysis showed the following factors to be significantly associated with better survival: relapse at one site (P=0.0006), large-cell histology (P=0.012), initial prognostic group A or B with lactate dehydrogenase level below twice the normal value (P=0.005), and time to relapse more than 6 months (P=0.04). Copyright© Ferrata Storti Foundation.

Blindness and Glaucoma: A Multicenter Data Review from 7 Academic Eye Clinics

PubMed Central

Rossetti, Luca; Digiuni, Maurizio; Giovanni, Montesano; Centofanti, Marco; Fea, Antonio M.; Iester, Michele; Frezzotti, Paolo; Figus, Michele; Ferreras, Antonio; Oddone, Francesco; Tanga, Lucia; Rolle, Teresa; Battaglino, Valentina; Posarelli, Chiara; Motolese, Ilaria; Mittica, Pietro; Bagaglia, Simone Alex; Menicacci, Cristina; De Cilla’, Stefano; Autelitano, Alessandro; Fogagnolo, Paolo

2015-01-01

Purpose To evaluate frequency, conversion rate, and risk factors for blindness in glaucoma patients treated in European Universities. Methods This multicenter retrospective study included 2402 consecutive patients with glaucoma in at least one eye. Medical charts were inspected and patients were divided into those blind and the remainder (‘controls’). Blindness was defined as visual acuity≤0.05 and/or visual field loss to less than 10°. Results Unilateral and bilateral blindness were respectively 11.0% and 1.6% at the beginning, and 15.5% and 3.6% at the end of the observation period (7.5±5.5 years, range:1–25 years); conversion to blindness (at least unilateral) was 1.1%/year. 134 eyes (97 patients) developed blindness by POAG during the study. At the first access to study centre, they had mean deviation (MD) of -17.1±8.3 dB and treated intraocular pressure (IOP) of 17.1±6.6 mmHg. During follow-up the IOP decreased by 14% in these eyes but MD deteriorated by 1.1±3.5 dB/year, which was 5-fold higher than controls (0.2±1.6 dB/year). In a multivariate model, the best predictors for blindness by glaucoma were initial MD (p<0.001), initial IOP (p<0.001), older age at the beginning of follow-up (p<0.001), whereas final IOP was found to be protective (p<0.05). Conclusions In this series of patients, blindness occurred in about 20%. Blindness by glaucoma had 2 characteristics: late diagnosis and/or late referral, and progression of the disease despite in most cases IOP was within the range of normality and target IOP was achieved; it could be predicted by high initial MD, high initial IOP, and old age. PMID:26302445

Expanding the Substantial Interactome of NEMO Using Protein Microarrays

PubMed Central

Fenner, Beau J.; Scannell, Michael; Prehn, Jochen H. M.

2010-01-01

Signal transduction by the NF-kappaB pathway is a key regulator of a host of cellular responses to extracellular and intracellular messages. The NEMO adaptor protein lies at the top of this pathway and serves as a molecular conduit, connecting signals transmitted from upstream sensors to the downstream NF-kappaB transcription factor and subsequent gene activation. The position of NEMO within this pathway makes it an attractive target from which to search for new proteins that link NF-kappaB signaling to additional pathways and upstream effectors. In this work, we have used protein microarrays to identify novel NEMO interactors. A total of 112 protein interactors were identified, with the most statistically significant hit being the canonical NEMO interactor IKKbeta, with IKKalpha also being identified. Of the novel interactors, more than 30% were kinases, while at least 25% were involved in signal transduction. Binding of NEMO to several interactors, including CALB1, CDK2, SAG, SENP2 and SYT1, was confirmed using GST pulldown assays and coimmunoprecipitation, validating the initial screening approach. Overexpression of CALB1, CDK2 and SAG was found to stimulate transcriptional activation by NF-kappaB, while SYT1 overexpression repressed TNFalpha-dependent NF-kappaB transcriptional activation in human embryonic kidney cells. Corresponding with this finding, RNA silencing of CDK2, SAG and SENP2 reduced NF-kappaB transcriptional activation, supporting a positive role for these proteins in the NF-kappaB pathway. The identification of a host of new NEMO interactors opens up new research opportunities to improve understanding of this essential cell signaling pathway. PMID:20098747

Synergistic effect of ozonation and ionizing radiation for PVA decomposition.

PubMed

Sun, Weihua; Chen, Lujun; Zhang, Yongming; Wang, Jianlong

2015-08-01

Ozonation and ionizing radiation are both advanced oxidation processes (AOPs) without chemical addition and secondary pollution. Also, the two processes' efficiency is determined by different pH conditions, which creates more possibilities for their combination. Importantly, the combined process of ozonation and ionizing radiation could be suitable for treating wastewaters with extreme pH values, i.e., textile wastewater. To find synergistic effects, the combined process of ozonation and ionizing radiation mineralization was investigated for degradation of polyvinyl alcohol (PVA) at different pH levels. A synergistic effect was found at initial pH in the range 3.0-9.4. When the initial pH was 3.0, the combined process of ozonation and ionizing radiation gave a PVA mineralization degree of 17%. This was 2.7 times the sum achieved by the two individual processes, and factors of 2.1 and 1.7 were achieved at initial pH of 7.0 and 9.4, respectively. The combined process of ozonation and ionizing radiation was demonstrated to be a feasible strategy for treatment of PVA-containing wastewater. Copyright © 2015. Published by Elsevier B.V.

Diverged composition and regulation of the Trypanosoma brucei origin recognition complex that mediates DNA replication initiation

PubMed Central

Marques, Catarina A.; Tiengwe, Calvin; Lemgruber, Leandro; Damasceno, Jeziel D.; Scott, Alan; Paape, Daniel; Marcello, Lucio; McCulloch, Richard

2016-01-01

Abstract Initiation of DNA replication depends upon recognition of genomic sites, termed origins, by AAA+ ATPases. In prokaryotes a single factor binds each origin, whereas in eukaryotes this role is played by a six-protein origin recognition complex (ORC). Why eukaryotes evolved a multisubunit initiator, and the roles of each component, remains unclear. In Trypanosoma brucei, an ancient unicellular eukaryote, only one ORC-related initiator, TbORC1/CDC6, has been identified by sequence homology. Here we show that three TbORC1/CDC6-interacting factors also act in T. brucei nuclear DNA replication and demonstrate that TbORC1/CDC6 interacts in a high molecular complex in which a diverged Orc4 homologue and one replicative helicase subunit can also be found. Analysing the subcellular localization of four TbORC1/CDC6-interacting factors during the cell cycle reveals that one factor, TbORC1B, is not a static constituent of ORC but displays S-phase restricted nuclear localization and expression, suggesting it positively regulates replication. This work shows that ORC architecture and regulation are diverged features of DNA replication initiation in T. brucei, providing new insight into this key stage of eukaryotic genome copying. PMID:26951375

Activation by Insulin and Amino Acids of Signaling Components Leading to Translation Initiation in Skeletal Muscle of Neonatal Pigs Is Developmentally Regulated

PubMed Central

Suryawan, Agus; Orellana, Renan A.; Nguyen, Hanh V.; Jeyapalan, Asumthia S.; Fleming, Jillian R.; Davis, Teresa A.

2009-01-01

Insulin (INS) and amino acids (AA) act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight fasted 6-day-old (n=4/group) and 26-day-old (n=6/group) pigs were studied during: 1) euinsulinemic-euglycemic-euaminoacidemic conditions (controls), 2) euinsulinemic-euglycemic-hyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and these responses were higher in 6-day-old compared to 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GβL) or mTORC2 (rictor, mTOR, and GβL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated kinase (AMPK) and eukaryotic elongation factor 2 (eEF2). Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs. PMID:17878222

Utility of combinations of biomarkers, cognitive markers, and risk factors to predict conversion from mild cognitive impairment to Alzheimer disease in patients in the Alzheimer's disease neuroimaging initiative.

PubMed

Gomar, Jesus J; Bobes-Bascaran, Maria T; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

2011-09-01

Biomarkers have become increasingly important in understanding neurodegenerative processes associated with Alzheimer disease. Markers include regional brain volumes, cerebrospinal fluid measures of pathological Aβ1-42 and total tau, cognitive measures, and individual risk factors. To determine the discriminative utility of different classes of biomarkers and cognitive markers by examining their ability to predict a change in diagnostic status from mild cognitive impairment to Alzheimer disease. Longitudinal study. We analyzed the Alzheimer's Disease Neuroimaging Initiative database to study patients with mild cognitive impairment who converted to Alzheimer disease (n = 116) and those who did not convert (n = 204) within a 2-year period. We determined the predictive utility of 25 variables from all classes of markers, biomarkers, and risk factors in a series of logistic regression models and effect size analyses. The Alzheimer's Disease Neuroimaging Initiative public database. Primary outcome measures were odds ratios, pseudo- R(2)s, and effect sizes. In comprehensive stepwise logistic regression models that thus included variables from all classes of markers, the following baseline variables predicted conversion within a 2-year period: 2 measures of delayed verbal memory and middle temporal lobe cortical thickness. In an effect size analysis that examined rates of decline, change scores for biomarkers were modest for 2 years, but a change in an everyday functional activities measure (Functional Assessment Questionnaire) was considerably larger. Decline in scores on the Functional Assessment Questionnaire and Trail Making Test, part B, accounted for approximately 50% of the predictive variance in conversion from mild cognitive impairment to Alzheimer disease. Cognitive markers at baseline were more robust predictors of conversion than most biomarkers. Longitudinal analyses suggested that conversion appeared to be driven less by changes in the neurobiologic trajectory of the disease than by a sharp decline in functional ability and, to a lesser extent, by declines in executive function.

Model of a ternary complex between activated factor VII, tissue factor and factor IX.

PubMed

Chen, Shu-wen W; Pellequer, Jean-Luc; Schved, Jean-François; Giansily-Blaizot, Muriel

2002-07-01

Upon binding to tissue factor, FVIIa triggers coagulation by activating vitamin K-dependent zymogens, factor IX (FIX) and factor X (FX). To understand recognition mechanisms in the initiation step of the coagulation cascade, we present a three-dimensional model of the ternary complex between FVIIa:TF:FIX. This model was built using a full-space search algorithm in combination with computational graphics. With the known crystallographic complex FVIIa:TF kept fixed, the FIX docking was performed first with FIX Gla-EGF1 domains, followed by the FIX protease/EGF2 domains. Because the FIXa crystal structure lacks electron density for the Gla domain, we constructed a chimeric FIX molecule that contains the Gla-EGF1 domains of FVIIa and the EGF2-protease domains of FIXa. The FVIIa:TF:FIX complex has been extensively challenged against experimental data including site-directed mutagenesis, inhibitory peptide data, haemophilia B database mutations, inhibitor antibodies and a novel exosite binding inhibitor peptide. This FVIIa:TF:FIX complex provides a powerful tool to study the regulation of FVIIa production and presents new avenues for developing therapeutic inhibitory compounds of FVIIa:TF:substrate complex.

NF-κB Is the Transcription Factor for FGF-2 That Causes Endothelial Mesenchymal Transformation in Cornea

PubMed Central

Lee, Jeong Goo

2012-01-01

Purpose. To determine the role of nuclear factor-κB (NF-κB) during FGF-2–mediated endothelial mesenchymal transformation (EMT) in response to interleukin (IL)-1β stimulation in corneal endothelial cells (CECs). Methods. Expression and/or activation of IL-1 receptor–associated protein kinase (IRAK), TNF receptor–associated factor 6 (TRAF6), phosphatidylinositol 3-kinase (PI 3-kinase), IκB kinase (IKK), IκB, NF-κB, and FGF-2 were analyzed by immunoblot analysis. Cell proliferation was measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. NF-κB activity was measured by NF-κB ELISA kit, while binding of NF-κB to the promoter region of FGF-2 gene was determined by chromatin immunoprecipitation. Results. Brief stimulation of CECs with IL-1β upregulated expression of IRAK and TRAF6 and activated PI 3-kinase; expression of IRAK and TRAF6 reached maximum within 60 minutes, after which the expression disappeared, while PI 3-kinase activity was observed up to 4 hours after IL-1β stimulation. Use of specific inhibitor to PI 3-kinase or IRAK demonstrated that IRAK activates PI 3-kinase, the signaling of which phosphorylates IKKα/β and degrades IκB, subsequently leading to activation of NF-κB. The induction of FGF-2 by IL-1β was completely blocked by inhibitors to NF-κB activation (sulfasalazine) or PI 3-kinase (LY294002), and both inhibitors greatly blocked cell proliferation of CECs. Chromatin immunoprecipitation further demonstrated that NF-κB is the transcription factor of FGF-2 as NF-κB binds the putative NF-κB binding site of the FGF-2 promoter. Conclusions. These data suggest that IL-1β signaling combines the canonical pathway and the PI 3-kinase signaling to upregulate FGF-2 production through NF-κB, which plays a key role as a transcription factor of FGF-2 gene. PMID:22323467

Hepatitis A, B, and A/B vaccination series completion among US adults: a claims-based analysis.

PubMed

Ghaswalla, Parinaz K; Patterson, Brandon J; Cheng, Wendy Y; Duchesneau, Emilie; Macheca, Monica; Duh, Mei Sheng

2018-06-20

Hepatitis A and B disease burden persists in the US. We assessed hepatitis A and hepatitis B vaccination series completion rates among 350,240 commercial/Medicare and 12,599 Medicaid enrollees aged ≥19 years. A vaccination series was considered as completed provided that the minimum interval between doses, as defined by the CDC, and the minimum number of doses were reached. We stratified completion rates by vaccine type (i.e. monovalent or bivalent) at initial vaccination for each cohort. In the commercial/Medicare cohort, the series completion rate was 32.0% for hepatitis A and 39.6% for hepatitis B among those who initiated with a monovalent vaccine, and it was 36.2% for hepatitis A and 48.9% for hepatitis B among those who initiated with a bivalent vaccine. In the Medicaid cohort, the series completion rate was 21.0% for hepatitis A and 24.0% for hepatitis B among those who initiated with a monovalent vaccine, and it was 19.0% for hepatitis A and 24.6% for hepatitis B among those who initiated with a bivalent vaccine. In conclusion, hepatitis A and B vaccination series completion rates were low, and appeared to be lower among Medicaid than among commercial/Medicare enrollees. Commercial/Medicare enrollees who initiated with a bivalent vaccine had higher series completion rates than those who initiated with monovalent vaccines - an observation that was not made among Medicaid enrollees.

The new albumin-free recombinant factor VIII concentrates for treatment of hemophilia: do they represent an actual incremental improvement?

PubMed

Josephson, Cassandra D; Abshire, Thomas

2004-07-01

The goal of eliminating the low levels of infectious disease risk from hemophilia treatment has resulted in the development of multiple generations of recombinant factor VIII (rFVIII) products. The ideal product should be devoid of human and animal proteins, which may transmit infectious agents. These products should also maintain molecular integrity, hemostatic efficacy, similar immunogenicity, and acceptable side effect profiles as compared to plasma-derived factor VIII. Currently available first-, second-, and third-generation rFVIII products include Recombinate; Kogenate FS/Helixate FS and ReFacto; and Advate, respectively. During the evolution of rFVIII products, either full-length or B-domain-deleted factor VIII were transfected into immortalized cell lines. The B-domain-deleted product, ReFacto, has resulted in an additional method to monitor factor VIII levels. The third-generation products offer the theoretical advantage of being produced without human and/or animal proteins. Upon initial introduction into the marketplace, the newer products have a higher cost. However, when analyzing historical trends, the prices of these products are almost equivalent to first-generation products within 3 years of licensure. Thus, the initial cost of the product may be a minimal issue in the medical decision process when selecting rFVIII replacement therapy.

Effect of Sodium Chloride and pH on Enterotoxin B Production

PubMed Central

Genigeorgis, Constantin; Sadler, Walter W.

1966-01-01

Genigeorgis, Constantin (University of California, Davis), and Walter W. Sadler. Effect of sodium chloride and pH on enterotoxin B production. J. Bacteriol. 92:1383–1387. 1966.—The growth and production of enterotoxin B by Staphylococcus aureus strain S-6 in Brain Heart Infusion broth with 2 to 16% sodium chloride and an initial pH of 5.1 to 6.9 was studied during a 10-day incubation period at 37 C. Growth was good at pH 6.9 and with a 16% concentration of salt, but no cells survived after 10 days of incubation at pH 5.1 and with a 16% concentration of salt. With geldiffusion technique, enterotoxin B was detected in broth with pH 6.9 and up to 10% salt or pH 5.1 and up to 4% salt. Growth and enterotoxin production were better when pH was increased and salt concentration was decreased. The dependence of toxin production on the interaction of these two factors was demonstrated. PMID:5924269

Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration

PubMed Central

Haynes, Tracy; Luz-Madrigal, Agustin; Reis, Edimara S.; Echeverri Ruiz, Nancy P.; Grajales-Esquivel, Erika; Tzekou, Apostolia; Tsonis, Panagiotis A.; Lambris, John D.; Del Rio-Tsonis, Katia

2013-01-01

Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology. Much of the research thus far has indicated that certain growth factors have key roles. Here we show that complement fragment C3a is sufficient to induce complete regeneration of the embryonic chick retina from stem/progenitor cells present in the eye, independent of fibroblast growth factor receptor signaling. Instead, C3a induces retina regeneration via STAT3 activation, which in turn activates the injury- and inflammation-responsive factors, IL-6, IL-8 and TNF-α. This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells. Thus, our results establish a mechanism for retina regeneration based on injury and inflammation signals. Furthermore, our results indicate a unique function for complement anaphylatoxins that implicate these molecules in the induction and complete regeneration of the retina, opening new avenues of experimentation in the field. PMID:23942241

Cathepsin B and uPAR regulate self-renewal of glioma-initiating cells through GLI-regulated Sox2 and Bmi1 expression

PubMed Central

Rao, Jasti S.

2013-01-01

Cancer-initiating cells comprise a heterogeneous population of undifferentiated cells with the capacity for self-renewal and high proliferative potential. We investigated the role of uPAR and cathepsin B in the maintenance of stem cell nature in glioma-initiating cells (GICs). Simultaneous knockdown of uPAR and cathepsin B significantly reduced the expression of CD133, Nestin, Sox2 and Bmi1 at the protein level and GLI1 and GLI2 at the messenger RNA level. Also, knockdown of uPAR and cathepsin B resulted in a reduction in the number of GICs as well as sphere size. These changes are mediated by Sox2 and Bmi1, downstream of hedgehog signaling. Addition of cyclopamine reduced the expression of Sox2 and Bmi1 along with GLI1 and GLI2 expression, induced differentiation and reduced subsphere formation of GICs thereby indicating that hedgehog signaling acts upstream of Sox2 and Bmi1. Further confirmation was obtained from increased luciferase expression under the control of a GLI-bound Sox2 and Bmi1 luciferase promoter. Simultaneous knockdown of uPAR and cathepsin B also reduced the expression of Nestin Sox2 and Bmi1 in vivo. Thus, our study highlights the importance of uPAR and cathepsin B in the regulation of malignant stem cell self-renewal through hedgehog components, Bmi1 and Sox2. PMID:23222817

Biosorption of lead, cadmium, and zinc by Citrobacter strain MCM B-181: Characterization studies

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

Puranik, P.R.; Paknikar, K.M.

1999-03-01

The biosorption process for removal of lead, cadmium, and zinc by Citrobacter strain MCM B-181, a laboratory isolate, was characterized. Effects of environmental factors and growth conditions on metal uptake capacity were studied. Pretreatment of biomass with chemical agents increased cadmium sorption efficiency; however, there was no significant enhancement in lead and zinc sorption capacity. Metal sorption by Citrobacter strain MCM B-181 was found to be influenced by the pH of the solution, initial metal concentration, biomass concentration, and type of growth medium. The metal sorption process was not affected by the age of the culture or change in temperature.more » Equilibrium metal sorption was found to fit the Langmuir adsorption model. Kinetic studies showed that metal uptake by Citrobacter strain MCm B-181 was a fast process, requiring < 20 min to achieve > 90% adsorption efficiency. The presence of cations reduced lead, zinc, and cadmium sorption to the extent of 11.8%, 84.3%, and 33.4%, respectively. When biomass was exposed to multimetal solutions, metals were adsorbed in the order Co{sup 2+} < Ni{sup 2+} < Cd{sup 2+} < Cu{sup 2+}, Zn{sup 2+} < Pb{sup 2+}. A new mathematical model used for batch kinetic studies was found to be highly useful in prediction of experimentally obtained metal concentration profiles as a function of time.« less

Zinc-induced Self-association of Complement C3b and Factor H

PubMed Central

Nan, Ruodan; Tetchner, Stuart; Rodriguez, Elizabeth; Pao, Po-Jung; Gor, Jayesh; Lengyel, Imre; Perkins, Stephen J.

2013-01-01

The sub-retinal pigment epithelial deposits that are a hallmark of age-related macular degeneration contain both C3b and millimolar levels of zinc. C3 is the central protein of complement, whereas C3u is formed by the spontaneous hydrolysis of the thioester bridge in C3. During activation, C3 is cleaved to form active C3b, then C3b is inactivated by Factor I and Factor H to form the C3c and C3d fragments. The interaction of zinc with C3 was quantified using analytical ultracentrifugation and x-ray scattering. C3, C3u, and C3b associated strongly in >100 μm zinc, whereas C3c and C3d showed weak association. With zinc, C3 forms soluble oligomers, whereas C3u and C3b precipitate. We conclude that the C3, C3u, and C3b association with zinc depended on the relative positions of C3d and C3c in each protein. Computational predictions showed that putative weak zinc binding sites with different capacities exist in all five proteins, in agreement with experiments. Factor H forms large oligomers in >10 μm zinc. In contrast to C3b or Factor H alone, the solubility of the central C3b-Factor H complex was much reduced at 60 μm zinc and even more so at >100 μm zinc. The removal of the C3b-Factor H complex by zinc explains the reduced C3u/C3b inactivation rates by zinc. Zinc-induced precipitation may contribute to the initial development of sub-retinal pigment epithelial deposits in the retina as well as reducing the progression to advanced age-related macular degeneration in higher risk patients. PMID:23661701

Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia.

PubMed

Nückel, Holger; Frey, Ulrich H; Bau, Maja; Sellmann, Ludger; Stanelle, Jens; Dürig, Jan; Jöckel, Karl-Heinz; Dührsen, Ulrich; Siffert, Winfried

2007-01-01

Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The -938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the -938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with -938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2-938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2-938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.

Cross Talk in HEK293 Cells Between Nrf2, HIF, and NF-κB Activities upon Challenges with Redox Therapeutics Characterized with Single-Cell Resolution.

PubMed

Johansson, Katarina; Cebula, Marcus; Rengby, Olle; Dreij, Kristian; Carlström, Karl E; Sigmundsson, Kristmundur; Piehl, Fredrik; Arnér, Elias S J

2017-02-20

Many transcription factors with importance in health and disease are redox regulated. However, how their activities may be intertwined in responses to redox-perturbing stimuli is poorly understood. To enable in-depth characterization of this aspect, we here developed a methodology for simultaneous determination of nuclear factor E2-related factor 2 (Nrf2), hypoxia-inducible factor (HIF), and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation at single-cell resolution, using a new tool named pTRAF (plasmid for transcription factor reporter activation based upon fluorescence). The pTRAF allowed determination of Nrf2, HIF, and NF-κB activities in a high-resolution and high-throughput manner, and we here assessed how redox therapeutics affected the activities of these transcription factors in human embryonic kidney cells (HEK293). Cross talk was detected between the three signaling pathways upon some types of redox therapeutics, also by using inducers typically considered specific for Nrf2, such as sulforaphane or auranofin, hypoxia for HIF activation, or tumor necrosis factor alpha (TNFα) for NF-κB stimulation. Doxorubicin, at low nontoxic doses, potentiated TNFα-induced activation of NF-κB and HIF, without effects in stand-alone treatment. Stochastic activation patterns in cell cultures were also considerable upon challenges with several redox stimuli. A novel strategy was here used to study simultaneous activation of Nrf2, HIF, and NF-κB in single cells. The method can also be adapted for studies of other transcription factors. The pTRAF provides new opportunities for in-depth studies of transcription factor activities. In this study, we found that upon challenges of cells with several redox-perturbing conditions, Nrf2, HIF, and NF-κB are uniquely responsive to separate stimuli, but can also display marked cross talk to each other within single cells. Antioxid. Redox Signal. 26, 229-246.

Brain-derived neurotrophic factor/neurotrophin 3 regulate axon initial segment location and affect neuronal excitability in cultured hippocampal neurons.

PubMed

Guo, Yu; Su, Zi-Jun; Chen, Yi-Kun; Chai, Zhen

2017-07-01

Plasticity of the axon initial segment (AIS) has aroused great interest in recent years because it regulates action potential initiation and neuronal excitability. AIS plasticity manifests as modulation of ion channels or variation in AIS structure. However, the mechanisms underlying structural plasticity of the AIS are not well understood. Here, we combined immunofluorescence, patch-clamp recordings, and pharmacological methods in cultured hippocampal neurons to investigate the factors participating in AIS structural plasticity during development. With lowered neuronal density, the distance between the AIS and the soma increased, while neuronal excitability decreased, as shown by the increased action potential threshold and current threshold for firing an action potential. This variation in the location of the AIS was associated with cellular secretory substances, including brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3). Indeed, blocking BDNF and NT3 with TrkB-Fc eliminated the effect of conditioned medium collected from high-density cultures on AIS relocation. Elevating the extracellular concentration of BDNF or NT3 promoted movement of the AIS proximally to the soma and increased neuronal excitability. Furthermore, knockdown of neurotrophin receptors TrkB and TrkC caused distal movement of the AIS. Our results demonstrate that BDNF and NT3 regulate AIS location and neuronal excitability. These regulatory functions of neurotrophic factors provide insight into the molecular mechanisms underlying AIS biology. © 2017 International Society for Neurochemistry.

Molecular tissue changes in early myocardial ischemia: from pathophysiology to the identification of new diagnostic markers.

PubMed

Aljakna, Aleksandra; Fracasso, Tony; Sabatasso, Sara

2018-03-01

Diagnosing early myocardial ischemia (the initial 4 to 6 h after interruption of blood flow to part of the myocardium) remains a challenge for clinical and forensic pathologists. Several immunohistochemical markers have been proposed for improving postmortem detection of early myocardial ischemia; however, no single marker appears to be both sufficiently specific as well as sensitive. This review summarizes the diverse categories of molecular tissue markers that have been investigated in human autopsy samples with acute myocardial infarction as well as in the well-established and widely used in vivo animal model of early myocardial ischemia (permanent ligation of the coronary artery). Recently identified markers appearing during the initial 2 h of myocardial ischemia are highlighted. Among them, only six were tested for specificity (C5b-9, hypoxia-inducible factor 1-alpha, vascular endothelial growth factor, heart fatty acid binding protein, connexin 43, and JunB). Despite the discovery of several potentially promising markers (in terms of early expression and specificity), many of them remain to be tested and validated for application in routine diagnostics in clinical and forensic pathology. In particular, research investigating the postmortem stability of these markers is required before any might be implemented into routine diagnostics. Establishing a standardized panel of immunohistochemical markers may be more useful for improving sensitivity and specificity than searching for a single marker.

40 CFR Table 2 to Subpart Rrr of... - Summary of Operating Requirements for New and Existing Affected Sources and Emission Units

Code of Federal Regulations, 2011 CFR

2011-07-01

... with fabric filter Bag leak detector or Initiate corrective action within 1-hr of alarm and complete in... operation Operate in accordance with OM&M plan. b Bag leak detector or Initiate corrective action within 1... accordance with OM&M plan. b Dross-only furnace with fabric filter Bag leak detector or Initiate corrective...

Market potential of nanoremediation in Europe - Market drivers and interventions identified in a deliberative scenario approach.

PubMed

Bartke, Stephan; Hagemann, Nina; Harries, Nicola; Hauck, Jennifer; Bardos, Paul

2018-04-01

A deliberate expert-based scenario approach is applied to better understand the likely determinants of the evolution of the market for nanoparticles use in remediation in Europe until 2025. An initial set of factors had been obtained from a literature review and was complemented by a workshop and key-informant interviews. In further expert engaging formats - focus groups, workshops, conferences, surveys - this initial set of factors was condensed and engaged experts scored the factors regarding their importance for being likely to influence the market development. An interaction matrix was obtained identifying the factors being most active in shaping the market development in Europe by 2025, namely "Science-Policy-Interface" and "Validated information on nanoparticle application potential". Based on these, potential scenarios were determined and development of factors discussed. Conclusions are offered on achievable interventions to enhance nanoremediation deployment. Copyright © 2017 Elsevier B.V. All rights reserved.

Considerations for initial dosing of botulinum toxin in treatment of adductor spasmodic dysphonia.

PubMed

Rosow, David E; Parikh, Punam; Vivero, Richard J; Casiano, Roy R; Lundy, Donna S

2013-06-01

To assess the effect on voice improvement and duration of breathiness based on initial dose of onabotulinum toxin A (BTX-A) in the management of adductor spasmodic dysphonia (SD) and to compare voice outcomes for initial bilaterally injected doses of 1.25 units (group A) vs 2.5 units (group B) of BTX-A. Case series with chart review of patients with adductor SD treated at a tertiary care facility from 1990 to 2011. Academic subspecialty laryngology practice. Demographic data (age and sex), voice rating, duration of voice improvement, and breathiness were evaluated and compared between groups A and B using the Student t test and χ(2) analysis. Of 478 patients identified, 305 (223 in group A, 82 in group B) patients met inclusion criteria. The average age was 56.2 years in group A and 57.4 years in group B (P = .5). The female to male ratio was 2.91 for group A vs 3.56 for group B (P = .61). Good voice outcomes (grade 3 or 4) were reported by 91% of group A patients vs 94% of group B (P = .75). The average duration of voice improvement was 99.7 days for group A and 108.3 days for group B (P = .54). The average duration of breathiness was 10.88 days for group A vs 15.42 days for group B (P = .02). Patients injected with 1.25 units bilaterally had a statistically significant shorter duration of breathiness without a statistically significant difference in clinical effectiveness or voice outcome. It is therefore recommended that a relatively low initial BTX-A dose be used with subsequent titration to achieve improved voice outcomes.

38 CFR 20.1508 - Rule 1508. Waiver.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) BOARD OF VETERANS' APPEALS: RULES OF PRACTICE Expedited Claims Adjudication Initiative-Pilot Program... virtue of electing participation in the Initiative. (b) Evidence obtained or submitted after the... revocation of participation in the Initiative, as provided by § 20.1509(c)(2). (2) Evidence submitted by...

Changes in metformin use and other antihyperglycemic therapies after insulin initiation in patients with type 2 diabetes.

PubMed

Pilla, Scott J; Dotimas, James R; Maruthur, Nisa M; Clark, Jeanne M; Yeh, Hsin-Chieh

2018-05-01

When patients with type 2 diabetes initiate insulin, metformin should be continued while continuation of other antihyperglycemics has unclear benefit. We aimed to identify practice patterns in antihyperglycemic therapy during the insulin transition, and determine factors associated with metformin continuation. We performed a retrospective analysis of the Look AHEAD (Action for Health in Diabetes) trial which randomized overweight/obese adults under ambulatory care for type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. Among the 931 participants who initiated insulin over ten years, we described longitudinal changes in antihyperglycemic medications during the insulin transition, and performed multivariable logistic regression to estimate the association between patient characteristics and metformin continuation. Before insulin initiation, 81.0% of patients used multiple antihyperglycemics, the most common being metformin, sulfonylureas, and thiazolidinediones. After insulin initiation, metformin was continued in 80.3% of patients; other antihyperglycemics were continued less often, yet 58.0% of patients were treated with multiple non-insulin antihyperglycemics. Metformin continuation was inversely associated with age (fully adjusted (a) OR 0.60 per 10 years [0.42-0.86]), serum creatinine above safety thresholds (aOR 0.09 [0.02-0.36]), lower income (P = 0.025 for trend), taking more medications (aOR 0.92 per medication [0.86-0.98]), and initiating rapid, short, or premixed insulin (aOR 0.59 [0.39-0.89]). The vast majority of patients with type 2 diabetes continue metformin after insulin initiation, consistent with guidelines. Other antihyperglycemics are frequently continued along with insulin, and further research is needed to determine which, if any, patients may benefit from this. Copyright © 2018 Elsevier B.V. All rights reserved.

Porous carbon-coated silica macroparticles as anode materials for lithium ion batteries: Effect of boric acid

NASA Astrophysics Data System (ADS)

Kim, Young-Kuk; Moon, Jong-Woo; Lee, Jung-Goo; Baek, Youn-Kyung; Hong, Seong-Hyun

2014-12-01

We report carbon-coated porous silica macroparticles (SiO2@C) prepared using polymeric templates and subsequent carbonization with sucrose for improved electrochemical energy storage in lithium-ion batteries (LIBs). In addition, boron is introduced to improve the stability of electrochemical cells by pyrolyzing mixtures of sucrose and boric acid (SiO2@C + B) under inert atmosphere. The initially large surface area of porous SiO2 (SBET ∼ 658 m2 g-1) is reduced to 102 m2 g-1 after carbonization and introduction of boric acid. Surface of both SiO2@C and SiO2@C + B are covered with amorphous carbon. In particular, SiO2@C + B particles containing borosilicate (Si-O-B) phase and B-O bondings and Si-C-O bondings are also detected from the X-ray photoelectron spectra. The SiO2@C + B macroparticles shows high reversible charge capacity up to 503 mAh g-1 after 103 cycles of Li intercalation/de-intercalation although initial capacity was 200 mAh g-1. The improved charge capacity of SiO2@C + B is attributed to formation of advantageous microstructures induced from boric acid.

Appropriate and inappropriate methods for investigating the "gateway" hypothesis, with a review of the evidence linking prior snus use to later cigarette smoking.

PubMed

Lee, Peter N

2015-03-20

The "gateway hypothesis" usually refers to the possibility that the taking up of habit A, which is considered harmless (or less harmful), may lead to the subsequent taking up of another habit, B, which is considered harmful (or more harmful). Possible approaches to designing and analysing studies to test the hypothesis are discussed. Evidence relating to the use of snus (A) as a gateway for smoking (B) is then evaluated in detail. The importance of having appropriate data available on the sequence of use of A and B and on other potential confounding factors that may lead to the taking up of B is emphasised. Where randomised trials are impractical, the preferred designs include the prospective cohort study in which ever use of A and of B is recorded at regular intervals, and the cross-sectional survey in which time of starting to use A and B is recorded. Both approaches allow time-stratified analytical methods to be used, in which, in each time period, risk of initiating B among never users of B at the start of the interval is compared according to prior use of A. Adjustment in analysis for the potential confounding factors is essential. Of 11 studies of possible relevance conducted in Sweden, Finland or Norway, only one seriously addresses potential confounding by those other factors involved in the initiation of smoking. Furthermore, 5 of the 11 studies are of a design that does not allow proper testing of the gateway hypothesis for various reasons, and the analysis is unsatisfactory, sometimes seriously, in all the remaining six. While better analyses could be attempted for some of the six studies identified as having appropriate design, the issues of confounding remain, and more studies are clearly needed. To obtain a rapid answer, a properly designed cross-sectional survey is recommended.

Timing of anticoagulant re-initiation following intracerebral hemorrhage in mechanical heart valves: Survey of neurosurgeons and thrombosis experts.

PubMed

AlKherayf, Fahad; Xu, Yan; Westwick, Harrison; Moldovan, Ioana Doina; Wells, Philip S

2017-03-01

While oral anticoagulation (OAC) is universally indicated for patients with mechanical heart valves (MHVs), OAC resumption following anticoagulant-associated intracerebral hemorrhage (ICH) is an area of uncertainty. We sought to determine the practice preferences of North American neurosurgeons and thrombosis experts on optimal timing of OAC re-initiation. A cross-sectional survey was disseminated to North American members of the American Association of Neurological Surgeons and the International Society for Thrombosis and Haemostasis. Demographic factors, as well as a clinical scenario with 14 modifiable clinical risk factors were included in the survey. 504 physicians completed our survey (response rate 34.3%). Majority of participants were affiliated with academic centres, and managed≤10 ICH patients with MHV per year. There was wide distribution in response in optimal timing for OAC resumption following an ICH: 59% and 60% preferred to re-start OAC between 3 and 14 days following the hemorrhagic event (median of 6-7 days). Smaller hemorrhages (<30cm 2 ). CHADS 2 score ≥2, concomitant venous thromboembolism, mitral valve prosthesis, caged-ball valves and multiple valves prompted earlier OAC resumption. Wide variation in the current practice of neurosurgeons and thrombosis specialists exist when they encounter patients with ICH and MHV, though decisions were influenced by patient- and valve-related factors. As our observed variation likely reflects the immense gap in current evidence, prospective randomized trials in this population are therefore urgently needed. Copyright © 2017 Elsevier B.V. All rights reserved.

Pretranslational regulation of the synthesis of the third component of complement in human mononuclear phagocytes by the lipid A portion of lipopolysaccharide.

PubMed Central

Strunk, R C; Whitehead, A S; Cole, F S

1985-01-01

The third component of complement (C3) is a plasma glycoprotein with a variety of biologic functions in the initiation and maintenance of host response to infectious agents. While the hepatocyte is the primary source of plasma C3, mononuclear phagocytes contribute to the regulation of tissue availability of C3. Lipopolysaccharide (LPS), a constituent of cell walls of gram-negative bacteria, consists of a polysaccharide moiety (core polysaccharide and O antigen) covalently linked to a lipid portion (lipid A). Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-polyacrylamide gel electrophoresis, we examined the effects of LPS on synthesis of C3 by human mononuclear phagocytes as well as synthesis of the second component of complement (C2), factor B, lysozyme, and total protein. LPS increased C3 synthesis 5-30-fold without affecting the kinetics of secretion of C3 or the synthesis of C2, lysozyme, or total protein. Factor B synthesis was consistently increased by LPS. Experiments with lipid A-inactivated LPS (alkaline treated), LPS from a polysaccharide mutant strain, and lipid X (a lipid A precursor) indicated that the lipid A portion is the structural element required for this effect. Northern blot analysis demonstrated at least a fivefold increase in C3 mRNA in LPS-treated monolayers, which suggests that the regulation of the increase in C3 synthesis is pretranslational. C2 mRNA and factor B mRNA were increased approximately twofold. The availability of specific gene products in human mononuclear phagocytes that respond to LPS should permit understanding of the molecular regulation of more complex functions of these cells elicited by LPS in which multiple gene products are coordinately expressed. Images PMID:3900137

A malaria protein factor induces IL-4 production by dendritic cells via PI3K-Akt-NF-κB signaling independent of MyD88/TRIF and promotes Th2 response.

PubMed

Wu, Xianzhu; Gowda, Nagaraj M; Kawasawa, Yuka I; Gowda, D Channe

2018-04-17

Dendritic cells (DC) and cytokines produced by DC play crucial roles in inducing and regulating pro-/anti-inflammatory and Th1/Th2 responses. DC are known to produce Th1-promoting cytokine, IL-12, in response to malaria and other pathogenic infections, but it is thought that DC do not produce Th2-promoting cytokine, IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11c hi MHCII hi CD3ε - CD49b - CD19 - FcεRI - DC via PI3K-Akt-NF-κB signaling independent of TLR-MyD88/TRIF. Malaria parasite-activated DC induced IL-4 responses by T cells both in vitro and in vivo , favoring Th2, and il-4 deficient DC were unable to induce IL-4 expression by T cell.  Interestingly, lethal parasites, Plasmodium falciparum and P. berghei ANKA, induced IL-4 response primarily by CD8a - DC, whereas nonlethal P. yoelii induced IL-4 by both CD8α + and CD8α - DC. In both P. berghei ANKA- and P. yoelii -infected mice, IL-4-expressing CD8α - DC did not express IL-12, but a distinct CD8α - DC subset expressed IL-12. In P. berghei ANKA infection, CD8α + DC expressed IL-12 but not IL-4, whereas in P. yoelii infection CD8α + DC expressed IL-4 but not IL-12. This differential IL-4 and IL-12 responses by DC subsets may contribute to different Th1/Th2 development and clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrate that a malaria protein factor induces IL-4 production by DC via PI3K-Akt-NF-κB signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Implementation of Video Teleconferencing for the Republic of China Navy

DTIC Science & Technology

1990-03-01

INTRODUCTION 1 A. BACKGROUND 1 1. Communications Environment, Needs, and Plans 1 2. Republic of China History and Threat of Invasion 4 B ...TELECONFERENCING 8 1. Definition 8 2. History of Video Teleconferencing 9 B . CATEGORIES OF TELECONFERENCING 11 1. Audio Conferencing 11 2. Audio...RELATED TO TELECONFERENCING 52 A. PNTRODUCTION OF HUMAN FACTORS 52 1. Definition of Human Factors 52 2. History of Human Factors 53 IV B

Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

PubMed Central

Shakhov, Alexander N.; Singh, Vijay K.; Bone, Frederick; Cheney, Alec; Kononov, Yevgeniy; Krasnov, Peter; Bratanova-Toshkova, Troitza K.; Shakhova, Vera V.; Young, Jason; Weil, Michael M.; Panoskaltsis-Mortari, Angela; Orschell, Christie M.; Baker, Patricia S.; Gudkov, Andrei; Feinstein, Elena

2012-01-01

Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios. PMID:22479357

Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2).

PubMed

Shakhov, Alexander N; Singh, Vijay K; Bone, Frederick; Cheney, Alec; Kononov, Yevgeniy; Krasnov, Peter; Bratanova-Toshkova, Troitza K; Shakhova, Vera V; Young, Jason; Weil, Michael M; Panoskaltsis-Mortari, Angela; Orschell, Christie M; Baker, Patricia S; Gudkov, Andrei; Feinstein, Elena

2012-01-01

Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios.

An Analysis of the U.S. Navy Enlisted Separation Questionnaire

DTIC Science & Technology

1981-06-01

on the amount of variance which will give a satis- factory and acceptable solution, only a small number (less than n) of factors will be needed to...three factors rather than nine initi al categories of data classification. C. FACTOR ANALISIS OF SUBSETS OF THE DATA During this phase of the analysis...Harm.an, H. H. & Holzinger, K. J., Factnr Anali• , Synthesis of Factorial Methods, University of Chicago PFess, 1941. 27. Fruchter, B., Introduction to

Extranodal Marginal Zone B-cell Lymphoma of the Ocular Adnexa.

PubMed

Guffey Johnson, Jean; Terpak, Lauren A; Margo, Curtis E; Setoodeh, Reza

2016-04-01

Low-grade B-cell lymphomas located around the eye present unique challenges in diagnosis and treatment. Extranodal marginal zone B-cell lymphoma is the most common lymphoma of the ocular adnexa (conjunctiva, orbit, lacrimal gland, and eyelid). A systematic search of the relevant literature was performed. Material pertinent to the diagnosis, prognosis, pathogenesis, and treatment of extranodal marginal zone B-cell lymphoma of the ocular adnexa was identified, reviewed, and analyzed, focusing on management strategies for primary localized disease. The primary cause of extranodal marginal zone B-cell lymphoma of the ocular adnexa remains elusive, although an infectious agent is suspected. Radiotherapy is the most common initial treatment for localized disease. Initial treatment with chemotherapy, immunotherapy, and antibiotics has shown promising results, but the number of series is limited and controlled trials do not exist. Although the long-term outcome of localized extranodal marginal zone B-cell lymphoma of the ocular adnexa is good, optimal treatment remains a goal. The variation in rates of local and systemic relapse among treated stage 1E tumors suggests that critical factors affecting outcomes are not fully understood. Radiotherapy is the standard of care; at this time, the evidence is insufficient to recommend chemotherapy, immunotherapy, or antibiotics for initial treatment of extranodal marginal zone B-cell lymphoma localized to the ocular adnexa. Well-controlled comparative studies are needed.

Zebrafish WNK Lysine Deficient Protein Kinase 1 (wnk1) Affects Angiogenesis Associated with VEGF Signaling

PubMed Central

Chen, Wen-Chuan; Kou, Fong-Ji; Lu, Jeng-Wei; Wang, Horng-Dar; Huang, Chou-Long; Yuh, Chiou-Hwa

2014-01-01

The WNK1 (WNK lysine deficient protein kinase 1) protein is a serine/threonine protein kinase with emerging roles in cancer. WNK1 causes hypertension and hyperkalemia when overexpressed and cardiovascular defects when ablated in mice. In this study, the role of Wnk1 in angiogenesis was explored using the zebrafish model. There are two zebrafish wnk1 isoforms, wnk1a and wnk1b, and both contain all the functional domains found in the human WNK1 protein. Both isoforms are expressed in the embryo at the initiation of angiogenesis and in the posterior cardinal vein (PCV), similar to fms-related tyrosine kinase 4 (flt4). Using morpholino antisense oligonucleotides against wnk1a and wnk1b, we observed that wnk1 morphants have defects in angiogenesis in the head and trunk, similar to flk1/vegfr2 morphants. Furthermore, both wnk1a and wnk1b mRNA can partially rescue the defects in vascular formation caused by flk1/vegfr2 knockdown. Mutation of the kinase domain or the Akt/PI3K phosphorylation site within wnk1 destroys this rescue capability. The rescue experiments provide evidence that wnk1 is a downstream target for Vegfr2 (vascular endothelial growth factor receptor-2) and Akt/PI3K signaling and thereby affects angiogenesis in zebrafish embryos. Furthermore, we found that knockdown of vascular endothelial growth factor receptor-2 (flk1/vegfr2) or vascular endothelial growth factor receptor-3 (flt4/vegfr3) results in a decrease in wnk1a expression, as assessed by in situ hybridization and q-RT-PCR analysis. Thus, the Vegf/Vegfr signaling pathway controls angiogenesis in zebrafish via Akt kinase-mediated phosphorylation and activation of Wnk1 as well as transcriptional regulation of wnk1 expression. PMID:25171174

Predictors of Virological Response in 3,235 Chronic HCV Egyptian Patients Treated with Peginterferon Alpha-2a Compared with Peginterferon Alpha-2b Using Statistical Methods and Data Mining Techniques.

PubMed

El Raziky, Maissa; Fathalah, Waleed Fouad; Zakaria, Zeinab; Eldeen, Hadeel Gamal; Abul-Fotouh, Amr; Salama, Ahmed; Awad, Abubakr; Esmat, Gamal; Mabrouk, Mahasen

2016-05-01

Despite the appearance of new oral antiviral drugs, pegylated interferon (PEG-IFN)/RBV may remain the standard of care therapy for some time, and several viral and host factors are reported to be correlated with therapeutic effects. This study aimed to reveal the independent variables associated with failure of sustained virological response (SVR) to PEG-IFN alpha-2a versus PEG-IFN alpha-2b in treatment of naive chronic hepatitis C virus (HCV) Egyptian patients using both statistical methods and data mining techniques. This retrospective cohort study included 3,235 chronic hepatitis C patients enrolled in a large Egyptian medical center: 1,728 patients had been treated with PEG-IFN alpha-2a plus ribavirin (RBV) and 1,507 patients with PEG-IFN alpha-2b plus RBV between 2007 and 2011. Both multivariate analysis and Reduced Error Pruning Tree (REPTree)-based model were used to reveal the independent variables associated with treatment response. In both treatment types, alpha-fetoprotein (AFP) >10 ng/mL and HCV viremia >600 × 10(3) IU/mL were the independent baseline variables associated with failure of SVR, while male gender, decreased hemoglobin, and thyroid-stimulating hormone were the independent variables associated with good response (P < 0.05). Using REPTree-based model showed that low AFP was the factor of initial split (best predictor) of response for either PEG-IFN alpha-2a or PEG-IFN alpha-2b (cutoff value 8.53, 4.89 ng/mL, AUROC = 0.68 and 0.61, P = 0.05). Serum AFP >10 ng/mL and viral load >600 × 10(3) IU/mL are variables associated with failure of response in both treatment types. REPTree-based model could be used to assess predictors of response.

30 CFR 715.10 - Information collection.

Code of Federal Regulations, 2014 CFR

2014-07-01

... collection requirements contained in 30 CFR 715.13(d); 715.17 (b)(1)(v) and (j)(3); 715.18(b) (2) and (6... performance standards in section 515(b)(2) of P.L. 95-87 and are applicable during the initial regulatory...

30 CFR 715.10 - Information collection.

Code of Federal Regulations, 2013 CFR

2013-07-01

... collection requirements contained in 30 CFR 715.13(d); 715.17 (b)(1)(v) and (j)(3); 715.18(b) (2) and (6... performance standards in section 515(b)(2) of P.L. 95-87 and are applicable during the initial regulatory...

Cynaropicrin is dual regulator for both degradation factors and synthesis factors in the cartilage metabolism.

PubMed

Masutani, Teruaki; Tanaka, Yuka Tsuda; Kojima, Hiroyuki; Tsuboi, Makoto; Hara, Akira; Niwa, Masayuki

2016-08-01

The molecular mechanism of osteoarthritis (OA) has never been understood clearly, but it has been suggested that imbalance of degradation and synthesis in cartilage contribute to the underlying mechanisms of OA. In this study, we investigated the effectiveness in the cartilage metabolism of the artichoke extract that includes the compound cynaropicrin. We evaluated the efficacy of the artichoke extract or cynaropicrin in the cartilage metabolism factors and NF-κB signaling activity stimulated by inflammatory cytokine in chondrogenic cell lines, OUMS-27 and SW1353, using qRT-PCR, immunofluorescence and immunoblotting. We initially found that an artichoke extract and cynaropicrin both inhibited the increase of cartilage degradation factor MMP13 and further decreased the synthesis factor aggrecan induced by TNF-α in OUMS-27. In addition, cynaropicrin suppressed the enhancement of master regulator HIF-2α on cartilage degradation and further reduced the master regulator Sox9 on cartilage synthesis induced by TNF-α. We observed that cynaropicrin suppresses NF-κB signaling, which controls HIF-2α and Sox9. Since, HIF-2α is induced by p65 (RelA), we evaluated the effect of cynaropicrin and observed that it suppressed the nuclear transport of p65 (RelA) by inhibiting phosphorylation of IκBα. Moreover, cynaropicrin not only suppressed TNF-α stimulation, it had a similar effect on IL-1β stimulation. No significant cytotoxicity with cynaropicrin was observed. These finding suggest that cynaropicrin is an effective substance that can improve the balance of cartilage metabolism, by altering the equilibrium of cartilage degradation and synthesis induced by multiple mediators know to contribute to OA. Copyright © 2016 Elsevier Inc. All rights reserved.

NF-κB activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer

PubMed Central

Blakely, Collin M.; Pazarentzos, Evangelos; Olivas, Victor; Asthana, Saurabh; Yan, Jenny Jiacheng; Tan, Irena; Hrustanovic, Gorjan; Chan, Elton; Lin, Luping; Neel, Dana S.; Newton, William; Bobb, Kathryn; Fouts, Timothy; Meshulam, Jeffrey; Gubens, Matthew A.; Jablons, David M.; Johnson, Jeffrey R.; Bandyopadhyay, Sourav; Krogan, Nevan J.; Bivona, Trever G.

2015-01-01

Summary Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses. PMID:25843712

Basic helix-loop-helix transcription factors in evolution: Roles in development of mesoderm and neural tissues.

PubMed

Gyoja, Fuki

2017-09-01

Basic helix-loop-helix (bHLH) transcription factors have attracted the attention of developmental and evolutionary biologists for decades because of their conserved functions in mesodermal and neural tissue formation in both vertebrates and fruit flies. Their evolutionary history is of special interest because it will likely provide insights into developmental processes and refinement of metazoan-specific traits. This review briefly considers advances in developmental biological studies on bHLHs/HLHs. I also discuss recent genome-wide surveys and molecular phylogenetic analyses of these factors in a wide range of metazoans. I hypothesize that interactions between metazoan-specific Group A, D, and E bHLH/HLH factors enabled a sophisticated transition system from cell proliferation to differentiation in multicellular development. This control mechanism probably emerged initially to organize a multicellular animal body and was subsequently recruited to form evolutionarily novel tissues, which differentiated during a later ontogenetic phase. © 2017 Wiley Periodicals, Inc.

41.4 DEPLOYMENT OF DEDICATED NURSING STAFF TO STIMULATE THE INITIATION OF CLOZAPINE. A CLUSTER-RANDOMIZED TRIAL

PubMed Central

Van der Zalm, Yvonne; Schulte, Raphael; Bogers, Jan; Marcelis, Machteld; Sommer, Iris; Selten, Jean-Paul

2018-01-01

Abstract Background For patients with refractory schizophrenia, clozapine is the drug of first choice. However, many refractory patients never receive this drug. The underutilization of clozapine may be caused by the labour-intensive white blood cell monitoring during the first months and the concerns about the safety of outpatient clozapine initiation. A recent survey concluded that professionals “perceived the presence of dedicated staff to arrange and monitor the initiation of clozapine in outpatients as the factor that would enable the use of clozapine most”. We examined whether the presence of such staff in Dutch teams for ambulatory care makes a difference. The primary objective is to examine whether clozapine monitoring by a Nurse Practitioner (NP) is at least as safe as monitoring by a physician. The secondary objective is to examine whether physicians are more likely to prescribe clozapine if they can delegate the monitoring tasks to a NP. Methods In this cluster-randomized trial, 23 Dutch ambulatory care teams were randomized into 2 conditions: (A) coordination of clozapine monitoring by a Nurse Practitioner, versus (B) Treatment As Usual: coordination of clozapine monitoring by the responsible physician (usually a psychiatrist). We followed the teams for 15 months, during which period we counted the numbers of patients who started with clozapine. We assessed the safety of the clozapine monitoring by measuring the number of weekly lab exams performed during the first 18 weeks of treatment and counting serious adverse events (SAE). It is important to note that the staff of teams remained blind to the secondary research question. Results Of the 2643 patients with a diagnosis of non-affective psychotic disorder, 66 patients started using clozapine during the follow-up, 48 in condition A and 18 in condition B (RR: 2.14, 95% CI: 1.24–3.70; p=.005). The provisional results showed no significant differences between conditions A and B in the mean number of lab exams performed. In condition A, 65% of the mandatory lab exams were carried out compared to 60% in condition B. No agranulocytosis or other SAE occurred in Conditions A or B. Discussion Physicians prescribed over 2 times more often clozapine to patients when they could delegate the white blood cell monitoring to a NP. Clozapine-monitoring by an NP appears to be just as safe as monitoring by a physician. These results strongly support the idea that the presence of dedicated staff to arrange and monitor the initiation of clozapine enables the use of this drug.

Using Factor Mixture Models to Evaluate the Type A/B Classification of Alcohol Use Disorders in a Heterogeneous Treatment Sample

PubMed Central

Hildebrandt, Tom; Epstein, Elizabeth E.; Sysko, Robyn; Bux, Donald A.

2017-01-01

Background The type A/B classification model for alcohol use disorders (AUDs) has received considerable empirical support. However, few studies examine the underlying latent structure of this subtyping model, which has been challenged as a dichotomization of a single drinking severity dimension. Type B, relative to type A, alcoholics represent those with early age of onset, greater familial risk, and worse outcomes from alcohol use. Method We examined the latent structure of the type A/B model using categorical, dimensional, and factor mixture models in a mixed gender community treatment-seeking sample of adults with an AUD. Results Factor analytic models identified 2-factors (drinking severity/externalizing psychopathology and internalizing psychopathology) underlying the type A/B indicators. A factor mixture model with 2-dimensions and 3-classes emerged as the best overall fitting model. The classes reflected a type A class and two type B classes (B1 and B2) that differed on the respective level of drinking severity/externalizing pathology and internalizing pathology. Type B1 had a greater prevalence of women and more internalizing pathology and B2 had a greater prevalence of men and more drinking severity/externalizing pathology. The 2-factor, 3-class model also exhibited predictive validity by explaining significant variance in 12-month drinking and drug use outcomes. Conclusions The model identified in the current study may provide a basis for examining different sources of heterogeneity in the course and outcome of AUDs. PMID:28247423

The ν process in the innermost supernova ejecta

NASA Astrophysics Data System (ADS)

Sieverding, Andre; Martínez Pinedo, Gabriel; Langanke, Karlheinz; Harris, J. Austin; Hix, W. Raphael

2018-01-01

The neutrino-induced nucleosynthesis (ν process) in supernova explosions of massive stars of solar metallicity with initial main sequence masses between 13 and 30 M⊙ has been studied with an analytic explosion model using a new extensive set of neutrino-nucleus cross-sections and spectral properties that agree with modern supernova simulations. The production factors for the nuclei 7Li, 11B, 19F, 138La and 180Ta, are still significantly enhanced but do not reproduce the full solar abundances. We study the possible contribution of the innermost supernova eject to the production of the light elements 7Li and 11B with tracer particles based on a 2D supernova simulation of a 12 M⊙ progenitor and conclude, that a contribution exists but is negligible for the total yield for this explosion model.

Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C.

PubMed

Siebert, U; Sroczynski, G; Rossol, S; Wasem, J; Ravens-Sieberer, U; Kurth, B M; Manns, M P; McHutchison, J G; Wong, J B

2003-03-01

Peginterferon alpha-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. To estimate the cost effectiveness of treatment with peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon alpha-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11,800 euros and 6600 euros per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. Peginterferon alpha-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.

Ephrin reverse signaling mediates palatal fusion and epithelial-to-mesenchymal transition independently of Tgfß3.

PubMed

Serrano, Maria J; Liu, Jingpeng; Svoboda, Kathy K H; Nawshad, Ali; Benson, M Douglas

2015-12-01

The mammalian secondary palate forms from shelves of epithelia-covered mesenchyme that meet at midline and fuse. The midline epithelial seam (MES) is thought to degrade by apoptosis, epithelial-to-mesenchymal transition (EMT), or both. Failure to degrade the MES blocks fusion and causes cleft palate. It was previously thought that transforming growth factor ß3 (Tgfß3) is required to initiate fusion. Members of the Eph tyrosine kinase receptor family and their membrane-bound ephrin ligands are expressed on the MES. We demonstrated that treatment of mouse palates with recombinant EphB2/Fc to activate ephrin reverse signaling (where the ephrin acts as a receptor and transduces signals from its cytodomain) was sufficient to cause mouse palatal fusion when Tgfß3 signaling was blocked by an antibody against Tgfß3 or by an inhibitor of the TgfßrI serine/threonine receptor kinase. Cultured palatal epithelial cells traded their expression of epithelial cell markers for that of mesenchymal cells and became motile after treatment with EphB2/Fc. They concurrently increased their expression of the EMT-associated transcription factors Snail, Sip1, and Twist1. EphB2/Fc did not cause apoptosis in these cells. These data reveal that ephrin reverse signaling directs palatal fusion in mammals through a mechanism that involves EMT but not apoptosis and activates a gene expression program not previously associated with ephrin reverse signaling. © 2015 Wiley Periodicals, Inc.

Effect of sibutramine on weight reduction in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.

PubMed

Lindholm, Asa; Bixo, Marie; Björn, Inger; Wölner-Hanssen, Pål; Eliasson, Mats; Larsson, Anders; Johnson, Owe; Poromaa, Inger Sundström

2008-05-01

To examine the efficacy of sibutramine together with brief lifestyle modification for weight reduction in obese women with polycystic ovary syndrome (PCOS). Investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial. Departments of Obstetrics and Gynecology in primary care, referral centers, and private practice. Forty-two patients with confirmed PCOS were included in the study, and 34 patients completed the study. Sibutramine 15 mg once daily together with brief lifestyle modification was compare with placebo together with brief lifestyle modification. The primary endpoint was to assess weight loss. Secondary endpoints included the efficacy of sibutramine for treatment of menstrual pattern and cardiovascular risk factors. After 6 months the sibutramine group had lost 7.8 +/- 5.1 kg compared with a weight loss of 2.8 +/- 6.2 kg in the placebo group. Sibutramine treatment resulted in significant decreases in apolipoprotein B, apolipoprotein B/apolipoprotein A ratio, triglycerides, and cystatin C levels. Sibutramine in combination with lifestyle intervention results in significant weight reduction in obese patients with PCOS. In addition to the weight loss, sibutramine seems to have beneficial effects on metabolic and cardiovascular risk factors.

Type 1 IFN-independent activation of a subset of interferon stimulated genes in West Nile virus Eg101-infected mouse cells

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

Pulit-Penaloza, Joanna A.; Scherbik, Svetlana V.; Brinton, Margo A., E-mail: mbrinton@gsu.edu

2012-04-10

Although infection of mouse embryofibroblasts (MEFs) with WNV Eg101 induced interferon (IFN) beta production and STAT1 and STAT2 phosphorylation, these transcription factors (TFs) were not detected in the nucleus or on the promoters of four IRF-3-independent interferon stimulated genes (ISGs): Oas1a and Irf7 (previously characterized as IFN/ISGF3-dependent), Oas1b and Irf1. These ISGs were upregulated in WNV Eg101-infected STAT1-/-, STAT2-/-, and IFN alpha/beta receptor -/- MEFs. Although either IRF-3 or IRF-7 could amplify/sustain Oas1a and Oas1b upregulation at later times after infection, these factors were not required for the initial gene activation. The lack of upregulation of these ISGs in WNVmore » Eg101-infected IRF-3/9-/- MEFs suggested the involvement of IRF-9. Activation of Irf1 in infected MEFs did not depend on any of these IRFs. The data indicate that additional alternative activation mechanisms exist for subsets of ISGs when a virus infection has blocked ISG activation by the canonical IFN-mediated pathway.« less

Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated.

PubMed

Suryawan, Agus; Orellana, Renan A; Nguyen, Hanh V; Jeyapalan, Asumthia S; Fleming, Jillian R; Davis, Teresa A

2007-12-01

Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight-fasted 6- (n = 4/group) and 26-day-old (n = 6/ group) pigs were studied during 1) euinsulinemic-euglycemiceuaminoacidemic conditions (controls), 2) euinsulinemic-euglycemichyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1), and these responses were higher in 6-day-old compared with 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GbetaL) or mTORC2 (rictor, mTOR, and GbetaL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated protein kinase and eukaryotic elongation factor 2. Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs.

Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor κB (NF-κB) activation.

PubMed

Kelleher, Zachary T; Sha, Yonggang; Foster, Matthew W; Foster, W Michael; Forrester, Michael T; Marshall, Harvey E

2014-01-31

S-nitrosylation of nuclear factor κB (NF-κB) on the p65 subunit of the p50/p65 heterodimer inhibits NF-κB DNA binding activity. We have recently shown that p65 is constitutively S-nitrosylated in the lung and that LPS-induced injury elicits a decrease in SNO-p65 levels concomitant with NF-κB activation in the respiratory epithelium and initiation of the inflammatory response. Here, we demonstrate that TNFα-mediated activation of NF-κB in the respiratory epithelium similarly induces p65 denitrosylation. This process is mediated by the denitrosylase thioredoxin (Trx), which becomes activated upon cytokine-induced degradation of thioredoxin-interacting protein (Txnip). Similarly, inhibition of Trx activity in the lung attenuates LPS-induced SNO-p65 denitrosylation, NF-κB activation, and airway inflammation, supporting a pathophysiological role for this mechanism in lung injury. These data thus link stimulus-coupled activation of NF-κB to a specific, protein-targeted denitrosylation mechanism and further highlight the importance of S-nitrosylation in the regulation of the immune response.

Engineering the Enantioselectivity and Thermostability of a (+)-γ-Lactamase from Microbacterium hydrocarbonoxydans for Kinetic Resolution of Vince Lactam (2-Azabicyclo[2.2.1]hept-5-en-3-one)

PubMed Central

Gao, Shuaihua; Zhu, Shaozhou; Huang, Rong; Li, Hongxia; Wang, Hao

2017-01-01

ABSTRACT To produce promising biocatalysts, natural enzymes often need to be engineered to increase their catalytic performance. In this study, the enantioselectivity and thermostability of a (+)-γ-lactamase from Microbacterium hydrocarbonoxydans as the catalyst in the kinetic resolution of Vince lactam (2-azabicyclo[2.2.1]hept-5-en-3-one) were improved. Enantiomerically pure (−)-Vince lactam is the key synthon in the synthesis of antiviral drugs, such as carbovir and abacavir, which are used to fight against HIV and hepatitis B virus. The work was initialized by using the combinatorial active-site saturation test strategy to engineer the enantioselectivity of the enzyme. The approach resulted in two mutants, Val54Ser and Val54Leu, which catalyzed the hydrolysis of Vince lactam to give (−)-Vince lactam, with 99.2% (enantiomeric ratio [E] > 200) enantiomeric excess (ee) and 99.5% ee (E > 200), respectively. To improve the thermostability of the enzyme, 11 residues with high temperature factors (B-factors) calculated by B-FITTER or high root mean square fluctuation (RMSF) values from the molecular dynamics simulation were selected. Six mutants with increased thermostability were obtained. Finally, the mutants generated with improved enantioselectivity and mutants evolved for enhanced thermostability were combined. Several variants showing (+)-selectivity (E value > 200) and improved thermostability were observed. These engineered enzymes are good candidates to serve as enantioselective catalysts for the preparation of enantiomerically pure Vince lactam. IMPORTANCE Enzymatic kinetic resolution of the racemic Vince lactam using (+)-γ-lactamase is the most often utilized means of resolving the enantiomers for the preparation of carbocyclic nucleoside compounds. The efficiency of the native enzymes could be improved by using protein engineering methods, such as directed evolution and rational design. In our study, two properties (enantioselectivity and thermostability) of a γ-lactamase identified from Microbacterium hydrocarbonoxydans were tackled using a semirational design. The protein engineering was initialized by combinatorial active-site saturation test to improve the enantioselectivity. At the same time, two strategies were applied to identify mutation candidates to enhance the thermostability based on calculations from both a static (B-FITTER based on the crystal structure) and a dynamic (root mean square fluctuation [RMSF] values based on molecular dynamics simulations) way. After combining the mutants, we successfully obtained the final mutants showing better properties in both properties. The engineered (+)-lactamase could be a candidate for the preparation of (−)-Vince lactam. PMID:29054871

Engineering the Enantioselectivity and Thermostability of a (+)-γ-Lactamase from Microbacterium hydrocarbonoxydans for Kinetic Resolution of Vince Lactam (2-Azabicyclo[2.2.1]hept-5-en-3-one).

PubMed

Gao, Shuaihua; Zhu, Shaozhou; Huang, Rong; Li, Hongxia; Wang, Hao; Zheng, Guojun

2018-01-01

To produce promising biocatalysts, natural enzymes often need to be engineered to increase their catalytic performance. In this study, the enantioselectivity and thermostability of a (+)-γ-lactamase from Microbacterium hydrocarbonoxydans as the catalyst in the kinetic resolution of Vince lactam (2-azabicyclo[2.2.1]hept-5-en-3-one) were improved. Enantiomerically pure (-)-Vince lactam is the key synthon in the synthesis of antiviral drugs, such as carbovir and abacavir, which are used to fight against HIV and hepatitis B virus. The work was initialized by using the combinatorial active-site saturation test strategy to engineer the enantioselectivity of the enzyme. The approach resulted in two mutants, Val54Ser and Val54Leu, which catalyzed the hydrolysis of Vince lactam to give (-)-Vince lactam, with 99.2% (enantiomeric ratio [E] > 200) enantiomeric excess (ee) and 99.5% ee (E > 200), respectively. To improve the thermostability of the enzyme, 11 residues with high temperature factors (B-factors) calculated by B-FITTER or high root mean square fluctuation (RMSF) values from the molecular dynamics simulation were selected. Six mutants with increased thermostability were obtained. Finally, the mutants generated with improved enantioselectivity and mutants evolved for enhanced thermostability were combined. Several variants showing (+)-selectivity (E value > 200) and improved thermostability were observed. These engineered enzymes are good candidates to serve as enantioselective catalysts for the preparation of enantiomerically pure Vince lactam. IMPORTANCE Enzymatic kinetic resolution of the racemic Vince lactam using (+)-γ-lactamase is the most often utilized means of resolving the enantiomers for the preparation of carbocyclic nucleoside compounds. The efficiency of the native enzymes could be improved by using protein engineering methods, such as directed evolution and rational design. In our study, two properties (enantioselectivity and thermostability) of a γ-lactamase identified from Microbacterium hydrocarbonoxydans were tackled using a semirational design. The protein engineering was initialized by combinatorial active-site saturation test to improve the enantioselectivity. At the same time, two strategies were applied to identify mutation candidates to enhance the thermostability based on calculations from both a static (B-FITTER based on the crystal structure) and a dynamic (root mean square fluctuation [RMSF] values based on molecular dynamics simulations) way. After combining the mutants, we successfully obtained the final mutants showing better properties in both properties. The engineered (+)-lactamase could be a candidate for the preparation of (-)-Vince lactam. Copyright © 2017 American Society for Microbiology.

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

PubMed Central

Chenoweth, Meghan J.; Sylvestre, Marie-Pierre; Contreras, Gisele; Novalen, Maria; O’Loughlin, Jennifer; Tyndale, Rachel F.

2015-01-01

Background Smoking is influenced by genetic factors including variation in CYP2A6 and CYP2B6, which encode nicotine-metabolizing enzymes. In early adolescence, CYP2A6 slow nicotine metabolism was associated with higher dependence acquisition, but reduced cigarette consumption. Here we extend this work by examining associations of CYP2A6 and CYP2B6 with tobacco dependence acquisition in a larger sample of smokers followed throughout adolescence. Methods White participants from the Nicotine Dependence in Teens cohort that had ever inhaled (n=421) were followed frequently from age 12–18 years. Cox’s proportional hazards models compared the risk of ICD-10 tobacco dependence acquisition (score 3+) for CYP2A6 and CYP2B6 metabolism groups. Early smoking experiences, as well as amount smoked at end of follow-up, was also computed. At age 24 (N=162), we assessed concordance between self-reported cigarette consumption and salivary cotinine. Results In those who initiated inhalation during follow-up, CYP2A6 slow (vs. normal) metabolizers were at greater risk of dependence (hazards ratio (HR)=2.3; 95% CI=1.1, 4.8); CYP2B6 slow (vs. normal) metabolizers had non-significantly greater risk (HR=1.5; 95% CI=0.8, 2.6). Variation in CYP2A6 or CYP2B6 was not significantly associated with early smoking symptoms or cigarette consumption at end of follow-up. At age 24, neither gene was significantly associated with dependence status. Self-reported consumption was associated with salivary cotinine, a biomarker of tobacco exposure, acquired at age 24 (B=0.37; P<0.001). Conclusions Our findings extend previous work indicating that slow nicotine metabolism mediated by CYP2A6, and perhaps CYP2B6, increases risk for tobacco dependence throughout adolescence. PMID:26644138

Astaxanthin inhibits tumor invasion by decreasing extracellular matrix production and induces apoptosis in experimental rat colon carcinogenesis by modulating the expressions of ERK-2, NFkB and COX-2.

PubMed

Nagendraprabhu, Ponnuraj; Sudhandiran, Ganapasam

2011-04-01

Colon cancer is the third most malignant neoplasm in the world and it remains an important cause of mortality in Asian and Western countries. Astaxanthin (AST), a major component of carotenoids possesses attractive remedial features. The purpose of this study is to investigate the possible mechanism of action of astaxanthin against 1, 2 dimethyl hydrazine (DMH)-induced rat colon carcinogenesis. Wistar male rats were randomized into five groups, group 1 were control rats, group 2 were rats that received AST (15 mg/kg body wt p.o. everyday), rats in group 3 were induced with DMH (40 mg/kg body wt, s.c.), DMH-induced rats in groups 4 and 5 were either pre or post initiated with AST, respectively as in group 2. DMH-induced rats exhibited elevated expressions of Nuclear factor kappa B-p65 (NF-κB-p65), Cyclooxygenase-2 (COX-2), Matrixmetallo proteinases (MMP) 2/9, Proliferating cell nuclear antigen (PCNA), and Extracellular signal-regulated kinase-2 (ERK-2) as confirmed by immunofluorescence. Further, Westernblot analysis of MMPs-2/9, ERK-2 and Protein kinase B (Akt) revealed increased expressions of these proteins in DMH-induced groups of rats. AST-treatment decreased the expressions of all these vital proteins, involved in colon carcinogenesis. The ability of AST to induce apoptosis in the colon of DMH-induced rats was confirmed by Annexin-V/PI staining in a confocal microscopy, DNA fragmentation analysis and expression of caspase-3 by Western blotting. In conclusion, astaxanthin exhibits anti-inflammatory and anti-cancer effects by inducing apoptosis in DMH-induced rat colon carcinogenesis by modulating the expressions of NFkB, COX-2, MMPs-2/9, Akt and ERK-2.

Retention in Care among HIV-Infected Pregnant Women in Haiti with PMTCT Option B.

PubMed

Dionne-Odom, Jodie; Massaro, Courtney; Jogerst, Kristen M; Li, Zhongze; Deschamps, Marie-Marcelle; Destine, Cleonas Junior; Senecharles, Redouin; Aristhene, Moleine Moles; Domercant, Joseph Yves; Rouzier, Vanessa; Wright, Peter F

2016-01-01

Background. Preventing mother-to-child transmission of HIV relies on engagement in care during the prenatal, peripartum, and postpartum periods. Under PMTCT Option B, pregnant women with elevated CD4 counts are provided with antiretroviral prophylaxis until cessation of breastfeeding. Methods. Retrospective analysis of retention in care among HIV-infected pregnant women in Haiti was performed. Logistic regression was used to identify risk factors associated with loss to follow-up (LFU) defined as no medical visit for at least 6 months and Kaplan-Meier curves were created to show LFU timing. Results. Women in the cohort had 463 pregnancies between 2009 and 2012 with retention rates of 80% at delivery, 67% at one year, and 59% at 2 years. Among those who were LFU, the highest risk period was during pregnancy (60%) or shortly afterwards (24.4% by 12 months). Never starting on antiretroviral therapy (aRR 2.29, 95% CI 1.4-3.8) was associated with loss to follow-up. Conclusions. Loss to follow-up during and after pregnancy was common in HIV-infected women in Haiti under PMTCT Option B. Since sociodemographic factors and distance from home to facility did not predict LFU, future work should elicit and address barriers to retention at the initial prenatal care visit in all women. Better tracking systems to capture engagement in care in the wider network are needed.

Retention in Care among HIV-Infected Pregnant Women in Haiti with PMTCT Option B

PubMed Central

Massaro, Courtney; Li, Zhongze; Deschamps, Marie-Marcelle; Destine, Cleonas Junior; Senecharles, Redouin; Aristhene, Moleine Moles; Domercant, Joseph Yves; Rouzier, Vanessa; Wright, Peter F.

2016-01-01

Background. Preventing mother-to-child transmission of HIV relies on engagement in care during the prenatal, peripartum, and postpartum periods. Under PMTCT Option B, pregnant women with elevated CD4 counts are provided with antiretroviral prophylaxis until cessation of breastfeeding. Methods. Retrospective analysis of retention in care among HIV-infected pregnant women in Haiti was performed. Logistic regression was used to identify risk factors associated with loss to follow-up (LFU) defined as no medical visit for at least 6 months and Kaplan-Meier curves were created to show LFU timing. Results. Women in the cohort had 463 pregnancies between 2009 and 2012 with retention rates of 80% at delivery, 67% at one year, and 59% at 2 years. Among those who were LFU, the highest risk period was during pregnancy (60%) or shortly afterwards (24.4% by 12 months). Never starting on antiretroviral therapy (aRR 2.29, 95% CI 1.4–3.8) was associated with loss to follow-up. Conclusions. Loss to follow-up during and after pregnancy was common in HIV-infected women in Haiti under PMTCT Option B. Since sociodemographic factors and distance from home to facility did not predict LFU, future work should elicit and address barriers to retention at the initial prenatal care visit in all women. Better tracking systems to capture engagement in care in the wider network are needed. PMID:27651953

Gustatory papillae and taste bud development and maintenance in the absence of TrkB ligands BDNF and NT-4.

PubMed

Ito, Akira; Nosrat, Christopher A

2009-09-01

Taste buds and the peripheral nerves innervating them are two important components of the peripheral gustatory system. They require appropriate connections for the taste system to function. Neurotrophic factors play crucial roles in the innervation of peripheral sensory organs and tissues. Both brain-derived neurotrophic factor (BDNF) null-mutated and neurotrophin-4 (NT-4) null-mutated mice exhibit peripheral gustatory deficits. BDNF and NT-4 bind to a common high affinity tyrosine kinase receptor, TrkB (NTRK-2), and a common p75 neurotrophin receptor (NGFR). We are currently using a transgenic mouse model to study peripheral taste system development and innervation in the absence of both TrkB ligands. We show that taste cell progenitors express taste cell markers during early stages of taste bud development in both BDNF(-/-)xNT-4(-/-) and wild-type mice. At early embryonic stages, taste bud progenitors express Troma-1, Shh, and Sox2 in all mice. At later stages, lack of innervation becomes a prominent feature in BDNF(-/-)xNT-4(-/-) mice leading to a decreasing number of fungiform papillae and morphologically degenerating taste cells. A total loss of vallate taste cells also occurs in postnatal transgenic mice. Our data indicate an initial independence but a later permissive and essential role for innervation in taste bud development and maintenance.

A Mutation in the bHLH Domain of the SPCH Transcription Factor Uncovers a BR-Dependent Mechanism for Stomatal Development.

PubMed

de Marcos, Alberto; Houbaert, Anaxi; Triviño, Magdalena; Delgado, Dolores; Martín-Trillo, Mar; Russinova, Eugenia; Fenoll, Carmen; Mena, Montaña

2017-06-01

The asymmetric cell divisions necessary for stomatal lineage initiation and progression in Arabidopsis ( Arabidopsis thaliana ) require the function of the basic helix-loop-helix (bHLH) transcription factor SPEECHLESS ( SPCH ). Mutants lacking SPCH do not produce stomata or lineages. Here, we isolated a new spch-5 allele carrying a point mutation in the bHLH domain that displayed normal growth, but had an extremely low number of sometimes clustered stomata in the leaves, whereas the hypocotyls did not have any stomata. In vivo tracking of leaf epidermal cell divisions, combined with marker lines and genetic analysis, showed that the spch-5 leaf phenotype is dosage dependent and results from the decreased ability to initiate and amplify lineages, defects in asymmetric cell fate allocation, and misorientation of asymmetric division planes. Notably, application of brassinosteroids (BRs) partly rescued the stomatal leaf phenotype of spch-5 Transcriptomic analysis combining spch-5 with BR treatments revealed that the expression of a set of SPCH target genes was restored by BRs. Our results also show that BR-dependent stomata formation and expression of some, but not all, SPCH target genes require the integrity of the bHLH domain of SPCH. © 2017 American Society of Plant Biologists. All Rights Reserved.

A Mutation in the bHLH Domain of the SPCH Transcription Factor Uncovers a BR-Dependent Mechanism for Stomatal Development1

PubMed Central

Triviño, Magdalena; Delgado, Dolores; Martín-Trillo, Mar

2017-01-01

The asymmetric cell divisions necessary for stomatal lineage initiation and progression in Arabidopsis (Arabidopsis thaliana) require the function of the basic helix-loop-helix (bHLH) transcription factor SPEECHLESS (SPCH). Mutants lacking SPCH do not produce stomata or lineages. Here, we isolated a new spch-5 allele carrying a point mutation in the bHLH domain that displayed normal growth, but had an extremely low number of sometimes clustered stomata in the leaves, whereas the hypocotyls did not have any stomata. In vivo tracking of leaf epidermal cell divisions, combined with marker lines and genetic analysis, showed that the spch-5 leaf phenotype is dosage dependent and results from the decreased ability to initiate and amplify lineages, defects in asymmetric cell fate allocation, and misorientation of asymmetric division planes. Notably, application of brassinosteroids (BRs) partly rescued the stomatal leaf phenotype of spch-5. Transcriptomic analysis combining spch-5 with BR treatments revealed that the expression of a set of SPCH target genes was restored by BRs. Our results also show that BR-dependent stomata formation and expression of some, but not all, SPCH target genes require the integrity of the bHLH domain of SPCH. PMID:28507175

40 CFR 63.3883 - When do I have to comply with this subpart?

Code of Federal Regulations, 2013 CFR

2013-07-01

... compliance date is the applicable date in paragraph (a)(1) or (2) of this section: (1) If the initial startup... January 2, 2004. (2) If the initial startup of your new or reconstructed affected source occurs after January 2, 2004, the compliance date is the date of initial startup of your affected source. (b) For an...

40 CFR 63.3883 - When do I have to comply with this subpart?

Code of Federal Regulations, 2010 CFR

2010-07-01

... compliance date is the applicable date in paragraph (a)(1) or (2) of this section: (1) If the initial startup... January 2, 2004. (2) If the initial startup of your new or reconstructed affected source occurs after January 2, 2004, the compliance date is the date of initial startup of your affected source. (b) For an...

40 CFR 63.3883 - When do I have to comply with this subpart?

Code of Federal Regulations, 2012 CFR

2012-07-01

... compliance date is the applicable date in paragraph (a)(1) or (2) of this section: (1) If the initial startup... January 2, 2004. (2) If the initial startup of your new or reconstructed affected source occurs after January 2, 2004, the compliance date is the date of initial startup of your affected source. (b) For an...

40 CFR 63.3883 - When do I have to comply with this subpart?

Code of Federal Regulations, 2014 CFR

2014-07-01

... compliance date is the applicable date in paragraph (a)(1) or (2) of this section: (1) If the initial startup... January 2, 2004. (2) If the initial startup of your new or reconstructed affected source occurs after January 2, 2004, the compliance date is the date of initial startup of your affected source. (b) For an...

Statistical Analysis of Main and Interaction Effects on Cu(II) and Cr(VI) Decontamination by Nitrogen-Doped Magnetic Graphene Oxide

NASA Astrophysics Data System (ADS)

Hu, Xinjiang; Wang, Hui; Liu, Yunguo

2016-10-01

A nitrogen-doped magnetic graphene oxide (NMGO) was synthesized and applied as an adsorbent to remove Cu(II) and Cr(VI) ions from aqueous solutions. The individual and combined effects of various factors (A: pH, B: temperature, C: initial concentration of metal ions, D: CaCl2, and E: humic acid [HA]) on the adsorption were analyzed by a 25-1 fractional factorial design (FFD). The results from this study indicated that the NMGO had higher adsorption capacities for Cu(II) ions than for Cr(VI) ions under most conditions, and the five selected variables affected the two adsorption processes to different extents. A, AC, and C were the very important factors and interactions for Cu(II) adsorption. For Cr(VI) adsorption, A, B, C, AB, and BC were found to be very important influencing variables. The solution pH (A) was the most important influencing factor for removal of both the ions. The main effects of A-E on the removal of Cu(II) were positive. For Cr(VI) adsorption, the main effects of A and D were negative, while B, C, and E were observed to have positive effects. The maximum adsorption capacities for Cu(II) and Cr(VI) ions over NMGO were 146.365 and 72.978 mg/g, respectively, under optimal process conditions.

Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysis

PubMed Central

Qu, Yanyan; Olonisakin, Tolani; Bain, William; Zupetic, Jill; Brown, Rebecca; Hulver, Mei; Xiong, Zeyu; Shanks, Robert M.Q.; Bomberger, Jennifer M.; Cooper, Vaughn S.; Zegans, Michael E.; Han, Jongyoon; Pilewski, Joseph; Ray, Anuradha; Ray, Prabir; Lee, Janet S.

2018-01-01

Acute lung injury is characterized by excessive extracellular matrix proteolysis and neutrophilic inflammation. A major risk factor for lung injury is bacterial pneumonia. However, host factors that protect against pathogen-induced and host-sustained proteolytic injury following infection are poorly understood. Pseudomonas aeruginosa (PA) is a major cause of nosocomial pneumonia and secretes proteases to amplify tissue injury. We show that thrombospondin-1 (TSP-1), a matricellular glycoprotein released during inflammation, dose-dependently inhibits PA metalloendoprotease LasB, a virulence factor. TSP-1–deficient (Thbs1–/–) mice show reduced survival, impaired host defense, and increased lung permeability with exaggerated neutrophil activation following acute intrapulmonary PA infection. Administration of TSP-1 from platelets corrects the impaired host defense and aberrant injury in Thbs1–/– mice. Although TSP-1 is cleaved into 2 fragments by PA, TSP-1 substantially inhibits Pseudomonas elastolytic activity. Administration of LasB inhibitor, genetic disabling of the PA type II secretion system, or functional deletion of LasB improves host defense and neutrophilic inflammation in mice. Moreover, TSP-1 provides an additional line of defense by directly subduing host-derived proteolysis, with dose-dependent inhibition of neutrophil elastase from airway neutrophils of mechanically ventilated critically ill patients. Thus, a host matricellular protein provides dual levels of protection against pathogen-initiated and host-sustained proteolytic injury following microbial trigger. PMID:29415890

IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system

PubMed Central

Raasch, Jenni; Zeller, Nicolas; van Loo, Geert; Merkler, Doron; Mildner, Alexander; Erny, Daniel; Knobeloch, Klaus-Peter; Bethea, John R.; Waisman, Ari; Knust, Markus; Del Turco, Domenico; Deller, Thomas; Blank, Thomas; Priller, Josef; Brück, Wolfgang

2011-01-01

The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IκB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IκB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IκB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IκB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IκB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases. PMID:21310728

Ultrasound-detected bone erosion is a relapse risk factor after discontinuation of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis whose ultrasound power Doppler synovitis activity and clinical disease activity are well controlled.

PubMed

Kawashiri, Shin-Ya; Fujikawa, Keita; Nishino, Ayako; Okada, Akitomo; Aramaki, Toshiyuki; Shimizu, Toshimasa; Umeda, Masataka; Fukui, Shoichi; Suzuki, Takahisa; Koga, Tomohiro; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Mizokami, Akinari; Nakamura, Hideki; Origuchi, Tomoki; Ueki, Yukitaka; Aoyagi, Kiyoshi; Maeda, Takahiro; Kawakami, Atsushi

2017-05-25

In the present study, we explored the risk factors for relapse after discontinuation of biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) whose ultrasound power Doppler (PD) synovitis activity and clinical disease activity were well controlled. In this observational study in clinical practice, the inclusion criteria were based on ultrasound disease activity and clinical disease activity, set as low or remission (Disease Activity Score in 28 joints based on erythrocyte sedimentation rate <3.2). Ultrasound was performed in 22 joints of bilateral hands at discontinuation for evaluating synovitis severity and presence of bone erosion. Patients with a maximum PD score ≤1 in each joint were enrolled. Forty patients with RA were consecutively recruited (November 2010-March 2015) and discontinued bDMARD therapy. Variables at the initiation and discontinuation of bDMARD therapy that were predictive of relapse during the 12 months after discontinuation were assessed. The median patient age was 54.5 years, and the median disease duration was 3.5 years. Nineteen (47.5%) patients relapsed during the 12 months after the discontinuation of bDMARD therapy. Logistic regression analysis revealed that only the presence of bone erosion detected by ultrasound at discontinuation was predictive of relapse (OR 8.35, 95% CI 1.78-53.2, p = 0.006). No clinical characteristics or serologic biomarkers were significantly different between the relapse and nonrelapse patients. The ultrasound synovitis scores did not differ significantly between the groups. Our findings are the first evidence that ultrasound bone erosion may be a relapse risk factor after the discontinuation of bDMARD therapy in patients with RA whose PD synovitis activity and clinical disease activity are well controlled.

Emergence in Taiwan of novel imipenem-resistant Acinetobacter baumannii ST455 causing bloodstream infection in critical patients.

PubMed

Lee, Hao-Yuan; Huang, Chih-Wei; Chen, Chyi-Liang; Wang, Yi-Hsin; Chang, Chee-Jen; Chiu, Cheng-Hsun

2015-12-01

Acinetobacter baumannii is one of the most important nosocomial pathogens worldwide. This study aimed to use multilocus sequence typing (MLST) for the epidemiological surveillance of A. baumannii isolates in Taiwan and analyze the clinical presentations and patients' outcome. MLST according to both Bartual's PubMLST and Pasteur's MLST schemes was applied to characterize bloodstream imipenem-resistant A. baumannii (IRAB) infection in intensive care units in a medical center. A total of 39 clinical IRAB bloodstream isolates in 2010 were enrolled. We also collected 13 imipenem-susceptible A. baumannii (ISAB) bloodstream isolates and 30 clinical sputum isolates (24 IRAB and 6 ISAB) for comparison. Clinical presentations and outcome of the patients were analyzed. We found that infection by ST455(B)/ST2(P) and inappropriate initial therapy were statistically significant risk factors for mortality. More than one-third of the IRAB isolates belonged to ST455(B)/ST2(P). Most ST455(B)/ST2(P) (80%) carried ISAba1-blaOXA-23, including 10 (66.7%) with Tn2006 (ISAba1-blaOXA-23-ISAba1) in an AbaR4-type resistance island. ST455(B)/ST2(P) appears to evolve from ST208(B)/ST2(P) of clonal complex (CC) 92(B)/CC2(P). In this hospital-based study, A. baumannii ST455 accounted for 38.5% of IRAB bacteremia, with a high mortality of 86.7%. Approximately 85% of ST455(B)/ST2(P)bacteremia had a primary source of ventilation-associated pneumonia. We report the emergence in Taiwan of IRAB ST455(B)/ST2(P), which is the current predominant clone of IRAB in our hospital and has been causing bacteremia with high mortality in critical patients. Copyright © 2015. Published by Elsevier B.V.

The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling.

PubMed

Devallière, Julie; Charreau, Béatrice

2011-11-15

A better knowledge of the process by which inflammatory extracellular signals are relayed from the plasma membrane to specific intracellular sites is a key step to understand how inflammation develops and how it is regulated. This review focuses on Lnk (SH2B3) a member, with SH2B1 and SH2B2, of the SH2B family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase and receptor tyrosine kinases. SH2B adaptor proteins contain conserved dimerization, pleckstrin homology, and SH2 domains. Initially described as a regulator of hematopoiesis and lymphocyte differentiation, Lnk now emerges as a key regulator in hematopoeitic and non hematopoeitic cells such as endothelial cells (EC) moderating growth factor and cytokine receptor-mediated signaling. In EC, Lnk is a negative regulator of TNF signaling that reduce proinflammatory phenotype and prevent EC from apoptosis. Lnk is a modulator in integrin signaling and actin cytoskeleton organization in both platelets and EC with an impact on cell adhesion, migration and thrombosis. In this review, we discuss some recent insights proposing Lnk as a key regulator of bone marrow-endothelial progenitor cell kinetics, including the ability to cell growth, endothelial commitment, mobilization, and recruitment for vascular regeneration. Finally, novel findings also provided evidences that mutations in Lnk gene are strongly linked to myeloproliferative disorders but also autoimmune and inflammatory syndromes where both immune and vascular cells display a role. Overall, these studies emphasize the importance of the Lnk adaptor molecule not only as prognostic marker but also as potential therapeutic target. Copyright © 2011 Elsevier Inc. All rights reserved.

SU-E-T-169: Initial Investigation into the Use of Optically Stimulated Luminescent Dosimeters (OSLDs) for In-Vivo Dosimetry of TBI Patients.

PubMed

Paloor, S; Aland, T; Mathew, J; Al-Hammadi, N; Hammoud, R

2012-06-01

To report on an initial investigation into the use of optically stimulated luminescent dosimeters (OSLDs) for in-vivo dosimetry for total body irradiation (TBI) treatments. Specifically, we report on the determination of angular dependence, sensitivity correction factors and the dose calibration factors. The OSLD investigated in our work was InLight/OSL nanoDot dosimeters (Landauer Inc.). Nanodots are 5 mm diameter, 0.2 mm thick disk-shaped Carbon-doped Al2O3, and were read using a Landauer InLight microstar reader and associated software.OSLDs were irradiated under two setup conditions: a) typical clinical reference conditions (95cm SSD, 5cm depth in solid water, 10×10 cm field size), and b) TBI conditions (520cm SSD, 5cm depth in solid water, 40×40 cm field size,). The angular dependence was checked for angles ranging ±60 degree from normal incidence. In order to directly compare the sensitivity correction factors, a common dose was delivered to the OSLDs for the two setups. Pre- and post-irradiation readings were acquired. OSLDs were optically annealed under various techniques (1) by keeping over a film view box, (2) Using multiple scan on a flat bed optical scanner and (3) Using natural room light. Under reference conditions, the calculated sensitivity correction factors of the OSLDs had a SD of 2.2% and a range of 5%. Under TBI conditions, the SD increased to 3.4% and the range to 6.0%. The variation in sensitivity correction factors between individual OSLDs across the two measurement conditions was up to 10.3%. Angular dependence of less than 1% is observed. The best bleaching method we found is to keep OSLDs for more than 3 hours on a film viewer which will reduce normalized response to less than 1%. In order to obtain the most accurate results when using OSLDs for in-vivo dosimetry for TBI treatments, sensitivity correction factors and dose calibration factors should all be determined under clinical TBI conditions. © 2012 American Association of Physicists in Medicine.

24 CFR 125.104 - Program administration.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HOUSING FAIR HOUSING INITIATIVES PROGRAM § 125.104 Program administration. (a) FHIP is administered by the Assistant Secretary. (b) FHIP funding is made available under the following initiatives: (1) The Administrative Enforcement Initiative; (2) The Education and Outreach Initiative; (3) The Private Enforcement...

Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

PubMed

Vergidis, Paschalis; Avery, Robin K; Wheat, L Joseph; Dotson, Jennifer L; Assi, Maha A; Antoun, Smyrna A; Hamoud, Kassem A; Burdette, Steven D; Freifeld, Alison G; McKinsey, David S; Money, Mary E; Myint, Thein; Andes, David R; Hoey, Cynthia A; Kaul, Daniel A; Dickter, Jana K; Liebers, David E; Miller, Rachel A; Muth, William E; Prakash, Vidhya; Steiner, Frederick T; Walker, Randall C; Hage, Chadi A

2015-08-01

Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Stimulation of EphB2/ephrin-B1 signalling by tumour necrosis factor alpha in human dental pulp stem cells.

PubMed

Zhu, Lifang; Dissanayaka, Waruna Lakmal; Green, David William; Zhang, Chengfei

2015-04-01

The aim of this study was to investigate whether in vitro stimulation of dental pulp stem cells (DPSCs) by tumour necrosis factor alpha (TNF-α) would induce secretion of EphB2/ephrin-B1 signalling. Dental pulp stem cells isolated from human dental pulp were treated with TNF-α (5-100 ng/ml) over 2-48 h. EphB2/ephrin-B1 mRNA and protein levels were measured by real-time polymerase chain reaction (RT-PCR) and western blot analysis respectively. Additionally, DPSCs were pre-incubated with TNF-α receptor neutralizing antibodies or infected with nuclear factor-kappa B (NF-ĸB) inhibitor, p38 MAPK inhibitor, Jun N-terminal kinase (JNK) inhibitor and MEK inhibitor before TNF-α treatment. Results were analysed by one-way ANOVA. Tumour necrosis factor alpha increased EphB2 mRNA expression in DPSCs at concentrations up to 20 ng/ml and ephrin-B1 at concentrations up to 40 ng/ml (P < 0.05). Its mRNA expression reached maximum at 24 h when treated with TNF-α at 20 ng/ml (P < 0.05). EphB2/ephrin-B1 protein expression levels were high at 16 and 24 h as shown by western blotting. Neutralizing antibodies for TNFR1/2 receptors down-regulated EphB2/ephrin-B1 mRNA expression (P < 0.05) and ephrin-B1 protein expression, but not EphB2 protein expression. JNK-inhibitor inhibited EphB2 mRNA expression only (P < 0.05). EphB2/ephrin-B1 were invoked in DPSCs with TNF-α treatment via the JNK-dependent pathway, but not NF-ĸB, p38 MAPK or MEK signalling. © 2015 John Wiley & Sons Ltd.

Autophagic-lysosomal dysregulation downstream of cathepsin B inactivation in human skin fibroblasts exposed to UVA

PubMed Central

Lamore, Sarah D.; Wondrak, Georg T.

2014-01-01

Recently, using 2D-DIGE proteomics we have identified cathepsin B as a novel target of UVA in human Hs27 skin fibroblasts. In response to chronic exposure to noncytotoxic doses of UVA (9.9 J/cm2, twice a week, 3 weeks), photooxidative impairment of cathepsin B enzymatic activity occurred with accumulation of autofluorescent aggregates colocalizing with lysosomes, an effect mimicked by pharmacological antagonism of cathepsin B using the selective inhibitor CA074Me. Here, we have further explored the mechanistic involvement of cathepsin B inactivation in UVA-induced autophagic-lysosomal alterations using autophagy-directed PCR expression array analysis as a discovery tool. Consistent with lysosomal expansion, UVA upregulated cellular protein levels of the lysosomal marker glycoprotein Lamp-1, and increased levels of the lipidated autophagosomal membrane constituent LC3-II were detected. UVA did not alter expression of beclin 1 (BECN1), an essential factor for initiation of autophagy, but upregulation of p62 (sequestosome 1, SQSTM1), a selective autophagy substrate, and α-synuclein (SNCA), an autophagic protein substrate and aggresome component, was observed at the mRNA and protein level. Moreover, UVA downregulated transglutaminase-2 (TGM2), an essential enzyme involved in autophagolysosome maturation. Strikingly, UVA effects on Lamp-1, LC3-II, beclin 1, p62, α-synuclein, and transglutaminase-2 were mimicked by CA074Me treatment. Taken together, our data suggest that UVA-induced autophagic-lysosomal alterations occur as a consequence of impaired autophagic flux downstream of cathepsin B inactivation, a novel molecular mechanism potentially involved in UVA-induced skin photodamage. PMID:21773629

Silica nanoparticles induce cytokine responses in lung epithelial cells through activation of a p38/TACE/TGF-α/EGFR-pathway and NF-κΒ signalling

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

Skuland, Tonje, E-mail: tonje.skuland@fhi.no; Øvrevik, Johan; Låg, Marit

2014-08-15

Amorphous silica nanoparticles (SiNPs) have previously been shown to induce marked cytokine (interleukin-6; IL-6 and interleukin-8; CXCL8/IL-8) responses independently of particle uptake in human bronchial epithelial BEAS-2B cells. In this study the involvement of the mitogen-activated protein kinases (MAP-kinases), nuclear factor-kappa Β (NF-κΒ) and in particular tumour necrosis factor-α converting enzyme (TACE) and—epidermal growth factor receptor (EGFR) signalling pathways were examined in triggering of IL-6 and CXCL8 release after exposure to a 50 nm silica nanoparticle (Si50). Exposure to Si50 increased phosphorylation of NF-κΒ p65 and MAP-kinases p38 and JUN-N-terminal protein kinase pathways (JNK), but not extracellular signal regulated kinasesmore » (ERK). Inhibition of NF-κΒ and p38 reduced the cytokine responses to Si50, whereas neither JNK- nor ERK-inhibition exerted any significant effect on the responses to Si50. Increases in membrane-bound transforming growth factor-α (TGF-α) release and EGFR phosphorylation were also observed after Si50 exposure, and pre-treatment with inhibitors of these pathways reduced the release of IL-6 and CXCL8, but did not affect the Si50-induced phosphorylation of p38 and p65. In contrast, p38-inhibition partially reduced Si50-induced TGF-α release, while the p65-inhibition was without effect. Overall, our results indicate that Si50-induced IL-6 and CXCL8 responses in BEAS-2B cells were regulated through combined activation of several pathways, including NF-κΒ and p38/TACE/TGF-α/EGFR signalling. The study identifies critical, initial events in the triggering of pro-inflammatory responses by nanoparticles. - Highlights: • Silica nanoparticles induce IL-6 and CXCL8 via NFκB and MAPKinase p38 in BEAS-2B • Silica nanoparticles induce release of the EGF-receptor ligand TGF-α • TGF-α release contributes to the IL-6 and CXCL8 release • Phosphorylation of p38 is involved in release of TGF-α.« less

NF-κB, inflammation, immunity and cancer: coming of age.

PubMed

Taniguchi, Koji; Karin, Michael

2018-05-01

Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.

Seroprevalence and risk factors of glanders in working equines - Findings of a cross-sectional study in Punjab province of Pakistan.

PubMed

Ghori, Muhammad Taslim; Khan, Muhammad Sarwar; Khan, Jawaria Ali; Rabbani, Masood; Shabbir, Muhammad Zubair; Chaudhry, Haroon Rashid; Ali, Muhammad Asad; Muhammad, Javed; Elschner, Mandy Carolina; Jayarao, Bhushan M

2017-12-01

Glanders is an infectious and contagious bacterial disease of equines. A little is known about its seroprevalence and risk factors in working equines in countries where the disease is endemic. Also, there are no reports on prevalence of the disease in areas where there is a prior evidence of Burkholderia (B.) mallei detection in soil. A cross-sectional study was conducted in selected districts (n=09) of Punjab province of Pakistan during 2014-2015. A total of 1008 serum samples were screened for detection of antibodies to B. mallei with complement fixation test followed by western blot. The overall seroprevalence was found to be 3.17% (95% CI: 2.25-4.44). The seropositivity was significantly higher from the sampling sites where B. mallei was detected in soil [OR: 10.66 (95% CI: 4.42-31.66), p=0.00]. Other risk factors significantly associated with animal seropositivity were: age group [OR: 1.78 (95% CI: 4.58-15.56), p=0.00], location in urban area [OR: 2.99 (95% CI: 1.46-6.51), p=0.00],body condition [OR: 3.47 (95% CI: 1.64-7.99), p=0.00], presence of farcy lesion[OR: 7.71 (95% CI: 3.47-19.50), p=0.00], proximity to water bodies [OR: 7.71 (95% CI: 3.47-19.50), p=0.00]; domestic animal population [OR: 3.20 (95% CI: 1.24-10.87), p=0.03] and number of households in sampling area [OR: 4.18 (95%CI: 1.82-11.30), p=0.00]. The study provides an estimate of prevalence of glanders and a potential link between animal seropositivity and presence of B. mallei in soil. The risk factors identified in this study can be used in surveillance and disease awareness. The high prevalence of disease in draught horses and contact of infected animals with their care-takers in developing countries signify need to initiate progressive control of the disease using one health approach. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain.

PubMed

Dziedzic, Barbara; Prevot, Vincent; Lomniczi, Alejandro; Jung, Heike; Cornea, Anda; Ojeda, Sergio R

2003-02-01

Hypothalamic astroglial erbB tyrosine kinase receptors are required for the timely initiation of mammalian puberty. Ligand-dependent activation of these receptors sets in motion a glia-to-neuron signaling pathway that prompts the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development, from hypothalamic neuroendocrine neurons. The neuronal systems that may regulate this growth factor-mediated back signaling to neuroendocrine neurons have not been identified. Here we demonstrate that hypothalamic astrocytes contain metabotropic receptors of the metabotropic glutamate receptor 5 subtype and the AMPA receptor subunits glutamate receptor 2 (GluR2) and GluR3. As in excitatory synapses, these receptors are in physical association with their respective interacting/clustering proteins Homer and PICK1. In addition, they are associated with erbB-1 and erbB-4 receptors. Concomitant activation of astroglial metabotropic and AMPA receptors results in the recruitment of erbB tyrosine kinase receptors and their respective ligands to the glial cell membrane, transactivation of erbB receptors via a mechanism requiring metalloproteinase activity, and increased erbB receptor gene expression. By facilitating erbB-dependent signaling and promoting erbB receptor gene expression in astrocytes, a neuron-to-glia glutamatergic pathway may represent a basic cell-cell communication mechanism used by the neuroendocrine brain to coordinate the facilitatory transsynaptic and astroglial input to LHRH neurons during sexual development.

2B4 expression on natural killer cells increases in HIV-1 infected patients followed prospectively during highly active antiretroviral therapy

PubMed Central

Ostrowski, S R; Ullum, H; Pedersen, B K; Gerstoft, J; Katzenstein, T L

2005-01-01

Human immunodeficiency virus (HIV)-1 infection influences natural killer (NK) cell expression of inhibitory NK receptors and activating natural cytotoxicity receptors. It is unknown whether expression of the co-stimulatory NK cell receptor 2B4 (CD244) on NK cells and CD3+ CD8+ cells are affected by highly active antiretroviral therapy (HAART), low-level viraemia, proviral-DNA or immune activation in HIV-1 infected patients. A total of 101 HAART-treated HIV-1 infected patients with ≤ 200 HIV-RNA copies/ml were followed prospectively for 24 months. HIV-RNA was investigated 3-monthly and 2B4 expression on CD3− CD16+ NK cells and CD3+ CD8+ cells, proviral-DNA and plasma soluble tumour necrosis factor receptor (sTNFr)-II were investigated 6-monthly. For comparison, 2B4 expression was investigated in 20 healthy individuals. The concentration of 2B4+ NK cells was initially reduced in HIV-1 infected patients (P < 0·001) but increased to a normal level during the 24 months’ follow-up. The concentration of CD3+ CD8+ 2B4+ cells in HIV-1 infected patients was normal and did not change during follow-up. The relative fluorescence intensity (RFI) of 2B4 increased on both NK cells and CD3+ CD8+ cells during follow-up (both P < 0·001). Higher levels of proviral-DNA carrying cells and plasma sTNFrII were associated with reductions in the concentration of 2B4+ NK cells (all P < 0·05). HIV-RNA had no effect on 2B4 expression on NK cells or CD3+ CD8+ cells. These findings demonstrate that the concentration of 2B4+ NK cells normalizes during long-term HAART in HIV-1 infected patients. The finding that proviral-DNA and sTNFrII were associated negatively with the concentration of 2B4+ NK cells suggests that immune activation in HIV-1 infected patients receiving HAART influences the target cell recognition by NK cells. PMID:16045743

2B4 expression on natural killer cells increases in HIV-1 infected patients followed prospectively during highly active antiretroviral therapy.

PubMed

Ostrowski, S R; Ullum, H; Pedersen, B K; Gerstoft, J; Katzenstein, T L

2005-09-01

Human immunodeficiency virus (HIV)-1 infection influences natural killer (NK) cell expression of inhibitory NK receptors and activating natural cytotoxicity receptors. It is unknown whether expression of the co-stimulatory NK cell receptor 2B4 (CD244) on NK cells and CD3+ CD8+ cells are affected by highly active antiretroviral therapy (HAART), low-level viraemia, proviral-DNA or immune activation in HIV-1 infected patients. A total of 101 HAART-treated HIV-1 infected patients with < or = 200 HIV-RNA copies/ml were followed prospectively for 24 months. HIV-RNA was investigated 3-monthly and 2B4 expression on CD3- CD16+ NK cells and CD3+ CD8+ cells, proviral-DNA and plasma soluble tumour necrosis factor receptor (sTNFr)-II were investigated 6-monthly. For comparison, 2B4 expression was investigated in 20 healthy individuals. The concentration of 2B4+ NK cells was initially reduced in HIV-1 infected patients (P < 0.001) but increased to a normal level during the 24 months' follow-up. The concentration of CD3+ CD8+ 2B4+ cells in HIV-1 infected patients was normal and did not change during follow-up. The relative fluorescence intensity (RFI) of 2B4 increased on both NK cells and CD3+ CD8+ cells during follow-up (both P < 0.001). Higher levels of proviral-DNA carrying cells and plasma sTNFrII were associated with reductions in the concentration of 2B4+ NK cells (all P < 0.05). HIV-RNA had no effect on 2B4 expression on NK cells or CD3+ CD8+ cells. These findings demonstrate that the concentration of 2B4+ NK cells normalizes during long-term HAART in HIV-1 infected patients. The finding that proviral-DNA and sTNFrII were associated negatively with the concentration of 2B4+ NK cells suggests that immune activation in HIV-1 infected patients receiving HAART influences the target cell recognition by NK cells.

The serial use of child neurocognitive tests: development versus practice effects.

PubMed

Slade, Peter D; Townes, Brenda D; Rosenbaum, Gail; Martins, Isabel P; Luis, Henrique; Bernardo, Mario; Martin, Michael D; Derouen, Timothy A

2008-12-01

When serial neurocognitive assessments are performed, 2 main factors are of importance: test-retest reliability and practice effects. With children, however, there is a third, developmental factor, which occurs as a result of maturation. Child tests recognize this factor through the provision of age-corrected scaled scores. Thus, a ready-made method for estimating the relative contribution of developmental versus practice effects is the comparison of raw (developmental and practice) and scaled (practice only) scores. Data from a pool of 507 Portuguese children enrolled in a study of dental amalgams (T. A. DeRouen, B. G. Leroux, et al., 2002; T. A. DeRouen, M. D. Martin, et al., 2006) showed that practice effects over a 5-year period varied on 8 neurocognitive tests. Simple regression equations are provided for calculating individual retest scores from initial test scores. (c) 2008 APA, all rights reserved.

The role of Krüppel-like factor 14 in the pathogenesis of atherosclerosis.

PubMed

Xie, Wei; Li, Liang; Zheng, Xi-Long; Yin, Wei-Dong; Tang, Chao-Ke

2017-08-01

The Krüppel-like factor (KLF) family, as the SP/XKLF transcription factors, plays important roles in regulating the expression of genes required for the proper execution of important biological and pathological processes. Recent studies have demonstrated that KLF14, a member of the KLF family, participates in the initiation and progression of atherosclerotic cardiovascular disease (CVD). From the molecular function aspect, this review focuses on the impact of KLF14-mediated regulation in major atherosclerosis-related diseases and pathological processes, such as insulin resistance, type 2 diabetes, dyslipidemia, inflammation, obesity, metabolic syndrome, cell proliferation and differentiation. This review was designed to help understand the roles of KLF14 in the pathogenesis of atherosclerosis and define KLF14 as a potential disease biomarker and a novel therapeutic target in CVD. Copyright © 2017 Elsevier B.V. All rights reserved.

Telomeric 3' overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST.

PubMed

Wu, Peng; Takai, Hiroyuki; de Lange, Titia

2012-07-06

A 3' overhang is critical for the protection and maintenance of mammalian telomeres, but its synthesis must be regulated to avoid excessive resection of the 5' end, which could cause telomere shortening. How this balance is achieved in mammals has not been resolved. Here, we determine the mechanism for 3' overhang synthesis in mouse cells by evaluating changes in telomeric overhangs throughout the cell cycle and at leading- and lagging-end telomeres. Apollo, a nuclease bound to the shelterin subunit TRF2, initiates formation of the 3' overhang at leading-, but not lagging-end telomeres. Hyperresection by Apollo is blocked at both ends by the shelterin protein POT1b. Exo1 extensively resects both telomere ends, generating transient long 3' overhangs in S/G2. CST/AAF, a DNA polα.primase accessory factor, binds POT1b and shortens the extended overhangs produced by Exo1, likely through fill-in synthesis. 3' overhang formation is thus a multistep, shelterin-controlled process, ensuring functional telomeric overhangs at chromosome ends. Copyright © 2012 Elsevier Inc. All rights reserved.

Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+}: A novel blue emitting phosphor for white LEDs

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

Li, Panlai, E-mail: li_panlai@126.com; Wang, Zhijun, E-mail: wangzj1998@126.com; Yang, Zhiping

2014-12-15

Graphical abstract: Under the 350 nm radiation excitation, Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} has a broad blue emission band. When the temperature turned up to 150 °C, the emission intensity of Ba{sub 1.97}B{sub 2}O{sub 5}:0.03Ce{sup 3+} is 63.4% of the initial value at room temperature. The activation energy ΔE is calculated to be 0.25 eV, which prove the good thermal stability of Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+}. All the properties indicate that Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} may have potential application in white LEDs. - Highlights: • Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} has a broad blue emission band under themore » 350 nm radiation excitation. • Emission intensity of Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} is 63.4% (150 °C) of the initial value (30 °C). • The activation energy ΔE for thermal quenching is 0.25 eV. - Abstract: A novel blue emitting phosphor Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} is synthesized by a high temperature solid state method. The luminescent property and the thermal stability of Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} are investigated. Under the 350 nm radiation excitation, Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} has a broad blue emission band, and the peak locates at 417 nm which is assigned to the 5d{sup 1}–4f{sup 1} transition of Ce{sup 3+}. It is further proved that the dipole–dipole interaction results in the concentration quenching of Ce{sup 3+} in Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+}. When the temperature turned up to 150 °C, the emission intensity of Ba{sub 1.97}B{sub 2}O{sub 5}:0.03Ce{sup 3+} is 63.4% of the initial value at room temperature. The activation energy ΔE is calculated to be 0.25 eV, which prove the good thermal stability of Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+}. All the properties indicate that Ba{sub 2}B{sub 2}O{sub 5}:Ce{sup 3+} may have potential application in white LEDs.« less

Analysis of T cell-replacing factor-like activity: potent induction of T helper activity for human B cells by residual concanavalin A and interleukin 2.

PubMed

Sauerwein, R W; Van der Meer, W G; Aarden, L A

1987-08-01

At least two factors with the capacity to induce IgM synthesis in human B cells were found to be present in the 15-20-kDa fraction of the supernatant of mononuclear cells activated with concanavalin A (Con A) and phorbol ester. Previously, it has been shown (Sauerwein, R. W. et al., Eur. J. Immunol. 1985. 15: 611) that interleukin 2 (IL2) in this material is able to induce T cell-dependent IgM secretion in normal B cells. Evidence was obtained for the presence of another factor distinct from IL2 that could replace T cells in the induction of B cell differentiation. We have analyzed this factor with the use of a neoplastic B cell population of prolymphocytic origin that was functionally nonresponsive to IL2. T cell-replacing factor (TRF)-like activity and IL2 could be separated by ion-exchange chromatography, although a small amount of IL2 was recovered in the TRF fractions. This small amount of IL2 was found to be crucial for the observed TRF activity. Moreover, a substantial amount of monomeric Con A was detected in the TRF preparation. Our studies show that Con A in the presence of IL2 can act as a potent inducer of helper function in lower numbers of T cells for normal and neoplastic B cells. Functional assays for T cell contamination in B cell suspensions are therefore of limited value because they are determined by the efficiency of the stimulating signal. Particularly in those B cell factor preparations, obtained from mitogen-activated T cells with an obligatory or unidentified role of IL2, the possible effect of a contaminating mitogen must be considered.

Hydroxysafflor Yellow A Attenuates Neuron Damage by Suppressing the Lipopolysaccharide-Induced TLR4 Pathway in Activated Microglial Cells.

PubMed

Lv, Yanni; Qian, Yisong; Ou-Yang, Aijun; Fu, Longsheng

2016-11-01

Microglia activation initiates a neurological deficit cascade that contributes to substantial neuronal damage and impairment following ischemia stroke. Toll-like receptor 4 (TLR4) has been demonstrated to play a critical role in this cascade. In the current study, we tested the hypothesis that hydroxysafflor yellow A (HSYA), an active ingredient extracted from Flos Carthami tinctorii, alleviated inflammatory damage, and mediated neurotrophic effects in neurons by inducing the TLR4 pathway in microglia. A non-contact Transwell co-culture system comprised microglia and neurons was treated with HSYA followed by a 1 mg/mL lipopolysaccharide (LPS) stimulation. The microglia were activated prior to neuronal apoptosis, which were induced by increasing TLR4 expression in the activated microglia. However, HSYA suppressed TLR4 expression in the activated microglia, resulting in less neuronal damage at the early stage of LPS stimulation. Western blot analysis and immunofluorescence indicated that dose-dependently HSYA down-regulated TLR4-induced downstream effectors myeloid differentiation factor 88 (MyD88), nuclear factor kappa b (NF-κB), and the mitogen-activated protein kinases (MAPK)-regulated proteins c-Jun NH2-terminal protein kinase (JNK), protein kinase (ERK) 1/2 (ERK1/2), p38 MAPK (p38), as well as the LPS-induced inflammatory cytokine release. However, HSYA up-regulated brain-derived neurotrophic factor (BDNF) expression. Our data suggest that HSYA could exert neurotrophic and anti-inflammatory functions in response to LPS stimulation by inhibiting TLR4 pathway-mediated signaling.

Lipid-related markers and cardiovascular disease prediction.

PubMed

Di Angelantonio, Emanuele; Gao, Pei; Pennells, Lisa; Kaptoge, Stephen; Caslake, Muriel; Thompson, Alexander; Butterworth, Adam S; Sarwar, Nadeem; Wormser, David; Saleheen, Danish; Ballantyne, Christie M; Psaty, Bruce M; Sundström, Johan; Ridker, Paul M; Nagel, Dorothea; Gillum, Richard F; Ford, Ian; Ducimetiere, Pierre; Kiechl, Stefan; Koenig, Wolfgang; Dullaart, Robin P F; Assmann, Gerd; D'Agostino, Ralph B; Dagenais, Gilles R; Cooper, Jackie A; Kromhout, Daan; Onat, Altan; Tipping, Robert W; Gómez-de-la-Cámara, Agustín; Rosengren, Annika; Sutherland, Susan E; Gallacher, John; Fowkes, F Gerry R; Casiglia, Edoardo; Hofman, Albert; Salomaa, Veikko; Barrett-Connor, Elizabeth; Clarke, Robert; Brunner, Eric; Jukema, J Wouter; Simons, Leon A; Sandhu, Manjinder; Wareham, Nicholas J; Khaw, Kay-Tee; Kauhanen, Jussi; Salonen, Jukka T; Howard, William J; Nordestgaard, Børge G; Wood, Angela M; Thompson, Simon G; Boekholdt, S Matthijs; Sattar, Naveed; Packard, Chris; Gudnason, Vilmundur; Danesh, John

2012-06-20

The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation.

PubMed

Huang, Shijiao; Xu, Xiaowei; Wang, Guopeng; Lu, Guoliang; Xie, Wenbing; Tao, Wei; Zhang, Hongyin; Jiang, Qing; Zhang, Chuanmao

2016-04-01

RNA-polymerase-I-dependent ribosomal DNA (rDNA) transcription is fundamental to rRNA processing, ribosome assembly and protein synthesis. However, how this process is initiated during the cell cycle is not fully understood. By performing a proteomic analysis of transcription factors that bind RNA polymerase I during rDNA transcription initiation, we identified that the DNA replication initiator Cdc6 interacts with RNA polymerase I and its co-factors, and promotes rDNA transcription in G1 phase in an ATPase-activity-dependent manner. We further showed that Cdc6 is targeted to the nucleolus during late mitosis and G1 phase in a manner that is dependent on B23 (also known as nucleophosmin, NPM1), and preferentially binds to the rDNA promoter through its ATP-binding domain. Overexpression of Cdc6 increases rDNA transcription, whereas knockdown of Cdc6 results in a decreased association of both RNA polymerase I and the RNA polymerase I transcription factor RRN3 with rDNA, and a reduction of rDNA transcription. Furthermore, depletion of Cdc6 impairs the interaction between RRN3 and RNA polymerase I. Taken together, our data demonstrate that Cdc6 also serves as a regulator of rDNA transcription initiation, and indicate a mechanism by which initiation of rDNA transcription and DNA replication can be coordinated in cells. © 2016. Published by The Company of Biologists Ltd.

Processes regulating the initiation and postejaculatory resumption of copulatory behavior in male hamsters.

PubMed

Floody, Owen R

2014-06-01

Studies using factor analysis have helped describe the organization of copulatory behavior in male rodents. However, the focus of these studies on a few traditional measures may have limited their results. To test this possibility, 74 sexually-experienced male hamsters were observed as they copulated with stimulus females. The measures collected exceeded the conventional ones in number, variety and independence. The factor analysis of these data revealed a structure with seven factors collectively accounting for 80% of the variance. Most resembled the factors in previous reports, reinforcing the contributions that the processes suggested by these factors make to the organization of male behavior. But several other factors were more novel, possibly reflecting the use of measures that were novel or revised for greater independence. The most interesting of these were two factors focusing on early steps in the progression leading to ejaculation. Importantly, both incorporated measures from each of the three copulatory series that were observed. Past work suggests that independent processes control the times required to initiate copulation and later resume it after an ejaculation. In contrast, these results suggest the existence of two processes, each of which contributes to both the initiation and reinitiation of copulation. Copyright © 2014 Elsevier B.V. All rights reserved.

[Prevalence of HIV, hepatitis B virus and Treponema pallidum in inmates in the Preventive Detention Center of Arica, Chile].

PubMed

Bórquez, Celia; Lobato, Ismelda; Gazmuri, Paola; Hurtado, Romina; Llanqui, Valerie; Vivanco, Mauricio; Reyes, Teresa; Villanueva, Hilda; Salgado, Katherine; Martínez, M Angélica; Vega, Juan

2017-10-01

The risk groups for sexual transmitted diseases (STDs) are sex workers, drug addicts, young people in early sexual initiation, and population in prison. To determine the prevalence of HIV, Treponema pallidum and hepatitis B Virus (HBV) in male inmates at the Preventive Detention Center (CDP) of Arica. The study was conducted in 140 inmates, with informed consent. Epidemiological survey and blood sampling was conducted. The positive tests were sent to the Hospital Regional of Arica for confirmation and the National Reference Laboratory for confirmation. STD prevalence was 13.6%. The most prevalent was VDRL positive (7.1%) followed by HIV infection (5.7%) and HBV (2.9%). The highest rate (57.9%) occurred in individuals under 31 years old. 63.2% were in an overcrowded situation, 42.1% of cases corresponded to those whose age of sexual activity onset of was before age 15 and 94.7% used drugs. The study reasserts the predisposing factors for the transmission of STDs as age, early sexual debut, drug abuse and overcrowding, noting that prisons are highly vulnerable environments where overcrowding, sexual condition, early sexual initiation, high drug abuse and the lacking spouses visits provide an epidemiological context favorable for increased STD.

Initial 12-h operative fluid volume is an independent risk factor for pleural effusion after hepatectomy.

PubMed

Cheng, Xiang; Wu, Jia-Wei; Sun, Ping; Song, Zi-Fang; Zheng, Qi-Chang

2016-12-01

Pleural effusion after hepatectomy is associated with significant morbidity and prolonged hospital stays. Several studies have addressed the risk factors for postoperative pleural effusion. However, there are no researches concerning the role of the initial 12-h operative fluid volume. The aim of this study was to evaluate whether the initial 12-h operative fluid volume during liver resection is an independent risk factor for pleural effusion after hepatectomy. In this study, we retrospectively analyzed clinical data of 470 patients consecutively undergoing elective hepatectomy between January 2011 and December 2012. We prospectively collected and retrospectively analyzed baseline and clinical data, including preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were carried out to identify whether the initial 12-h operative fluid volume was an independent risk factor for pleural effusion after hepatectomy. The multivariate analysis identified 2 independent risk factors for pleural effusion: operative time [odds ratio (OR)=10.2] and initial 12-h operative fluid volume (OR=1.0003). Threshold effect analyses revealed that the initial 12 h operative fluid volume was positively correlated with the incidence of pleural effusion when the initial 12-h operative fluid volume exceeded 4636 mL. We conclude that the initial 12-h operative fluid volume during liver resection and operative time are independent risk factors for pleural effusion after hepatectomy. Perioperative intravenous fluids should be restricted properly.

Using the Internet for B2B Activities: A Review and Future Directions for Research.

ERIC Educational Resources Information Center

Gattiker, Urs E.; Perlusz, Stefano; Bohmann, Kristoffer

2000-01-01

Illustrates some of the challenges that electronic commerce practitioners and researchers face, focusing on business to business (B2B) transactions. Highlights include a conceptual framework of Web user behavior; purchasing context; socio-demographic characteristics; cultural factors; economic factors; attitudes toward information technology;…

Logarithmic speed-up of relaxation in A -B annihilation with exclusion

NASA Astrophysics Data System (ADS)

Dandekar, Rahul

2018-04-01

We show that the decay of the density of active particles in the reaction A +B →0 in one dimension, with exclusion interaction, results in logarithmic corrections to the expected power law decay, when the starting initial condition (i.c.) is periodic. It is well known that the late-time density of surviving particles goes as t-1 /4 with random initial conditions, and as t-1 /2 with alternating initial conditions (A B A B A B ⋯ ). We show that the decay for periodic i.c.'s made of longer blocks (AnBnAnBn⋯ ) do not show a pure power-law decay when n is even. By means of first-passage Monte Carlo simulations, and a mapping to a q -state coarsening model which can be solved in the independent interval approximation (IIA), we show that the late-time decay of the density of surviving particles goes as t-1 /2[ln(t ) ] -1 for n even, but as t-1 /2 when n is odd. We relate this kinetic symmetry breaking in the Glauber Ising model. We also see a very slow crossover from a t-1 /2[ln(t ) ] -1 regime to eventual t-1 /2 behavior for i.c.'s made of mixtures of odd- and even-length blocks.

Assessing the Association Between Asthma and Air Quality in the Presence of Wildfires

NASA Technical Reports Server (NTRS)

Young, L. J.; Lopiano, K. K.; Xu, X.; Holt, N. M.; Leary, E.; Al-Hamdan, M. Z.; Crosson, W. L.; Estes, M. G.; Luvall, J. C.; Estes, S. M.;

Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

PubMed

Mellon, S H; Wolkowitz, O M; Schonemann, M D; Epel, E S; Rosser, R; Burke, H B; Mahan, L; Reus, V I; Stamatiou, D; Liew, C-C; Cole, S W

2016-05-24

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

10 CFR 75.32 - Initial inventory report.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Initial inventory report. 75.32 Section 75.32 Energy... AGREEMENT Reports § 75.32 Initial inventory report. (a) The initial inventory reporting date shall be the... inventory report is required. (b) The initial inventory report, to be submitted to the Commission as...

Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling

PubMed Central

2010-01-01

Background Coronary heart disease (CHD) and stroke were key outcomes in the Women's Health Initiative (WHI) randomized trials of postmenopausal estrogen and estrogen plus progestin therapy. We recently reported a large number of changes in blood protein concentrations in the first year following randomization in these trials using an in-depth quantitative proteomics approach. However, even though many affected proteins are in pathways relevant to the observed clinical effects, the relationships of these proteins to CHD and stroke risk among postmenopausal women remains substantially unknown. Methods The same in-depth proteomics platform was applied to plasma samples, obtained at enrollment in the WHI Observational Study, from 800 women who developed CHD and 800 women who developed stroke during cohort follow-up, and from 1-1 matched controls. A plasma pooling strategy, followed by extensive fractionation prior to mass spectrometry, was used to identify proteins related to disease incidence, and the overlap of these proteins with those affected by hormone therapy was examined. Replication studies, using enzyme-linked-immunosorbent assay (ELISA), were carried out in the WHI hormone therapy trial cohorts. Results Case versus control concentration differences were suggested for 37 proteins (nominal P < 0.05) for CHD, with three proteins, beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), and insulin-like growth factor binding protein acid labile subunit (IGFALS) having a false discovery rate < 0.05. Corresponding numbers for stroke were 47 proteins with nominal P < 0.05, three of which, apolipoprotein A-II precursor (APOA2), peptidyl-prolyl isomerase A (PPIA), and insulin-like growth factor binding protein 4 (IGFBP4), have a false discovery rate < 0.05. Other proteins involved in insulin-like growth factor signaling were also highly ranked. The associations of B2M with CHD (P < 0.001) and IGFBP4 with stroke (P = 0.005) were confirmed using ELISA in replication studies, and changes in these proteins following the initiation of hormone therapy use were shown to have potential to help explain hormone therapy effects on those diseases. Conclusions In-depth proteomic discovery analysis of prediagnostic plasma samples identified B2M and IGFBP4 as risk markers for CHD and stroke respectively, and provided a number of candidate markers of disease risk and candidate mediators of hormone therapy effects on CHD and stroke. Clinical Trials Registration ClinicalTrials.gov identifier: NCT00000611 PMID:20667078

Enhancing E. coli isobutanol tolerance through engineering its global transcription factor cAMP receptor protein (CRP).

PubMed

Chong, Huiqing; Geng, Hefang; Zhang, Hongfang; Song, Hao; Huang, Lei; Jiang, Rongrong

2014-04-01

The limited isobutanol tolerance of Escherichia coli is a major drawback during fermentative isobutanol production. Different from classical strain engineering approaches, this work was initiated to improve E. coli isobutanol tolerance from its transcriptional level by engineering its global transcription factor cAMP receptor protein (CRP). Random mutagenesis libraries were generated by error-prone PCR of crp, and the libraries were subjected to isobutanol stress for selection. Variant IB2 (S179P, H199R) was isolated and exhibited much better growth (0.18 h(-1) ) than the control (0.05 h(-1) ) in 1.2% (v/v) isobutanol (9.6 g/L). Genome-wide DNA microarray analysis revealed that 58 and 308 genes in IB2 had differential expression (>2-fold, p < 0.05) in the absence and presence of 1% (v/v) isobutanol, respectively. When challenged with isobutanol, genes related to acid resistance (gadABCE, hdeABD), nitrate reduction (narUZYWV), flagella and fimbrial activity (lfhA, yehB, ycgR, fimCDF), and sulfate reduction and transportation (cysIJH, cysC, cysN) were the major functional groups that were up-regulated, whereas most of the down-regulated genes were enzyme (tnaA) and transporters (proVWX, manXYZ). As demonstrated by single-gene knockout experiments, gadX, nirB, rhaS, hdeB, and ybaS were found associated with strain isobutanol resistance. The intracellular reactive oxygen species (ROS) level in IB2 was only half of that of the control when facing stress, indicating that IB2 can withstand toxic isobutanol much better than the control. © 2013 Wiley Periodicals, Inc.

Zebrafish pax8 is required for otic placode induction and plays a redundant role with Pax2 genes in the maintenance of the otic placode.

PubMed

Mackereth, Melinda D; Kwak, Su-Jin; Fritz, Andreas; Riley, Bruce B

2005-01-01

Vertebrate Pax2 and Pax8 proteins are closely related transcription factors hypothesized to regulate early aspects of inner ear development. In zebrafish and mouse, Pax8 expression is the earliest known marker of otic induction, and Pax2 homologs are expressed at slightly later stages of placodal development. Analysis of compound mutants has not been reported. To facilitate analysis of zebrafish pax8, we completed sequencing of the entire gene, including the 5' and 3' UTRs. pax8 transcripts undergo complex alternative splicing to generate at least ten distinct isoforms. Two different subclasses of pax8 splice isoforms encode different translation initiation sites. Antisense morpholinos (MOs) were designed to block translation from both start sites, and four additional MOs were designed to target different exon-intron boundaries to block splicing. Injection of MOs, individually and in various combinations, generated similar phenotypes. Otic induction was impaired, and otic vesicles were small. Regional ear markers were expressed correctly, but hair cell production was significantly reduced. This phenotype was strongly enhanced by simultaneously disrupting either of the co-inducers fgf3 or fgf8, or another early regulator, dlx3b, which is thought to act in a parallel pathway. In contrast, the phenotype caused by disrupting foxi1, which is required for pax8 expression, was not enhanced by simultaneously disrupting pax8. Disrupting pax8, pax2a and pax2b did not further impair otic induction relative to loss of pax8 alone. However, the amount of otic tissue gradually decreased in pax8-pax2a-pax2b-deficient embryos such that no otic tissue was detectable by 24 hours post-fertilization. Loss of otic tissue did not correlate with increased cell death, suggesting that otic cells dedifferentiate or redifferentiate as other cell type(s). These data show that pax8 is initially required for normal otic induction, and subsequently pax8, pax2a and pax2b act redundantly to maintain otic fate.

Evidence-based guides in tracheostomy use in critical patients.

PubMed

Raimondi, N; Vial, M R; Calleja, J; Quintero, A; Cortés Alban, A; Celis, E; Pacheco, C; Ugarte, S; Añón, J M; Hernández, G; Vidal, E; Chiappero, G; Ríos, F; Castilleja, F; Matos, A; Rodriguez, E; Antoniazzi, P; Teles, J M; Dueñas, C; Sinclair, J; Martínez, L; Von der Osten, I; Vergara, J; Jiménez, E; Arroyo, M; Rodriguez, C; Torres, J; Fernandez-Bussy, S; Nates, J L

2017-03-01

Provide evidence based guidelines for tracheostomy in critically ill adult patients and identify areas needing further research. A task force composed of representatives of 10 member countries of the Pan-American and Iberic Federation of Societies of Critical and Intensive Therapy Medicine and of the Latin American Critical Care Trial Investigators Network developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation system. The group identified 23 relevant questions among 87 issues that were initially identified. In the initial search, 333 relevant publications were identified of which 226 publications were chosen. The task force generated a total of 19 recommendations: 10 positive (1B=3, 2C=3, 2D=4) and 9 negative (1B=8, 2C=1). A recommendation was not possible in six questions. Percutaneous techniques are associated with a lower risk of infections compared to surgical tracheostomy. Early tracheostomy only seems to reduce the duration of ventilator use but not the incidence of pneumonia, the length of stay, or the long-term mortality rate. The evidence does not support the use of routine bronchoscopy guidance or laryngeal masks during the procedure. Finally, proper prior training is as important or even a more significant factor in reducing complications than the technique used. Copyright © 2017 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Changes in growth conditions alter the male strobilus gene expression pattern in Cryptomeria japonica.

PubMed

Fukui, Mitsue

2003-11-01

Two-year old saplings grown from cuttings of Cryptomeria japonica D. Don initiate strobilus development following treatment with gibberellic acid under long-day photoperiods. At 25 degrees C with a 14-h photoperiod in a phytotron, male strobili initiated normally; however, they remained green and fell from the saplings prematurely. To examine the change in male strobilus development at the molecular level, three genes expressed specifically in male strobili were analyzed. Two were MADS box genes homologous to the B-function genes in angiosperms, CjMADS1 and CjMADS2, and the third was Cry j I, which encodes an allergen protein, and this gene is expressed mainly in microspores. Under phytotron growing conditions, the homeotic genes were expressed constantly, which reflected the extended early developmental stage of male strobili. On the other hand, Cry j I expression was detected after a long delay just before strobilus development ceased. These results indicate that the expression of the genes related to male reproductive development in C. japonica is regulated by a factor(s) that is sensitive to environmental signals.

Factors associated with the decision of the rheumatologist to order sacroiliac joints magnetic resonance imaging (SI-MRI) or HLA-B27 testing in the diagnostic work-up of patients with spondyloarthritis in clinical practice.

PubMed

Bautista-Molano, Wilson; Landewé, Robert B M; Serna, Cesar; Valle-Oñate, Rafael; van der Heijde, Désirée

2017-01-01

To evaluate the patients' characteristics associated with the clinical decision to request SI-MRI and/or HLA-B27 in patients with SpA in daily practice. Patients referred to a rheumatology outpatient-clinic in a national referral-centre were selected. Patients with a clinical diagnosis of SpA according to the rheumatologist were included. SI-MRI and HLA-B27 was available for patients in whom the rheumatologists had ordered these tests. Characteristics associated with ordering SI-MRI or HLA-B27 were identified with univariable analyses. Variables with p-value <0.05 and >80% completeness were selected for further analysis. A multivariable logistic regression analysis was used to evaluate the determinants related with the decision to perform SI-MRI and/or HLA-B27 and odds ratios with 95% confidence intervals were calculated. In total, 581 patients with SpA were included in the cohort, 72% were men, mean age 34.6±12.1 and disease duration 7.3±9.7 years. Of these patients, 24% (n=137) had SI-MRI and 77% (n=441) had HLA-B27 tests ordered. Independently predictive factors for ordering a SI-MRI were the presence of IBP (OR=1.81), enthesitis (OR=1.57) and the number of initial-symptoms at presentation (OR=1.27 per additional symptom present). Independently predictive factors of HLA-B27 testing were the number of initial-symptoms (OR=1.45 per symptom) and uveitis (OR=3.19). This study strongly suggests that rheumatologists use certain clinical clues to decide if they order expensive and scarce tests in the diagnostic work-up of SpA patients. These manifestations may increase the efficiency of these tests in clinical practice and suggest that clinical reasoning follows principles of Bayesian theory.

Bubble CPAP to support preterm infants in rural Rwanda: a retrospective cohort study.

PubMed

Nahimana, Evrard; Ngendahayo, Masudi; Magge, Hema; Odhiambo, Jackline; Amoroso, Cheryl L; Muhirwa, Ernest; Uwilingiyemungu, Jean Nepo; Nkikabahizi, Fulgence; Habimana, Regis; Hedt-Gauthier, Bethany L

2015-09-24

Complications from premature birth contribute to 35% of neonatal deaths globally; therefore, efforts to improve clinical outcomes of preterm (PT) infants are imperative. Bubble continuous positive airway pressure (bCPAP) is a low-cost, effective way to improve the respiratory status of preterm and very low birth weight (VLBW) infants. However, bCPAP remains largely inaccessible in resource-limited settings, and information on the scale-up of this technology in rural health facilities is limited. This paper describes health providers' adherence to bCPAP protocols for PT/VLBW infants and clinical outcomes in rural Rwanda. This retrospective chart review included all newborns admitted to neonatal units in three rural hospitals in Rwanda between February 1st and October 31st, 2013. Analysis was restricted to PT/VLBW infants. bCPAP eligibility, identification of bCPAP eligibility and complications were assessed. Final outcome was assessed overall and by bCPAP initiation status. There were 136 PT/VLBW infants. For the 135 whose bCPAP eligibility could be determined, 83 (61.5%) were bCPAP-eligible. Of bCPAP-eligible infants, 49 (59.0%) were correctly identified by health providers and 43 (51.8%) were correctly initiated on bCPAP. For the 52 infants who were not bCPAP-eligible, 45 (86.5%) were correctly identified as not bCPAP-eligible, and 46 (88.5%) did not receive bCPAP. Overall, 90 (66.2%) infants survived to discharge, 35 (25.7%) died, 3 (2.2%) were referred for tertiary care and 8 (5.9%) had unknown outcomes. Among the bCPAP eligible infants, the survival rates were 41.8% (18 of 43) for those in whom the procedure was initiated and 56.5% (13 of 23) for those in whom it was not initiated. No complications of bCPAP were reported. While the use of bCPAP in this rural setting appears feasible, correct identification of eligible newborns was a challenge. Mentorship and refresher trainings may improve guideline adherence, particularly given high rates of staff turnover. Future research should explore implementation challenges and assess the impact of bCPAP on long-term outcomes.

NF-{kappa}B inhibition is involved in tobacco smoke-induced apoptosis in the lungs of rats

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

Zhong Caiyun; Zhou Yamei; Pinkerton, Kent E.

2008-07-15

Apoptosis is a vital mechanism for the regulation of cell turnover and plays a critical role in tissue homeostasis and development of many disease processes. Previous studies have demonstrated the apoptotic effect of tobacco smoke; however, the molecular mechanisms by which tobacco smoke triggers apoptosis remain unclear. In the present study we investigated the effects of tobacco smoke on the induction of apoptosis in the lungs of rats and modulation of nuclear factor-kappa B (NF-{kappa}B) in this process. Exposure of rats to 80 mg/m{sup 3} tobacco smoke significantly induced apoptosis in the lungs. Tobacco smoke resulted in inhibition of NF-{kappa}Bmore » activity, noted by suppression of inhibitor of {kappa}B (I{kappa}B) kinase (IKK), accumulation of I{kappa}B{alpha}, decrease of NF-{kappa}B DNA binding activity, and downregulation of NF-{kappa}B-dependent anti-apoptotic proteins, including Bcl-2, Bcl-xl, and inhibitors of apoptosis. Initiator caspases for the death receptor pathway (caspase 8) and the mitochondrial pathway (caspase 9) as well as effector caspase 3 were activated following tobacco smoke exposure. Tobacco smoke exposure did not alter the levels of p53 and Bax proteins. These findings suggest the role of NF-{kappa}B pathway in tobacco smoke-induced apoptosis.« less

Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy.

PubMed

Kutoh, Eiji; Wada, Asuka; Murayama, Teruma; Takizawa, Yui

2017-06-01

The aim of this study is to investigate canagliflozin as an initial therapy in type 2 diabetes mellitus and to explore the effects on metabolic parameters in relation to effects on glycemic control. Treatment-naïve subjects with type 2 diabetes mellitus received canagliflozin 50-100 mg/day monotherapy. At 3 months, levels of glycemic and non-glycemic parameters were compared with those at baseline (n = 39). As a comparator, our previous data of baseline glycosylated hemoglobin (HbA 1c )-matched treatment-naïve subjects with ipragliflozin 25-50 mg monotherapy (n = 27) were employed. Significant reductions in HbA 1c (from 9.96 to 8.33%), fasting blood glucose (-23.9%), homeostasis model assessment-R (HOMA-R, -33.5%), body mass index (-1.8%), and uric acid (UA, -5.2%) levels and significant increases in homeostasis model assessment-B (HOMA-B, 30.1%) levels were observed. Approximately one third of the subjects experienced certain adverse events. Similar results were obtained with ipragliflozin. Baseline levels of HbA 1c , triglycerides, non-high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were chosen as significant contributing factors for the changes in HbA 1c levels with canagliflzoin, while only baseline HbA 1c levels were selected as such a factor with ipragliflozin. Significant positive correlations between the changes in HbA 1c and changes in non-HDL-C (R = 0.3954) or between changes in HbA 1c and changes in LDL-C (R = 0.4317) were observed with canagliflozin. With ipragliflozin, no such correlations were noted. No correlations between the changes in HbA 1c and changes in body mass index were seen with both drugs. These results suggest that (1) canagliflozin appears to offer clinically beneficial outcomes as an initial therapy in subjects with type 2 diabetes mellitus, although with certain adverse events. (2) Atherogenic cholesterols including non-HDL-C and LDL-C could be involved in the glycemic efficacy of canagliflozin. This was not the case with ipragliflozin. (3) Unexpectedly, weight reductions with canagliflozin are not associated with its glycemic efficacy.

Expression and associations of TRAF1, BMI-1, ALDH1, and Lin28B in oral squamous cell carcinoma.

PubMed

Wu, Tian-Fu; Li, Yi-Cun; Ma, Si-Rui; Bing-Liu; Zhang, Wen-Feng; Sun, Zhi-Jun

2017-04-01

Tumor necrosis factor receptor-associated factor 1, an adaptor protein of tumor necrosis factor 2, is involved in classical nuclear factor (NF)-κB activation and lymphocyte recruitment. However, less is known about the expression and association of tumor necrosis factor receptor-associated factor 1 with cancer stem cell markers in oral squamous cell carcinoma. This study aimed to investigate the expression of tumor necrosis factor receptor-associated factor 1 and stem cell characteristic markers (lin28 homolog B, B cell-specific Moloney murine leukemia virus integration site 1, and aldehyde dehydrogenase 1) in oral squamous cell carcinoma and analyze their relations. Paraffin-embedded tissues of 78 oral squamous cell carcinomas, 39 normal oral mucosa, and 12 oral dysplasia tissues were employed in tissue microarrays, and the expression of tumor necrosis factor receptor-associated factor 1, B cell-specific Moloney murine leukemia virus integration site 1, aldehyde dehydrogenase 1, and lin28 homolog B was measured by immunohistostaining and digital pathological analysis. The expression of tumor necrosis factor receptor-associated factor 1 was higher in the oral squamous cell carcinoma group as compared with the expression in the oral mucosa (p < 0.01) and oral dysplasia (p < 0.001) groups. In addition, the expression of tumor necrosis factor receptor-associated factor 1 was associated with those of B cell-specific Moloney murine leukemia virus integration site 1, aldehyde dehydrogenase 1, and lin28 homolog B (p = 0.032, r 2  = 0.109; p < 0.0001, r 2  = 0.64; and p < 0.001, r 2  = 0.16) in oral squamous cell carcinoma. The patient survival rate was lower in the highly expressed tumor necrosis factor receptor-associated factor 1 group, although the difference was not significant. The clustering analysis showed that tumor necrosis factor receptor-associated factor 1 was most related to aldehyde dehydrogenase 1. These findings suggest that tumor necrosis factor receptor-associated factor 1 has potential direct/indirect regulations with the cancer stem cell markers in oral squamous cell carcinoma, which may help in further analysis of the cancer stem cell characteristics.

Continued importance of family factors in youth smoking behavior.

PubMed

Mahabee-Gittens, E Melinda; Xiao, Yang; Gordon, Judith S; Khoury, Jane C

2012-12-01

Although it is known that levels of family factors (FF) such as parental monitoring and parent-adolescent connectedness vary during adolescence, it is unknown which factors remain protective, preventing smoking initiation, in youth of differing racial/ethnic groups. Using a longitudinal, nationally representative sample, we examined which FF protect against smoking initiation in White, Black, and Hispanic youth. A total of 3,473 parent-nonsmoking youth dyads from Round 1 (T1) of the National Survey of Parents and Youth were followed to Round 3 (T2). Youth smoking status at T2 was assessed as the primary outcome. We examined changes in FF (T2 - T1) and the protection afforded by these factors at T1 and T2 for smoking initiation, both by race/ethnicity and overall. There were statistically significant decreases in levels of protective FF from T1 to T2 across all racial/ethnic groups; however, FF levels were higher in never-smokers compared with smoking initiators at both T1 and T2 (p < .05). Separate models by race/ethnicity showed the protective effect of increased perceived punishment in all racial/ethnic groups and protection against initiation by increased parental monitoring in Black and Hispanic youth. Overall, higher parental monitoring at T1 was associated with decreased odds of smoking initiation (33%); decreased parental monitoring and perceived punishment from T1 to T2 were associated with increased odds of smoking initiation (55% and 17%, respectively). Smoking prevention interventions should encourage parents to both enforce consistent consequences of smoking behavior, and continue monitoring, especially in minority groups.

Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-κB activation.

PubMed

Yamaguchi, Masayoshi; Weitzmann, M Neale

2011-01-01

Several bone protective factors are reported to exhibit stimulatory activities on bone formation coupled with inhibitory effects on bone resorption; one such factor is vitamin K2. Vitamin K species [K1 (phylloquinone) and K2 (menaquinone)] have long been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans. However, the mechanisms of vitamin K action on the skeleton are poorly defined. Activation of the nuclear factor κB (NF-κB) signal transduction pathway is essential for osteoclast formation and resorption. By contrast, NF-κB signaling potently antagonizes osteoblast differentiation and function, prompting us to speculate that NF-κB antagonists may represent a novel class of dual anti-catabolic and pro-anabolic agents. We now show that vitamin K2 action on osteoblast and osteoclast formation and activity is accomplished by down-regulating basal and cytokine-induced NF-κB activation, by increasing IκB mRNA, in a γ-carboxylation-independent manner. Furthermore, vitamin K2 prevented repression by tumor necrosis factor α (TNFα) of SMAD signaling induced by either transforming growth factor ß (TGFß) or bone morphogenetic protein-2 (BMP-2). Vitamin K2 further antagonized receptor activator of NF-κB (RANK) ligand (RANKL)-induced NF-κB activation in osteoclast precursors. Our data provide a novel mechanism to explain the dual pro-anabolic and anti-catabolic activities of vitamin K2, and may further support the concept that pharmacological modulation of NF-κB signal transduction may constitute an effective mechanism for ameliorating pathological bone loss and for promoting bone health.

Predictors of Infant Hepatitis B Immunization in Cameroon: Data to Inform Implementation of a Hepatitis B Birth Dose.

PubMed

Dionne-Odom, Jodie; Westfall, Andrew O; Nzuobontane, Divine; Vinikoor, Michael J; Halle-Ekane, Gregory; Welty, Thomas; Tita, Alan T N

2018-01-01

Although most African countries offer hepatitis B immunization through a 3-dose vaccine series recommended at 6, 10 and 14 weeks of age, very few provide birth dose vaccination. In support of Cameroon's national plan to implement the birth dose vaccine in 2017, we investigated predictors of infant hepatitis B virus (HBV) vaccination under the current program. Using the 2011 Demographic Health Survey in Cameroon, we identified women with at least one living child (age 12-60 months) and information about the hepatitis B vaccine series. Vaccination rates were calculated, and logistic regression modeling was used to identify factors associated with 3-dose series completion. Changes over time were assessed with linear logistic model. Among 4594 mothers analyzed, 66.7% (95% confidence interval [CI]: 64.1-69.3) of infants completed the hepatitis B vaccine series; however, an average 4-week delay in series initiation was noted with median dose timing at 10, 14 and 19 weeks of age. Predictors of series completion included facility delivery (adjusted odds ratio [aOR]: 2.1; 95% CI: 1.7-2.6), household wealth (aOR: 1.9; 95% CI: 1.2-3.1 comparing the highest and lowest quintiles), Christian religion (aOR: 1.8; 95% CI: 1.3-2.5 compared with Muslim religion) and older maternal age (aOR: 1.4; 95% CI: 1.2-1.7 for 10 year units). Birth dose vaccination to reduce vertical and early childhood transmission of hepatitis B may overcome some of the obstacles to timely and complete HBV immunization in Cameroon. Increased awareness of HBV is needed among pregnant women and high-risk groups about vertical transmission, the importance of facility delivery and the effectiveness of prevention beginning with monovalent HBV vaccination at birth.

Winning in sequential Parrondo games by players with short-term memory

NASA Astrophysics Data System (ADS)

Cheung, K. W.; Ma, H. F.; Wu, D.; Lui, G. C.; Szeto, K. Y.

2016-05-01

The original Parrondo game, denoted as AB3, contains two independent games: A and B. The winning or losing of games A and B is defined by the change of one unit of capital. Game A is a losing game if played continuously, with winning probability p=0.5-ɛ , where ɛ =0.003 . Game B is also losing and has two coins: a good coin with winning probability {{p}\\text{g}}=0.75-ɛ is used if the player’s capital is not divisible by 3, otherwise a bad coin with winning probability {{p}\\text{b}}=0.1-ɛ is used. The Parrondo paradox refers to the situation where the mixture of games A and B in a sequence leads to winning in the long run. The paradox can be resolved using Markov chain analysis. We extend this setting of the Parrondo game to involve players with one-step memory. The player can win by switching his choice of A or B game in a Parrondo game sequence. If the player knows the identity of the game he plays and the state of his capital, then the player can win maximally. On the other hand, if the player does not know the nature of the game, then he is playing a (C, D) game, where either (C  =  A, D  =  B), or (C  =  B, D  =  A). For a player with one-step memory playing the AB3 game, he can achieve the highest expected gain with switching probability equal to 3/4 in the (C, D) game sequence. This result has been found first numerically and then proven analytically. Generalization to an AB mod(M) Parrondo game for other integers M has been made for the general domain of parameters {{p}\\text{b}}\\text{A}}<{{p}\\text{g}} . We find that for odd M the Parrondo effect does exist. However, for even M, there is no Parrondo effect for two cases: the initial game is A and the initial capital is even, or the initial game is B and the initial capital is odd. There is still a possibility of the Parrondo effect for the other two cases when M is even: the initial game is A and the initial capital is odd, or the initial game is B and the initial capital is even. These observations from numerical experiments can be understood as the factorization of the Markov chains into two distinct cycles. Discussion of these effects on games is also made in the context of feedback control of the Brownian ratchet.

1α,25-dihydroxyvitamin D3 modulates the hair-inductive capacity of dermal papilla cells: therapeutic potential for hair regeneration.

PubMed

Aoi, Noriyuki; Inoue, Keita; Chikanishi, Toshihiro; Fujiki, Ryoji; Yamamoto, Hanako; Kato, Harunosuke; Eto, Hitomi; Doi, Kentaro; Itami, Satoshi; Kato, Shigeaki; Yoshimura, Kotaro

2012-08-01

Dermal papilla cells (DPCs) have the potential to induce differentiation of epithelial stem cells into hair, and Wnt signaling is deeply involved in the initiation process. The functional limitation of expanded adult DPCs has been a difficult challenge for cell-based hair regrowth therapy. We previously reported that 1α,25-dihydroxyvitamin D(3) (VD(3)) upregulates expression of transforming growth factor (TGF)-β2 and alkaline phosphatase (ALP) activity, both features of hair-inducing human DPCs (hDPCs). In this study, we further examined the effects and signaling pathways associated with VD(3) actions on DPCs. VD(3) suppressed hDPC proliferation in a dose-dependent, noncytotoxic manner. Among the Wnt-related genes investigated, Wnt10b expression was significantly upregulated by VD(3) in hDPCs. Wnt10b upregulation, as well as upregulation of ALPL (ALP, liver/bone/kidney) and TGF-β2, by VD(3) was specific in hDPCs and not detected in human dermal fibroblasts. Screening of paracrine or endocrine factors in the skin indicated that all-trans retinoic acid (atRA) upregulated Wnt10b gene expression, although synergistic upregulation (combined atRA and VD(3)) was not seen. RNA interference with vitamin D receptor (VDR) revealed that VD(3) upregulation of Wnt10b, ALPL, and TGF-β2 was mediated through the genomic VDR pathway. In a rat model of de novo hair regeneration by murine DPC transplantation, pretreatment with VD(3) significantly enhanced hair folliculogenesis. Specifically, a greater number of outgrowing hair shafts and higher maturation of regenerated follicles were observed. Together, these data suggest that VD(3) may promote functional differentiation of DPCs and be useful in preserving the hair follicle-inductive capacity of cultured DPCs for hair regeneration therapies.

Associations among animal, carcass, muscle characteristics, and fresh meat color traits in Charolais cattle.

PubMed

Gagaoua, Mohammed; Picard, Brigitte; Monteils, Valérie

2018-06-01

This study investigated the effects of animal, carcass and muscle characteristics on initial color traits of steaks from 887 Charolais cattle. First, the fixed factors of year of birth, experiment and sex had strong impacts on color traits. From the covariates, increased age lead to intense color (low h*, -1.55 units) and darker and vivid meat (high a*, b* and C*: +4.56, +3.41 and +5.61, respectively). Increases in fatness score and carcass fat weight were associated with increases in a*, b* and C* (redness; +2.90 to +4.06 for a*; yellowness; +2.60 to +3.76 for b*; and vividness, +3.87 to +5.49 for C*) and a darker colored lean (L*; -1.56 to -3.23). As pH24h increased, a* (less red) and C* (less vivid) decreased (-3.06), whereas hue angle increased (+2.69) leading to poorer color. The selection of animals for high degree of muscularity or slaughter weight resulted in lighter and darker meat, respectively. The studied covariates could be used as indicators of Charolais beef color traits. Copyright © 2018 Elsevier Ltd. All rights reserved.

Investigation of Room Temperature Mössbauer Spectroscopy and Initial Permeability Properties of Al3+ Substituted Cobalt Ferrites

NASA Astrophysics Data System (ADS)

Pandit, Rabia; Kaur, Pawanpreet; Sharma, K. K.; Hashim, Mohd.; Kumar, Ravi

In the present work, Al3+ substituted cobalt ferrites (CoFe2‑xAlxO4, x=0.2, 0.4, 0.6, 0.8) have been synthesized via standard solid-state reaction technique. The incorporation of Al3+ ions in cobalt ferrite has been shown to play an important role in modifying the magnetic properties. The room temperature (300K) 57Fe Mössbauer spectra reveals that the studied samples show two characteristic ferromagnetic zeeman sextets at A and B-sites at lower Al3+ ion concentration (i.e., up to x=0.4). However, a paramagnetic relaxation has been noted for higher Al3+ substitution (for x=0.6 and 0.8) samples. The dependence of the Mössbauer parameters such as isomer shift, quadrupole splitting, line width and magnetic hyperfine field on Al3+ ion concentration has also been noted. The variations in initial permeability over a wide frequency range (125kHz to 30MHz) at 300K have been recorded. The fairly constant values of initial permeability and the low values of the relative loss factor of the order of 10‑4 to 10‑5 over the wide frequency range are the important findings of the present work. The observed low values of relative loss factor at high frequencies suggest that the studied ferrites are promising materials to be used in microwave applications.

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells.

PubMed

Zacharopoulou, Nefeli; Tsapara, Anna; Kallergi, Galatea; Schmid, Evi; Alkahtani, Saad; Alarifi, Saud; Tsichlis, Philip N; Kampranis, Sotirios C; Stournaras, Christos

2018-05-14

The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins. We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells. These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors. © 2018 The Author(s). Published by S. Karger AG, Basel.

Analysing pseudoephedrine/methamphetamine policy options in Australia using multi-criteria decision modelling.

PubMed

Manning, Matthew; Wong, Gabriel T W; Ransley, Janet; Smith, Christine

2016-06-01

In this paper we capture and synthesize the unique knowledge of experts so that choices regarding policy measures to address methamphetamine consumption and dependency in Australia can be strengthened. We examine perceptions of the: (1) influence of underlying factors that impact on the methamphetamine problem; (2) importance of various models of intervention that have the potential to affect the success of policies; and (3) efficacy of alternative pseudoephedrine policy options. We adopt a multi-criteria decision model to unpack factors that affect decisions made by experts and examine potential variations on weight/preference among groups. Seventy experts from five groups (i.e. academia (18.6%), government and policy (27.1%), health (18.6%), pharmaceutical (17.1%) and police (18.6%)) in Australia participated in the survey. Social characteristics are considered the most important underlying factor, prevention the most effective strategy and Project STOP the most preferred policy option with respect to reducing methamphetamine consumption and dependency in Australia. One-way repeated ANOVAs indicate a statistically significant difference with regards to the influence of underlying factors (F(2.3, 144.5)=11.256, p<.001), effectiveness of interventions (F(2.4, 153.1)=28.738, p<.001) and policy options (F(2.8, 175.5)=70.854, p<.001). A majority of respondents believed that genetic, biological, emotional, cognitive and social factors are the most influential explanatory variables in terms of methamphetamine consumption and dependency. Most experts support the use of preventative mechanisms to inhibit drug initiation and delayed drug uptake. Compared to other policies, Project STOP (which aims to disrupt the initial diversion of pseudoephedrine) appears to be a more preferable preventative mechanism to control the production and subsequent sale and use of methamphetamine. This regulatory civil law lever engages third parties in controlling drug-related crime. The literature supports third-party partnerships as it engages experts who have knowledge and expertise with respect to prevention and harm minimization. Copyright © 2016 Elsevier B.V. All rights reserved.

Levels of circulating soluble receptor activator of NF-κB and interleukins-1 predicting outcome of locally advanced basal cell carcinoma.

PubMed

Lin, Quan; Li, Yan; Zhang, Duo; Jin, Hongjuan

2016-12-01

Decreasing levels of cytokines are associated with better responses to therapies, while increasing levels are related to progression or recurrence and decreased survival. NF-κB's role in the cell cycle and its ubiquity are only stressed out by the evidence for the importance of activation (aberrant activation in the majority of cancers) of both canonical and non-canonical pathways in advanced basal cell carcinomas (aBCCs), a subset of basal cell carcinoma (BCC). NF-κB acts through its canonical, or classical, form activated by interleukin-1 (IL-1), regulates cytoprotective, innate, and adaptive immune responses. However, NF-κB2 often acts through its non-canonical or alternate pathway. During the two-year study period, we selected 21 patients presenting with aBCCs due to delay in accessing medical attention with an advanced form of BCCs (n = 19) and infiltrative BCCs (n = 2). Initial diagnosis of BCCs of head and neck was made clinically and verified by skin biopsy. Venous blood was drawn and serum was obtained. Samples were collected at baseline and every three days thereafter (days 3, 6, 9, etc. until surgery). Antigenes' quantities (cytokines) were determined by ELISA kits. Initially, the mean value of all cytokine subjects was significantly different related to the control group (P <0.05). Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) were observed following the surgery. Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) are evident throughout our study period and a certain regularity in its dynamics is evident as the follow-up period moves away. It was therefore concluded that measurement of these factors might be useful in predicting the overall outcome of patients with aBCCs. This study highlights the systemic effects of aBCCs, but further studies are required on this topic. © The Author(s) 2016.

Focus expansion and stability of the spread parameter estimate of the power law model for dispersal gradients

PubMed Central

Gent, David H.; Mehra, Lucky K.; Christie, David; Magarey, Roger

2017-01-01

Empirical and mechanistic modeling indicate that pathogens transmitted via aerially dispersed inoculum follow a power law, resulting in dispersive epidemic waves. The spread parameter (b) of the power law model, which is an indicator of the distance of the epidemic wave front from an initial focus per unit time, has been found to be approximately 2 for several animal and plant diseases over a wide range of spatial scales under conditions favorable for disease spread. Although disease spread and epidemic expansion can be influenced by several factors, the stability of the parameter b over multiple epidemic years has not been determined. Additionally, the size of the initial epidemic area is expected to be strongly related to the final epidemic extent for epidemics, but the stability of this relationship is also not well established. Here, empirical data of cucurbit downy mildew epidemics collected from 2008 to 2014 were analyzed using a spatio-temporal model of disease spread that incorporates logistic growth in time with a power law function for dispersal. Final epidemic extent ranged from 4.16 ×108 km2 in 2012 to 6.44 ×108 km2 in 2009. Current epidemic extent became significantly associated (P < 0.0332; 0.56 < R2 < 0.99) with final epidemic area beginning near the end of April, with the association increasing monotonically to 1.0 by the end of the epidemic season in July. The position of the epidemic wave-front became exponentially more distant with time, and epidemic velocity increased linearly with distance. Slopes from the temporal and spatial regression models varied with about a 2.5-fold range across epidemic years. Estimates of b varied substantially ranging from 1.51 to 4.16 across epidemic years. We observed a significant b ×time (or distance) interaction (P < 0.05) for epidemic years where data were well described by the power law model. These results suggest that the spread parameter b may not be stable over multiple epidemic years. However, b ≈ 2 may be considered the lower limit of the distance traveled by epidemic wave-fronts for aerially transmitted pathogens that follow a power law dispersal function. PMID:28649473

9 CFR 318.304 - Operations in the thermal processing area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... factor over the specified thermal processing operation times. Temperature/time recording devices shall... minimum initial temperatures and operating procedures for thermal processing equipment, shall be posted in... available to the thermal processing system operator and the inspector. (b) Process indicators and retort...

9 CFR 318.304 - Operations in the thermal processing area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... factor over the specified thermal processing operation times. Temperature/time recording devices shall... minimum initial temperatures and operating procedures for thermal processing equipment, shall be posted in... available to the thermal processing system operator and the inspector. (b) Process indicators and retort...

9 CFR 318.304 - Operations in the thermal processing area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... factor over the specified thermal processing operation times. Temperature/time recording devices shall... minimum initial temperatures and operating procedures for thermal processing equipment, shall be posted in... available to the thermal processing system operator and the inspector. (b) Process indicators and retort...

9 CFR 318.304 - Operations in the thermal processing area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... factor over the specified thermal processing operation times. Temperature/time recording devices shall... minimum initial temperatures and operating procedures for thermal processing equipment, shall be posted in... available to the thermal processing system operator and the inspector. (b) Process indicators and retort...

Interleukin-1 gene polymorphisms in chronic gastritis patients infected with Helicobacter pylori as risk factors of gastric cancer development.

PubMed

Hnatyszyn, Andrzej; Wielgus, Karolina; Kaczmarek-Rys, Marta; Skrzypczak-Zielinska, Marzena; Szalata, Marlena; Mikolajczyk-Stecyna, Joanna; Stanczyk, Jerzy; Dziuba, Ireneusz; Mikstacki, Adam; Slomski, Ryszard

2013-12-01

Epidemiological investigations indicated association of the Helicobacter pylori infections with the occurrence of inflammatory conditions of the gastric mucosa and development of chronic gastritis and intestinal type of gastric cancer. IL1A and IL1B genes have been proposed as key factors in determining risk of gastritis and malignant transformation. The aim of this paper was to evaluate association of interleukin-1 gene polymorphisms with chronic gastritis, atrophy, intestinal metaplasia, dysplasia and intestinal type of gastric cancer in H. pylori-infected patients. Patients subjected to analysis represent group of 144 consecutive cases that suffered from dyspepsia with coexisting infection of H. pylori and chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer. Molecular studies involved analysis of -889C>T polymorphism of IL1A gene and +3954C>T polymorphism of IL1B gene. Statistical analysis of association of polymorphism -889C>T of gene IL1A with changes in gastric mucosa showed lack of significance, whereas +3954C>T polymorphism of IL1B gene showed significant association. Frequency of allele T of +3954C>T polymorphism of IL1B gene was higher in group of patients with chronic gastritis, atrophy, intestinal metaplasia, dysplasia or intestinal type of gastric cancer (32.1 %) as compared with population group (23 %), χ(2) = 4.61 and p = 0.03. This corresponds to odds ratio: 1.58, 95 % CI: 1.04-2.4. Our results indicate that +3954C>T polymorphism of IL1B gene increase susceptibility to inflammatory response of gastric mucosa H. pylori-infected patients and plays a significant role in the development of chronic gastritis, atrophy, intestinal metaplasia, dysplasia and the initiation of carcinogenesis.

The bHLH transcription factor Hand is regulated by Alk in the Drosophila embryonic gut

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

Varshney, Gaurav K.; Palmer, Ruth H.

2006-12-29

During embryonic development the midgut visceral muscle is formed by fusion of cells within the visceral mesoderm, a process initiated by the specification of a specialised cell type, the founder cell, within this tissue. Activation of the receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) in the developing visceral muscle of Drosophila melanogaster initiates a signal transduction pathway required for muscle fusion. In this paper, we have investigated downstream components which are regulated by this novel signalling pathway. Here we show that Alk-mediated signal transduction drives the expression of the bHLH transcription factor Hand in vivo. Loss of Alk function resultsmore » in a complete lack of Hand expression in this tissue, whereas Alk gain of function results in an expansion of Hand expression. Finally, we have investigated the process of muscle fusion in the gut of Hand mutant animals and can find no obvious defects in this process, suggesting that Hand is not critical for visceral muscle fusion per se.« less

Differential Phosphorylation of Plant Translation Initiation Factors by Arabidopsis thaliana CK2 Holoenzymes*

PubMed Central

Dennis, Michael D.; Browning, Karen S.

2009-01-01

A previously described wheat germ protein kinase (Yan, T. F., and Tao, M. (1982) J. Biol. Chem. 257, 7037–7043) was identified unambiguously as CK2 using mass spectrometry. CK2 is a ubiquitous eukaryotic protein kinase that phosphorylates a wide range of substrates. In previous studies, this wheat germ kinase was shown to phosphorylate eIF2α, eIF3c, and three large subunit (60 S) ribosomal proteins (Browning, K. S., Yan, T. F., Lauer, S. J., Aquino, L. A., Tao, M., and Ravel, J. M. (1985) Plant Physiol. 77, 370–373). To further characterize the role of CK2 in the regulation of translation initiation, Arabidopsis thaliana catalytic (α1 and α2) and regulatory (β1, β2, β3, and β4) subunits of CK2 were cloned and expressed in Escherichia coli. Recombinant A. thaliana CK2β subunits spontaneously dimerize and assemble into holoenzymes in the presence of either CK2α1 or CK2α2 and exhibit autophosphorylation. The purified CK2 subunits were used to characterize the properties of the individual subunits and their ability to phosphorylate various plant protein substrates. CK2 was shown to phosphorylate eIF2α, eIF2β, eIF3c, eIF4B, eIF5, and histone deacetylase 2B but did not phosphorylate eIF1, eIF1A, eIF4A, eIF4E, eIF4G, eIFiso4E, or eIFiso4G. Differential phosphorylation was exhibited by CK2 in the presence of various regulatory β-subunits. Analysis of A. thaliana mutants either lacking or overexpressing CK2 subunits showed that the amount of eIF2β protein present in extracts was affected, which suggests that CK2 phosphorylation may play a role in eIF2β stability. These results provide evidence for a potential mechanism through which the expression and/or subcellular distribution of CK2 β-subunits could participate in the regulation of the initiation of translation and other physiological processes in plants. PMID:19509278

Depressive symptoms predict cancer caregivers' physical health decline.

PubMed

Shaffer, Kelly M; Kim, Youngmee; Carver, Charles S; Cannady, Rachel S

2017-11-01

Cancer caregiving has been associated with worsening health among caregivers themselves, yet demographic and psychosocial predictors of their long-term health decline are less known. This study examines changes in caregivers' physical health 2 to 8 years after their family members' cancer diagnosis and prospective predictors of that change. Caregivers (n = 664; mean age, 53.2 years) participated in a nationwide study at 2 (T1), 5 (T2), and 8 (T3) years after their family members' cancer diagnosis. Physical health (12-item Medical Outcomes Study Short Form Health Survey Physical Component Scale) was assessed T1 through T3 as outcome. Predictors were self-reported at T1, including caregiver demographics (age, sex, education, income, relationship to patient, and employment status), patient cancer severity (from medical records), and caregiver psychosocial factors (caregiving stress, caregiving esteem, social support, and depressive symptoms). Latent growth modeling tested predictors of caregivers' initial physical health and their physical health change across time. At T1, caregivers reported slightly better physical health than the US population (M = 51.22, P = .002), which declined over the following 6 years (M slope = -0.27, P < .001). All demographic factors, patient cancer severity, and T1 caregiving stress were related to caregivers' initial physical health (P ≤ .03). Higher depressive symptoms were unrelated to caregivers' initial physical health, but were the only significant predictor of caregivers' more rapid physical health decline (B = -0.02, P = .004). Findings highlight the unique contribution of caregivers' depressive symptoms to their physical health decline. Assessing and addressing depressive symptoms among caregivers early in the cancer survivorship trajectory may help to prevent premature health decline among this important yet vulnerable population. Cancer 2017;123:4277-4285. © 2017 American Cancer Society. © 2017 American Cancer Society.