Interlocked positive and negative feedback network motifs regulate β-catenin activity in the adherens junction pathway

PubMed Central

Klinke, David J.; Horvath, Nicholas; Cuppett, Vanessa; Wu, Yueting; Deng, Wentao; Kanj, Rania

2015-01-01

The integrity of epithelial tissue architecture is maintained through adherens junctions that are created through extracellular homotypic protein–protein interactions between cadherin molecules. Cadherins also provide an intracellular scaffold for the formation of a multiprotein complex that contains signaling proteins, including β-catenin. Environmental factors and controlled tissue reorganization disrupt adherens junctions by cleaving the extracellular binding domain and initiating a series of transcriptional events that aim to restore tissue homeostasis. However, it remains unclear how alterations in cell adhesion coordinate transcriptional events, including those mediated by β-catenin in this pathway. Here were used quantitative single-cell and population-level in vitro assays to quantify the endogenous pathway dynamics after the proteolytic disruption of the adherens junctions. Using prior knowledge of isolated elements of the overall network, we interpreted these data using in silico model-based inference to identify the topology of the regulatory network. Collectively the data suggest that the regulatory network contains interlocked network motifs consisting of a positive feedback loop, which is used to restore the integrity of adherens junctions, and a negative feedback loop, which is used to limit β-catenin–induced gene expression. PMID:26224311

Tight junctions negatively regulate mechanical forces applied to adherens junctions in vertebrate epithelial tissue.

PubMed

Hatte, Guillaume; Prigent, Claude; Tassan, Jean-Pierre

2018-02-05

Epithelia are layers of polarised cells tightly bound to each other by adhesive contacts. Epithelia act as barriers between an organism and its external environment. Understanding how epithelia maintain their essential integrity while remaining sufficiently plastic to allow events such as cytokinesis to take place is a key biological problem. In vertebrates, the remodelling and reinforcement of adherens junctions maintains epithelial integrity during cytokinesis. The involvement of tight junctions in cell division, however, has remained unexplored. Here, we examine the role of tight junctions during cytokinesis in the epithelium of the Xenopus laevis embryo. Depletion of the tight junction-associated proteins ZO-1 and GEF-H1 leads to altered cytokinesis duration and contractile ring geometry. Using a tension biosensor, we show that cytokinesis defects originate from misregulation of tensile forces applied to adherens junctions. Our results reveal that tight junctions regulate mechanical tension applied to adherens junctions, which in turn impacts cytokinesis.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Triptolide disrupts the actin-based Sertoli-germ cells adherens junctions by inhibiting Rho GTPases expression

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

Wang, Xiang; Zhao, Fang

Triptolide (TP), derived from the medicinal plant Triterygium wilfordii Hook. f. (TWHF), is a diterpene triepoxide with variety biological and pharmacological activities. However, TP has been restricted in clinical application due to its narrow therapeutic window especially in reproductive system. During spermatogenesis, Sertoli cell cytoskeleton plays an essential role in facilitating germ cell movement and cell-cell actin-based adherens junctions (AJ). At Sertoli cell-spermatid interface, the anchoring device is a kind of AJ, known as ectoplasmic specializations (ES). In this study, we demonstrate that β-actin, an important component of cytoskeleton, has been significantly down-regulated after TP treatment. TP can inhibit themore » expression of Rho GTPase such as, RhoA, RhoB, Cdc42 and Rac1. Downstream of Rho GTPase, Rho-associated protein kinase (ROCKs) gene expressions were also suppressed by TP. F-actin immunofluorescence proved that TP disrupts Sertoli cells cytoskeleton network. As a result of β-actin down-regulation, TP treatment increased expression of testin, which indicating ES has been disassembled. In summary, this report illustrates that TP induces cytoskeleton dysfunction and disrupts cell-cell adherens junctions via inhibition of Rho GTPases. - Highlights: • Triptolide induced the disruption of Sertoli-germ cell adherens junction. • Rho GTPases expression and actin dynamics have been suppressed by triptolide. • Actin-based adherens junction is a potential antifertility target of triptolide. • Rho-Rock is involved in the regulation of actin dynamics.« less

AMS Radiocarbon Dating of Large Za Baobabs (Adansonia za) of Madagascar.

PubMed

Patrut, Adrian; Patrut, Roxana T; Danthu, Pascal; Leong Pock-Tsy, Jean-Michel; Rakosy, Laszlo; Lowy, Daniel A; von Reden, Karl F

2016-01-01

The article reports the radiocarbon investigation of Anzapalivoro, the largest za baobab (Adansonia za) specimen of Madagascar and of another za, namely the Big cistern baobab. Several wood samples collected from the large inner cavity and from the outer part/exterior of the tree were investigated by AMS (accelerator mass spectrometry) radiocarbon dating. For samples collected from the cavity walls, the age values increase with the distance into the wood up to a point of maximum age, after which the values decrease toward the outer part. This anomaly of age sequences indicates that the inner cavity of Anzapalivoro is a false cavity, practically an empty space between several fused stems disposed in a ring-shaped structure. The radiocarbon date of the oldest sample was 780 ± 30 bp, which corresponds to a calibrated age of around 735 yr. Dating results indicate that Anzapalivoro has a closed ring-shaped structure, which consists of 5 fused stems that close a false cavity. The oldest part of the biggest za baobab has a calculated age of 900 years. We also disclose results of the investigation of a second za baobab, the Big cistern baobab, which was hollowed out for water storage. This specimen, which consists of 4 fused stems, was found to be around 260 years old.

AMS Radiocarbon Dating of Large Za Baobabs (Adansonia za) of Madagascar

PubMed Central

Patrut, Adrian; Patrut, Roxana T.; Danthu, Pascal; Leong Pock-Tsy, Jean-Michel; Rakosy, Laszlo; Lowy, Daniel A.; von Reden, Karl F.

2016-01-01

The article reports the radiocarbon investigation of Anzapalivoro, the largest za baobab (Adansonia za) specimen of Madagascar and of another za, namely the Big cistern baobab. Several wood samples collected from the large inner cavity and from the outer part/exterior of the tree were investigated by AMS (accelerator mass spectrometry) radiocarbon dating. For samples collected from the cavity walls, the age values increase with the distance into the wood up to a point of maximum age, after which the values decrease toward the outer part. This anomaly of age sequences indicates that the inner cavity of Anzapalivoro is a false cavity, practically an empty space between several fused stems disposed in a ring-shaped structure. The radiocarbon date of the oldest sample was 780 ± 30 bp, which corresponds to a calibrated age of around 735 yr. Dating results indicate that Anzapalivoro has a closed ring-shaped structure, which consists of 5 fused stems that close a false cavity. The oldest part of the biggest za baobab has a calculated age of 900 years. We also disclose results of the investigation of a second za baobab, the Big cistern baobab, which was hollowed out for water storage. This specimen, which consists of 4 fused stems, was found to be around 260 years old. PMID:26760300

Myosin-dependent remodeling of adherens junctions protects junctions from Snail-dependent disassembly

PubMed Central

Weng, Mo

2016-01-01

Although Snail is essential for disassembly of adherens junctions during epithelial–mesenchymal transitions (EMTs), loss of adherens junctions in Drosophila melanogaster gastrula is delayed until mesoderm is internalized, despite the early expression of Snail in that primordium. By combining live imaging and quantitative image analysis, we track the behavior of E-cadherin–rich junction clusters, demonstrating that in the early stages of gastrulation most subapical clusters in mesoderm not only persist, but move apically and enhance in density and total intensity. All three phenomena depend on myosin II and are temporally correlated with the pulses of actomyosin accumulation that drive initial cell shape changes during gastrulation. When contractile myosin is absent, the normal Snail expression in mesoderm, or ectopic Snail expression in ectoderm, is sufficient to drive early disassembly of junctions. In both cases, junctional disassembly can be blocked by simultaneous induction of myosin contractility. Our findings provide in vivo evidence for mechanosensitivity of cell–cell junctions and imply that myosin-mediated tension can prevent Snail-driven EMT. PMID:26754645

Exploiting the Gastric Epithelial Barrier: Helicobacter pylori's Attack on Tight and Adherens Junctions.

PubMed

Backert, Steffen; Schmidt, Thomas P; Harrer, Aileen; Wessler, Silja

2017-01-01

Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which control the microbiota and protect against intruding pathogens in humans. Alterations in these complexes represent key events in the development and progression of multiple infectious diseases as well as various cancers. The gastric pathogen Helicobacter pylori exerts an amazing set of strategies to manipulate these epithelial cell-to-cell junctions, which are implicated in changing cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses. This chapter focuses on the H. pylori pathogenicity factors VacA, CagA, HtrA and urease, and how they can induce host cell signaling involved in altering cell-to-cell permeability. We propose a stepwise model for how H. pylori targets components of tight and adherens junctions in order to disrupt the gastric epithelial cell layer, giving fresh insights into the pathogenesis of this important bacterium.

Structural and functional diversity of cadherin at the adherens junction

PubMed Central

2011-01-01

Adhesion between cells is essential to the evolution of multicellularity. Indeed, morphogenesis in animals requires firm but flexible intercellular adhesions that are mediated by subcellular structures like the adherens junction (AJ). A key component of AJs is classical cadherins, a group of transmembrane proteins that maintain dynamic cell–cell associations in many animal species. An evolutionary reconstruction of cadherin structure and function provides a comprehensive framework with which to appreciate the diversity of morphogenetic mechanisms in animals. PMID:21708975

Structural Basis of a Key Factor Regulating the Affinity between the Zonula Occludens First PDZ Domain and Claudins.

PubMed

Nomme, Julian; Antanasijevic, Aleksandar; Caffrey, Michael; Van Itallie, Christina M; Anderson, James M; Fanning, Alan S; Lavie, Arnon

2015-07-03

The molecular seal between epithelial cells, called the tight junction (TJ), is built by several membrane proteins, with claudins playing the most prominent role. The scaffold proteins of the zonula occludens family are required for the correct localization of claudins and hence formation of the TJ. The intracellular C terminus of claudins binds to the N-terminal PDZ domain of zonula occludens proteins (PDZ1). Of the 23 identified human claudin proteins, nine possess a tyrosine at the -6 position. Here we show that the claudin affinity for PDZ1 is dependent on the presence or absence of this tyrosine and that the affinity is reduced if the tyrosine is modified by phosphorylation. The PDZ1 β2-β3 loop undergoes a significant conformational change to accommodate this tyrosine. Cell culture experiments support a regulatory role for this tyrosine. Plasticity has been recognized as a critical property of TJs that allow cell remodeling and migration. Our work provides a molecular framework for how TJ plasticity may be regulated. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

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

Bajenova, Olga, E-mail: o.bazhenova@spbu.ru; Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034; Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178

2014-06-10

Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA andmore » beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein.« less

Photoperiod-Dependent Effects of 4-tert-Octylphenol on Adherens and Gap Junction Proteins in Bank Vole Seminiferous Tubules

PubMed Central

Kuras, Paulina; Lydka-Zarzycka, Marta; Bilinska, Barbara

2013-01-01

In the present study we evaluated in vivo and in vitro effects of 4-tert-octylphenol (OP) on the expression and distribution of adherens and gap junction proteins, N-cadherin, β-catenin, and connexin 43 (Cx43), in testes of seasonally breeding rodents, bank voles. We found that in bank vole testes expression and distribution of N-cadherin, β-catenin, and Cx43 were photoperiod dependent. Long-term treatment with OP (200 mg/kg b.w.) resulted in the reduction of junction proteins expressions (P < 0.05, P < 0.01) and their delocalization in the testes of males kept in long photoperiod, whereas in short-day animals slight increase of Cx43 (P < 0.05), N-cadherin, and β-catenin (statistically nonsignificant) levels was observed. Effects of OP appeared to be independent of FSH and were maintained during in vitro organ culture, indicating that OP acts directly on adherens and gap junction proteins in the testes. An experiment performed using an antiestrogen ICI 182,780 demonstrated that the biological effects of OP on β-catenin and Cx43 involve an estrogen receptor-mediated response. Taken together, in bank vole organization of adherens and gap junctions and their susceptibility to OP are related to the length of photoperiod. Alterations in cadherin/catenin and Cx43-based junction may partially result from activation of estrogen receptor α and/or β signaling pathway. PMID:23737770

C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions.

PubMed

Mohanan, Vishnu; Nakata, Toru; Desch, A Nicole; Lévesque, Chloé; Boroughs, Angela; Guzman, Gaelen; Cao, Zhifang; Creasey, Elizabeth; Yao, Junmei; Boucher, Gabrielle; Charron, Guy; Bhan, Atul K; Schenone, Monica; Carr, Steven A; Reinecker, Hans-Christian; Daly, Mark J; Rioux, John D; Lassen, Kara G; Xavier, Ramnik J

2018-03-09

Polymorphisms in C1orf106 are associated with increased risk of inflammatory bowel disease (IBD). However, the function of C1orf106 and the consequences of disease-associated polymorphisms are unknown. Here we demonstrate that C1orf106 regulates adherens junction stability by regulating the degradation of cytohesin-1, a guanine nucleotide exchange factor that controls activation of ARF6. By limiting cytohesin-1-dependent ARF6 activation, C1orf106 stabilizes adherens junctions. Consistent with this model, C1orf106 -/- mice exhibit defects in the intestinal epithelial cell barrier, a phenotype observed in IBD patients that confers increased susceptibility to intestinal pathogens. Furthermore, the IBD risk variant increases C1orf106 ubiquitination and turnover with consequent functional impairments. These findings delineate a mechanism by which a genetic polymorphism fine-tunes intestinal epithelial barrier integrity and elucidate a fundamental mechanism of cellular junctional control. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions.

PubMed

Wylezinski, Lukasz S; Hawiger, Jacek

2016-10-28

The pleiotropic cytokine interleukin 2 (IL2) disrupts the blood-brain barrier and alters brain microcirculation, underlying vascular leak syndrome that complicates cancer immunotherapy with IL2. The microvascular effects of IL2 also play a role in the development of multiple sclerosis and other chronic neurological disorders. The mechanism of IL2-induced disruption of brain microcirculation has not been determined previously. We found that both human and murine brain microvascular endothelial cells express constituents of the IL2 receptor complex. Then we established that signaling through this receptor complex leads to activation of the transcription factor, nuclear factor κB, resulting in expression of proinflammatory interleukin 6 and monocyte chemoattractant protein 1. We also discovered that IL2 induces disruption of adherens junctions, concomitant with cytoskeletal reorganization, ultimately leading to increased endothelial cell permeability. IL2-induced phosphorylation of vascular endothelial cadherin (VE-cadherin), a constituent of adherens junctions, leads to dissociation of its stabilizing adaptor partners, p120-catenin and β-catenin. Increased phosphorylation of VE-cadherin was also accompanied by a reduction of Src homology 2 domain-containing protein-tyrosine phosphatase 2, known to maintain vascular barrier function. These results unravel the mechanism of deleterious effects induced by IL2 on brain microvascular endothelial cells and may inform the development of new measures to improve IL2 cancer immunotherapy, as well as treatments for autoimmune diseases affecting the central nervous system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins.

PubMed

Guerrera, Diego; Shah, Jimit; Vasileva, Ekaterina; Sluysmans, Sophie; Méan, Isabelle; Jond, Lionel; Poser, Ina; Mann, Matthias; Hyman, Anthony A; Citi, Sandra

2016-05-20

PLEKHA7 is a junctional protein implicated in stabilization of the cadherin protein complex, hypertension, cardiac contractility, glaucoma, microRNA processing, and susceptibility to bacterial toxins. To gain insight into the molecular basis for the functions of PLEKHA7, we looked for new PLEKHA7 interactors. Here, we report the identification of PDZ domain-containing protein 11 (PDZD11) as a new interactor of PLEKHA7 by yeast two-hybrid screening and by mass spectrometry analysis of PLEKHA7 immunoprecipitates. We show that PDZD11 (17 kDa) is expressed in epithelial and endothelial cells, where it forms a complex with PLEKHA7, as determined by co-immunoprecipitation analysis. The N-terminal Trp-Trp (WW) domain of PLEKHA7 interacts directly with the N-terminal 44 amino acids of PDZD11, as shown by GST-pulldown assays. Immunofluorescence analysis shows that PDZD11 is localized at adherens junctions in a PLEKHA7-dependent manner, because its junctional localization is abolished by knock-out of PLEKHA7, and is rescued by re-expression of exogenous PLEKHA7. The junctional recruitment of nectin-1 and nectin-3 and their protein levels are decreased via proteasome-mediated degradation in epithelial cells where either PDZD11 or PLEKHA7 have been knocked-out. PDZD11 forms a complex with nectin-1 and nectin-3, and its PDZ domain interacts directly with the PDZ-binding motif of nectin-1. PDZD11 is required for the efficient assembly of apical junctions of epithelial cells at early time points in the calcium-switch model. These results show that the PLEKHA7-PDZD11 complex stabilizes nectins to promote efficient early junction assembly and uncover a new molecular mechanism through which PLEKHA7 recruits PDZ-binding membrane proteins to epithelial adherens junctions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

FSGS3/CD2AP is a barbed-end capping protein that stabilizes actin and strengthens adherens junctions

PubMed Central

Brieher, William M.

2013-01-01

By combining in vitro reconstitution biochemistry with a cross-linking approach, we have identified focal segmental glomerulosclerosis 3/CD2-associated protein (FSGS3/CD2AP) as a novel actin barbed-end capping protein responsible for actin stability at the adherens junction. FSGS3/CD2AP colocalizes with E-cadherin and α-actinin-4 at the apical junction in polarized Madin-Darby canine kidney (MDCK) cells. Knockdown of FSGS3/CD2AP compromised actin stability and decreased actin accumulation at the adherens junction. Using a novel apparatus to apply mechanical stress to cell–cell junctions, we showed that knockdown of FSGS3/CD2AP compromised adhesive strength, resulting in tearing between cells and disruption of barrier function. Our results reveal a novel function of FSGS3/CD2AP and a previously unrecognized role of barbed-end capping in junctional actin dynamics. Our study underscores the complexity of actin regulation at cell–cell contacts that involves actin activators, inhibitors, and stabilizers to control adhesive strength, epithelial behavior, and permeability barrier integrity. PMID:24322428

CMTM3 (CKLF-Like Marvel Transmembrane Domain 3) Mediates Angiogenesis by Regulating Cell Surface Availability of VE-Cadherin in Endothelial Adherens Junctions.

PubMed

Chrifi, Ihsan; Louzao-Martinez, Laura; Brandt, Maarten; van Dijk, Christian G M; Burgisser, Petra; Zhu, Changbin; Kros, Johan M; Duncker, Dirk J; Cheng, Caroline

2017-06-01

Decrease in VE-cadherin adherens junctions reduces vascular stability, whereas disruption of adherens junctions is a requirement for neovessel sprouting during angiogenesis. Endocytosis plays a key role in regulating junctional strength by altering bioavailability of cell surface proteins, including VE-cadherin. Identification of new mediators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we assessed the function of CMTM3 (CKLF-like MARVEL transmembrane domain 3), which we have previously identified as highly expressed in Flk1 + endothelial progenitor cells during embryonic development. Using a 3-dimensional coculture of human umbilical vein endothelial cells-GFP (green fluorescent protein) and pericytes-RFP (red fluorescent protein), we demonstrated that siRNA-mediated CMTM3 silencing in human umbilical vein endothelial cells impairs angiogenesis. In vivo CMTM3 inhibition by morpholino injection in developing zebrafish larvae confirmed that CMTM3 expression is required for vascular sprouting. CMTM3 knockdown in human umbilical vein endothelial cells does not affect proliferation or migration. Intracellular staining demonstrated that CMTM3 colocalizes with early endosome markers EEA1 (early endosome marker 1) and Clathrin + vesicles and with cytosolic VE-cadherin in human umbilical vein endothelial cells. Adenovirus-mediated CMTM3 overexpression enhances endothelial endocytosis, shown by an increase in Clathrin + , EEA1 + , Rab11 + , Rab5 + , and Rab7 + vesicles. CMTM3 overexpression enhances, whereas CMTM3 knockdown decreases internalization of cell surface VE-cadherin in vitro. CMTM3 promotes loss of endothelial barrier function in thrombin-induced responses, shown by transendothelial electric resistance measurements in vitro. In this study, we have identified a new regulatory function for CMTM3 in angiogenesis. CMTM3 is involved in VE-cadherin turnover and is a regulator of the cell surface pool of VE-cadherin. Therefore, CMTM

Zonula occludens-1 (ZO-1) is involved in morula to blastocyst transformation in the mouse

PubMed Central

Wang, Hehai; Ding, Tianbing; Brown, Naoko; Yamamoto, Yasutoshi; Prince, Lawrence S.; Reese, Jeff; Paria, B. C.

2008-01-01

It is unknown whether or not tight junction formation plays any role in morula to blastocyst transformation that is associated with development of polarized trophoblast cells and fluid accumulation. Tight junctions are a hallmark of polarized epithelial cells and zonula occludens-1 (ZO-1) is a known key regulator of tight junction formation. Here we show that ZO-1 protein is first expressed during compaction of 8-cell embryos. This stage-specific appearance of ZO-1 suggests its participation in morula to blastocyst transition. Consistent with this idea, we demonstrate that ZO-1 siRNA delivery inside the blastomeres of zona-weakened embryos using electroporation not only knocks down ZO-1 gene and protein expressions, but also inhibits morula to blastocyst transformation in a concentration dependent manner. In addition, ZO-1 inactivation reduced the expression of Cdx2 and Oct-4, but not ZO-2 and F-actin. These results provide the first evidence that ZO-1 is involved in blastocyst formation from the morula by regulating accumulation of fluid and differentiation of nonpolar blastomeres to polar trophoblast cells. PMID:18423437

Ultrastructure of the external gill epithelium of the axolotl, Ambystoma mexicanum with reference to ionic transport.

PubMed

Jarial, M S; Wilkins, J H

2003-10-01

The ultrastructure of the external gill epithelium of the axolotl, Ambystoma mexicanum, has been examined using conventional transmission electron microscopy to elucidate its role in ionic transport. Four cell types are identified in the gill filament and primary gill bar epithelium. These are granular, ciliated, Leydig and basal cells. A fifth cell type, the flat mitochondria-rich cell is only found in the gill bar epithelium. The predominant granular cells display microvilli at their surface and their cytoplasm contains abundant mitochondria, rough endoplasmic reticulum, Golgi complexes, vesicles and PAS+ secretory granules that are extruded at the surface, which along with secretions from the Leydig cells form a mucous coat. The granular cells are joined apically by junctional complexes consisting of zonulae occludens, zonulae adherens and desmosomes. The lateral membranes of granular cells enclose large intercellular spaces that are closed at the apical ends but remain open at the basal ends adjoining capillaries. In AgNO3-treated axolotl, the gills become darkly stained, the silver grains penetrate apical membranes and appear in the cytoplasm, accumulating near the lateral membranes and also enter the intercellular spaces. These findings are consistent with the dual role of the gill epithelium in mucus production and active ionic transport.

[Collation between Za Liao of Qian Jin Yi Fang and Xin Xiu Ben Cao].

PubMed

Liang, Fei; Jiang, Li-Sheng; Li, Jian; Zhang, Wei; Zhang, Rui-Xian

2012-10-01

To analyze specific content of Za Liao of Qian Jin Yi Fang, this essay compares its content with related content of Xin Xiu Ben Cao, finding that Za Liao of Qian Jin Yi Fang is derived from the part of Jin An of Xin Xiu Ben Cao, which complements with herbal chapters from volume II to IV of Qian Jin Yi Fang. The texts in Za Liao can verify and collate part of Jin An, and thereby showing important literature value and great help for further studies on traditional Chinese medicines of Tang dynasty.

Conversational Russian in Russkij Jazyk Za Rubezom

ERIC Educational Resources Information Center

Morgan, Thomas W.

1976-01-01

Reviews materials relating to Russian speech which have appeared in the journal "Russkij Jazyk Za Rubezom" since its first issue in 1967. The articles reviewed are divided into three categories: the stylistics of Russian speech, specific conversation expressions, and methodology. (CLK)

Neogenin recruitment of the WAVE regulatory complex maintains adherens junction stability and tension

PubMed Central

Lee, Natalie K.; Fok, Ka Wai; White, Amanda; Wilson, Nicole H.; O'Leary, Conor J.; Cox, Hayley L.; Michael, Magdalene; Yap, Alpha S.; Cooper, Helen M.

2016-01-01

To maintain tissue integrity during epithelial morphogenesis, adherens junctions (AJs) must resist the mechanical stresses exerted by dynamic tissue movements. Junctional stability is dependent on actomyosin contractility within the actin ring. Here we describe a novel function for the axon guidance receptor, Neogenin, as a key component of the actin nucleation machinery governing junctional stability. Loss of Neogenin perturbs AJs and attenuates junctional tension. Neogenin promotes actin nucleation at AJs by recruiting the Wave regulatory complex (WRC) and Arp2/3. A direct interaction between the Neogenin WIRS domain and the WRC is crucial for the spatially restricted recruitment of the WRC to the junction. Thus, we provide the first example of a functional WIRS–WRC interaction in epithelia. We further show that Neogenin regulates cadherin recycling at the AJ. In summary, we identify Neogenin as a pivotal component of the AJ, where it influences both cadherin dynamics and junctional tension. PMID:27029596

Alpha-catenin-dependent recruitment of the centrosomal protein CAP350 to adherens junctions allows epithelial cells to acquire a columnar shape.

PubMed

Gavilan, Maria P; Arjona, Marina; Zurbano, Angel; Formstecher, Etienne; Martinez-Morales, Juan R; Bornens, Michel; Rios, Rosa M

2015-03-01

Epithelial morphogenesis involves a dramatic reorganisation of the microtubule cytoskeleton. How this complex process is controlled at the molecular level is still largely unknown. Here, we report that the centrosomal microtubule (MT)-binding protein CAP350 localises at adherens junctions in epithelial cells. By two-hybrid screening, we identified a direct interaction of CAP350 with the adhesion protein α-catenin that was further confirmed by co-immunoprecipitation experiments. Block of epithelial cadherin (E-cadherin)-mediated cell-cell adhesion or α-catenin depletion prevented CAP350 localisation at cell-cell junctions. Knocking down junction-located CAP350 inhibited the establishment of an apico-basal array of microtubules and impaired the acquisition of columnar shape in Madin-Darby canine kidney II (MDCKII) cells grown as polarised epithelia. Furthermore, MDCKII cystogenesis was also defective in junctional CAP350-depleted cells. CAP350-depleted MDCKII cysts were smaller and contained either multiple lumens or no lumen. Membrane polarity was not affected, but cortical microtubule bundles did not properly form. Our results indicate that CAP350 may act as an adaptor between adherens junctions and microtubules, thus regulating epithelial differentiation and contributing to the definition of cell architecture. We also uncover a central role of α-catenin in global cytoskeleton remodelling, in which it acts not only on actin but also on MT reorganisation during epithelial morphogenesis.

Alpha-catenin-Dependent Recruitment of the Centrosomal Protein CAP350 to Adherens Junctions Allows Epithelial Cells to Acquire a Columnar Shape

PubMed Central

Zurbano, Angel; Formstecher, Etienne; Martinez-Morales, Juan R.; Bornens, Michel; Rios, Rosa M.

2015-01-01

Epithelial morphogenesis involves a dramatic reorganisation of the microtubule cytoskeleton. How this complex process is controlled at the molecular level is still largely unknown. Here, we report that the centrosomal microtubule (MT)-binding protein CAP350 localises at adherens junctions in epithelial cells. By two-hybrid screening, we identified a direct interaction of CAP350 with the adhesion protein α-catenin that was further confirmed by co-immunoprecipitation experiments. Block of epithelial cadherin (E-cadherin)-mediated cell-cell adhesion or α-catenin depletion prevented CAP350 localisation at cell-cell junctions. Knocking down junction-located CAP350 inhibited the establishment of an apico-basal array of microtubules and impaired the acquisition of columnar shape in Madin-Darby canine kidney II (MDCKII) cells grown as polarised epithelia. Furthermore, MDCKII cystogenesis was also defective in junctional CAP350-depleted cells. CAP350-depleted MDCKII cysts were smaller and contained either multiple lumens or no lumen. Membrane polarity was not affected, but cortical microtubule bundles did not properly form. Our results indicate that CAP350 may act as an adaptor between adherens junctions and microtubules, thus regulating epithelial differentiation and contributing to the definition of cell architecture. We also uncover a central role of α-catenin in global cytoskeleton remodelling, in which it acts not only on actin but also on MT reorganisation during epithelial morphogenesis. PMID:25764135

Exosomes Secreted under Hypoxia Enhance Invasiveness and Stemness of Prostate Cancer Cells by Targeting Adherens Junction Molecules

PubMed Central

Ramteke, Anand; Ting, Harold; Agarwal, Chapla; Mateen, Samiha; Somasagara, Ranganathan; Hussain, Anowar; Graner, Michael; Frederick, Barbara; Agarwal, Rajesh; Deep, Gagan

2015-01-01

Hypoxic conditions in prostate cancer (PCA) are associated with poor prognosis; however, precise mechanism/s through which hypoxia promotes malignant phenotype remains unclear. Here, we analyzed the role of exosomes from hypoxic PCA cells in enhancing the invasiveness and stemness of naïve PCA cells, as well as in promoting cancer-associated fibroblast (CAF) phenotype in prostate stromal cells (PrSC). Human PCA LNCaP and PC3 cells were exposed to hypoxic (1% O2) or normoxic (21% O2) conditions, and exosomes secreted under hypoxic (ExoHypoxic) and normoxic (ExoNormoxic) conditions were isolated from conditioned media. Nanoparticle tracking analysis revealed that ExoHypoxic have smaller average size as compared to ExoNormoxic. Immunoblotting results showed a higher level of tetraspanins (CD63 and CD81), heat shock proteins (HSP90 and HSP70) and Annexin II in ExoHypoxic compared to ExoNormoxic. Co-culturing with ExoHypoxic increased the invasiveness and motility of naïve LNCaP and PC3 cells, respectively. ExoHypoxic also promoted prostasphere formation by both LNCaP and PC3 cells, and enhanced α-SMA (a CAF biomarker) expression in PrSC. Compared to ExoNormoxic, ExoHypoxic showed higher metalloproteinases activity and increased level of diverse signaling molecules (TGF-β2, TNF1α, IL6, TSG101, Akt, ILK1, and β-catenin). Furthermore, proteome analysis revealed a higher number of proteins in ExoHypoxic (160 proteins) compared to ExoNormoxic (62 proteins), primarily associated with the remodeling of epithelial adherens junction pathway. Importantly, ExoHypoxic targeted the expression of adherens junction proteins in naïve PC3 cells. These findings suggest that ExoHypoxic are loaded with unique proteins that could enhance invasiveness, stemness and induce microenvironment changes; thereby, promoting PCA aggressiveness. PMID:24347249

Sedimentation survey of Lago Loíza, Trujillo Alto, Puerto Rico, July 2009

USGS Publications Warehouse

Soler-López, Luis R.; Licha-Soler, N.A.

2014-01-01

Lago Loíza is a reservoir formed at the confluence of Río Gurabo and Río Grande de Loíza in the municipality of Trujillo Alto in central Puerto Rico, about 10 kilometers (km) north of the town of Caguas, about 9 km northwest of Gurabo, and about 3 km south of Trujillo Alto (fig. 1). The Carraizo Dam is owned and operated by the Puerto Rico Aqueduct and Sewer Authority (PRASA), and was constructed in 1953 as a water-supply reservoir for the San Juan Metropolitan area. The dam is a concrete gravity structure that is located in a shallow valley and has a gently sloping left abutment and steep right abutment. Non-overflow sections flank the spillway section. Waterways include an intake structure for the pumping station and power plant, sluiceways, a trash sluice, and a spillway. The reservoir was built to provide a storage capacity of 26.8 million cubic meters (Mm3) of water at the maximum pool elevation of 41.14 meters (m) above mean sea level (msl) for the Sergio Cuevas Filtration Plant that serves the San Juan metropolitan area. The reservoir has a drainage area of 538 square kilometers (km2) and receives an annual mean rainfall that ranges from 1,600 to 5,000 millimeters per year (mm/yr). The principal streams that drain into Lago Loíza are the Río Grande de Loíza, Río Gurabo, and Río Cañas. Two other rivers, the Río Bairoa and Río Cagüitas, discharge into the Río Grande de Loíza just before it enters the reservoir. The combined mean annual runoff of the Río Grande de Loíza and the Río Gurabo for the 1960–2009 period of record is 323 Mm3. Flow from these streams constitutes about 89 percent of the total mean annual inflow of 364 Mm3 to the reservoir (U.S. Geological Survey, 2009). Detailed information about Lago Loíza reservoir structures, historical sediment accumulation, and a dredge conducted in 1999 are available in Soler-López and Gómez-Gómez (2005). During July 8–15, 2009, the U.S. Geological Survey (USGS) Caribbean Water Science

The Interaction of CD97/ADGRE5 With β-Catenin in Adherens Junctions Is Lost During Colorectal Carcinogenesis.

PubMed

Hilbig, Doris; Dietrich, Norman; Wandel, Elke; Gonsior, Susann; Sittig, Doreen; Hamann, Jörg; Aust, Gabriela

2018-01-01

The adhesion G-protein-coupled receptor CD97/ADGRE5 is present in adherens junctions of human normal intestinal cells and upregulated in colorectal carcinomas. Here, we examined whether CD97 directly interacts with junctional proteins in normal and malignant colorectal tissue. We identified an association of CD97 with β-catenin using a proximity ligation assay and confirmed the interaction between both endogenous proteins at the biochemical level by co-immunoprecipitation in human and mouse tissues and cell lines. Glutathione S-transferase-pulldown revealed that CD97 binds β-catenin through its seven-span transmembrane/intracellular domain(s). To study tumor-associated changes in the interaction of CD97 and β-catenin in situ , we quantified and correlated both proteins at the membrane, and in the cytoplasm and nuclei of colorectal carcinomas and their corresponding normal tissues ( n  = 111). In normal colon, membranous levels of CD97 and β-catenin correlated strongly ( p  < 0.0001). To some degree both molecules disappeared in carcinomas simultaneously from the membrane of tumor cells ( p  = 0.017). CD97 accumulated in the cytoplasm, whereas β-catenin emerged in the cytoplasm and nuclei. CD97 and β-catenin levels in the cytoplasm correlated well ( p  < 0.0001). Irrespective of their subcellular localization, interaction of CD97 with β-catenin in tumor cells was also restricted to the cell contacts. Accordingly, CD97 did not regulate β-catenin-dependent TCF-mediated transcriptional activity. In summary, while CD97 and β-catenin interact in adherens junctions, their interaction is lost and both molecules follow different functional paths inside tumor cells.

Cytokine-mediated dysregulation of zonula occludens-1 properties in human brain microvascular endothelium.

PubMed

Rochfort, Keith D; Cummins, Philip M

2015-07-01

Zonula occludens-1 (ZO-1) is essential to the proper assembly of interendothelial junction complexes that control blood-brain barrier (BBB) integrity. The goal of the current paper was to improve our understanding of how proinflammatory cytokines modulate ZO-1 properties within the human BBB microvascular endothelium. In this respect, we investigated the effects of TNF-α and IL-6 on ZO-1 using human brain microvascular endothelial cells (HBMvECs). Following treatment of HBMvECs with either cytokine (0-100 ng/ml, 18 h), we observed significantly decreased ZO-1 expression and ZO-1:occludin co-association, in parallel with increased ZO-1 phosphorylation (pTyr and pThr). All effects were dose-dependent. Either cytokine also caused extensive cell-cell border delocalization of ZO-1 in parallel with elevated HBMvEC permeability. Furthermore, pre-treatment of HBMvECs with antioxidants (superoxide dismutase, catalase, apocynin, N-acetylcysteine), or employing targeted inhibition of NADPH oxidase activation (NSC23766, gp91/p47 siRNA), were all found to comparably attenuate the cytokine-dependent decrease in ZO-1 protein expression. In summary, we present an in vitro model of how different proinflammatory cytokines can dysregulate ZO-1 properties in HBMvECs. A causal role for NADPH oxidase activation and oxidant signalling is also confirmed. Our findings add mechanistic depth to current in vivo models of BBB injury manifesting ZO-1 dysregulation. Copyright © 2015 Elsevier Inc. All rights reserved.

ZaP-HD: High Energy Density Z-Pinch Plasmas using Sheared Flow Stabilization

NASA Astrophysics Data System (ADS)

Golingo, R. P.; Shumlak, U.; Nelson, B. A.; Claveau, E. L.; Doty, S. A.; Forbes, E. G.; Hughes, M. C.; Kim, B.; Ross, M. P.; Weed, J. R.

2015-11-01

The ZaP-HD flow Z-pinch project investigates scaling the flow Z-pinch to High Energy Density Plasma, HEDP, conditions by using sheared flow stabilization. ZaP used a single power supply to produce 100 cm long Z-pinches that were quiescent for many radial Alfven times and axial flow-through times. The flow Z-pinch concept provides an approach to achieve HED plasmas, which are dimensionally large and persist for extended durations. The ZaP-HD device replaces the single power supply from ZaP with two separate power supplies to independently control the plasma flow and current in the Z-pinch. Equilibrium is determined by diagnostic measurements of the density with interferometry and digital holography, the plasma flow and temperature with passive spectroscopy, the magnetic field with surface magnetic probes, and plasma emission with optical imaging. The diagnostics fully characterize the plasma from its initiation in the coaxial accelerator, through the pinch, and exhaust from the assembly region. The plasma evolution is modeled with high resolution codes: Mach2, WARPX, and NIMROD. Experimental results and scaling analyses are presented. This work is supported by grants from the U.S. Department of Energy and the U.S. National Nuclear Security Administration.

Quantitative cell polarity imaging defines leader-to-follower transitions during collective migration and the key role of microtubule-dependent adherens junction formation.

PubMed

Revenu, Céline; Streichan, Sebastian; Donà, Erika; Lecaudey, Virginie; Hufnagel, Lars; Gilmour, Darren

2014-03-01

The directed migration of cell collectives drives the formation of complex organ systems. A characteristic feature of many migrating collectives is a 'tissue-scale' polarity, whereby 'leader' cells at the edge of the tissue guide trailing 'followers' that become assembled into polarised epithelial tissues en route. Here, we combine quantitative imaging and perturbation approaches to investigate epithelial cell state transitions during collective migration and organogenesis, using the zebrafish lateral line primordium as an in vivo model. A readout of three-dimensional cell polarity, based on centrosomal-nucleus axes, allows the transition from migrating leaders to assembled followers to be quantitatively resolved for the first time in vivo. Using live reporters and a novel fluorescent protein timer approach, we investigate changes in cell-cell adhesion underlying this transition by monitoring cadherin receptor localisation and stability. This reveals that while cadherin 2 is expressed across the entire tissue, functional apical junctions are first assembled in the transition zone and become progressively more stable across the leader-follower axis of the tissue. Perturbation experiments demonstrate that the formation of these apical adherens junctions requires dynamic microtubules. However, once stabilised, adherens junction maintenance is microtubule independent. Combined, these data identify a mechanism for regulating leader-to-follower transitions within migrating collectives, based on the relocation and stabilisation of cadherins, and reveal a key role for dynamic microtubules in this process.

[The life and work of Zaíra Cintra Vidal].

PubMed

Lopes, G T; Caldas, N P; Lima, T C; Martingil, I C

2001-01-01

This is a social-historical study that aims at describing the trajectory of Zaíra Cintra Vidal, her participation in the Nursing School Rachel Haddock Lobo and in the Brazilian Association of Nursing (ABEn). The study is based on the concepts of symbolic power, habitus and symbolic struggle of Pierre Bourdieu. The primary sources are documents which were collected in the Documentation Center of Escola de Enfermagem Ana Neri (EEAN--Ana Neri School of Nursing) in the Federeal University of Rio de Janeiro (UFRJ) and at the Memory Center of the Faculty of Nursing (FENF) in the State University of Rio de Janeiro (UERJ). The data was collected between August 2000 and April 2001 by means of document analysis script. The outcomes showed that Zaíra Cintra Vidal was born on 5 May 1903; graduated from the Nursing School of the National Public Health Department in 1926; studied and post-graduated in the United States from 1927 until 1929 and returned to Brazil in 1943. Zaíra Cintra Vidal was the founder of the Nursing School Rachel Haddock Lobo and was its first director for nine years. She also and took part in ABEn's Direction Board and in the Revista Anais de Enfermagem (Nursing Magazine).

CLASP2 interacts with p120-catenin and governs microtubule dynamics at adherens junctions

PubMed Central

Shahbazi, Marta N.; Megias, Diego; Epifano, Carolina; Akhmanova, Anna; Gundersen, Gregg G.; Fuchs, Elaine

2013-01-01

Classical cadherins and their connections with microtubules (MTs) are emerging as important determinants of cell adhesion. However, the functional relevance of such interactions and the molecular players that contribute to tissue architecture are still emerging. In this paper, we report that the MT plus end–binding protein CLASP2 localizes to adherens junctions (AJs) via direct interaction with p120-catenin (p120) in primary basal mouse keratinocytes. Reductions in the levels of p120 or CLASP2 decreased the localization of the other protein to cell–cell contacts and altered AJ dynamics and stability. These features were accompanied by decreased MT density and altered MT dynamics at intercellular junction sites. Interestingly, CLASP2 was enriched at the cortex of basal progenitor keratinocytes, in close localization to p120. Our findings suggest the existence of a new mechanism of MT targeting to AJs with potential functional implications in the maintenance of proper cell–cell adhesion in epidermal stem cells. PMID:24368809

Effects on asylum seekers of ill treatment in Zaïre.

PubMed Central

Peel, M. R.

1996-01-01

To describe the health effects of the political system in Zaïre on asylum seekers seen at the Medical Foundation for the Care of Victims of Torture a retrospective study was performed of the records of 92 asylum seekers from Zaïre who were seen for medical reports at the medical foundation in 1993 and 1994. Eighty one had been imprisoned; the others had been severely treated at home by the security services. Sixty six had been detained for up to one year. Prison conditions were invariably unsanitary, and food of poor quality when provided. All had been beaten on arrest, and all but two had been beaten repeatedly in prison. Nearly all the women and some of the men described sexual abuse. Almost all left prison through bribery or because a guard had a similar background. Seventy two asylum seekers had scarring, consider to be consistent with the history, and 70 were considered to have suffered persistent psychological damage. Asylum seekers from Zaïre will have health effects from experiences unimaginable to the ordinary Briton. An understanding of the background will help clinicians manage them. PMID:8611788

Effects on asylum seekers of ill treatment in Zaïre.

PubMed

Peel, M R

1996-02-03

To describe the health effects of the political system in Zaïre on asylum seekers seen at the Medical Foundation for the Care of Victims of Torture a retrospective study was performed of the records of 92 asylum seekers from Zaïre who were seen for medical reports at the medical foundation in 1993 and 1994. Eighty one had been imprisoned; the others had been severely treated at home by the security services. Sixty six had been detained for up to one year. Prison conditions were invariably unsanitary, and food of poor quality when provided. All had been beaten on arrest, and all but two had been beaten repeatedly in prison. Nearly all the women and some of the men described sexual abuse. Almost all left prison through bribery or because a guard had a similar background. Seventy two asylum seekers had scarring, consider to be consistent with the history, and 70 were considered to have suffered persistent psychological damage. Asylum seekers from Zaïre will have health effects from experiences unimaginable to the ordinary Briton. An understanding of the background will help clinicians manage them.

Iterative Tensor Voting for Perceptual Grouping of Ill-Defined Curvilinear Structures: Application to Adherens Junctions

PubMed Central

Loss, Leandro A.; Bebis, George; Parvin, Bahram

2012-01-01

In this paper, a novel approach is proposed for perceptual grouping and localization of ill-defined curvilinear structures. Our approach builds upon the tensor voting and the iterative voting frameworks. Its efficacy lies on iterative refinements of curvilinear structures by gradually shifting from an exploratory to an exploitative mode. Such a mode shifting is achieved by reducing the aperture of the tensor voting fields, which is shown to improve curve grouping and inference by enhancing the concentration of the votes over promising, salient structures. The proposed technique is applied to delineation of adherens junctions imaged through fluorescence microscopy. This class of membrane-bound macromolecules maintains tissue structural integrity and cell-cell interactions. Visually, it exhibits fibrous patterns that may be diffused, punctate and frequently perceptual. Besides the application to real data, the proposed method is compared to prior methods on synthetic and annotated real data, showing high precision rates. PMID:21421432

New nematotoxic indoloditerpenoid produced by Gymnoascus reessii za-130

USDA-ARS?s Scientific Manuscript database

Chemical investigation of the fungal strain Gymnoascus reessii za-130, which was previously isolated from the rhizosphere of tomato plants infected by the root-knot nematode Meloidogyne incognita, led to the isolation and identification of a new indoloditerpenoid metabolite designated gymnoascole ac...

The frontal gland in workers of Neotropical soldierless termites

NASA Astrophysics Data System (ADS)

Šobotník, Jan; Sillam-Dussès, David; Weyda, František; Dejean, Alain; Roisin, Yves; Hanus, Robert; Bourguignon, Thomas

2010-05-01

The presence of the frontal gland is well established in termite soldiers of Rhinotermitidae, Serritermitidae, and Termitidae. It is one of their main defensive adaptations or even an exclusive weapon. The gland was also occasionally reported in alate imagoes, but never in the worker caste. Here, we report the first observation of a frontal gland in workers of several Neotropical and one African species of Apicotermitinae. The ultrastructure of Aparatermes cingulatus and Anoplotermes nr. subterraneus is described in detail. In these two species, the gland is well-developed, functional and consists of class 1 secretory cells. The presence of envelope cells, wrapping the gland, is an unusual feature, as well as the presence of several zonulae adherens, connecting neighbouring glandular cells. The frontal gland of workers is homologous to this organ in soldiers and imagoes, as evidenced by the same position in the head and its connection to the same muscle. However, the defensive role of the frontal gland in workers remains to be confirmed.

First heat flow density determinations from Southeastern Zaïre (Central Africa)

NASA Astrophysics Data System (ADS)

Sebagenzi, M. N.; Vasseur, G.; Louis, P.

1993-05-01

First heat flow density determinations from southeastern Zaïre are presented. Sites are located in the late Proterozoic metasedimentary cover of the Pan-African belt (600 Ma.). For each individual boreholes, heat flow ranges between 48 and 72 mWm -2. The average value of 62 mW m -2 for the sites is similar to that of 66 mW m -2 observed in Zambia. Both values are higher than what is expected for Pan-African terranes. These heat flow determinations in Shaba province of southeastern Zaïre, together with gravity and seismological observations, support the hypothesis of lithospheric thinning for this area. As already suggested for Zambia, this lithospheric thinning may be associated with a southwestern extension of the East African Rift System from Tanganyika across the central African plateau.

Why Baby Why: Howard Broomfield's Documentation of the Dunne-za Soundscape.

ERIC Educational Resources Information Center

Ridington, Robin

1988-01-01

Examines the acoustic environment and aural culture of the Dunne-za of northeastern British Columbia. Discusses the changing soundscape of a northern hunting people, techniques for recording and cataloging an ethnographic soundscape archive, and the use of audio actualities in producing ethnographic audio documentaries. (Author/SV)

Protein myozap--a late addition to the molecular ensembles of various kinds of adherens junctions.

PubMed

Rickelt, Steffen; Kuhn, Caecilia; Winter-Simanowski, Stefanie; Zimbelmann, Ralf; Frey, Norbert; Franke, Werner Wilhelm

2011-12-01

The protein myozap, a polypeptide of 54 kDa, has recently been identified as a component of the cytoplasmic plaques of the composite junctions (areae compositae) in the myocardiac intercalated disks and of the adherens junctions (AJs) in vascular endothelia. Now we report that using very sensitive new antibodies and drastic localization methods, we have also identified this protein as a component of the AJ plaques in simple and complex epithelia, in the adluminal cell layer of the transitional epithelium of the urinary tract and in certain cell layers of diverse stratified epithelia, including gingiva, tongue, pharynx and esophagus, cervix, vagina and epidermis. Myozap has not been identified in desmosomal and tight junction plaques. We have also detected protein myozap in AJ structures of carcinomas. The discovery of a novel major protein in AJ plaques now calls for re-examinations of molecular interactions in AJ formation and maintenance and also offers a new marker for diagnostic immunocytochemistry. We also discuss the need for progressive unravelling, extractive treatments and buffer rinses of sections and cultured cells to reveal obscured or masked antigens, before definitive negative conclusions in immunohistochemistry can be made.

Branched actin networks push against each other at adherens junctions to maintain cell-cell adhesion.

PubMed

Efimova, Nadia; Svitkina, Tatyana M

2018-05-07

Adherens junctions (AJs) are mechanosensitive cadherin-based intercellular adhesions that interact with the actin cytoskeleton and carry most of the mechanical load at cell-cell junctions. Both Arp2/3 complex-dependent actin polymerization generating pushing force and nonmuscle myosin II (NMII)-dependent contraction producing pulling force are necessary for AJ morphogenesis. Which actin system directly interacts with AJs is unknown. Using platinum replica electron microscopy of endothelial cells, we show that vascular endothelial (VE)-cadherin colocalizes with Arp2/3 complex-positive actin networks at different AJ types and is positioned at the interface between two oppositely oriented branched networks from adjacent cells. In contrast, actin-NMII bundles are located more distally from the VE-cadherin-rich zone. After Arp2/3 complex inhibition, linear AJs split, leaving gaps between cells with detergent-insoluble VE-cadherin transiently associated with the gap edges. After NMII inhibition, VE-cadherin is lost from gap edges. We propose that the actin cytoskeleton at AJs acts as a dynamic push-pull system, wherein pushing forces maintain extracellular VE-cadherin transinteraction and pulling forces stabilize intracellular adhesion complexes. © 2018 Efimova and Svitkina.

Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution.

PubMed

Suzuki, Takahiro; Yoshida, Norimasa; Nakabe, Nami; Isozaki, Yutaka; Kajikawa, Hirokazu; Takagi, Tomohisa; Handa, Osamu; Kokura, Satoshi; Ichikawa, Hiroshi; Naito, Yuji; Matsui, Hirofumi; Yoshikawa, Toshikazu

2008-03-01

Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and anti-inflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.

Zonula occludens-1, occludin and E-cadherin expression and organization in salivary glands with Sjögren's syndrome.

PubMed

Mellas, Rachel E; Leigh, Noel J; Nelson, Joel W; McCall, Andrew D; Baker, Olga J

2015-01-01

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder that causes secretory dysfunction of the salivary glands leading to dry mouth. Previous studies reported that tight junction (TJ) proteins are down-regulated and lose polarity in human minor salivary glands with SS, suggesting that TJ structure is compromised in SS patients. In this paper, we utilized the NOD/ShiLtJ mouse with the main goal of evaluating this model for future TJ research. We found that the organization of apical proteins in areas proximal and distal to lymphocytic infiltration remained intact in mouse and human salivary glands with SS. These areas looked comparable to control glands (i.e., with no lymphocytic infiltration). TJ staining was absent in areas of lymphocytic infiltration coinciding with the loss of salivary epithelium. Gene expression studies show that most TJs are not significantly altered in 20-week-old NOD/ShiLtJ mice as compared with age-matched C57BL/6 controls. Protein expression studies revealed that the TJ proteins, zonula occludens-1 (ZO-1), occludin, claudin-12, as well as E-cadherin, do not significantly change in NOD/ShiLtJ mice. Our results suggest that ZO-1, occludin and E-cadherin are not altered in areas without lymphocytic infiltration. However, future studies will be necessary to test the functional aspect of these results. © The Author(s) 2014.

Detection of cholera (ctx) and zonula occludens (zot) toxin genes in Vibrio cholerae O1, O139 and non-O1 strains.

PubMed

Rivera, I G; Chowdhury, M A; Sanchez, P S; Sato, M I; Huq, A; Colwell, R R; Martins, M T

1995-09-01

Vibrio cholerae O1 and V. cholerae non-O1 strains isolated from environmental samples collected in São Paulo, Brazil, during cholera epidemics and pre-epidemic periods were examined for the presence of toxin genes. V. cholerae O1 strains isolated from clinical samples in Peru and Mexico, and V. cholerae O139 strains from India were also examined for the presence of ctx (cholera toxin gene) and zot (zonula occludens toxin gene) by polymerase chain reaction (PCR). A modified DNA-extraction method applied in this study yielded satisfactory recovery of genomic DNA from vibrios. Results showed that strains of V. cholerae O1 isolated during the preepidemic period were ctx (-)/zot (-) whereas strains isolated during the epidemic were ctx (+)/zot (+). All V. cholerae non-O1 strains tested in the study were ctx (-)/zot (-), whereas all V. cholerae O139 strains were ctx (+)/zot (+). Rapid detection of the virulence genes (ctx and zot) can be achieved by PCR and this can serve as an important tool in the epidemiology and surveillance of V. cholerae.

Ralstonia eutropha's Poly(3-hydroxybutyrate)(PHB) polymerase PhaC1 and PHB depolymerase PhaZa1 are phosphorylated in vivo.

PubMed

Jüngert, Janina R; Patterson, Cameron; Jendrossek, Dieter

2018-04-20

In this study, we screened PHB synthase PhaC1 and PHB depolymerase PhaZa1 of Ralstonia eutropha for the presence of phosphorylated residues during the PHB accumulation and PHB degradation phase. Thr373 of PHB synthase PhaC1 was phosphorylated in the stationary growth phase but was not modified in the exponential and PHB accumulation phases. Ser35 of PHB depolymerase PhaZa1 was identified in phosphorylated form both in the exponential and in the stationary growth phase. Additional phosphosites were identified for both proteins in sample-dependent forms. Site-directed mutagenesis of the codon for Thr373 and other phosphosites of PhaC1 revealed a strong negative impact on PHB synthase activity. Modification of Thr26 and Ser35 of PhaZa1 reduced the ability of R. eutropha to mobilize PHB in the stationary growth phase. Our results show that phosphorylation of PhaC1 and PhaZa1 can be important for modulation of the activities of PHB synthase and PHB depolymerase. Importance Polyhydroxybutyrate (PHB) and related polyhydroxyalkanoates (PHAs) are important intracellular carbon and energy storage compounds in many prokaryotes. The accumulation of PHB or PHAs increases the fitness of cells during periods of starvation and other stress conditions. The simultaneous presence of poly(3-hydroxybutyrate) (PHB) synthase (PhaC1) and PHB depolymerase (PhaZa1) on synthesized PHB granules in Ralstonia eutropha (alternative designation Cupriavidus necator ) has been previously shown in several laboratories. These findings imply that the activities of PHB synthase and PHB depolymerase should be regulated to avoid a futile cycle of simultaneous synthesis and degradation of PHB. Here, we addressed this question by identifying phosphorylation sites on PhaC1 and PhaZa1 and by site-directed mutagenesis of identified residues. Furthermore, we conducted in vitro and in vivo analysis of PHB synthase activity and PHB contents. Copyright © 2018 American Society for Microbiology.

Decreased expression of zonula occludens-1 and occludin in the bladder urothelium of patients with interstitial cystitis/painful bladder syndrome.

PubMed

Lee, Jane-Dar; Lee, Ming-Huei

2014-01-01

Unique barrier properties of the urothelial surface membrane permit urine storage without contents leak into the bloodstream. Previous reports suggested that the bladder urothelial barrier might be compromised in interstitial cystitis/painful bladder syndrome (IC/PBS). We examined the changes of tight junction proteins (zonula occludens-1 (ZO-1) and occludin) in IC/PBS patients. Bladder samples were derived from of 32 patients with IC/PBS and eight controls. We detected the tight junction proteins of ZO-1 and occludin expression by immunoblotting, immunohistochemical (IHC) staining and double immunofluorescent (IF) staining with confocal microscopy. Data were analyzed using the Mann-Whitney U-test. Expression of ZO-1 and occludin in the IC/PBS group was reduced compared to the control group by immunoblotting and IHC staining. Also, the thinning and denudation of urothelium were demonstrated in the IC/PBS group by histological study. IF staining showed the interruption of bladder urothelium in IC/PBS patients under confocal microscopy. Our data showed that decreased expression of tight junction proteins (ZO-1 and occludin) and interruption of bladder urothelium in IC/PBS patients. Treatment to repair the discontinuous urothelium may be useful to relieve some clinical symptoms of patients with IC/PBS. Copyright © 2012. Published by Elsevier B.V.

Altered expression of zonula occludens-2 precedes increased blood-brain barrier permeability in a murine model of fulminant hepatic failure.

PubMed

Shimojima, Naoki; Eckman, Christopher B; McKinney, Michael; Sevlever, Daniel; Yamamoto, Satoshi; Lin, Wenlang; Dickson, Dennis W; Nguyen, Justin H

2008-01-01

Brain edema secondary to increased blood-brain barrier (BBB) permeability is a lethal complication in fulminant hepatic failure (FHF). Intact tight junctions (TJ) between brain capillary endothelial cells are critical for normal BBB function. However, the role of TJ in FHF has not been explored. We hypothesized that alterations in the composition of TJ proteins would result in increased BBB permeability in FHF. In this study, FHF was induced in C57BL/6J mice by using azoxymethane. BBB permeability was assessed with sodium fluorescein. Expression of TJ proteins was determined by Western blot, and their cellular distribution was examined using immunofluorescent microscopy. Comatose FHF mice had significant cerebral sodium fluorescein extravasation compared with control and precoma FHF mice, indicating increased BBB permeability. Western blot analysis showed a significant decrease in zonula occludens (ZO)-2 expression starting in the precoma stage. Immunofluorescent microscopy showed a significantly altered distribution pattern of ZO-2 in isolated microvessels from precoma FHF mice. These changes were more prominent in comatose FHF animals. Significant alterations in ZO-2 expression and distribution in the tight junctions preceded the increased BBB permeability in FHF mice. These results suggest that ZO-2 may play an important role in the pathogenesis of brain edema in FHF.

'Special K' and a Loss of Cell-To-Cell Adhesion in Proximal Tubule-Derived Epithelial Cells: Modulation of the Adherens Junction Complex by Ketamine

PubMed Central

Hills, Claire E.; Jin, Tianrong; Siamantouras, Eleftherios; Liu, Issac K-K; Jefferson, Kieran P.; Squires, Paul E.

2013-01-01

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention. PMID:24009666

Zonula Occludens-1, Occludin and E-cadherin Expression and Organization in Salivary Glands with Sjögren’s Syndrome

PubMed Central

Mellas, Rachel E.; Leigh, Noel J.; Nelson, Joel W.; McCall, Andrew D.

2015-01-01

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disorder that causes secretory dysfunction of the salivary glands leading to dry mouth. Previous studies reported that tight junction (TJ) proteins are down-regulated and lose polarity in human minor salivary glands with SS, suggesting that TJ structure is compromised in SS patients. In this paper, we utilized the NOD/ShiLtJ mouse with the main goal of evaluating this model for future TJ research. We found that the organization of apical proteins in areas proximal and distal to lymphocytic infiltration remained intact in mouse and human salivary glands with SS. These areas looked comparable to control glands (i.e., with no lymphocytic infiltration). TJ staining was absent in areas of lymphocytic infiltration coinciding with the loss of salivary epithelium. Gene expression studies show that most TJs are not significantly altered in 20-week-old NOD/ShiLtJ mice as compared with age-matched C57BL/6 controls. Protein expression studies revealed that the TJ proteins, zonula occludens-1 (ZO-1), occludin, claudin-12, as well as E-cadherin, do not significantly change in NOD/ShiLtJ mice. Our results suggest that ZO-1, occludin and E-cadherin are not altered in areas without lymphocytic infiltration. However, future studies will be necessary to test the functional aspect of these results. PMID:25248927

Dust and Diffuse Interstellar Bands in the za = 0.524 Absorption System toward AO 0235+164

NASA Astrophysics Data System (ADS)

Junkkarinen, V. T.; Cohen, Ross D.; Beaver, E. A.; Burbidge, E. M.; Lyons, R. W.; Madejski, G.

2004-10-01

We present new Hubble Space Telescope (HST) Space Telescope Imaging Spectrograph (STIS) NUV-MAMA and STIS CCD observations of the BL Lac object AO 0235+164 and the intervening damped Lyα (DLA) line at za=0.524. The line profile gives N(HI)=(5+/-1)×1021 cm-2 and, combined with the H I 21 cm absorption data, leads to a spin temperature of Ts=220+/-60 K. Those spectra also show a strong, broad feature at the expected position of the 2175 Å graphitic dust feature at za=0.524. Assuming a Galactic-type dust extinction curve at za=0.524 gives a dust-to-gas ratio of 0.19 times the Galactic value, but the fit, assuming that the underlying, unreddened spectrum is a single power law, is poor in the far-UV. A dust-to-gas ratio of 0.19 times the Galactic value is similar to the LMC, but the AO 0235+164 spectrum does not fit either the LMC extinction curve or the SMC extinction curve (which has practically no 2175 Å feature). A possible interpretation includes dust similar to that in the Galaxy, but with fewer of the small particles that produce the far-UV extinction. The metallicity of the za=0.524 absorber, estimated from the observed N(HI) and excess X-ray absorption (beyond Galactic) derived from contemporaneous and archival ASCA and ROSAT X-ray data, is Z=0.72+/-0.28 Zsolar, implying in turn a dust-to-metals ratio of 0.27 times the Galactic value. If the dust mass density is the same in the za=0.524 DLA system as in our Galaxy, only 14% (+/-6%) of the metals (by mass) are in dust, compared to 51%, 36%, and 46% for the Galaxy, LMC, and SMC, respectively. Such a dusty za=0.524 AO 0235+164 absorption system is a good example of the kind of DLA system that will be missed because of selection effects, which in turn can bias the measurement of the comoving density of interstellar gas (in units of the closure density), Ωg, as a function of z. Based on observations with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by

Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.

PubMed

Wu, Jiawen; Peng, Dungeng; Zhang, Yang; Lu, Zhenwei; Voehler, Markus; Sanders, Charles R; Li, Jun

2015-03-27

Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ₁ domain of zonula occludens (ZO₁ or ZO₂) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ₁ domain of ZO₂ and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ₁ of ZO₂. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ₁, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO₂. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves. Published by Elsevier Inc.

Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

PubMed Central

Bahloul, Amel; Simmler, Marie-Christine; Michel, Vincent; Leibovici, Michel; Perfettini, Isabelle; Roux, Isabelle; Weil, Dominique; Nouaille, Sylvie; Zuo, Jian; Zadro, Cristina; Licastro, Danilo; Gasparini, Paolo; Avan, Paul; Hardelin, Jean-Pierre; Petit, Christine

2009-01-01

Loud sound exposure is a significant cause of hearing loss worldwide. We asked whether a lack of vezatin, an ubiquitous adherens junction protein, could result in noise-induced hearing loss. Conditional mutant mice bearing non-functional vezatin alleles only in the sensory cells of the inner ear (hair cells) indeed exhibited irreversible hearing loss after only one minute exposure to a 105 dB broadband sound. In addition, mutant mice spontaneously underwent late onset progressive hearing loss and vestibular dysfunction related to substantial hair cell death. We establish that vezatin is an integral membrane protein with two adjacent transmembrane domains, and cytoplasmic N- and C-terminal regions. Late recruitment of vezatin at junctions between MDCKII cells indicates that the protein does not play a role in the formation of junctions, but rather participates in their stability. Moreover, we show that vezatin directly interacts with radixin in its actin-binding conformation. Accordingly, we provide evidence that vezatin associates with actin filaments at cell–cell junctions. Our results emphasize the overlooked role of the junctions between hair cells and their supporting cells in the auditory epithelium resilience to sound trauma. PMID:20049712

PTB deficiency causes the loss of adherens junctions in the dorsal telencephalon and leads to lethal hydrocephalus.

PubMed

Shibasaki, Takayuki; Tokunaga, Akinori; Sakamoto, Reiko; Sagara, Hiroshi; Noguchi, Shigeru; Sasaoka, Toshikuni; Yoshida, Nobuaki

2013-08-01

Polypyrimidine tract-binding protein (PTB) is a well-characterized RNA-binding protein and known to be preferentially expressed in neural stem cells (NSCs) in the central nervous system; however, its role in NSCs in the developing brain remains unclear. To explore the role of PTB in embryonic NSCs in vivo, Nestin-Cre-mediated conditional Ptb knockout mice were generated for this study. In the mutant forebrain, despite the depletion of PTB protein, neither abnormal neurogenesis nor flagrant morphological abnormalities were observed at embryonic day 14.5 (E14.5). Nevertheless, by 10 weeks, nearly all mutant mice succumbed to hydrocephalus (HC), which was caused by a lack of the ependymal cell layer in the dorsal cortex. Upon further analysis, a gradual loss of adherens junctions (AJs) was observed in the ventricular zone (VZ) of the dorsal telencephalon in the mutant brains, beginning at E14.5. In the AJs-deficient VZ, impaired interkinetic nuclear migration and precocious differentiation of NSCs were observed after E14.5. These findings demonstrated that PTB depletion in the dorsal telencephalon is causally involved in the development of HC and that PTB is important for the maintenance of AJs in the NSCs of the dorsal telencephalon.

SRC-induced disintegration of adherens junctions of madin-darby canine kidney cells is dependent on endocytosis of cadherin and antagonized by Tiam-1.

PubMed

Palovuori, Riitta; Sormunen, Raija; Eskelinen, Sinikka

2003-12-01

The effects of Src tyrosine kinase activation in subconfluent temperature sensitive (ts)-Src-transformed Madin-Darby canine kidney (MDCK) cells were analyzed by shifting them from nonpermissive (40.5 degrees C) to permissive (35 degrees C) temperature. Already, in 15 minutes, adherens junction components were released from the lateral walls and accumulated to basal surfaces. Simultaneously, membranous actin staining vanished, actin bundles appeared at the basal surface, and the cells flattened. The only component phosphorylated and translocated after the shift to 35 degrees C was p120ctn. The epithelial-mesenchymal transition could be inhibited by a specific inhibitor of Src kinase, PP2, or by inhibiting endocytosis. Therefore, Src activation was responsible for the transition, but not because of phosphorylation of adherens junction components but by way of activation of endocytic machinery and RhoGTPase. Expression of an RacGEF, Tiam-1 (T-lymphoma invasion and metastasis gene 1), prevented flattening of Src-transformed MDCK cells at 35 degrees C and resulted in accumulation of cadherin to lateral membranes. In the case where the Src-MDCK cells were cultivated at 35 degrees C and shifted for short time periods to 40.5 degrees C, cadherin rapidly returned to lateral membranes, whereas actin and p120ctn followed hours afterward. This further supports the view that cadherin internalization is the primary target of Src kinase. We also looked at the cell morphology and distribution of cadherin and Tiam-1 in cells grown in three-dimensional gels composed of collagen and laminin or in Matrigel. At nonpermissive temperature, both Src-MDCK and Tiam-1-transfected Src-MDCK cells exhibited nonpolarized morphology in collagen I, a loose cluster in the mixture of collagen I and laminin, and a differentiated cyst in Matrigel. In growth factor-depleted Matrigel, the Src-MDCK cells grew in nondifferentiated clusters, whereas Tiam-1-transfected cells went to apoptosis. The

VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the α-catenin-vinculin module.

PubMed

Oldenburg, Joppe; van der Krogt, Gerard; Twiss, Floor; Bongaarts, Annika; Habani, Yasmin; Slotman, Johan A; Houtsmuller, Adriaan; Huveneers, Stephan; de Rooij, Johan

2015-11-27

Mechanical forces are integrated at cadherin-based adhesion complexes to regulate morphology and strength of cell-cell junctions and organization of associated F-actin. A central mechanosensor at the cadherin complex is α-catenin, whose stretching recruits vinculin to regulate adhesion strength. The identity of the F-actin regulating signals that are also activated by mechanical forces at cadherin-based junctions has remained elusive. Here we identify the actin-regulators VASP, zyxin and TES as members of punctate, tensile cadherin-based junctions called Focal Adherens Junctions (FAJ) and show that they display mechanosensitive recruitment similar to that of vinculin. However, this recruitment is not altered by destroying or over-activating the α-catenin/vinculin module. Structured Illumination Microscopy (SIM) indicates that these tension sensitive proteins concentrate at locations within FAJs that are distinct from the core cadherin complex proteins. Furthermore, localization studies using mutated versions of VASP and zyxin indicate that these two proteins require binding to each other in order to localize to the FAJs. We conclude that there are multiple force sensitive modules present at the FAJ that are activated at distinct locations along the cadherin-F-actin axis and regulate specific aspects of junction dynamics.

Investigating plasma viscosity with fast framing photography in the ZaP-HD Flow Z-Pinch experiment

NASA Astrophysics Data System (ADS)

Weed, Jonathan Robert

The ZaP-HD Flow Z-Pinch experiment investigates the stabilizing effect of sheared axial flows while scaling toward a high-energy-density laboratory plasma (HEDLP > 100 GPa). Stabilizing flows may persist until viscous forces dissipate a sheared flow profile. Plasma viscosity is investigated by measuring scale lengths in turbulence intentionally introduced in the plasma flow. A boron nitride turbulence-tripping probe excites small scale length turbulence in the plasma, and fast framing optical cameras are used to study time-evolved turbulent structures and viscous dissipation. A Hadland Imacon 790 fast framing camera is modified for digital image capture, but features insufficient resolution to study turbulent structures. A Shimadzu HPV-X camera captures the evolution of turbulent structures with great spatial and temporal resolution, but is unable to resolve the anticipated Kolmogorov scale in ZaP-HD as predicted by a simplified pinch model.

Interleukin-4 and interleukin-13 compromise the sinonasal epithelial barrier and perturb intercellular junction protein expression.

PubMed

Wise, Sarah K; Laury, Adrienne M; Katz, Elizabeth H; Den Beste, Kyle A; Parkos, Charles A; Nusrat, Asma

2014-05-01

Altered expression of epithelial intercellular junction proteins has been observed in sinonasal biopsies from nasal polyps and epithelial layers cultured from nasal polyp patients. These alterations comprise a "leaky" epithelial barrier phenotype. We hypothesize that T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13 modulate epithelial junction proteins, thereby contributing to the leaky epithelial barrier. Differentiated primary sinonasal epithelial layers cultured at the air-liquid interface were exposed to IL-4, IL-13, and controls for 24 hours at 37°C. Epithelial resistance measurements were taken every 4 hours during cytokine exposure. Western blot and immunofluorescence staining/confocal microscopy were used to assess changes in a panel of tight and adherens junction proteins. Western blot densitometry was quantified with image analysis. IL-4 and IL-13 exposure resulted in a mean decrease in transepithelial resistance at 24 hours to 51.6% (n = 6) and 68.6% (n = 8) of baseline, respectively. Tight junction protein junctional adhesion molecule-A (JAM-A) expression decreased 42.2% with IL-4 exposure (n = 9) and 37.5% with IL-13 exposure (n = 9). Adherens junction protein E-cadherin expression decreased 35.3% with IL-4 exposure (n = 9) and 32.9% with IL-13 exposure (n = 9). Tight junction protein claudin-2 showed more variability but had a trend toward higher expression with Th2 cytokine exposure. There were no appreciable changes in claudin-1, occludin, or zonula occludens-1 (ZO-1) with IL-4 or IL-13 exposure. Sinonasal epithelial exposure to Th2 cytokines IL-4 and IL-13 results in alterations in intercellular junction proteins, reflecting increased epithelial permeability. Such changes may explain some of the phenotypic manifestations of Th2-mediated sinonasal disease, such as edema, nasal discharge, and environmental reactivity. © 2014 ARS-AAOA, LLC.

The formation of quiescent glomerular endothelial cell monolayer in vitro is strongly dependent on the choice of extracellular matrix coating

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

Pajęcka, Kamilla, E-mail: kpaj@novonordisk.com; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus; Nielsen, Malik Nygaard

Background and aims: Nephropathy involves pathophysiological changes to the glomerulus. The primary glomerular endothelial cells (GEnCs) have emerged as an important tool for studying glomerulosclerotic mechanisms and in the screening process for drug-candidates. The success of the studies is dependent on the quality of the cell model. Therefore, we set out to establish an easy, reproducible model of the quiescent endothelial monolayer with the use of commercially available extracellular matrices (ECMs). Methods: Primary hGEnCs were seeded on various ECMs. Cell adhesion was monitored by an impedance sensing system. The localization of junctional proteins was assessed by immunofluorescence and the barriermore » function by passage of fluorescent dextrans and magnitude of VEGF response. Results: All ECM matrices except recombinant human laminin 111 (rhLN111) supported comparable cell proliferation. Culturing hGEnCs on rhLN521, rhLN511 or fibronectin resulted in a physiologically relevant barrier to 70 kDa dextrans which was 82% tighter than that formed on collagen type IV. Furthermore, only hGEnCs cultured on rhLN521 or rhLN511 showed plasma-membrane localized zonula occludens-1 and vascular endothelial cadherin indicative of proper tight and adherens junctions (AJ). Conclusion: We recommend culturing hGEnCs on the mature glomerular basement membrane laminin - rhLN521 – which, as the only commercially available ECM, promotes all of the characteristics of the quiescent hGEnC monolayer: cobblestone morphology, well-defined AJs and physiological perm-selectivity. - Highlights: • rhLN521, rhLN511 and hFN assure physiologically relevant permeability. • rhLN521 and rhLN511 ensure best cell morphology and adherens junction formation. • Collagen IV and I based coating results in disorganized hGEnC monolayer. • Physiologically relevant ECM may lead to down-regulation of self-produced matrices.« less

Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium.

PubMed

Samak, Geetha; Chaudhry, Kamaljit K; Gangwar, Ruchika; Narayanan, Damodaran; Jaggar, Jonathan H; Rao, RadhaKrishna

2015-02-01

Disruption of intestinal epithelial tight junctions is an important event in the pathogenesis of ulcerative colitis. Dextran sodium sulfate (DSS) induces colitis in mice with symptoms similar to ulcerative colitis. However, the mechanism of DSS-induced colitis is unknown. We investigated the mechanism of DSS-induced disruption of intestinal epithelial tight junctions and barrier dysfunction in Caco-2 cell monolayers in vitro and mouse colon in vivo. DSS treatment resulted in disruption of tight junctions, adherens junctions and actin cytoskeleton leading to barrier dysfunction in Caco-2 cell monolayers. DSS induced a rapid activation of c-Jun N-terminal kinase (JNK), and the inhibition or knockdown of JNK2 attenuated DSS-induced tight junction disruption and barrier dysfunction. In mice, DSS administration for 4 days caused redistribution of tight junction and adherens junction proteins from the epithelial junctions, which was blocked by JNK inhibitor. In Caco-2 cell monolayers, DSS increased intracellular Ca(2+) concentration, and depletion of intracellular Ca(2+) by 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM) or thapsigargin attenuated DSS-induced JNK activation, tight junction disruption and barrier dysfunction. Knockdown of apoptosis signal-regulated kinase 1 (Ask1) or MKK7 blocked DSS-induced tight junction disruption and barrier dysfunction. DSS activated c-Src by a Ca2+ and JNK-dependent mechanism. Inhibition of Src kinase activity or knockdown of c-Src blocked DSS-induced tight junction disruption and barrier dysfunction. DSS increased tyrosine phosphorylation of occludin, zonula occludens-1 (ZO-1), E-cadherin and β-catenin. SP600125 abrogated DSS-induced tyrosine phosphorylation of junctional proteins. Recombinant JNK2 induced threonine phosphorylation and auto-phosphorylation of c-Src. The present study demonstrates that Ca(2+)/Ask1/MKK7/JNK2/cSrc signalling cascade mediates DSS-induced tight

Association of Endothelial Glycocalyx and Tight and Adherens Junctions With Severity of Plasma Leakage in Dengue Infection

PubMed Central

Sasmono, R. Tedjo; Sinto, Robert; Ibrahim, Eppy; Suryamin, Maulana

2017-01-01

Abstract Background. The role of vascular endothelial (VE) components in dengue infection with plasma leakage is unknown. Therefore, we conducted a study to determine the adjusted association of the endothelial glycocalyx layer (EGL) and tight and adherens junction markers with plasma leakage. Methods. A prospective observational study was conducted at Cipto Mangunkusumo Hospital and Persahabatan Hospital, Jakarta, Indonesia. Adult dengue patients admitted to the hospital on the third day of fever from November 2013 through August 2015 were included in the study. Multiple regression analysis was used to determine the adjusted association of the VE biomarkers with the severity of the plasma leakage. Results. A total of 103 dengue-infected patients participated in the study. In the critical phase, levels of syndecan-1 (odds ratio [OR] = 1.004; 95% confidence interval [CI] = 1.001–1.007) and chondroitin sulfate (OR = 1.157; 95% CI = 1.025–1.307) had an adjusted association with plasma leakage, whereas levels of syndecan-1 (OR = 1.004; 95% CI = 1.000–1.008) and claudin-5 (OR = 1.038; 95% CI = 1.004–1.074) had an adjusted association with severe plasma leakage. Conclusions. In dengue-infected patients, elevated levels of syndecan-1 and chondroitin sulfate are strongly associated with plasma leakage, and elevated levels of syndecan-1 and claudin-5 are strongly associated with severe plasma leakage. PMID:28453844

VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the α-catenin-vinculin module

PubMed Central

Oldenburg, Joppe; van der Krogt, Gerard; Twiss, Floor; Bongaarts, Annika; Habani, Yasmin; Slotman, Johan A.; Houtsmuller, Adriaan; Huveneers, Stephan; de Rooij, Johan

2015-01-01

Mechanical forces are integrated at cadherin-based adhesion complexes to regulate morphology and strength of cell-cell junctions and organization of associated F-actin. A central mechanosensor at the cadherin complex is α-catenin, whose stretching recruits vinculin to regulate adhesion strength. The identity of the F-actin regulating signals that are also activated by mechanical forces at cadherin-based junctions has remained elusive. Here we identify the actin-regulators VASP, zyxin and TES as members of punctate, tensile cadherin-based junctions called Focal Adherens Junctions (FAJ) and show that they display mechanosensitive recruitment similar to that of vinculin. However, this recruitment is not altered by destroying or over-activating the α-catenin/vinculin module. Structured Illumination Microscopy (SIM) indicates that these tension sensitive proteins concentrate at locations within FAJs that are distinct from the core cadherin complex proteins. Furthermore, localization studies using mutated versions of VASP and zyxin indicate that these two proteins require binding to each other in order to localize to the FAJs. We conclude that there are multiple force sensitive modules present at the FAJ that are activated at distinct locations along the cadherin-F-actin axis and regulate specific aspects of junction dynamics. PMID:26611125

Aberrant expression of the tight junction molecules claudin-1 and zonula occludens-1 mediates cell growth and invasion in oral squamous cell carcinoma.

PubMed

Babkair, Hamzah; Yamazaki, Manabu; Uddin, Md Shihab; Maruyama, Satoshi; Abé, Tatsuya; Essa, Ahmed; Sumita, Yoshimasa; Ahsan, Md Shahidul; Swelam, Wael; Cheng, Jun; Saku, Takashi

2016-11-01

We reported that altered cell contact mediated by E-cadherin is an initial event in the pathogenesis of oral epithelial malignancies. To assess other effects of cell adhesion, we examined the expression levels of tight junction (TJ) molecules in oral carcinoma in situ (CIS) and squamous cell carcinoma (SCC). To identify changes in the expression of TJ molecules, we conducted an analysis of the immunohistochemical profiles of claudin-1 (CLDN-1) and zonula occludens-1 (ZO-1) in surgical specimens acquired from patients with oral SCC containing foci of epithelial dysplasia or from patients with CIS. We used immunofluorescence, Western blotting, reverse-transcription polymerase chain reaction, and RNA interference to evaluate the functions of CLDN-1 and ZO-1 in cultured oral SCC cells. TJ molecules were not detected in normal oral epithelial tissues but were expressed in SCC/CIS cells. ZO-1 was localized within the nucleus of proliferating cells. When CLDN-1 expression was inhibited by transfecting cells with specific small interference RNAs, SCC cells dissociated, and their ability to proliferate and invade Matrigel was inhibited. In contrast, although RNA interference-mediated inhibition of ZO-1 expression did not affect cell morphology, it inhibited cell proliferation and invasiveness. Our findings indicated that the detection of TJ molecules in the oral epithelia may serve as a marker for the malignant phenotype of cells in which CLDN-1 regulates proliferation and invasion. Copyright © 2016 Elsevier Inc. All rights reserved.

RhoA/rho kinase signaling reduces connexin43 expression in high glucose-treated glomerular mesangial cells with zonula occludens-1 involvement

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

Xie, Xi; Department of Pharmaceutical Engineering, Ocean College, Hainan University, Haikou 570228; Chen, Cheng

RhoA/Rho kinase (ROCK) signaling has been suggested to be involved in diabetic nephropathy (DN) pathogenesis. Altered expression of connexin43 (Cx43) has been found in kidneys of diabetic animals. Both of them have been found to regulate nuclear factor kappa-B (NF-κB) activation in high glucose-treated glomerular mesangial cells (GMCs). The aim of this study was to investigate the relationship between RhoA/ROCK signaling and Cx43 in the DN pathogenesis. We found that upregulation of Cx43 expression inhibited NF-κB p65 nuclear translocation induced by RhoA/ROCK signaling in GMCs. Inhibition of RhoA/ROCK signaling attenuated the high glucose-induced decrease in Cx43. F-actin accumulation and anmore » enhanced interaction between zonula occludens-1 (ZO-1) and Cx43 were observed in high glucose-treated GMCs. ZO-1 depletion or disruption of F-actin formation also inhibited the reduction in Cx43 protein levels induced by high glucose. In conclusion, activated RhoA/ROCK signaling induces Cx43 degradation in GMCs cultured in high glucose, depending on F-actin regulation. Increased F-actin induced by RhoA/ROCK signaling promotes the association between ZO-1 and Cx43, which possibly triggered Cx43 endocytosis, a mechanism of NF-κB activation in high glucose-treated GMCs. - Highlights: • RhoA/ROCK signaling induces Cx43 degradation in GMCs. • F-actin and ZO-1 have functions in the regulation of Cx43 by RhoA/ROCK signaling. • We reveal the relationship between RhoA/ROCK and Cx43 in the activation of NF-κB.« less

Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function.

PubMed

Fernández-Martín, Laura; Marcos-Ramiro, Beatriz; Bigarella, Carolina L; Graupera, Mariona; Cain, Robert J; Reglero-Real, Natalia; Jiménez, Anaïs; Cernuda-Morollón, Eva; Correas, Isabel; Cox, Susan; Ridley, Anne J; Millán, Jaime

2012-08-01

Endothelial cells provide a barrier between the blood and tissues, which is reduced during inflammation to allow selective passage of molecules and cells. Adherens junctions (AJ) play a central role in regulating this barrier. We aim to investigate the role of a distinctive 3-dimensional reticular network of AJ found in the endothelium. In endothelial AJ, vascular endothelial-cadherin recruits the cytoplasmic proteins β-catenin and p120-catenin. β-catenin binds to α-catenin, which links AJ to actin filaments. AJ are usually described as linear structures along the actin-rich intercellular contacts. Here, we show that these AJ components can also be organized in reticular domains that contain low levels of actin. Reticular AJ are localized in areas where neighboring cells overlap and encompass the cell adhesion receptor platelet endothelial cell adhesion molecule-1 (PECAM-1). Superresolution microscopy revealed that PECAM-1 forms discrete structures distinct from and distributed along AJ, within the voids of reticular domains. Inflammatory tumor necrosis factor-α increases permeability by mechanisms that are independent of actomyosin-mediated tension and remain incompletely understood. Reticular AJ, but not actin-rich linear AJ, were disorganized by tumor necrosis factor-α. This correlated with PECAM-1 dispersal from cell borders. PECAM-1 inhibition with blocking antibodies or small interfering RNA specifically disrupted reticular AJ, leaving linear AJ intact. This disruption recapitulated typical tumor necrosis factor-α-induced alterations of barrier function, including increased β-catenin phosphorylation, without altering the actomyosin cytoskeleton. We propose that reticular AJ act coordinately with PECAM-1 to maintain endothelial barrier function in regions of low actomyosin-mediated tension. Selective disruption of reticular AJ contributes to permeability increase in response to tumor necrosis factor-α.

IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells.

PubMed

Krishnan, Subramanian; Fernandez, G Esteban; Sacks, David B; Prasadarao, Nemani V

2012-09-01

The transcellular entry of Escherichia coli K1 through human brain microvascular endothelial cells (HBMEC) is responsible for tight junction disruption, leading to brain oedema in neonatal meningitis. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with its receptor, Ecgp96, to induce PKC-α phosphorylation, adherens junction (AJ) disassembly (by dislodging β-catenin from VE-cadherin), and remodelling of actin in HBMEC. We report here that IQGAP1 mediates β-catenin dissociation from AJs to promote actin polymerization required for E. coli K1 invasion of HBMEC. Overexpression of C-terminal truncated IQGAP1 (IQΔC) that cannot bind β-catenin prevents both AJ disruption and E. coli K1 entry. Of note, phospho-PKC-α interacts with the C-terminal portion of Ecgp96 as well as with VE-cadherin after IQGAP1-mediated AJ disassembly. HBMEC overexpressing either C-terminal truncated Ecgp96 (Ecgp96Δ200) or IQΔC upon infection with E. coli showed no interaction of phospho-PKC-α with Ecgp96. These data indicate that the binding of OmpA to Ecgp96 induces PKC-α phosphorylation and association of phospho-PKC-α with Ecgp96, and then signals IQGAP1 to detach β-catenin from AJs. Subsequently, IQGAP1/β-catenin bound actin translocates to the site of E. coli K1 attachment to promote invasion. © 2012 Blackwell Publishing Ltd.

IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells

PubMed Central

Krishnan, Subramanian; Fernandez, G. Esteban; Sacks, David B.; Prasadarao, Nemani V.

2012-01-01

The transcellular entry of E. coli K1 through human brain microvascular endothelial cells (HBMEC) is responsible for tight junction disruption, leading to brain edema in neonatal meningitis. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with its receptor, Ecgp96 to induce PKC-α phosphorylation, adherens junction (AJ) disassembly (by dislodging β-catenin from VE-cadherin), and remodeling of actin in HBMEC. We report here that IQGAP1 mediates β-catenin dissociation from AJs to promote actin polymerization required for E. coli K1 invasion of HBMEC. Overexpression of C-terminal truncated IQGAP1 (IQΔC) that cannot bind β-catenin prevents both AJ disruption and E. coli K1 entry. Of note, phospho-PKC-α interacts with the C-terminal portion of Ecgp96 as well as with VE-cadherin after IQGAP1 mediated AJ disassembly. HBMEC overexpressing either C-terminal truncated Ecgp96 (Ecgp96Δ200) or IQΔC upon infection with E. coli showed no interaction of phospho-PKC-α with Ecgp96. These data indicate that the binding of OmpA to Ecgp96 induces PKC-α phosphorylation and association of phospho-PKC-α with Ecgp96, and then signals IQGAP1 to detach β-catenin from AJs. Subsequently, IQGAP1/β-catenin bound actin translocates to the site of E. coli K1 attachment to promote invasion. PMID:22519731

Requirement of the actin cytoskeleton for the association of nectins with other cell adhesion molecules at adherens and tight junctions in MDCK cells.

PubMed

Yamada, Akio; Irie, Kenji; Fukuhara, Atsunori; Ooshio, Takako; Takai, Yoshimi

2004-09-01

Nectins, Ca(2+)-independent immunoglobulin-like cell adhesion molecules (CAMs), first form cell-cell adhesion where cadherins are recruited, forming adherens junctions (AJs) in epithelial cells and fibroblasts. In addition, nectins recruit claudins, occludin, and junctional adhesion molecules (JAMs) to the apical side of AJs, forming tight junctions (TJs) in epithelial cells. Nectins are associated with these CAMs through peripheral membrane proteins (PMPs), many of which are actin filament-binding proteins. We examined here the roles of the actin cytoskeleton in the association of nectins with other CAMs in MDCK cells stably expressing exogenous nectin-1. The nectin-1-based cell-cell adhesion was formed and maintained irrespective of the presence and absence of the actin filament-disrupting agents, such as cytochalasin D and latrunculin A. In the presence of these agents, only afadin remained at the nectin-1-based cell-cell adhesion sites, whereas E-cadherin and other PMPs at AJs, alpha-catenin, beta-catenin, vinculin, alpha-actinin, ADIP, and LMO7, were not concentrated there. The CAMs at TJs, claudin-1, occludin and JAM-1, or the PMPs at TJs, ZO-1 and MAGI-1, were not concentrated there, either. These results indicate that the actin cytoskeleton is required for the association of the nectin-afadin unit with other CAMs and PMPs at AJs and TJs.

Detoxification of diphenyl ether herbicide lactofen by Bacillus sp. Za and enantioselective characteristics of an esterase gene lacE.

PubMed

Zhang, Jing; Lu, Luyao; Chen, Feng; Chen, Lingling; Yin, Jingang; Huang, Xing

2018-01-05

A bacterial strain Za capable of degrading diphenyl ether herbicide lactofen was isolated and identified as Bacillus sp. This strain could degrade 94.8% of 50mgL -1 lactofen after 4days of inoculation in flasks. It was revealed that lactofen was initially hydrolyzed to desethyl lactofen, which was further transformed to acifluorfen, followed by the reduction of the nitro group to yield aminoacifluorfen. The phytotoxicity of the transformed product aminoacifluorfen to maize was decreased significantly compared with the lactofen. A gene lacE, encoding an esterase responsible for lactofen hydrolysis to desethyl lactofen and acifluorfen continuously, was cloned from Bacillus sp. Za. The deduced amino acid belonging to the esterase family VII contained a typical Ser-His-Asp/Glu catalytic triad and the conserved motifs GXSXG. The purified recombinant protein LacE displayed maximal esterase activity at 40°C and pH 7.0. Additionally, LacE had broad substrate specificity and was capable of hydrolyzing p-nitrophenyl esters. The enantioselectivity of LacE during lactofen degradation was further studied, and the results indicated that the (S)-(+)-lactofen was degraded faster than the (R)-(-)-lactofen, which could illustrate the reported phenomenon that (S)-(+)-lactofen was preferentially degraded in soil and sediment. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuronal connexin36 association with zonula occludens-1 protein (ZO-1) in mouse brain and interaction with the first PDZ domain of ZO-1

PubMed Central

Li, Xinbo; Olson, Carl; Lu, Shijun; Kamasawa, Naomi; Yasumura, Thomas; Rash, John E.; Nagy, James I.

2007-01-01

Among the 20 members in the connexin family of gap junction proteins, only connexin36 (Cx36) is firmly established to be expressed in neurons and to form electrical synapses at widely distributed interneuronal gap junctions in mammalian brain. Several connexins have recently been reported to interact with the PDZ domain-containing protein zonula occludens-1 (ZO-1), which was originally considered to be associated only with tight junctions, but has recently been reported to associate with other structures including gap junctions in various cell types. Based on the presence of sequence corresponding to a putative PDZ binding motif in Cx36, we investigated anatomical relationships and molecular association of Cx36 with ZO-1. By immunofluorescence, punctate Cx36/ZO-1 colocalization was observed throughout the central nervous system of wild-type mice, whereas labelling for Cx36 was absent in Cx36 knockout mice, confirming the specificity of the anti-Cx36 antibodies employed. By freeze-fracture replica immunogold labelling, Cx36 and ZO-1 in brain were found colocalized within individual ultrastructurally identified gap junction plaques, although some plaques contained only Cx36 whereas others contained only ZO-1. Cx36 from mouse brain and Cx36-transfected HeLa cells was found to coimmunoprecipitate with ZO-1. Unlike other connexins that bind the second of the three PDZ domains in ZO-1, glutathione S-transferase-PDZ pull-down and mutational analyses indicated Cx36 interaction with the first PDZ domain of ZO-1, which required at most the presence of the four c-terminus amino acids of Cx36. These results demonstrating a Cx36/ZO-1 association suggest a regulatory and/or scaffolding role of ZO-1 at gap junctions that form electrical synapses between neurons in mammalian brain. PMID:15090040

Id-1 promotes TGF-{beta}1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells

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

Di Kaijun; Wong, Y.C.; Wang Xianghong

Id-1 (inhibitor of differentiation or DNA binding-1) has been positively associated with cell proliferation, cell cycle progression, and invasiveness during tumorigenesis. In addition, Id-1 has been shown to modulate cellular sensitivity to TGF-{beta}1 (transforming growth factor {beta}1). Here we demonstrate a novel role of Id-1 in promoting TGF-{beta}1-induced cell motility in a non-malignant prostate epithelial cell line, NPTX. We found that Id-1 promoted F-actin stress fiber formation in response to TGF-{beta}1, which was associated with increased cell-substrate adhesion and cell migration in NPTX cells. In addition, this positive effect of Id-1 on TGF-{beta}1-induced cell motility was mediated through activation ofmore » MEK-ERK signaling pathway and subsequent phosphorylation of HSP27 (heat shock protein 27). Furthermore, Id-1 disrupted the adherens junction complex in TGF-{beta}1-treated cells through down-regulation of E-cadherin, redistribution of {beta}-catenin, along with up-regulation of N-cadherin. These lines of evidence reveal a novel tumorigenic role of Id-1 through reorganization of actin cytoskeleton and disassembly of cell-cell adhesion in response to TGF-{beta}1 in human prostate epithelial cells, and suggest that intracellular Id-1 levels might be a determining factor for switching TGF-{beta}1 from a growth inhibitor to a tumor promoter during prostate carcinogenesis.« less

New Nematotoxic Indoloditerpenoid Produced by Gymnoascus reessii za-130.

PubMed

Liu, Ting; Meyer, Susan L F; Chitwood, David J; Chauhan, Kamlesh R; Dong, Dan; Zhang, TaoTao; Li, Jun; Liu, Wei-Cheng

2017-04-19

Chemical investigation of the fungal strain Gymnoascus reessii za-130, which was previously isolated from the rhizosphere of tomato plants infected by the root-knot nematode Meloidogyne incognita, led to the isolation and identification of a new indoloditerpenoid metabolite designated gymnoascole acetate. Its structure was established by spectroscopic methods including 1D- and 2D-NMR and MS analyses. Gymnoascole acetate demonstrated strong adverse effects on M. incognita second-stage juvenile (J2) viability; exposure to 36 μg/mL for 24 h induced 100% paralysis of J2 (EC 50 = 47.5 μg/mL). Gymnoascole acetate suppressed M. incognita egg hatch relative to controls by >90% at 133 μg/mL after 7 days of exposure. The numbers of root galls and J2 in both soil and roots were significantly reduced (p = 0.05) by treatment with 2-200 μg/mL gymnoascole acetate/kg soil, compared to untreated control plants; nematode suppression increased with gymnoascole acetate concentration. This study demonstrated the nematotoxicity of gymnoascole acetate and indicates that it might be a potential biobased component in integrated management of M. incognita.

The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.

PubMed

Bharatham, Nagakumar; Slavish, Peter J; Shadrick, William R; Young, Brandon M; Shelat, Anang A

2018-05-01

The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties. In BRD2-4, this residue is glutamine in BD1 and lysine in BD2; in BRDT, this residue is arginine in BD1 and asparagine in BD2. Using molecular modeling, we identified differences in the water-mediated network at this position between bromodomains. Molecular dynamics simulations helped rationalize the observed bromodomain selectivity for exemplar BET inhibitors and a congeneric series of tetrahydroquinolines (THQ) that differed by a single heteroatom near the ZA channel. The 2-furan SJ830599, the most BD2-selective THQ analog, did not disrupt the water-mediated networks in either domain, but was electrostatically-repulsed by the specific arrangement of the W5 water dipole in BD1. Our work underscores the value of exploring water-mediated interactions to study ligand binding, and highlights the difficulty of optimizing polar interactions due to high desolvation penalties. Finally, we suggest further modifications to THQ-based BET inhibitors that would increase BD2-selectivity in BRD2-4, while minimizing affinity for one or both bromodomains of BRDT. Copyright © 2018 Elsevier Inc. All rights reserved.

P-glycoprotein regulates blood–testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK)

PubMed Central

Su, Linlin; Mruk, Dolores D.; Lui, Wing-Yee; Lee, Will M.; Cheng, C. Yan

2011-01-01

The blood–testis barrier (BTB), one of the tightest blood–tissue barriers in the mammalian body, creates an immune-privileged site for postmeiotic spermatid development to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. However, the BTB undergoes extensive restructuring at stage VIII of the epithelial cycle to facilitate the transit of preleptotene spermatocytes and to prepare for meiosis. This action thus prompted us to investigate whether this stage can be a physiological window for the delivery of therapeutic and/or contraceptive drugs across the BTB to exert their effects at the immune-privileged site. Herein, we report findings that P-glycoprotein, an ATP-dependent efflux drug transporter and an integrated component of the occludin/zonula occludens 1 (ZO-1) adhesion complex at the BTB, structurally interacted with focal adhesion kinase (FAK), creating the occludin/ZO-1/FAK/P-glycoprotein regulatory complex. Interestingly, a knockdown of P-glycoprotein by RNAi was found to impede Sertoli cell BTB function, making the tight junction (TJ) barrier “leaky.” This effect was mediated by changes in the protein phosphorylation status of occludin via the action of FAK, thereby affecting the endocytic vesicle-mediated protein trafficking events that destabilized the TJ barrier. However, the silencing of P-glycoprotein, although capable of impeding drug transport across the BTB and TJ permeability barrier function, was not able to induce the BTB to be “freely” permeable to adjudin. These findings indicate that P-glycoprotein is involved in BTB restructuring during spermatogenesis but that P-glycoprotein–mediated restructuring does not “open up” the BTB to make it freely permeable to drugs. PMID:22106313

Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC.

PubMed

Haidari, Mehran; Zhang, Wei; Wakame, Koji

2013-12-18

The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ). The molecular mechanism underlying the anti-metastatic effects of mushroom-derived active hexode correlated compound (AHCC) remains elusive. Several cellular and biochemical techniques were used to determine the contribution of oxidative stress in the disruption of EAJ and to test this hypothesis that AHCC inhibits the breast cancer cell-induced disruption of EAJ. Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of β-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells. Induction of VE-cadherin tyrosine phosphorylation by PMA or by interaction of MDA-MB-231 cells with HUVECs was mediated by HRas and protein kinase C-α signaling pathways. Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDA-MB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs. Our studies suggest that ROS contributes to disruption of EAJ induced by interaction of MDA-MB-231 cells with HUVECs and AHCC attenuates this alteration. Copyright © 2013 Elsevier Inc. All rights reserved.

Leptospira interrogans causes quantitative and morphological disturbances in adherens junctions and other biological groups of proteins in human endothelial cells

PubMed Central

Sato, Hiromi

2017-01-01

Pathogenic Leptospira transmits from animals to humans, causing the zoonotic life-threatening infection called leptospirosis. This infection is reported worldwide with higher risk in tropical regions. Symptoms of leptospirosis range from mild illness to severe illness such as liver damage, kidney failure, respiratory distress, meningitis, and fatal hemorrhagic disease. Invasive species of Leptospira rapidly disseminate to multiple tissues where this bacterium damages host endothelial cells, increasing vascular permeability. Despite the burden in humans and animals, the pathogenic mechanisms of Leptospira infection remain to be elucidated. The pathogenic leptospires adhere to endothelial cells and permeabilize endothelial barriers in vivo and in vitro. In this study, human endothelial cells were infected with the pathogenic L. interrogans serovar Copenhageni or the saprophyte L. biflexa serovar Patoc to investigate morphological changes and other distinctive phenotypes of host cell proteins by fluorescence microscopy. Among those analyzed, 17 proteins from five biological classes demonstrated distinctive phenotypes in morphology and/or signal intensity upon infection with Leptospira. The affected biological groups include: 1) extracellular matrix, 2) intercellular adhesion molecules and cell surface receptors, 3) intracellular proteins, 4) cell-cell junction proteins, and 5) a cytoskeletal protein. Infection with the pathogenic strain most profoundly disturbed the biological structures of adherens junctions (VE-cadherin and catenins) and actin filaments. Our data illuminate morphological disruptions and reduced signals of cell-cell junction proteins and filamentous actin in L. interrogans-infected endothelial cells. In addition, Leptospira infection, regardless of pathogenic status, influenced other host proteins belonging to multiple biological classes. Our data suggest that this zoonotic agent may damage endothelial cells via multiple cascades or pathways

Leptospira interrogans causes quantitative and morphological disturbances in adherens junctions and other biological groups of proteins in human endothelial cells.

PubMed

Sato, Hiromi; Coburn, Jenifer

2017-07-01

Pathogenic Leptospira transmits from animals to humans, causing the zoonotic life-threatening infection called leptospirosis. This infection is reported worldwide with higher risk in tropical regions. Symptoms of leptospirosis range from mild illness to severe illness such as liver damage, kidney failure, respiratory distress, meningitis, and fatal hemorrhagic disease. Invasive species of Leptospira rapidly disseminate to multiple tissues where this bacterium damages host endothelial cells, increasing vascular permeability. Despite the burden in humans and animals, the pathogenic mechanisms of Leptospira infection remain to be elucidated. The pathogenic leptospires adhere to endothelial cells and permeabilize endothelial barriers in vivo and in vitro. In this study, human endothelial cells were infected with the pathogenic L. interrogans serovar Copenhageni or the saprophyte L. biflexa serovar Patoc to investigate morphological changes and other distinctive phenotypes of host cell proteins by fluorescence microscopy. Among those analyzed, 17 proteins from five biological classes demonstrated distinctive phenotypes in morphology and/or signal intensity upon infection with Leptospira. The affected biological groups include: 1) extracellular matrix, 2) intercellular adhesion molecules and cell surface receptors, 3) intracellular proteins, 4) cell-cell junction proteins, and 5) a cytoskeletal protein. Infection with the pathogenic strain most profoundly disturbed the biological structures of adherens junctions (VE-cadherin and catenins) and actin filaments. Our data illuminate morphological disruptions and reduced signals of cell-cell junction proteins and filamentous actin in L. interrogans-infected endothelial cells. In addition, Leptospira infection, regardless of pathogenic status, influenced other host proteins belonging to multiple biological classes. Our data suggest that this zoonotic agent may damage endothelial cells via multiple cascades or pathways

Glycogen Synthase Kinase 3 (GSK-3) influences epithelial barrier function by regulating Occludin, Claudin-1 and E-cadherin expression

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

Severson, Eric A.; Kwon, Mike; Hilgarth, Roland S.

2010-07-02

The Apical Junctional Complex (AJC) encompassing the tight junction (TJ) and adherens junction (AJ) plays a pivotal role in regulating epithelial barrier function and epithelial cell proliferative processes through signaling events that remain poorly characterized. A potential regulator of AJC protein expression is Glycogen Synthase Kinase-3 (GSK-3). GSK-3 is a constitutively active kinase that is repressed during epithelial-mesenchymal transition (EMT). In the present study, we report that GSK-3 activity regulates the structure and function of the AJC in polarized model intestinal (SK-CO15) and kidney (Madin-Darby Canine Kidney (MDCK)) epithelial cells. Reduction of GSK-3 activity, either by small molecule inhibitors ormore » siRNA targeting GSK-3 alpha and beta mRNA, resulted in increased permeability to both ions and bulk solutes. Immunofluorescence labeling and immunoblot analyses revealed that the barrier defects correlated with decreased protein expression of AJC transmembrane proteins Occludin, Claudin-1 and E-cadherin without influencing other TJ proteins, Zonula Occludens-1 (ZO-1) and Junctional Adhesion Molecule A (JAM-A). The decrease in Occludin and E-cadherin protein expression correlated with downregulation of the corresponding mRNA levels for these respective proteins following GSK-3 inhibition. These observations implicate an important role of GSK-3 in the regulation of the structure and function of the AJC that is mediated by differential modulation of mRNA transcription of key AJC proteins, Occludin, Claudin-1 and E-cadherin.« less

Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium

PubMed Central

Ewald, Andrew J.; Huebner, Robert J.; Palsdottir, Hildur; Lee, Jessie K.; Perez, Melissa J.; Jorgens, Danielle M.; Tauscher, Andrew N.; Cheung, Kevin J.; Werb, Zena; Auer, Manfred

2012-01-01

Normal mammary morphogenesis involves transitions between simple and multilayered epithelial organizations. We used electron microscopy and molecular markers to determine whether intercellular junctions and apico-basal polarity were maintained in the multilayered epithelium. We found that multilayered elongating ducts had polarized apical and basal tissue surfaces both in three-dimensional culture and in vivo. However, individual cells were only polarized on surfaces in contact with the lumen or extracellular matrix. The basolateral marker scribble and the apical marker atypical protein kinase C zeta localized to all interior cell membranes, whereas PAR3 displayed a cytoplasmic localization, suggesting that the apico-basal polarity was incomplete. Despite membrane localization of E-cadherin and β-catenin, we did not observe a defined zonula adherens connecting interior cells. Instead, interior cells were connected through desmosomes and exhibited complex interdigitating membrane protrusions. Single-cell labeling revealed that individual cells were both protrusive and migratory within the epithelial multilayer. Inhibition of Rho kinase (ROCK) further reduced intercellular adhesion on apical and lateral surfaces but did not disrupt basal tissue organization. Following morphogenesis, segregated membrane domains were re-established and junctional complexes re-formed. We observed similar epithelial organization during mammary morphogenesis in organotypic culture and in vivo. We conclude that mammary epithelial morphogenesis involves a reversible, spatially limited, reduction in polarity and intercellular junctions and active individualistic cell migration. Our data suggest that reductions in polarity and adhesion during breast cancer progression might reflect partial recapitulation of a normal developmental program. PMID:22344263

Quantifying cadherin mechanotransduction machinery assembly/disassembly dynamics using fluorescence covariance analysis.

PubMed

Vedula, Pavan; Cruz, Lissette A; Gutierrez, Natasha; Davis, Justin; Ayee, Brian; Abramczyk, Rachel; Rodriguez, Alexis J

2016-06-30

Quantifying multi-molecular complex assembly in specific cytoplasmic compartments is crucial to understand how cells use assembly/disassembly of these complexes to control function. Currently, biophysical methods like Fluorescence Resonance Energy Transfer and Fluorescence Correlation Spectroscopy provide quantitative measurements of direct protein-protein interactions, while traditional biochemical approaches such as sub-cellular fractionation and immunoprecipitation remain the main approaches used to study multi-protein complex assembly/disassembly dynamics. In this article, we validate and quantify multi-protein adherens junction complex assembly in situ using light microscopy and Fluorescence Covariance Analysis. Utilizing specific fluorescently-labeled protein pairs, we quantified various stages of adherens junction complex assembly, the multiprotein complex regulating epithelial tissue structure and function following de novo cell-cell contact. We demonstrate: minimal cadherin-catenin complex assembly in the perinuclear cytoplasm and subsequent localization to the cell-cell contact zone, assembly of adherens junction complexes, acto-myosin tension-mediated anchoring, and adherens junction maturation following de novo cell-cell contact. Finally applying Fluorescence Covariance Analysis in live cells expressing fluorescently tagged adherens junction complex proteins, we also quantified adherens junction complex assembly dynamics during epithelial monolayer formation.

Hyperpolarization of the plasma membrane potential provokes reorganization of the actin cytoskeleton and increases the stability of adherens junctions in bovine corneal endothelial cells in culture.

PubMed

Nin, Verónica; Hernández, Julio A; Chifflet, Silvia

2009-12-01

In previous works we showed that the depolarization of the plasma membrane potential (PMP) determines a reorganization of the cytoskeleton of diverse epithelia in culture, consisting mainly of a reallocation of peripheral actin toward the cell center, ultimately provoking intercellular disruption. In view of this evidence, we explored in this study the possible effects of membrane potential hyperpolarization on the cytoskeletal organization and adherens junction (AJ) morphology and the stability of confluent bovine corneal endothelial cells in culture. For this purpose, hyperpolarization was achieved by substitution of extracellular sodium by nondiffusible cations or via the incorporation of valinomycin to the control solution. Actin compactness at the cell periphery was assessed by quantitative analysis of fluorescence microscopy images. The stability of the AJ was challenged by calcium deprivation or temperature decrease. Our results showed that plasma membrane hyperpolarization provokes a compaction of AJ-associated actin filaments toward the plasma membrane and an increase in the stability of the AJs. We also observed that the hyperpolarizing procedures determined similar modifications in the actin cytoskeleton of endothelial cells in whole bovine corneas. Together with our previous work, the results of this study contribute to the idea that modifications in the PMP of nonexcitable cells participate in cellular adaptive responses involving reorganization of cytoskeletal components. (c) 2009 Wiley-Liss, Inc.

Ectoplasmic specialization, a testis-specific cell-cell actin-based adherens junction type: is this a potential target for male contraceptive development?

PubMed

Lee, Nikki P Y; Cheng, C Yan

2004-01-01

The seminiferous tubule of the mammalian testis is largely composed of Sertoli and germ cells, which coordinate with Leydig cells in the interstitium and perform two major physiological functions, namely spermatogenesis and steroidogenesis respectively. Each tubule is morphologically divided into (i) the seminiferous epithelium composing Sertoli and germ cells, and (ii) the basement membrane (a modified form of extracellular matrix); underneath this lies the collagen fibril network, the myoid cell layer, and the lymphatic vessel, which collectively constitute the tunica propia. In the seminiferous epithelium, of rodent testes each type A1 spermatogonium (diploid, 2n) differentiates into 256 elongated spermatids (haploid, 1n) during spermatogenesis. Additionally, developing germ cells must migrate progressively from the basal to the luminal edge of the adluminal compartment so that fully developed spermatids can be released into the lumen at spermiation. Without this timely event of cell movement, spermatogenesis cannot reach completion and infertility will result. Yet developing round elongating/elongated spermatids must remain attached to the epithelium via a specialized Sertoli-germ cell actin-based adherens junction (AJ) type known as ectoplasmic specialization (ES), which is crucial not only for cell attachment but also for spermatid movement and orientation in the epithelium. However, the biochemical composition and molecular architecture of the protein complexes that constitute the ES have only recently been studied. Furthermore, the signalling pathways that regulate ES dynamics are virtually unknown. This review highlights recent advances in these two areas of research. It is expected that, if adequately expanded, these studies should yield new insights into the development of novel contraceptives targeted to perturb ES function in the testis. The potential to specifically target the ES may also mean that contraceptive action could be achieved without

Mild hypothermia alleviates brain oedema and blood-brain barrier disruption by attenuating tight junction and adherens junction breakdown in a swine model of cardiopulmonary resuscitation

PubMed Central

Li, Jiebin; Li, Chunsheng; Yuan, Wei; Wu, Junyuan; Li, Jie; Li, Zhenhua; Zhao, Yongzhen

2017-01-01

Mild hypothermia improves survival and neurological recovery after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). However, the mechanism underlying this phenomenon is not fully elucidated. The aim of this study was to determine whether mild hypothermia alleviates early blood–brain barrier (BBB) disruption. We investigated the effects of mild hypothermia on neurologic outcome, survival rate, brain water content, BBB permeability and changes in tight junctions (TJs) and adherens junctions (AJs) after CA and CPR. Pigs were subjected to 8 min of untreated ventricular fibrillation followed by CPR. Mild hypothermia (33°C) was intravascularly induced and maintained at this temperature for 12 h, followed by active rewarming. Mild hypothermia significantly reduced cortical water content, decreased BBB permeability and attenuated TJ ultrastructural and basement membrane breakdown in brain cortical microvessels. Mild hypothermia also attenuated the CPR-induced decreases in TJ (occludin, claudin-5, ZO-1) and AJ (VE-cadherin) protein and mRNA expression. Furthermore, mild hypothermia decreased the CA- and CPR-induced increases in matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression and increased angiogenin-1 (Ang-1) expression. Our findings suggest that mild hypothermia attenuates the CA- and resuscitation-induced early brain oedema and BBB disruption, and this improvement might be at least partially associated with attenuation of the breakdown of TJ and AJ, suppression of MMP-9 and VEGF expression, and upregulation of Ang-1 expression. PMID:28355299

Microstructure-fatigue crack propagation relationship in TiB{sub 2} particulate reinforced Zn (ZA-8) alloy

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

Hua, W.; Zhang, J.; Wang, Z.

1995-10-01

The relationship between microstructure and propagation behavior of fatigue crack in TiB{sub 2} particulate reinforced ZA-8 Zn alloy and in the corresponding constituent matrix material was studied in three point bending fatigue tests with well-polished and pre-etched specimens. Special attention was paid to the observation of microstructure along the crack path as well as on the fracture surface. Mechanism for the difference in fatigue crack growth behavior of the two materials was investigated. The present results indicate that the addition of reinforcement modified the solidification process of the matrix material leading to a considerable change in the matrix microstructure. Thismore » change in the matrix microstructure and the presence of reinforcing particles considerably affected the fatigue crack propagation behavior in the material.« less

Disruption of adherens junction and alterations in YAP-related proliferation behavior as part of the underlying cell transformation process of alcohol-induced oral carcinogenesis.

PubMed

Husari, Ayman; Hülter-Hassler, Diana; Steinberg, Thorsten; Schulz, Simon Daniel; Tomakidi, Pascal

2018-01-01

Accumulating evidences indicate that alcohol might play a causative in oral cancer. Unfortunately, in vitro cell systems, uncovering the molecular background of the underlying cell transformation process, are rare. Therefore, this study was conducted, to identify molecular changes and characterize their putative cell behavioral consequences in epitheloid (EPI) and fibroblastoid (FIB) oral keratinocyte phenotypes, arising from chronical alcohol treatment. Concerning adherens junctions (AJs), both EPI and FIB showed membrane-bound β-catenin, but exhibited differences for E-cadherin and zyxin. While EPI revealed E-cadherin/β-catenin membrane co-localization, which in parts also applied for zyxin, FIB membranes were devoid of E-cadherin and exhibited marginal zyxin expression. Fetal calf serum (FCS) administration in starved cells promoted proliferation in both keratinocyte phenotypes, whereat EPI and FIB yielded a strikingly modified FCS sensitivity on the temporal scale. Impedance measurement-based cell index detection yielded proliferation stimulation occurring much earlier in FIB (<20h) compared to EPI (>45h). Nuclear preference of the proliferation-associated YAP co-transcription factor in FIB was FCS independent, while it required FCS in EPI. Taken together, the lack of membrane-inherent E-cadherin/β-catenin co-localization together with low zyxin - reveals perturbation of AJ integrity in FIB. Regarding cell behavior, perturbed AJs in FIB correlate with temporal proliferation sensitivity towards FCS. CYF of 5.6 strongly suggests involvement of chromatin-bound YAP in FIB's proliferation temperosensitivity. These molecular differences detected for EPI and FIB are part of the underlying cell transformation process of alcohol-induced oral carcinogenesis, and indicate FIB being in a more advanced transformation stage. Copyright © 2017 Elsevier B.V. All rights reserved.

The gray area between synapse structure and function-Gray's synapse types I and II revisited.

PubMed

Klemann, Cornelius J H M; Roubos, Eric W

2011-11-01

On the basis of ultrastructural parameters, the concept was formulated that asymmetric Type I and symmetric Type II synapses are excitatory and inhibitory, respectively. This "functional Gray synapses concept" received strong support from the demonstration of the excitatory neurotransmitter glutamate in Type I synapses and of the inhibitory neurotransmitter γ-aminobutyric acid in Type II synapses, and is still frequently used in modern literature. However, morphological and functional evidence has accumulated that the concept is less tenable. Typical features of synapses like shape and size of presynaptic vesicles and synaptic cleft and presence of a postsynaptic density (PsD) do not always fit the postulated (excitatory/inhibitory) function of Gray's synapses. Furthermore, synapse function depends on postsynaptic receptors and associated signal transduction mechanisms rather than on presynaptic morphology and neurotransmitter type. Moreover, the notion that many synapses are difficult to classify as either asymmetric or symmetric has cast doubt on the assumption that the presence of a PsD is a sign of excitatory synaptic transmission. In view of the morphological similarities of the PsD in asymmetric synapses with membrane junctional structures such as the zonula adherens and the desmosome, asymmetric synapses may play a role as links between the postsynaptic and presynaptic membrane, thus ensuring long-term maintenance of interneuronal communication. Symmetric synapses, on the other hand, might be sites of transient communication as takes place during development, learning, memory formation, and pathogenesis of brain disorders. Confirmation of this idea might help to return the functional Gray synapse concept its central place in neuroscience. Copyright © 2011 Wiley-Liss, Inc.

Platelet-derived growth factor BB and DD and angiopoietin1 are altered in follicular fluid from polycystic ovary syndrome patients.

PubMed

Scotti, Leopoldina; Parborell, Fernanda; Irusta, Griselda; De Zuñiga, Ignacio; Bisioli, Claudio; Pettorossi, Hernan; Tesone, Marta; Abramovich, Dalhia

2014-08-01

Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age, and is characterized by abnormalities in ovarian angiogenesis, among other features. Consistent with this association, follicular fluid (FF) concentration and ovarian expression of vascular endothelial growth factor (VEGF) are increased in PCOS patients. In this study, we examined the protein levels of platelet-derived growth factor (PDGF) BB and DD (PDGFBB and PDGFDD), angiopoietin 1 and 2 (ANGPT1 and ANGPT2), and their soluble receptor sTIE2 in FF from PCOS and control patients undergoing assisted reproductive techniques. We also analyzed the effect of FF from PCOS and control patients on tight and adherens junction protein expression in an endothelial cell line. PDGFBB and PDGFDD were significantly lower whereas ANGPT1 concentration was significantly higher in FF from PCOS patients than from control patients. No changes were found in the concentration of ANGPT2 or sTIE2. Expression of claudin-5 was significantly increased in endothelial cells incubated for 24 hr in the presence of FF from PCOS versus from control patients, while vascular-endothelial cadherin, β-catenin, and zonula occludens 1 expression were unchanged. The changes observed in the levels of PDGF isoforms and ANGPT1 may prevent VEGF-induced vascular permeability in the PCOS ovary by regulating endothelial-cell-junction protein levels. Restoring the levels of angiogenic factors may provide new insights into PCOS treatment and the prevention of ovarian hyperstimulation syndrome in affected women. © 2014 Wiley Periodicals, Inc.

Nested granites in question: Contrasted emplacement kinematics of independent magmas in the Zaër pluton, Morocco

NASA Astrophysics Data System (ADS)

Bouchez, Jean Luc; Diot, Herve

1990-10-01

The concentrically zoned Zaër pluton (Variscan Meseta of Morocco), previously modeled as the nesting of two magmas forming a ballooning pluton, is here subjected to a study of its internal magmatic and solid-state structures. The magmatic flow patterns, derived mainly from anisotropy of magnetic susceptibility measurements, together with structural observations down to thin-section scale, indicate that these two magmas have undergone totally independent kinematics of emplacement. This supports recent isotope geochemistry and geochronology data indicating independent origin of the magmas and diachronism of emplacement, respectively. Thus, we propose that a magma diapir, probably emplaced within a crustal fracture zone, cooled down to brittle conditions, before a likely flat-lying fracture was opened within the fracture zone and was filled with a new and compositionally different pulse of magma.

Mechanical properties of as-cast and heat-treated ZA-27 alloy/short glass fiber composites

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

Sharma, S.C.; Girish, B.M.; Satish, B.M.

1998-02-01

This paper reports on the mechanical properties of as-cast and heat-treated ZA-27 alloy composites reinforced with glass fibers from 1 to 5 wt%. The composites were fabricated using the Compocasting method, in which short glass fibers were introduced into the vortex created in the molten alloy through an impeller rotated at 500 rpm. The molten mass was thoroughly stirred and poured into permanent molds and squeezed under pressure. The specimens were heat treated at 320 C for 1, 2, 3, and 4 h. The tests on the as-cast composites revealed that as the glass content in the composites was increased,more » the ultimate tensile strength (UTS), compressive strength, and hardness of the composite increased, while the ductility and impact strength were decreased. Heat treatment was found to improve significantly the ductility, compressive strength, and impact strength, while the hardness and UTS were reduced. This paper discusses the behavior of these composites.« less

Hot Deformation Behavior and Intrinsic Workability of Carbon Nanotube-Aluminum Reinforced ZA27 Composites

NASA Astrophysics Data System (ADS)

Liu, Yang; Geng, Cong; Zhu, Yunke; Peng, Jinfeng; Xu, Junrui

2017-04-01

Using a controlled thermal simulator system, hybrid carbon nanotube-aluminum reinforced ZA27 composites were subjected to hot compression testing in the temperature range of 473-523 K with strain rates of 0.01-10 s-1. Based on experimental results, a developed-flow stress model was established using a constitutive equation coupled with strain to describe strain softening arising from dynamic recrystallization. The intrinsic workability was further investigated by constructing three-dimensional (3D) processing maps aided by optical observations of microstructures. The 3D processing maps were constructed based on a dynamic model of materials to delineate variations in the efficiency of power dissipation and flow instability domains. The instability domains exhibited adiabatic shear band and flow localization, which need to be prevented during hot processing. The recommended domain is predicated to be within the temperature range 550-590 K and strain rate range 0.01-0.35 s-1. In this state, the main softening mechanism is dynamic recrystallization. The results from processing maps agree well with the microstructure observations.

Inter-dependent apical microtubule and actin dynamics orchestrate centrosome retention and neuronal delamination

PubMed Central

Kasioulis, Ioannis

2017-01-01

Detachment of newborn neurons from the neuroepithelium is required for correct neuronal architecture and functional circuitry. This process, also known as delamination, involves adherens-junction disassembly and acto-myosin-mediated abscission, during which the centrosome is retained while apical/ciliary membranes are shed. Cell-biological mechanisms mediating delamination are, however, poorly understood. Using live-tissue and super-resolution imaging, we uncover a centrosome-nucleated wheel-like microtubule configuration, aligned with the apical actin cable and adherens-junctions within chick and mouse neuroepithelial cells. These microtubules maintain adherens-junctions while actin maintains microtubules, adherens-junctions and apical end-foot dimensions. During neuronal delamination, acto-myosin constriction generates a tunnel-like actin-microtubule configuration through which the centrosome translocates. This movement requires inter-dependent actin and microtubule activity, and we identify drebrin as a potential coordinator of these cytoskeletal dynamics. Furthermore, centrosome compromise revealed that this organelle is required for delamination. These findings identify new cytoskeletal configurations and regulatory relationships that orchestrate neuronal delamination and may inform mechanisms underlying pathological epithelial cell detachment. PMID:29058679

The role of loop ZA and Pro371 in the function of yeast Gcn5p bromodomain revealed through molecular dynamics and experiment.

PubMed

Pizzitutti, Francesco; Giansanti, Andrea; Ballario, Paola; Ornaghi, Prisca; Torreri, Paola; Ciccotti, Giovanni; Filetici, Patrizia

2006-01-01

Biological experiments were combined with molecular dynamics simulations to understand the importance of amino acidic residues present in the bromodomain of the yeast histone acetyltransferase Gcn5p. It was found that residue Pro371 plays an important role in the molecular recognition of the acetylated histone H4 tail by Gcn5p bromodomain. Crystallographic analysis of the complex showed that this residue does not directly interact with the histone substrate. It has been demonstrated that a double mutation Pro371Thr and Met372Ala in the Gcn5p bromodomain impairs chromatin remodeling activity. It is demonstrated here that, in this double mutant and in the fully deleted bromodomain strain, there is lower growth under amino acid deprivation conditions. By in vitro surface plasmon resonance (Biacore) experiments it is shown that the binding affinity of the double mutation to acetyl lysine 16 histone H4 peptide decreases. Molecular dynamics simulations were used to explain this loss in acetyl lysine-Gcn5p bromodomain affinity, in the double mutant. By comparing nanosecond molecular dynamics trajectories of the native as well as the single and doubly mutated bromodomain, it is concluded that the presence of Pro371 is important to the functionality of the Gcn5p bromodomain. In the simulation a point mutation involving this highly conserved residue induced an increase in the flexibility of the ZA loop, which in turn modulated the exposure of the binding pocket to the acetyl lysine. The combined double mutations (Pro371Thr-Met372Ala) not only markedly perturb the motion of the ZA loop but also destabilize the entire structure of the bromodomain. Copyright 2005 John Wiley & Sons, Ltd.

[The review of the composition of Za Liao Fang of Jinguiyaolue (Synopsis of Prescriptions of the Golden Chamber)].

PubMed

Zhao, Huai-Zhou; Liang, Yong-Xuan

2012-05-01

The contents of Jinguiyaolue (Synopsis of Prescriptions of the Golden Chamber) can mainly be divided into 2 parts, which are "text" and "attached formulas". It is mostly thought that the "text" has more content than the "attached formulas". After comparing the small character version of WU Qian's transcript, which was recently published,with the large character version of Jinguiyaolue, and doing textual research on the "attached formulas" in Za Liao Fang of Jinguiyaolue (Synopsis of Prescriptions of the Golden Chamber) according to the clues left by the Bureau of the Revision of Medical Books in Song Dynasty, we can find that there are only "chai hu decoction with addition or subtraction in four seasons" and "the Kele pear pill for taking for long periods" which belong to the Song masters' copy. However, another 22 prescriptions called "attached formulas" were added when the Song masters revised it.

Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120-catenin with the cytoplasmic tail of MUC1

PubMed Central

Zhang, Lili; Gallup, Marianne; Zlock, Lorna; Basbaum, Carol; Finkbeiner, Walter E.; McNamara, Nancy A.

2014-01-01

Adherens junctions (AJs) containing epithelial cadherin (E-cad) bound to p120-catenin (p120ctn) and β-catenin (β-ctn) play a crucial role in regulating cell–cell adhesion. Cigarette smoke abrogates cell–cell adhesion between epithelial cells by disrupting E-cad, a hallmark of epithelial–mesenchymal transition (EMT), yet the underlying mechanism remains unknown. We used an organotypic culture of primary human bronchial epithelial (HBE) cells treated with smoke-concentrated medium (Smk) to establish an essential role for the interaction between p120ctn and the cytoplasmic tail of MUC1 (MUC1-CT) in regulating E-cad disruption. Within the first 4 h of smoke exposure, apical MUC1-CT repositioned to the basolateral membrane of pseudo-stratified HBE cells, where it interacted with p120ctn. A time-dependent increase in MUC1-CT/p120ctn complexes occurred in conjunction with a time-dependent dissociation of p120ctn/E-cad/β-ctn complexes, as well as the coordinated degradation of p120ctn and E-cad. Interestingly, Smk induced a similar interaction between MUC1-CT and β-ctn, but this occurred 44 h after MUC1-CT’s initial interaction with p120ctn, and well after the AJs were destroyed. Blocking MUC1-CT’s interaction with p120ctn using a MUC1-CT dominant-negative peptide, PMIP, successfully abolished Smk’s disruptive effects on AJs and recovered apical-basolateral polarity of HBE cells. The MUC1-CT/p120ctn interaction was highly dependent on EGFR/Src/Jnk-mediated tyrosine phosphorylation (TyrP) of MUC1-CT. Accordingly, EGFR, Src or Jnk inhibitors (AG1478, PP2, SP600125, respectively) abrogated Smk-induced MUC1-CT-TyrP, MUC1-CT/p120ctn interaction, AJ disruption, and loss of cellular polarity. Our work identified MUC1-CT and p120ctn as important regulators of epithelial polarity and cell-cell adhesion during a smoke-induced EMT-like process. Novel therapeutics designed to inhibit MUC1-CT/p120ctn complex formation may prevent EMT in the smoker’s airway. PMID

The effector and scaffolding proteins AF6 and MUPP1 interact with connexin36 and localize at gap junctions that form electrical synapses in rodent brain.

PubMed

Li, X; Lynn, B D; Nagy, J I

2012-01-01

Electrical synapses formed by neuronal gap junctions composed of connexin36 (Cx36) occur in most major structures in the mammalian central nervous system. These synapses link ensembles of neurons and influence their network properties. Little is known about the macromolecular constituents of neuronal gap junctions or how transmission through electrical synapses is regulated at the level of channel conductance or gap junction assembly/disassembly. Such knowledge is a prerequisite to understanding the roles of gap junctions in neuronal circuitry. Gap junctions share similarities with tight and adhesion junctions in that all three reside at close plasma membrane appositions, and therefore may associate with similar structural and regulatory proteins. Previously, we reported that the tight junction-associated protein zonula occludens-1 (ZO-1) interacts with Cx36 and is localized at gap junctions. Here, we demonstrate that two proteins known to be associated with tight and adherens junctions, namely AF6 and MUPP1, are components of neuronal gap junctions in rodent brain. By immunofluorescence, AF6 and MUPP1 were co-localized with Cx36 in many brain areas. Co-immunoprecipitation and pull-down approaches revealed an association of Cx36 with AF6 and MUPP1, which required the C-terminus PDZ domain interaction motif of Cx36 for interaction with the single PDZ domain of AF6 and with the 10th PDZ domain of MUPP1. As AF6 is a target of the cAMP/Epac/Rap1 signalling pathway and MUPP1 is a scaffolding protein that interacts with CaMKII, the present results suggest that AF6 may be a target for cAMP/Epac/Rap1 signalling at electrical synapses, and that MUPP1 may contribute to anchoring CaMKII at these synapses. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant IBS.

PubMed

Wilcz-Villega, E; McClean, S; O'Sullivan, M

2014-03-01

Increased intestinal permeability and altered expression of tight junction (TJ) proteins may be implicated in the pathogenesis of irritable bowel syndrome (IBS). This study aimed to investigate the expression of adherens junction (AJ) protein E-cadherin and TJ proteins zonula occludens (ZO)-1 and claudin (CLD)-1 and associations with IBS symptoms. Junctional proteins were immunostained in cecal biopsy tissue of Rome II IBS patients (n = 34) comprising both alternating (IBS-A) and diarrhea predominant (IBS-D) subtypes, and controls (n = 12). IBS symptom duration, abdominal pain severity and stool frequency were assessed for IBS patients. Protein expression was determined by immunofluorescence. E-cadherin and ZO-1 protein expression was significantly lower (p = 0.03 and p = 0.016, respectively) in the cecal surface epithelium of the IBS group comprising both IBS-A and IBS-D subtypes. CLD-1 expression was not significantly altered compared with controls. On subtype analysis, ZO-1 expression was significantly reduced in both IBS-A and IBS-D compared with controls, whereas E-cadherin was reduced only in IBS-A. Lower E-cadherin expression was associated with longer symptoms duration specifically in IBS-A patients (rs = -0.76, p = 0.004). Reduced E-cadherin associated with abdominal pain severity in the overall IBS group (rs = -0.36, p = 0.041), but this association was unrelated to IBS subtype. E-cadherin protein expression in the cecum was significantly lower in IBS-A compared with controls and associated with longstanding symptoms. E-cadherin was further associated with abdominal pain severity in the IBS group overall, but unrelated to IBS subtype. Altered E-cadherin expression may provide novel insights into mechanisms underlying intestinal barrier dysfunction in IBS. © 2013 John Wiley & Sons Ltd.

Con-nectin axons and dendrites.

PubMed

Beaudoin, Gerard M J

2006-07-03

Unlike adherens junctions, synapses are asymmetric connections, usually between axons and dendrites, that rely on various cell adhesion molecules for structural stability and function. Two cell types of adhesion molecules found at adherens junctions, cadherins and nectins, are thought to mediate homophilic interaction between neighboring cells. In this issue, Togashi et al. (see p. 141) demonstrate that the differential localization of two heterophilic interacting nectins mediates the selective attraction of axons and dendrites in cooperation with cadherins.

Tribological and Corrosion Properties of Coatings Produced by Plasma Electrolytic Oxidation on the ZA27 Alloy

NASA Astrophysics Data System (ADS)

Li, Guangyin; Mao, Yifan; Li, Zhijian; Wang, Linlin; DaCosta, Herbert

2018-05-01

In this paper, a continuous and dense coating was deposited on samples of the ZA27 alloy through the plasma electrolytic oxidation (PEO) process to improve its wear and corrosion performance. A nontoxic and environmentally friendly inorganic salt, Na2SiO3, is chosen as electrolytes with different concentrations. The effect of the concentration of Na2SiO3 aqueous solutions on the coating performances was investigated. The coatings with 3Al2O3·2SiO2 (mullite), Zn2SiO4 and Al2O3 (either crystal phase or with some amorphous SiO2 phases) were formed by the PEO processes. It was found that the coating thickness increased with the increase in electrolyte concentration. However, the wear and corrosion resistance performance of the coatings did not improve as the coating's thickness increased. This was due to the fact that the coating produced with electrolytes of 10 g/L has a porous structure with large pore size. Among all the samples, coating produced by 15 g/L Na2SiO3 has the best wear and corrosion resistance, which is attributed to its continuous and dense structure with thickness of about 47 μm.

Tribological and Corrosion Properties of Coatings Produced by Plasma Electrolytic Oxidation on the ZA27 Alloy

NASA Astrophysics Data System (ADS)

Li, Guangyin; Mao, Yifan; Li, Zhijian; Wang, Linlin; DaCosta, Herbert

2018-04-01

In this paper, a continuous and dense coating was deposited on samples of the ZA27 alloy through the plasma electrolytic oxidation (PEO) process to improve its wear and corrosion performance. A nontoxic and environmentally friendly inorganic salt, Na2SiO3, is chosen as electrolytes with different concentrations. The effect of the concentration of Na2SiO3 aqueous solutions on the coating performances was investigated. The coatings with 3Al2O3·2SiO2 (mullite), Zn2SiO4 and Al2O3 (either crystal phase or with some amorphous SiO2 phases) were formed by the PEO processes. It was found that the coating thickness increased with the increase in electrolyte concentration. However, the wear and corrosion resistance performance of the coatings did not improve as the coating's thickness increased. This was due to the fact that the coating produced with electrolytes of 10 g/L has a porous structure with large pore size. Among all the samples, coating produced by 15 g/L Na2SiO3 has the best wear and corrosion resistance, which is attributed to its continuous and dense structure with thickness of about 47 μm.

Poly(ADP-ribosylation) is present in murine sciatic nerve fibers and is altered in a Charcot-Marie-Tooth-1E neurodegenerative model

PubMed Central

Romeo Cardeillac, Carlos J.; Cal Castillo, Karina B.; Vilchez Larrea, Salomé C.; Sotelo Sosa, José R.; Folle Ungo, Gustavo A.; Fernández Villamil, Silvia H.

2017-01-01

Background Poly-ADP-ribose (PAR) is a polymer synthesized by poly-ADP-ribose polymerases (PARPs) as a postranslational protein modification and catabolized mainly by poly-ADP-ribose glycohydrolase (PARG). In spite of the existence of cytoplasmic PARPs and PARG, research has been focused on nuclear PARPs and PAR, demonstrating roles in the maintenance of chromatin architecture and the participation in DNA damage responses and transcriptional regulation. We have recently detected non-nuclear PAR structurally and functionally associated to the E-cadherin rich zonula adherens and the actin cytoskeleton of VERO epithelial cells. Myelinating Schwann cells (SC) are stabilized by E-cadherin rich autotypic adherens junctions (AJ). We wondered whether PAR would map to these regions. Besides, we have demonstrated an altered microfilament pattern in peripheral nerves of Trembler-J (Tr-J) model of CMT1-E. We hypothesized that cytoplasmic PAR would accompany such modified F-actin pattern. Methods Wild-type (WT) and Tr-J mice sciatic nerves cryosections were subjected to immunohistofluorescence with anti-PAR antibodies (including antibody validation), F-actin detection with a phalloidin probe and DAPI/DNA counterstaining. Confocal image stacks were subjected to a colocalization highlighter and to semi-quantitative image analysis. Results We have shown for the first time the presence of PAR in sciatic nerves. Cytoplasmic PAR colocalized with F-actin at non-compact myelin regions in WT nerves. Moreover, in Tr-J, cytoplasmic PAR was augmented in close correlation with actin. In addition, nuclear PAR was detected in WT SC and was moderately increased in Tr-J SC. Discussion The presence of PAR associated to non-compact myelin regions (which constitute E-cadherin rich autotypic AJ/actin anchorage regions) and the co-alterations experienced by PAR and the actin cytoskeleton in epithelium and nerves, suggest that PAR may be a constitutive component of AJ/actin anchorage regions. Is PAR

Induction of Cell Scattering by Expression of β1 Integrins in β1-Deficient Epithelial Cells Requires Activation of Members of the Rho Family of Gtpases and Downregulation of Cadherin and Catenin Function

PubMed Central

Gimond, Clotilde; van der Flier, Arjan; van Delft, Sanne; Brakebusch, Cord; Kuikman, Ingrid; Collard, John G.; Fässler, Reinhard; Sonnenberg, Arnoud

1999-01-01

Adhesion receptors, which connect cells to each other and to the surrounding extracellular matrix (ECM), play a crucial role in the control of tissue structure and of morphogenesis. In this work, we have studied how intercellular adhesion molecules and β1 integrins influence each other using two different β1-null cell lines, epithelial GE11 and fibroblast-like GD25 cells. Expression of β1A or the cytoplasmic splice variant β1D, induced the disruption of intercellular adherens junctions and cell scattering in both GE11 and GD25 cells. In GE11 cells, the morphological change correlated with the redistribution of zonula occluden (ZO)-1 from tight junctions to adherens junctions at high cell confluency. In addition, the expression of β1 integrins caused a dramatic reorganization of the actin cytoskeleton and of focal contacts. Interaction of β1 integrins with their respective ligands was required for a complete morphological transition towards the spindle-shaped fibroblast-like phenotype. The expression of an interleukin-2 receptor (IL2R)-β1A chimera and its incorporation into focal adhesions also induced the disruption of cadherin-based adhesions and the reorganization of ECM–cell contacts, but failed to promote cell migration on fibronectin, in contrast to full-length β1A. This indicates that the disruption of cell–cell adhesion is not simply the consequence of the stimulated cell migration. Expression of β1 integrins in GE11 cells resulted in a decrease in cadherin and α-catenin protein levels accompanied by their redistribution from the cytoskeleton-associated fraction to the detergent-soluble fraction. Regulation of α-catenin protein levels by β1 integrins is likely to play a role in the morphological transition, since overexpression of α-catenin in GE11 cells before β1 prevented the disruption of intercellular adhesions and cell scattering. In addition, using biochemical activity assays for Rho-like GTPases, we show that the expression of β1A

Four-phonon scattering reduces intrinsic thermal conductivity of graphene and the contributions from flexural phonons

NASA Astrophysics Data System (ADS)

Feng, Tianli; Ruan, Xiulin

2018-01-01

We have developed a formalism of the exact solution to linearized phonon Boltzmann transport equation (BTE) for thermal conductivity calculation including three- and four-phonon scattering. We find strikingly high four-phonon scattering rates in single-layer graphene (SLG) based on the optimized Tersoff potential. The reflection symmetry in graphene, which forbids the three-ZA (out-of-plane acoustic) scattering, allows the four-ZA processes ZA +ZA ⇌ZA +ZA and ZA ⇌ZA +ZA + ZA. As a result, the large phonon population of the low-energy ZA branch originated from the quadratic phonon dispersion leads to high four-phonon scattering rates, even much higher than the three-phonon scattering rates at room temperature. These four-phonon processes are dominated by the normal processes, which lead to a failure of the single mode relaxation time approximation. Therefore, we have solved the exact phonon BTE using an iterative scheme and then calculated the length- and temperature-dependent thermal conductivities. We find that the predicted thermal conductivity of SLG is lower than the previously predicted value from the three-phonon scattering only. The relative contribution of the ZA branch is reduced from 70% to 30% when four-phonon scattering is included. Furthermore, we have demonstrated that the four-phonon scattering in multilayer graphene and graphite is not strong due to the ZA splitting by interlayer van der Waals interaction. We also demonstrate that the five-phonon process in SLG is not strong due to the restriction of reflection symmetry.

Géologie du synclinal de l'Itombwe (Zaïre oriental) et le problème de l'existence d'un sillon plissé pan-africain

NASA Astrophysics Data System (ADS)

Villeneuve, Michel

From the N.S. linear structure of the Itombwe syncline arise some problems in central Africa. Some authors considered it as a Kibarian structure and others as an isolated fold belt of Pan-African orogeny. This ambiguity is the result, in its greatest part, of the scarceness of field work and the lack of dating on the rocks of this syncline. A study on the central area showed the existence of two lithostructural units. The western area is correlated with a Kibarian structure while the eastern area had some similarities with the tectonic Pan-African troughts from NE of Zaïre and west of Uganda. The existence of an area folded during the Pan-African orogeny and in the same environment as the great African lakes area must be considered.

Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer.

PubMed

Hiroshima, Yukihiko; Maawy, Ali A; Katz, Matthew H G; Fleming, Jason B; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2015-03-01

Patient-derived orthotopic xenograft (PDOX) nude-mouse models replicate the behavior of clinical cancer, including metastasis. The objective of the study was to determine the efficacy of zoledronic acid (ZA) on metastasis of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of pancreatic cancer. In the present study, we examined the efficacy of ZA on pancreatic cancer growth and metastasis in a PDOX nude-mouse model. ZA monotherapy did not significantly suppress primary tumor growth. However, the primary tumor weight of gemcitabine (GEM) and combination GEM + ZA-treated mice was significantly decreased compared to the control group (GEM: P = 0.003; GEM + ZA: P = 0.002). The primary tumor weight of GEM + ZA-treated mice was significantly decreased compared to GEM-treated mice (P = 0.016). The metastasis weight decreased in ZA- or GEM-treated mice compared to the control group (ZA: P = 0.009; GEM: P = 0.007. No metastasis was detected in combination GEM + ZA-treated mice compared to the control group (GEM + ZA; P = 0.005). The results of the present study indicate that ZA can selectively target metastasis in a pancreatic cancer PDOX model and that the combination of ZA and GEM should be evaluated clinically in the near future for this highly treatment-resistant disease. © 2014 Wiley Periodicals, Inc.

Rheumatoid arthritis exacerbates the severity of osteonecrosis of the jaws (ONJ) in mice. A randomized, prospective, controlled animal study

PubMed Central

de Molon, Rafael Scaf; Hsu, Chingyun; Bezouglaia, Olga; Dry, Sarah M.; Pirih, Flavia Q.; Soundia, Akrivoula; Cunha, Fernando Queiroz; Cirelli, Joni Augusto; Aghaloo, Tara L.; Tetradis, Sotirios

2016-01-01

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J-mice were divided in 4 groups: control, zoledronic acid (ZA), collagen induced arthritis (CIA), and CIA-ZA. Animals were pre-treated with vehicle or ZA. Bovine collagen II emulsified in Freund’s adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8-weeks. ONJ indices were measured by micro-CT and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by micro-CT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, PDL space widening, lamina dura loss and cortex thinning. ZA prevented theses changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ

Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study.

PubMed

de Molon, Rafael Scaf; Hsu, Chingyun; Bezouglaia, Olga; Dry, Sarah M; Pirih, Flavia Q; Soundia, Akrivoula; Cunha, Fernando Queiroz; Cirelli, Joni Augusto; Aghaloo, Tara L; Tetradis, Sotirios

2016-08-01

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could

Proliferative defects and formation of a double cortex in mice lacking Mltt4 and Cdh2 in the dorsal telencephalon.

PubMed

Gil-Sanz, Cristina; Landeira, Bruna; Ramos, Cynthia; Costa, Marcos R; Müller, Ulrich

2014-08-06

Radial glial cells (RGCs) in the ventricular neuroepithelium of the dorsal telencephalon are the progenitor cells for neocortical projection neurons and astrocytes. Here we show that the adherens junction proteins afadin and CDH2 are critical for the control of cell proliferation in the dorsal telencephalon and for the formation of its normal laminar structure. Inactivation of afadin or CDH2 in the dorsal telencephalon leads to a phenotype resembling subcortical band heterotopia, also known as "double cortex," a brain malformation in which heterotopic gray matter is interposed between zones of white matter. Adherens junctions between RGCs are disrupted in the mutants, progenitor cells are widely dispersed throughout the developing neocortex, and their proliferation is dramatically increased. Major subtypes of neocortical projection neurons are generated, but their integration into cell layers is disrupted. Our findings suggest that defects in adherens junctions components in mice massively affects progenitor cell proliferation and leads to a double cortex-like phenotype. Copyright © 2014 the authors 0270-6474/14/3410475-13$15.00/0.

Retained placenta: will medical treatment ever be possible?

PubMed

Akol, Achier D; Weeks, Andrew D

2016-05-01

The standard treatment for retained placenta is manual removal whatever its subtype (adherens, trapped or partial accreta). Although medical treatment should reduce the risk of anesthetic and surgical complications, they have not been found to be effective. This may be due to the contrasting uterotonic needs of the different underlying pathologies. In placenta adherens, oxytocics have been used to contract the retro-placental myometrium. However, if injected locally through the umbilical vein, they bypass the myometrium and perfuse directly into the venous system. Intravenous injection is an alternative but exacerbates a trapped placenta. Conversely, for trapped placentas, a relaxant could help by resolving cervical constriction, but would worsen the situation for placenta adherens. This confusion over medical treatment will continue unless we can find a way to diagnose the underlying pathology. This will allow us to stop treating the retained placenta as a single entity and to deliver targeted treatments. © 2016 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).

DE-Cadherin regulates unconventional Myosin ID and Myosin IC in Drosophila left-right asymmetry establishment.

PubMed

Petzoldt, Astrid G; Coutelis, Jean-Baptiste; Géminard, Charles; Spéder, Pauline; Suzanne, Magali; Cerezo, Delphine; Noselli, Stéphane

2012-05-01

In bilateria, positioning and looping of visceral organs requires proper left-right (L/R) asymmetry establishment. Recent work in Drosophila has identified a novel situs inversus gene encoding the unconventional type ID myosin (MyoID). In myoID mutant flies, the L/R axis is inverted, causing reversed looping of organs, such as the gut, spermiduct and genitalia. We have previously shown that MyoID interacts physically with β-Catenin, suggesting a role of the adherens junction in Drosophila L/R asymmetry. Here, we show that DE-Cadherin co-immunoprecipitates with MyoID and is required for MyoID L/R activity. We further demonstrate that MyoIC, a closely related unconventional type I myosin, can antagonize MyoID L/R activity by preventing its binding to adherens junction components, both in vitro and in vivo. Interestingly, DE-Cadherin inhibits MyoIC, providing a protective mechanism to MyoID function. Conditional genetic experiments indicate that DE-Cadherin, MyoIC and MyoID show temporal synchronicity for their function in L/R asymmetry. These data suggest that following MyoID recruitment by β-Catenin at the adherens junction, DE-Cadherin has a twofold effect on Drosophila L/R asymmetry by promoting MyoID activity and repressing that of MyoIC. Interestingly, the product of the vertebrate situs inversus gene inversin also physically interacts with β-Catenin, suggesting that the adherens junction might serve as a conserved platform for determinants to establish L/R asymmetry both in vertebrates and invertebrates.

Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients.

PubMed

Conry, Robert M; Rodriguez, Michael G; Pressey, Joseph G

2016-01-01

Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression. In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18-20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA. Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.

Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients.

PubMed

Lescaille, Géraldine; Coudert, Amélie E; Baaroun, Vanessa; Ostertag, Agnès; Charpentier, Emmanuel; Javelot, Marie-José; Tolédo, Rafael; Goudot, Patrick; Azérad, Jean; Berdal, Ariane; Spano, Jean-Philippe; Ruhin, Blandine; Descroix, Vianney

2014-01-01

This study aimed to evaluate the effect of bevacizumab (BVZ) on the severity of osteonecrosis of the jaw (ONJ) in a cohort of cancer patients treated with intravenous zoledronic acid (ZA). We reviewed 42 oncologic patients with ONJ between 2007 and 2010. Only patients with solids tumors and who had received ZA were included. Data analyses included age, sex, underlying disease, ZA and BVZ dosages, dental history and ONJ characteristics. Of the 42 ONJ patients treated with ZA, 10 also received BVZ. In the 10 ZA/BVZ patients, the mean duration of ZA treatment at the time of ONJ diagnosis was 12.4 months (±6.8), compared to 22.9 months (±4.8) in the 32 patients who received ZA only (p<0.05). Cox's model analysis of the delay to ONJ diagnosis confirmed the impact of BVZ on ONJ diagnosis. In the ZA/BVZ-treated group, 7 (70%) patients developed spontaneous osteonecrosis. Multiple logistic regression analysis showed that ZA/BVZ is associated with increased risk of developing spontaneous ONJ (OR 6.07; 95% CI, [1.3-28.2], p<0.05). And finally, the number of ONJ lesions was increased in the ZA/BVZ-treated group compared to the ZA group (p<0.01). Other clinical conditions as type of tumor (prostate, breast…), cancer severity or other chemotherapy drugs also could be involved in ONJ evolution. However, this study demonstrates for the first time the potential negative influence of BVZ on the incidence and severity of ONJ in patients receiving ZA. Within the study limits, our results suggest that combination ZA/BVZ treatment may possibly predispose to the development of spontaneous and earlier ONJ. © 2013.

Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid.

PubMed

Liu, Hsien; Wang, Shih-Han; Chen, Shin-Cheh; Chen, Ching-Ying; Lo, Jo-Lin; Lin, Tsun-Mei

2016-11-25

CD4 + CD25 + regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. However, the interaction between ZA and Treg cells remained unclear. This study investigated the immune modulation of Treg cells by ZA. Flow cytometry was used to analyze the phenotypic and immunosuppressive characteristics of Treg cells treated with ZA. Chemotactic migration was evaluated using transwell assays. Quantitative real-time PCR (qRT-PCR) was used to investigate the effect of ZA on the expression of suppressive molecules by Treg cells. Proliferation of isolated Treg cells in culture was inhibited by ZA, although ZA did not induce apoptosis. qRT-PCR and flow cytometry showed that ZA significantly downregulated the expression of CCR4, CTLA4, PD-1 and RANKL on Treg cells. Chemotactic migration and immunosuppressive functions were also significantly attenuated in Treg cells pretreated with ZA, and these effects were dose-dependent. Co-culture with Treg cells significantly increased the migration rate of breast cancer cells, while pretreatment of Treg cells with ZA attenuated this effect. Our findings demonstrated that ZA acted as an immune modulator by significantly inhibiting the expansion, migration, immunosuppressive function and pro-metastatic ability of Treg cells. Immunomodulation of Treg cells by ZA represents a new strategy for cancer therapy.

Quantitation of zoledronic acid in murine bone by liquid chromatography coupled with tandem mass spectrometry.

PubMed

Raccor, Brianne S; Sun, Jianxun; Lawrence, Ross F; Li, Lei; Zhang, Hai; Somerman, Martha J; Totah, Rheem A

2013-09-15

An in vitro method for extraction and quantification of zoledronic acid (ZA) from murine bone was developed. Whole mouse bones were incubated in ZA solutions with predetermined concentrations and bound ZA was subsequently extracted from bone with phosphoric acid and derivatized using trimethylsilyl diazomethane (TMS-DAM). ZA tetra-methyl phosphonate was quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). This resulted in a sensitive, accurate, and precise method that was linear over three orders of magnitude (0.0250-50.0μg/mL ZA). For quality control (QC) samples, intra-and inter-day coefficients of variance were calculated and were less than 10%. This method was then applied to an in vivo model to quantitate ZA from the femur and mandible of three mice treated with ZA for two weeks. The mean ZA extracted from the mandible was four fold higher than that extracted from the femur (3.06±0.52 vs. 0.76±0.09ng/mg, respectively) indicating that ZA did not distribute equally in the skeleton and had a preference to the mandible. In conclusion, a highly sensitive method to measure ZA from mouse skeleton was developed, which can be easily adapted to multiple mammalian models including humans receiving ZA treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells

PubMed Central

Kwon, Eun-Bin; Kang, Myung-Ji; Kim, Soo-Yeon; Lee, Yong-Moon; Lee, Mi-Kyeong; Yuk, Heung Joo; Ryu, Hyung Won; Lee, Su Ui

2018-01-01

Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS) and TNF-α, suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells. PMID:29507591

Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells.

PubMed

Kwon, Eun-Bin; Kang, Myung-Ji; Kim, Soo-Yeon; Lee, Yong-Moon; Lee, Mi-Kyeong; Yuk, Heung Joo; Ryu, Hyung Won; Lee, Su Ui; Oh, Sei-Ryang; Moon, Dong-Oh; Lee, Hyun-Sun; Kim, Mun-Ock

2018-01-01

Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS) and TNF- α , suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells.

Activation of p38 MAPK-regulated Bcl-xL signaling increases survival against zoledronic acid-induced apoptosis in osteoclast precursors.

PubMed

Tai, Ta-Wei; Su, Fong-Chin; Chen, Ching-Yu; Jou, I-Ming; Lin, Chiou-Feng

2014-10-01

The nitrogen-containing bisphosphonate zoledronic acid (ZA) induces apoptosis in osteoclasts and inhibits osteoclast-mediated bone resorption. It is widely used to treat osteoporosis. However, some patients are less responsive to ZA treatment, and the mechanisms of resistance are still unclear. Here, we identified that murine osteoclast precursors may develop resistance to ZA-induced apoptosis. These resistant cells survived the apoptotic effect of ZA following an increase in anti-apoptotic Bcl-xL. Pharmacologically inhibiting Bcl-xL facilitated ZA-induced apoptosis. Treatment with ZA activated p38 MAPK, increasing Bcl-xL expression and cell survival. Nuclear import of β-catenin regulated by p38 MAPK determined Bcl-xL mRNA expression and cell survival in response to ZA. ZA also inactivated glycogen synthase kinase (GSK)-3β, a negative upstream regulator of β-catenin, in a p38 MAPK-mediated manner. Synergistic pharmacological inhibition of p38 MAPK with ZA attenuated receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and facilitated ZA-induced apoptosis. These results demonstrate that elevated Bcl-xL expression mediated by p38 MAPK-regulated GSK-3β/β-catenin signaling is required for cell survival of ZA-induced apoptosis in both osteoclast precursors and osteoclasts. Finally, we demonstrated that inhibiting p38 MAPK-mediated pathway enhanced ZA effect on increasing the bone mineral density of ovariectomized mice. This result suggests that targeting these pathways may represent a potential therapeutic strategy. Copyright © 2014 Elsevier Inc. All rights reserved.

Heme Oxygenase-1 Protects Corexit 9500A-Induced Respiratory Epithelial Injury across Species

PubMed Central

Oliva, Octavio M.; Karki, Suman; Surolia, Ranu; Wang, Zheng; Watson, R. Douglas; Thannickal, Victor J.; Powell, Mickie; Watts, Stephen; Kulkarni, Tejaswini; Batra, Hitesh; Bolisetty, Subhashini; Agarwal, Anupam; Antony, Veena B.

2015-01-01

The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE-induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its

Bisphosphonates inhibit bone remodeling in the jaw bones of rats and delay healing following tooth extractions.

PubMed

Jabbour, Zaher; El-Hakim, Michel; Henderson, Janet E; de Albuquerque, Rubens F

2014-05-01

This study aimed to evaluate the impact of concurrent administration of clinically relevant doses of zoledronic acid (ZA) and dexamethasone (DX) on bone healing after tooth extraction (EXO). Forty-four Sprague-Dawley rats (6-8 month old) were randomized into five groups: ZA + DX = weekly injection of ZA with DX for 7 weeks; WD = ZA with DX for 3 weeks then DX alone for 4 weeks; C = control saline for 7 weeks; ZA = ZA alone for 7 weeks and DX = DX alone for 7 weeks. ZA was administered at 0.13 mg/kg/week and DX at 3.8 mg/kg/week and body weights recorded at the time of injection. All rats underwent extraction (EXO) of the mandibular and maxillary first molars at 3 weeks and were euthanized at 7 weeks. The extracted and non-extracted sides of both jaws were harvested for micro-CT analyses. All rats, particularly those injected with ZA, exhibited weight gain till EXO followed by decline then recovery. ZA + DX group demonstrated highest fractional bone to tissue volume (BV/TV) in the non-extracted side. ZA + DX rats exhibited also highest volume and surface of sequestra. Only sequestra volume was statistically higher in the WD group compared to C group. Combined treatment with ZA and DX over a prolonged period inhibits bone remodeling and increased sequestra formation to a greater extent than either drug alone. Trauma caused by these sequestra cutting through the mucosa could play a key role in the development of BRONJ by potentially facilitating infection. ZA withdrawal may promote bone-remodeling reactivation following EXO. Copyright © 2014 Elsevier Ltd. All rights reserved.

The apoptotic effect of Zoledronic acid on the nasopharyngeal carcinoma cells via ROS mediated chloride channel activation.

PubMed

Wang, Liang; Gao, Hong; Yang, Xiaoya; Liang, Xiechou; Tan, Qiuchan; Chen, Zhanru; Zhao, Chan; Gu, Zhuoyu; Yu, Meisheng; Zheng, Yanfang; Huang, Yanqing; Zhu, Linyan; Jacob, Tim J C; Wang, Liwei; Chen, Lixin

2018-06-08

Zoledronic acid (ZA), a third-generation bisphosphonate, has been applied for treatment of bone metastases caused by malignant tumors. Recent studies have found its anti-cancer effects on various tumor cells. One of the mechanisms of anti-cancer effects of ZA is induction of apoptosis. However, the mechanisms of ZA-induced apoptosis in tumor cells have not been clarified clearly. In this study, we investigated the roles of chloride channels in ZA-induced apoptosis in nasopharyngeal carcinoma CNE-2Z cells. Apoptosis and chloride current were induced by ZA and suppressed by chloride channel blockers. After the knockdown of ClC-3 expression by ClC-3 siRNA, ZA-induced chloride current and apoptosis were significantly suppressed, indicating that the chloride channel participated in ZA-induced apoptosis may be ClC-3. When reactive oxygen species (ROS) generation was inhibited by the antioxidant N-acetyl-L-cysteine (L-NAC), ZA-induced apoptosis and chloride current were blocked accordingly, suggesting that ZA induces apoptosis through promoting ROS production and subsequently activating chloride channel. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Beta-catenin interacts with low-molecular-weight protein tyrosine phosphatase leading to cadherin-mediated cell-cell adhesion increase.

PubMed

Taddei, Maria Letizia; Chiarugi, Paola; Cirri, Paolo; Buricchi, Francesca; Fiaschi, Tania; Giannoni, Elisa; Talini, Doriana; Cozzi, Giacomo; Formigli, Lucia; Raugei, Giovanni; Ramponi, Giampietro

2002-11-15

Beta-catenin plays a dual role as a major constituent of cadherin-based adherens junctions and also as a transcriptional coactivator. In normal ephitelial cells, at adherens junction level, beta-catenin links cadherins to the actin cytoskeleton. The structure of adherens junctions is dynamically regulated by tyrosine phosphorylation. In particular, cell-cell adhesion can be negatively regulated through the tyrosine phosphorylation of beta-catenin. Furthermore, the loss of beta-catenin-cadherin association has been correlated with the transition from a benign tumor to an invasive, metastatic cancer. Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) is a ubiquitous PTP implicated in the regulation of mitosis and cytoskeleton rearrangement. Here we demonstrate that the amount of free cytoplasmic beta-catenin is decreased in NIH3T3, which overexpresses active LMW-PTP, and this results in a stronger association between cadherin complexes and the actin-based cytoskeleton with respect to control cells. Confocal microscopy analysis shows that beta-catenin colocalizes with LMW-PTP at the plasma membrane. Furthermore, we provide evidence that beta-catenin is able to associate with LMW-PTP both in vitro and in vivo. Moreover, overexpression of active LMW-PTP strongly potentiates cadherin-mediated cell-cell adhesion, whereas a dominant-negative form of LMW-PTP induces the opposite phenotype, both in NIH3T3 and in MCF-7 carcinoma cells. On the basis of these results, we propose that the stability of cell-cell contacts at the adherens junction level is positively influenced by LMW-PTP expression, mainly because of the beta-catenin and LMW-PTP interaction at the plasma membrane level with consequent dephosphorylation.

Diesel Exhaust Particle Exposure Causes Redistribution of Endothelial Tube VE-Cadherin

PubMed Central

Chao, Ming-Wei; Kozlosky, John; Po, Iris P.; Strickland, Pamela Ohman; Svoboda, Kathy K. H.; Cooper, Keith; Laumbach, Robert; Gordon, Marion K.

2010-01-01

Whether diesel exhaust particles (DEPs) potentially have a direct effect on capillary endothelia was examined by following the adherens junction component, vascular endothelial cell cadherin (VE-cadherin). This molecule is incorporated into endothelial adherens junctions at the cell surface, where it forms homodimeric associations with adjacent cells and contributes to the barrier function of the vasculature (Dejana et al., 2008; Venkiteswaran et al., 2002; Villasante et al., 2007). Human umbilical vein endothelial cells (HUVECs) that were pre-formed into capillary-like tube networks in vitro were exposed to DEPs for 24 hr. After exposure, the integrity of VE-cadherin in adherens junctions was assessed by immunofluorescence analysis, and demonstrated that increasing concentrations of DEPs caused increasing redistribution of VE-cadherin away from the cell-cell junctions toward intracellular locations. Since HUVEC tube networks are three-dimensional structures, whether particles entered the endothelial cells or tubular lumens was also examined. The data indicate that translocation of the particles does occur. The results, obtained in a setting that removes the confounding effects of inflammatory cells or blood components, suggest that if DEPs encounter alveolar capillaries in vivo, they may be able to directly affect the endothelial cell-cell junctions. PMID:20887764

THE CREEP BEHAVIOUR OF THE MAGNESIUM-ZIRCONIUM ALLOY ZA AT 400 AND 450 C IN CARBON DIOXIDE CONTAINING /approximately equals/200 PPM MOISTURE

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

Kent, R.P.; Wells, T.C.

1963-03-01

The creep behavior of the magnesium-zirconium alloy ZA was studied in tests of up to 5600 hr duration at 400 deg C and up to 12 600 hr duration at 450 deg C, in an atmosphere of carbon dioxide containing approximately 200 ppm water. The accompanying microstructural changes were observed by optical and electron microscopy. The alloy is stronger at 450 deg C than at 400 deg C and additional strengthening obtains from prestraining at 250 deg C prior to creep-testing. In stress rupture tests at 200 deg C subsequent to creep-testing, the time to rupture and the rupture ductilitymore » are lower in specimens previously tested at 450 deg C than in those tested at 400 deg C. The increase in creep strength at 450 deg C, and subsequent loss of ductility, are attributed principally to the precipitation of a zirconium-rich phase, tentatively identified as epsilon - zirconium hydride, which forms both intragranularly (as ribbons and thin hexagonal plates) and as intergranular particles. (auth)« less

Cost-Effectiveness Analysis of Monthly Zoledronic Acid, Zoledronic Acid Every 3 Months, and Monthly Denosumab in Women With Breast Cancer and Skeletal Metastases: CALGB 70604 (Alliance).

PubMed

Shapiro, Charles L; Moriarty, James P; Dusetzina, Stacie; Himelstein, Andrew L; Foster, Jared C; Grubbs, Stephen S; Novotny, Paul J; Borah, Bijan J

2017-12-10

Purpose Skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, or the necessity for radiation or surgery to bone metastasis cause considerable morbidity, decrements in quality of life, and costs to the health care system. The results of a recent large randomized trial (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology [CALGB/Alliance 70604]) showed that zoledronic acid (ZA) every 3 months was noninferior to monthly ZA in reducing the risks of SREs. We sought to determine the cost-effectiveness (CE) of monthly ZA, ZA every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases. Methods Using a Markov model, costs per SRE avoided were calculated for the three treatments. Sensitivity analyses were performed where denosumab SRE probabilities were assumed to be 50%, 75%, and 90% lower than the ZA SRE probabilities. Quality-adjusted life-years were also calculated. The analysis was from the US payer perspective. Results The mean costs of the denosumab treatment strategy are nine-fold higher than generic ZA every 3 months. Quality-adjusted life-years were virtually identical in all the three treatment arms; hence, the optimal treatment would be ZA every 3 months because it was the least costly treatment. The sensitivity analyses showed that relative to ZA every 3 months, the incremental costs per mean SRE avoided for denosumab ranged from $162,918 to $347,655. Conclusion ZA every 3 months was more CE in reducing the risks of SRE than monthly denosumab. This analysis was one of the first to incorporate the costs of generic ZA and one of the first independent CE analyses not sponsored by either Novartis or Amgen, the makers of ZA and denosumab, respectively. ZA every 3 months is the more CE option and more reasonable alternative to monthly denosumab.

Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

PubMed

Qiao, Han; Wang, Ting-yu; Yan, Wei; Qin, An; Fan, Qi-ming; Han, Xiu-guo; Wang, Yu-gang; Tang, Ting-ting

2015-09-01

Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2. Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

Rac1/Pak1/p38/MMP-2 axis regulates angiogenesis in ovarian cancer

PubMed Central

Gonzalez-Villasana, Vianey; Fuentes-Mattei, Enrique; Ivan, Cristina; Dalton, Heather J.; Rodriguez-Aguayo, Cristian; Fernandez-de Thomas, Ricardo J.; Aslan, Burcu; Monroig, Paloma del C.; Velazquez-Torres, Guermarie; Previs, Rebecca A.; Pradeep, Sunila; Kahraman, Nermin; Wang, Huamin; Kanlikilicer, Pinar; Ozpolat, Bulent; Calin, George; Sood, Anil K.; Lopez-Berestein, Gabriel

2015-01-01

Purpose Zoledronic acid (ZA) is being increasingly recognized for its anti-tumor properties, but the underlying functions are not well understood. In this study, we hypothesized that ZA inhibits ovarian cancer (OC) angiogenesis preventing Rac1 activation. Experimental Design The biological effects of ZA were examined using a series of in vitro (cell invasion, cytokine production, Rac1 activation, reverse-phase protein array and in vivo (orthotopic mouse models) experiments. Results There was significant inhibition of OC (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of pro-angiogenic cytokines in response to ZA treatment. Furthermore, ZA inactivated Rac1 and decreased the levels of Pak1/p-38/matrix metalloproteinase-2 in OC cells. In vivo, ZA reduced tumor growth, angiogenesis and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when ZA was combined with nab-paclitaxel. Conclusion ZA has robust anti-tumor and anti-angiogenic activity and merits further clinical development as OC treatment. PMID:25595279

Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect.

PubMed

Olejnik, Cécile; Falgayrac, Guillaume; During, Alexandrine; Cortet, Bernard; Penel, Guillaume

2016-08-01

Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n=80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120μgZA/kg, n=10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20μgZA/kg daily for 6days either a total of 120μg/kg, n=15), and 3°) a high fractionated doses, (100μgZA/kg weekly for 6weeks, n=15; equivalent to 6months of human bone metastasis treatment). For each treatment, a control "vehicle" treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (-25%, P< 0.05) and of the hydroxyproline-to-proline ratio (-30%, P<0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ=0.78, P<0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing. Copyright © 2016 Elsevier Inc. All rights reserved.

Is administration of trastuzumab an independent risk factor for developing osteonecrosis of the jaw among metastatic breast cancer patients under zoledronic acid treatment?

PubMed

Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-05-01

One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect.Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients' ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits.Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13-82) and the mean number of ZA infusions was 38 (range: 15-56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively).The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab.

Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements.

PubMed

Tisdale, James E; Allen, Matthew R; Overholser, Brian R; Jaynes, Heather A; Kovacs, Richard J

2015-06-01

Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. Ex vivo perfusion study: Isolated guinea pig hearts were perfused with modified Krebs-Henseleit (K-H) buffer with or without ZA 0.07 mg/kg/L (each n = 6). In ZA-perfused hearts, atrial action potential at 90% repolarization (APD90 ) decreased more from baseline than in controls (-23.2% ± -5.1% vs. -2.1% ± -8.1%, P < 0 .0001), as did APD30 (-28.8% ± -3.8% vs. -2.1% ± -2.1%, P < 0.0001). In vivo dose-response study: Guinea pigs underwent intraperitoneal injections every 2 weeks in 1 of 4 groups (each n = 8): ZA 0.007 mg/kg (low-dose), ZA 0.07 mg/kg (medium-dose), ZA 0.7 mg/kg (high-dose), or placebo. Hearts were excised at 8 weeks and perfused with modified K-H. Atrial effective refractory period (ERP) was lower with medium- and high-dose ZA versus placebo (P = 0.004). Atrial APD30 was lower with high-dose ZA versus placebo, low and medium doses (P < 0.001). Canine ECG study: Mature female beagles received intravenous ZA 0.067 mg/kg or saline (placebo; each n = 6) every 2 weeks for 12 weeks. P wave dispersion was greater in the ZA group (7.7 ± 3.7 vs. 3.4 ± 2.6 ms, P = 0.04). There were no significant differences in P wave index, maximum or minimum P wave duration, or PR interval. ZA shortens left atrial APD and ERP and increases P wave dispersion. © 2015 Wiley Periodicals, Inc.

Is Administration of Trastuzumab an Independent Risk Factor for Developing Osteonecrosis of the Jaw Among Metastatic Breast Cancer Patients Under Zoledronic Acid Treatment?

PubMed Central

Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-01-01

Abstract One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect. Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients’ ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits. Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13–82) and the mean number of ZA infusions was 38 (range: 15–56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively). The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

Investigating the compatibility of the biocontrol agent Clonostachys rosea IK726 with prodigiosin-producing Serratia rubidaea S55 and phenazine-producing Pseudomonas chlororaphis ToZa7.

PubMed

Kamou, Nathalie N; Dubey, Mukesh; Tzelepis, Georgios; Menexes, Georgios; Papadakis, Emmanouil N; Karlsson, Magnus; Lagopodi, Anastasia L; Jensen, Dan Funck

2016-05-01

This study was carried out to assess the compatibility of the biocontrol fungus Clonostachys rosea IK726 with the phenazine-producing Pseudomonas chlororaphis ToZa7 or with the prodigiosin-producing Serratia rubidaea S55 against Fusarium oxysporum f. sp. radicis-lycopersici. The pathogen was inhibited by both strains in vitro, whereas C. rosea displayed high tolerance to S. rubidaea but not to P. chlororaphis. We hypothesized that this could be attributed to the ATP-binding cassette (ABC) proteins. The results of the reverse transcription quantitative PCR showed an induction of seven genes (abcB1, abcB20, abcB26, abcC12, abcC12, abcG8 and abcG25) from subfamilies B, C and G. In planta experiments showed a significant reduction in foot and root rot on tomato plants inoculated with C. rosea and P. chlororaphis. This study demonstrates the potential for combining different biocontrol agents and suggests an involvement of ABC transporters in secondary metabolite tolerance in C. rosea.

Zoledronic acid induces dose-dependent increase of antigen-specific CD8 T-cell responses in combination with peptide/poly-IC vaccine.

PubMed

Park, Hye-Mi; Cho, Hyun-Il; Shin, Chang-Ae; Shon, Hyun-Jung; Kim, Tai-Gyu

2016-03-04

Zoledronic acid (ZA) is used for treating osteoporosis and for preventing skeletal fractures in cancer patients suffering from myeloma and prostate cancer. It is also reported to directly induce cancer cell apoptosis and indirectly modulate T-cell immune response as an antitumor agent. In this study, the effect of ZA following peptide/polyinosinic-polycytidylic acid (poly-IC) vaccination was investigated in a murine tumor model. The combination of ZA with peptide/poly-IC vaccine showed a synergistic effect on the induction of antigen-specific CD8 T-cell response. Three consecutive intravenous administrations of ZA was defined to induce the highest CD8 T-cell response. Further, total splenocyte counts and antigen-specific CD8 T-cell response gradually increased depending on the dose of ZA. In tumor-bearing mice, ZA showed a dose-dependent decrease of growth and prolonged survival. Treatment with ZA only decreased the number of CD11b(+)Gr1(+) myeloid cells in blood. Our results demonstrate that the use of ZA could improve antitumor immune responses induced by the peptide/poly-IC vaccine. Copyright © 2016 Elsevier Ltd. All rights reserved.

S-nitrosation of β-catenin and p120 catenin: a novel regulatory mechanism in endothelial hyperpermeability

PubMed Central

Marín, N.; Zamorano, P.; Carrasco, R.; Mujica, P.; González, FG.; Quezada, C.; Meininger, CJ.; Boric, MP.; Durán, WN.; Sánchez, FA.

2014-01-01

Rationale Endothelial adherens junction proteins constitute an important element in the control of microvascular permeability. Platelet-activating factor (PAF) increases permeability to macromolecules via translocation of eNOS to cytosol and stimulation of eNOS-derived NO signaling cascade. The mechanisms by which NO signaling regulates permeability at adherens junctions are still incompletely understood. Objective We explored the hypothesis that PAF stimulates hyperpermeability via S-nitrosation (SNO) of adherens junction proteins. Methods and Results We measured PAF-stimulated S-nitrosation of β-catenin and p120-catenin (p120) in three cell lines: ECV-eNOSGFP, EAhy926 (derived from human umbilical vein) and CVEC (derived from bovine heart endothelium) and in the mouse cremaster muscle in vivo. SNO correlated with diminished abundance of β-catenin and p120 at the adherens junction and with hyperpermeability. TNF-α increased NO production and caused similar increase in S-nitrosation as PAF. To ascertain the importance of eNOS subcellular location in this process, we used ECV-304 cells transfected with cytosolic eNOS (GFPeNOSG2A) and plasma membrane eNOS (GFPeNOSCAAX). PAF induced S-nitrosation of β-catenin and p120 and significantly diminished association between these proteins in cells with cytosolic eNOS but not in cells wherein eNOS is anchored to the cell membrane. Inhibitors of NO production and of S-nitrosation blocked PAF-induced S-nitrosation and hyperpermeability whereas inhibition of the cGMP pathway had no effect. Mass spectrometry analysis of purified p120 identified cysteine 579 as the main S-nitrosated residue in the region that putatively interacts with VE-cadherin. Conclusions Our results demonstrate that agonist-induced SNO contributes to junctional membrane protein changes that enhance endothelial permeability. PMID:22777005

The Hypoglycemic, Hypolipidemic, and Anti-Diabetic Nephritic Activities of Zeaxanthin in Diet-Streptozotocin-Induced Diabetic Sprague Dawley Rats.

PubMed

Kou, Ling; Du, Mingzhao; Zhang, Chaopu; Dai, Zhiyin; Li, Xuan; Zhang, Baohai

2017-07-01

Zeaxanthin (ZA), an important compound found in Lycium barbarum, shows various pharmacodynamic effects. In our present study, a high-fat, high-sucrose diet and streptozotocin (STZ)-induced diabetic rat model was used to investigate the antidiabetic activities of ZA. After a 4-week administration of 200 and 400 mg/kg of ZA and 100 mg/kg of metformin hydrochloride, various blood biochemical indexes were detected. ZA strongly normalized the reduced bodyweight and enhanced fasting blood glucose in diabetic rats. The positive data obtained from the oral glucose tolerance test further confirmed its antidiabetic effects. ZA displayed significant hypolipidemic activities indicated by its modulation of serum levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. The antidiabetic nephropathy of ZA was confirmed by its regulation of pathological kidney structures, urine levels of n-acetyl-β-d-glucosaminidase and albuminuria, and serum levels of urea nitrogen. ZA inhibited the serum levels of inflammatory factors including interleukin-2 (IL-2), IL-6, tumor necrosis factor-α, and nuclear factor kappa B, further confirming its renal protection. Moreover, the serum imbalances in superoxide dismutase, glutathione peroxidase, methane dicarboxylic aldehyde, and catalase were normalized by ZA, suggesting its antioxidant properties. Altogether, ZA produced hypoglycemic, hypolipidemic, and antidiabetic nephritic effects in a diet-STZ-induced diabetic rat model.

An individualised risk-adapted protocol of pre- and post transplant zoledronic acid reduces bone loss after allogeneic stem cell transplantation: results of a phase II prospective trial.

PubMed

Grigg, A; Butcher, B; Khodr, B; Bajel, A; Hertzberg, M; Patil, S; D'Souza, A B; Ganly, P; Ebeling, P; Wong, E

2017-09-01

Bone loss occurs frequently following allogeneic haematopoietic stem cell transplantation (alloSCT). The Australasian Leukaemia and Lymphoma Group conducted a prospective phase II study of pretransplant zoledronic acid (ZA) and individualised post-transplant ZA to prevent bone loss in alloSCT recipients. Patients received ZA 4 mg before conditioning. Administration of post-transplant ZA from days 100 to 365 post alloSCT was determined by a risk-adapted algorithm based on serial bone density assessments and glucocorticoid exposure. Of 82 patients enrolled, 70 were alive and without relapse at day 100. A single pretransplant dose of ZA prevented femoral neck bone loss at day 100 compared with baseline (mean change -2.6±4.6%). Using the risk-adapted protocol, 42 patients received ZA between days 100 and 365 post alloSCT, and this minimised bone loss at day 365 compared with pretransplant levels (mean change -2.9±5.3%). Femoral neck bone loss was significantly reduced in ZA-treated patients compared with historical untreated controls at days 100 and 365. This study demonstrates that a single dose of ZA pre-alloSCT prevents femoral neck bone loss at day 100 post alloSCT, and that a risk-adapted algorithm is able to guide ZA administration from days 100 to 365 post transplant and minimise further bone loss.

Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw.

PubMed

Higuchi, Tomoko; Soga, Yoshihiko; Muro, Misato; Kajizono, Makoto; Kitamura, Yoshihisa; Sendo, Toshiaki; Sasaki, Akira

2018-06-01

Intravenous zoledronic acid (ZA) is often replaced with subcutaneous denosumab in patients with bone metastatic cancer. Despite their different pharmacologic mechanisms of action, both denosumab and ZA are effective in bone metastasis but cause osteonecrosis of the jaw (ONJ) as a side effect. ZA persists in the body almost indefinitely, whereas denosumab does not persist for long periods. This study evaluated the risks of developing ONJ when replacing ZA with denosumab. In total, 161 Japanese patients administered ZA for bone metastatic cancer were enrolled in this single-center, retrospective, observational study. The risk of developing ONJ was evaluated by logistic regression analysis using the following factors: age, gender, cancer type, angiogenesis inhibitors, steroids, and replacement of ZA with denosumab. Seventeen patients (10.6%) developed ONJ. Multiple regression analysis indicated a significant difference in rate of ONJ associated with replacement of ZA with denosumab (odds ratio = 3.81; 95% confidence interval 1.04-13.97; P = .043). Replacing ZA with denosumab is a risk factor for the development of ONJ. Both binding of bisphosphonate to bone and receptor activator of nuclear factor-κ B ligand inhibition could additively increase the risk of ONJ. We bring the replacement of ZA with denosumab to the attention of clinical oncologists. Copyright © 2018 Elsevier Inc. All rights reserved.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01).

PubMed

Charehbili, A; van de Ven, S; Smit, V T H B M; Meershoek-Klein Kranenbarg, E; Hamdy, N A T; Putter, H; Heijns, J B; van Warmerdam, L J C; Kessels, L; Dercksen, M; Pepels, M J; Maartense, E; van Laarhoven, H W M; Vriens, B; Wasser, M N; van Leeuwen-Stok, A E; Liefers, G J; van de Velde, C J H; Nortier, J W R; Kroep, J R

2014-05-01

The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

A single dose of a MIV-150/Zinc acetate gel provides 24 h of protection against vaginal simian human immunodeficiency virus reverse transcriptase infection, with more limited protection rectally 8-24 h after gel use.

PubMed

Kenney, Jessica; Singer, Rachel; Derby, Nina; Aravantinou, Meropi; Abraham, Ciby J; Menon, Radhika; Seidor, Samantha; Zhang, Shimin; Gettie, Agegnehu; Blanchard, James; Piatak, Michael; Lifson, Jeffrey D; Fernández-Romero, José A; Zydowsky, Thomas M; Robbiani, Melissa

2012-11-01

Previously we showed that repeated vaginal application of a MIV-150/zinc acetate carrageenan (MIV-150/ZA/CG) gel and a zinc acetate carrageenan (ZA/CG) gel significantly protected macaques from vaginal simian human immunodeficiency virus reverse transcriptase (SHIV-RT) infection. Gels were applied either daily for 2 weeks or every other day for 4 weeks, and the animals were challenged 4-24 h later. Herein, we examined the effects of a single vaginal dose administered either before or after virus challenge. Encouraged by the vaginal protection seen with MIV-150/ZA/CG, we also tested it rectally. Vaginal applications of MIV-150/ZA/CG, ZA/CG, and CG gel were performed once 8-24 h before, 1 h after, or 24 h before and 1 h after vaginal challenge. Rectal applications of MIV-150/ZA/CG and CG gel were performed once 8 or 24 h before rectal challenge. While vaginal pre-challenge and pre/post-challenge application of MIV-150/ZA/CG gel offered significant protection (88%, p<0.002), post-challenge application alone did not significantly protect. ZA/CG gel reduced infection prechallenge, but not significantly, and the effect was completely lost post-challenge. Rectal application of MIV-150/ZA/CG gel afforded limited protection against rectal challenge when applied 8-24 h before challenge. Thus, MIV-150/ZA/CG gel is a highly effective vaginal microbicide that demonstrates 24 h of protection from vaginal infection and may demonstrate efficacy against rectal infection when given close to the time of HIV exposure.

Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion

PubMed Central

Rietkötter, Eva; Menck, Kerstin; Bleckmann, Annalen; Farhat, Katja; Schaffrinski, Meike; Schulz, Matthias; Hanisch, Uwe-Karsten; Binder, Claudia; Pukrop, Tobias

2013-01-01

The bisphosphonate zoledronic acid (ZA) significantly reduces complications of bone metastasis by inhibiting resident macrophages, the osteoclasts. Recent clinical trials indicate additional anti-metastatic effects of ZA outside the bone. However, which step of metastasis is influenced and whether this is due to direct toxicity on cancer cells or inhibition of the tumor promoting microenvironment, is unknown. In particular, tumor-associated and resident macrophages support each step of organ metastasis and could be a crucial target of ZA. Thus, we comparatively investigate the ZA effects on: i) different types of macrophages, ii) on breast cancer cells but also iii) on macrophage-induced invasion. We demonstrate that ZA concentrations reflecting the plasma level affected viability of human macrophages, murine bone marrow-derived macrophages as well as their resident brain equivalents, the microglia, while it did not influence the tested cancer cells. However, the effects on the macrophages subsequently reduced the macrophage/microglia-induced invasiveness of the cancer cells. In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma cells. The characterization of human macrophages after ZA treatment revealed a phenotype/response shift, in particular after external stimulation. In conclusion, we show that therapeutic concentrations of ZA affect all types of macrophages but not the cancer cells. Thus, anti-metastatic effects of ZA are predominantly caused by modulating the microenvironment. Most importantly, our findings demonstrate that ZA reduced microglia-assisted invasion of cancer cells to the brain tissue, indicating a potential therapeutic role in the prevention of cerebral metastasis. PMID:24036536

MIV-150 and zinc acetate combination provides potent and broad activity against HIV-1.

PubMed

Mizenina, Olga; Hsu, Mayla; Jean-Pierre, Ninochka; Aravantinou, Meropi; Levendosky, Keith; Paglini, Gabriela; Zydowsky, Thomas M; Robbiani, Melissa; Fernández-Romero, José A

2017-12-01

We previously showed that the combination of the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 with zinc acetate (ZA) formulated in a carrageenan (CG; MZC) gel provided macaques significant protection against vaginal simian-human immunodeficiency virus-RT (SHIV-RT) challenge, better than either MIV-150/CG or ZA/CG. The MZC gel was shown to be safe in a phase 1 clinical trial. Herein, we used in vitro approaches to study the antiviral properties of ZA and the MIV-150/ZA combination, compared to other NNRTIs. Like other NNRTIs, MIV-150 has EC 50 values in the subnanomolar to nanomolar range against wild type and NNRTI or RT-resistant HIVs. While less potent than NNRTIs, ZA was shown to be active in primary cells against laboratory-adapted and primary HIV-1 isolates and HIV-1 isolates/clones with NNRTI and RT resistance mutations, with EC 50 values between 20 and 110 μM. The MIV-150/ZA combination had a potent and broad antiviral activity in primary cells. In vitro resistance selection studies revealed that previously described NNRTI-resistant mutations were selected by MIV-150. ZA-resistant virus retained susceptibility to MIV-150 (and other RTIs) and MIV-150-selected virus remained sensitive to ZA. Notably, resistant virus was not selected when cultured in the presence of both ZA and MIV-150. This underscores the potency and breadth of the MIV-150/ZA combination, supporting preclinical macaque studies and the advancement of MZC microbicides into clinical testing.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience.

PubMed

George, Sobenna; Weber, David R; Kaplan, Paige; Hummel, Kelly; Monk, Heather M; Levine, Michael A

2015-11-01

Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025-0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience

PubMed Central

George, Sobenna; Weber, David R.; Kaplan, Paige; Hummel, Kelly; Monk, Heather M.

2015-01-01

Context: Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. Objective: The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. Design, Setting, and Participants: This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. Results: Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025–0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. Conclusion: Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population. PMID:26308295

Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro

PubMed Central

HUANG, XIN; HUANG, SHILONG; GUO, FENGJIN; XU, FEI; CHENG, PENG; YE, YAPING; DONG, YONGHUI; XIANG, WEI; CHEN, ANMIN

2016-01-01

Zoledronic acid (ZA), which is one of the most potent and efficacious bisphosphonates, has been commonly used in clinical practice for the treatment of various bone disorders. The extensive use of ZA has been associated with increasing occurrence of jaw complications, now known as bisphosphonate-associated osteonecrosis of the jaw (BRONJ). However, the mechanism underlying BRONJ remains to be fully elucidated. The aim of the present study was to investigate the effects of different concentrations of ZA on the MC3T3-E1 murine preosteoblast cell line cells and examine the possible pathogenesis of BRONJ. In the present study, the effect of ZA on the viability, apoptosis, differentiation and maturation of MC3T3-E1 cells, as well as its relevant molecular mechanism, were examined The results of a Cell Counting Kit 8 assay, a flow cytometric Annexin-V/propidium iodide assay and western blot analysis demonstrated that ZA exhibited a significant inhibition of cell viability and induction of apoptosis at concentrations >10 µM. Subsequently, the effect of ZA on cell differentiation at concentrations <1 µM were investigated. In this condition, ZA inhibited bone nodule formation and decreased the activity of alkaline phosphatase. The results of reverse transcription-quantitative polymerase chain reaction and western blot analyses indicated that ZA downregulated the expression levels of the marker genes and proteins associated with osteogenic differentiation. Further investigation revealed that the suppression of differentiation by ZA was associated with decreased expression of bone morphogenetic protein-2 (BMP-2) and downregulation of the phosphorylation levels in the downstream extracellular signal-regulated kinase 1/2 and p38 pathways. These adverse effects of ZA were observed to be concentration-dependent. The results from the present study suggested that ZA at higher concentrations induces cytotoxicity towards osteoblasts, and ZA at lower concentrations suppresses

Zoledronic acid increases the circulating soluble RANKL level in mice, with a further increase in lymphocyte-derived soluble RANKL in zoledronic acid- and glucocorticoid-treated mice stimulated with bacterial lipopolysaccharide.

PubMed

Abe, Takahiro; Sato, Tsuyoshi; Kokabu, Shoichiro; Hori, Naoko; Shimamura, Yumiko; Sato, Tomoya; Yoda, Tetsuya

2016-07-01

The nitrogen-containing bisphosphonate (BP) zoledronic acid (ZA) is a potent antiresorptive drug used in conjunction with standard cancer therapy to treat osteolysis or hypercalcemia due to malignancy. However, it is unclear how ZA influences the circulating levels of bone remodeling factors. The aim of this study was to evaluate the effects of ZA on the serum levels of soluble receptor activator of NF-kB ligand (sRANKL) and osteoprotegerin (OPG). The following four groups of C57BL/6 mice were used (five mice per group): (1) the placebo+phosphate-buffered saline (PBS) group, in which placebo-treated mice were injected once weekly with PBS for 4weeks; (2) the placebo+ZA group, in which placebo-treated mice were injected once weekly with ZA for 4weeks; (3) the prednisolone (PSL)+PBS group, in which PSL-treated mice were injected once weekly with PBS for 4weeks; and (4) the PSL+ZA group, in which PSL-treated mice were injected once weekly with ZA for 4weeks. At the 3-week time point, all mice were subjected to oral inflammatory stimulation with bacterial lipopolysaccharide (LPS). The sera of these mice were obtained every week and the levels of sRANKL and OPG were measured using enzyme-linked immunosorbent assay. At the time of sacrifice, femurs were prepared for micro-computed tomography (micro-CT), histological, and histomorphometric analyses. Our data indicated that ZA administration remarkably reduced bone turnover and significantly increased the basal level of sRANKL. Interestingly, the PSL+ZA group showed a dramatically elevated sRANKL level after LPS stimulation. In contrast, the PSL+ZA group in nonobese diabetic mice with severe combined immunodeficiency disease (NOD-SCID mice), which are characterized by the absence of functional T- and B-lymphocytes, showed no increase in the sRANKL level. Our data suggest that, particularly with combination treatment of ZA and glucocorticoids, surviving lymphocytes might be the source of inflammation-induced sRANKL. Thus

Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro.

PubMed

Huang, Xin; Huang, Shilong; Guo, Fengjin; Xu, Fei; Cheng, Peng; Ye, Yaping; Dong, Yonghui; Xiang, Wei; Chen, Anmin

2016-01-01

Zoledronic acid (ZA), which is one of the most potent and efficacious bisphosphonates, has been commonly used in clinical practice for the treatment of various bone disorders. The extensive use of ZA has been associated with increasing occurrence of jaw complications, now known as bisphosphonate‑associated osteonecrosis of the jaw (BRONJ). However, the mechanism underlying BRONJ remains to be fully elucidated. The aim of the present study was to investigate the effects of different concentrations of ZA on the MC3T3‑E1 murine preosteoblast cell line cells and examine the possible pathogenesis of BRONJ. In the present study, the effect of ZA on the viability, apoptosis, differentiation and maturation of MC3T3‑E1 cells, as well as its relevant molecular mechanism, were examined The results of a Cell Counting Kit 8 assay, a flow cytometric Annexin‑V/propidium iodide assay and western blot analysis demonstrated that ZA exhibited a significant inhibition of cell viability and induction of apoptosis at concentrations >10 µM. Subsequently, the effect of ZA on cell differentiation at concentrations <1 µM were investigated. In this condition, ZA inhibited bone nodule formation and decreased the activity of alkaline phosphatase. The results of reverse transcription-quantitative polymerase chain reaction and western blot analyses indicated that ZA downregulated the expression levels of the marker genes and proteins associated with osteogenic differentiation. Further investigation revealed that the suppression of differentiation by ZA was associated with decreased expression of bone morphogenetic protein‑2 (BMP‑2) and downregulation of the phosphorylation levels in the downstream extracellular signal‑regulated kinase 1/2 and p38 pathways. These adverse effects of ZA were observed to be concentration‑dependent. The results from the present study suggested that ZA at higher concentrations induces cytotoxicity towards osteoblasts, and ZA at lower concentrations

Effects of 18beta-glycyrrhetinic acid on the junctional complex and steroidogenesis in rat adrenocortical cells.

PubMed

Huang, Shih-Horng; Wu, Jiahn-Chun; Hwang, Ra-Der; Yeo, Hui-Lin; Wang, Seu-Mei

2003-09-01

Cellular junctions play important roles in cell differentiation, signal transduction, and cell function. This study investigated their function in steroid secretion by adrenal cells. Immunofluorescence staining revealed the presence of gap junctions and adherens junctions between adrenal cells. The major gap junction protein, connexin43, was seen as a linear dotted pattern of the typical gap junction plaques, in contrast to alpha-, beta-, and gamma-catenin, which were seen as continuous, linear staining of cell-cell adherens junction. Treatment with 18beta-glycyrrhetinic acid, a gap junction inhibitor, reduced the immunoreactivity of these proteins in a time- and dose-dependent manner, and caused the gap junction and adherens junction to separate longitudinally from the cell-cell contact sites, indicating the structural interdependency of these two junctions. Interestingly, 18beta-glycyrrhetinic acid stimulated a two- to three-fold increase in steroid production in these adrenal cells lacking intact cell junctions. These data raise the question of the necessity for cell communication for the endocrine function of adrenal cells. Pharmacological analyses indicated that the steroidogenic effect of 18beta-glycyrrhetinic acid was partially mediated by extracellular signal-related kinase and calcium/calmodulin-dependent kinase, a pathway distinct from the protein kinase A signaling pathway already known to mediate steroidogenesis in adrenal cells. Copyright 2003 Wiley-Liss, Inc.

A Single Dose of a MIV-150/Zinc Acetate Gel Provides 24 h of Protection Against Vaginal Simian Human Immunodeficiency Virus Reverse Transcriptase Infection, with More Limited Protection Rectally 8–24 h After Gel Use

PubMed Central

Kenney, Jessica; Singer, Rachel; Derby, Nina; Aravantinou, Meropi; Abraham, Ciby J.; Menon, Radhika; Seidor, Samantha; Zhang, Shimin; Gettie, Agegnehu; Blanchard, James; Piatak, Michael; Lifson, Jeffrey D.; Fernández-Romero, José A.; Zydowsky, Thomas M.

2012-01-01

Abstract Previously we showed that repeated vaginal application of a MIV-150/zinc acetate carrageenan (MIV-150/ZA/CG) gel and a zinc acetate carrageenan (ZA/CG) gel significantly protected macaques from vaginal simian human immunodeficiency virus reverse transcriptase (SHIV-RT) infection. Gels were applied either daily for 2 weeks or every other day for 4 weeks, and the animals were challenged 4–24 h later. Herein, we examined the effects of a single vaginal dose administered either before or after virus challenge. Encouraged by the vaginal protection seen with MIV-150/ZA/CG, we also tested it rectally. Vaginal applications of MIV-150/ZA/CG, ZA/CG, and CG gel were performed once 8–24 h before, 1 h after, or 24 h before and 1 h after vaginal challenge. Rectal applications of MIV-150/ZA/CG and CG gel were performed once 8 or 24 h before rectal challenge. While vaginal pre-challenge and pre/post-challenge application of MIV-150/ZA/CG gel offered significant protection (88%, p<0.002), post-challenge application alone did not significantly protect. ZA/CG gel reduced infection prechallenge, but not significantly, and the effect was completely lost post-challenge. Rectal application of MIV-150/ZA/CG gel afforded limited protection against rectal challenge when applied 8–24 h before challenge. Thus, MIV-150/ZA/CG gel is a highly effective vaginal microbicide that demonstrates 24 h of protection from vaginal infection and may demonstrate efficacy against rectal infection when given close to the time of HIV exposure. PMID:22737981

Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages.

PubMed

Jia, Xiao-Hua; Du, Yang; Mao, Duo; Wang, Zhong-Liang; He, Zhen-Qiang; Qiu, Jing-Dan; Ma, Xi-Bo; Shang, Wen-Ting; Ding, Dan; Tian, Jie

2015-09-22

Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment. To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumor-associated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR. In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth. Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.

Survival benefit of zoledronic Acid in postmenopausal breast cancer patients receiving aromatase inhibitors.

PubMed

Ahn, Sung Gwe; Kim, Sung Hyun; Lee, Hak Min; Lee, Seung Ah; Jeong, Joon

2014-12-01

A growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors. Between January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines. The baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99). Our findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.

A randomized phase II trial evaluating different schedules of zoledronic acid on bone mineral density in patients with prostate cancer beginning androgen deprivation therapy.

PubMed

Lang, Joshua M; Wallace, Marianne; Becker, Jordan T; Eickhoff, Jens C; Buehring, Bjoern; Binkley, Neil; Staab, Mary Jane; Wilding, George; Liu, Glenn; Malkovsky, Miroslav; McNeel, Douglas G

2013-12-01

To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer. In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3). Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events. Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk. Copyright © 2013 Elsevier Inc. All rights reserved.

Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts.

PubMed

Comito, Giuseppina; Pons Segura, Coral; Taddei, Maria Letizia; Lanciotti, Michele; Serni, Sergio; Morandi, Andrea; Chiarugi, Paola; Giannoni, Elisa

2017-01-03

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment.

A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration.

PubMed

Clark, Sarah L; Nystrom, Erin M

2016-04-01

Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient's nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat "usual" hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium-lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed. © The Author(s) 2016.

Zoledronic acid modulates maturation of human monocyte-derived dendritic cells.

PubMed

Orsini, Giulia; Failli, Alessandra; Legitimo, Annalisa; Adinolfi, Barbara; Romanini, Antonella; Consolini, Rita

2011-12-01

Zoledronic acid (ZA) is a drug of the bisphosphonate class, which is widely used for the treatment of both osteoporosis and skeletal metastasis. Besides its main bone antiresorptive activity, ZA displays antitumor properties, by triggering the expansion and activation of γδ T-cells, which exert an antitumor effect through dendritic cells (DCs). Several studies have reported the interaction between ZA and γδ T-cells, but the potential immunoregulatory activity of this drug on DCs has scarcely been investigated. Therefore, in this paper, we evaluated the effects of a therapeutic dose of ZA on the in vitro generation and maturation of DCs derived from peripheral blood monocytes of healthy adult donors. We demonstrate that ZA treatment did not affect DC differentiation, but inhibited DC maturation on lipopolysaccharide activation, as shown by the impaired expression of maturation surface markers and reduced ability to induce allogeneic T-cell proliferation. Interestingly, IL-10 secretion by mature DCs was significantly lower in ZA-treated cells than in controls. We conclude that ZA exerts its immunological in vitro activity also by modulating the maturation of DCs.

Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection

PubMed Central

Lee, Chia Min; Weight, Alisha K.; Haldar, Jayanta; Wang, Ling; Klibanov, Alexander M.; Chen, Jianzhu

2012-01-01

Covalently conjugating multiple copies of the drug zanamivir (ZA; the active ingredient in Relenza) via a flexible linker to poly-l-glutamine (PGN) enhances the anti-influenza virus activity by orders of magnitude. In this study, we investigated the mechanisms of this phenomenon. Like ZA itself, the PGN-attached drug (PGN-ZA) binds specifically to viral neuraminidase and inhibits both its enzymatic activity and the release of newly synthesized virions from infected cells. Unlike monomeric ZA, however, PGN-ZA also synergistically inhibits early stages of influenza virus infection, thus contributing to the markedly increased antiviral potency. This inhibition is not caused by a direct virucidal effect, aggregation of viruses, or inhibition of viral attachment to target cells and the subsequent endocytosis; rather, it is a result of interference with intracellular trafficking of the endocytosed viruses and the subsequent virus-endosome fusion. These findings both rationalize the great anti-influenza potency of PGN-ZA and reveal that attaching ZA to a polymeric chain confers a unique mechanism of antiviral action potentially useful for minimizing drug resistance. PMID:23185023

Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors.

PubMed

Madsen, Cecilie Maria; Boyd, Ben; Rades, Thomas; Müllertz, Anette

2016-08-25

Poor water solubility is a bottle neck in the development of many new drug candidates, and understanding and circumventing this is essential for a more effective drug development. Zafirlukast (ZA) is a leukotriene antagonist marketed for the treatment of asthma (Accolate®). ZA is poorly water soluble, and is formulated in an amorphous form (aZA) to improve its solubility and oral bioavailability. It has been shown that upon dissolution of aZa, the concentration of ZA in solution is supersaturated with respect to its stable crystalline form (ZA monohydrate), and thus, in theory, the bioavailability increases upon amorphization of ZA. The polymers hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP), often used as stabilizers of the supersaturated state, are in the excipient list of Accolate®. It is not recommended to take Accolate® with food, as this reduces the bioavailability by 40%. The aim of this study was to investigate the effect of simulated fasted and fed state intestinal media as well as the effect of HPMC and PVP on the supersaturation and precipitation of ZA in vitro. Supersaturation of aZA was studied in vitro in a small scale setup using the μDiss Profiler™. Several media were used for this study: One medium simulating the fasted state intestinal fluids and three media simulating different fed state intestinal fluids. Solid state changes of the drug were investigated by small angle x-ray scattering. The duration wherein aZA was maintained at a supersaturated state was prolonged in the presence of HPMC and lasted more than 20h in the presence of PVP in a fasted state intestinal medium. The presence of PVP increased the concentration of drug dissolved in the supersaturated state. The duration of supersaturation was shorter in fed than in a fasted state simulated intestinal media, but the concentration during supersaturation was higher. It was thus not possible to predict any positive or negative food effects from the dissolution

Adherens Junctions Revisualized: Organizing Cadherins as Nanoassemblies.

PubMed

Yap, Alpha S; Gomez, Guillermo A; Parton, Robert G

2015-10-12

This Perspective considers how classical cadherin cell-cell adhesion receptors are organized at the nanoscale to generate lateral clusters. Recent advances in optical microscopy reveal that clustering constitutes a general feature of cadherin organization, but one that takes diverse forms. Here we consider the molecular mechanisms responsible for cadherin clustering and their functional implications. We frame our discussion in light of what is known about how nanoscale organization is conferred upon the plasma membrane, through protein-protein interactions, regulation of the cortical actin cytoskeleton, and the lipid environment of the membrane. Copyright © 2015 Elsevier Inc. All rights reserved.

Guided bone regeneration with local zoledronic acid and titanium barrier: An experimental study.

PubMed

Dundar, Serkan; Ozgur, Cem; Yaman, Ferhan; Cakmak, Omer; Saybak, Arif; Ozercan, Ibrahim Hanifi; Alan, Hilal; Artas, Gokhan; Nacakgedigi, Onur

2016-10-01

The aim of this study was to evaluate the effects on new bone formation of autogenous blood alone or in combination with zoledronic acid (ZA), a β-tricalcium phosphate (β-TCP) graft or ZA plus a β-TCP graft placed under titanium barriers. For this purpose, eight adult male New Zealand white rabbits were used in the study, each with four titanium barriers fixed around four sets of nine holes drilled in the calvarial bones. The study included four groups, each containing 2 rabbits. In the autogenous blood (AB group), only autogeneous blood was placed under the titanium barriers. The three experimental groups were the AB+ZA group, with autogenous blood plus ZA, the AB+β-TCP group, with autogeneous blood plus a β-TCP graft, and the AB+β-TCP+ZA group, with autogeneous blood plus a β-TCP graft and ZA mixture under the titanium barriers. The animals were sacrificed after 3 months. The amounts of new bone formation identified histomorphometrically were found to be higher after 3 months than at the time of surgery in all groups. The differences between the groups were examined with histomorphometric analysis, and statistically significant differences were identified at the end of the 3 months. The bone formation rate in the AB+β-TCP+ZA group was determined to be significantly higher than that in the other groups (P<0.05). In the AB+ZA and AB+β-TCP groups, the bone formation rate was determined to be significantly higher than that in the AB group (P<0.05). No statistically significant difference in bone formation rate was observed between the AB+β-TCP and AB+ZA groups. Local ZA used with autogeneous blood and/or graft material appears to be a more effective method than the use of autogeneous blood or graft alone in bone augmentation executed with a titanium barrier.

Effects of Local and Systemic Zoledronic Acid Application on Titanium Implant Osseointegration: An Experimental Study Conducted on Two Surface Types.

PubMed

Dundar, Serkan; Yaman, Ferhan; Gecor, Orhan; Cakmak, Omer; Kirtay, Mustafa; Yildirim, Tuba Talo; Karaman, Tahir; Benlidayi, Mehmet Emre

2017-06-01

The aim of this study was to evaluate the effects of local and systemic zoledronic acid (ZA) applications on titaniumoksit ceramic blasted (TiO-CB)- and sandblasted large acid-grit (SLA)-surfaced titanium implant osseointegration. Twelve New Zealand White rabbits were used in the study, divided into 6 groups: the TiO-CB (TiO-CB-CNT) (n = 2) and SLA (SLA-CNT) (n = 2) control groups in which TiO-CB- and SLA-surfaced titanium implants were surgically inserted into rabbit tibias but no treatment was applied; the TiO-CB (TiO-CB-LZA) (n = 2) and SLA (SLA-LZA) (n = 2) local ZA groups in which 1 mL of normal saline solution containing 2 mg of ZA was injected into sockets and after this the implants were integrated; and the TiO-CB (TiO-CB-SZA) (n = 2) and SLA (SLA-SZA) (n = 2) systemic ZA groups in which a single infusion of 0.1 mg/kg of ZA was administered during surgical implant insertion. Following a period of osseointegration, bone implant contact (BIC) was recorded as a proportion of the total implant surface length in direct contact with the bone. Results of this study indicate that BIC was greater in the systemic ZA application groups than in the local ZA application groups, and BIC was greater in the local ZA groups than in the controls. Statistically significant differences in BIC were not detected between the TiO-CB- and SLA-surfaced implants in all the groups. Furthermore, this study did not reveal significant differences between the 2 types of surfaces due to similar average roughness values. Overall, systemic ZA application was found to be more effective in increasing BIC than local ZA application based on the results obtained by testing 2 implant surfaces.

Online solid phase extraction liquid chromatography using bonded zwitterionic stationary phases and tandem mass spectrometry for rapid environmental trace analysis of highly polar hydrophilic compounds - Application for the antiviral drug Zanamivir.

PubMed

Lindberg, Richard H; Fedorova, Ganna; Blum, Kristin M; Pulit-Prociak, Jolanta; Gillman, Anna; Järhult, Josef; Appelblad, Patrik; Söderström, Hanna

2015-08-15

Zanamivir (Za) is a highly polar and hydrophilic antiviral drug used for the treatment of influenza A viruses. Za has been detected in rivers of Japan and it's environmental occurrence has the risk of inducing antiviral resistant avian influenza viruses. In this study, a rapid automated online solid phase extraction liquid chromatography method using bonded zwitterionic stationary phases and tandem mass spectrometry (SPE/LC-MS/MS) for trace analysis of Za was developed. Furthermore, an internal standard (IS) calibration method capable of quantifying Za in Milli-Q, surface water, sewage effluent and sewage influent was evaluated. Optimum pre-extraction sample composition was found to be 95/5 v/v acetonitrile/water sample and 1% formic acid. The developed method showed acceptable linearities (r(2)≥0.994), filtration recovery (≥91%), and intra-day precisions (RSD≤16%), and acceptable and environmentally relevant LOQs (≤20ngL(-1)). Storage tests showed no significant losses of Za during 20 days and +4/-20°C (≤12%) with the exception of influent samples, which should be kept at -20°C to avoid significant Za losses. The applicability of the method was demonstrated in a study on phototransformation of Za in unfiltered and filtered surface water during 28 days of artificial UV irradiation exposure. No significant (≤12%) phototransformation was found in surface water after 28 days suggesting a relatively high photostability of Za and that Za should be of environmental concern. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Simple 3,4-Dihydroxy-L-Phenylalanine Surface Modification Enhances Titanium Implant Osseointegration in Ovariectomized Rats.

PubMed

Ma, Ting; Ge, Xi-Yuan; Hao, Ke-Yi; Zhang, Bi-Ru; Jiang, Xi; Lin, Ye; Zhang, Yu

2017-12-19

Osteoporosis presents a challenge to the long-term success of osseointegration of endosseous implants. The bio-inspired 3,4-dihydroxy-L-phenylalanine (Dopa) coating is widely used as a basic layer to bind osteogenetic molecules that may improve osseointegration. To date, little attention has focused on application of Dopa alone or binding inhibitors of bone resorption in osteoporosis. Local use of a bisphosphonate such as zoledronic acid (ZA), an inhibitor of osteoclast-mediated bone resorption, has been proven to improve implant osseointegration. In this study, ovariectomized rats were divided into four groups and implanted with implants with different surface modifications: sandblasted and acid-etched (SLA), SLA modified with Dopa (SLA-Dopa), SLA modified with ZA (SLA-ZA), and SLA modified with Dopa and ZA (SLA-Dopa + ZA). Measurement of removal torque, micro-computed tomography and histology revealed a greater extent of bone formation around the three surface-modified implants than SLA-controls. No synergistic effect was observed for combined Dopa + ZA coating. Microarray analysis showed the Dopa coating inhibited expression of genes associated with osteoclast differentiation, similarly to the mechanism of action of ZA. Simple Dopa modification resulted in a similar improvement in osseointegration compared to ZA. Thus, our data suggest simple Dopa coating is promising strategy to promote osseointegration of implants in patients with osteoporosis.

Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts

PubMed Central

Comito, Giuseppina; Segura, Coral Pons; Taddei, Maria Letizia; Lanciotti, Michele; Serni, Sergio; Morandi, Andrea; Chiarugi, Paola; Giannoni, Elisa

2017-01-01

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment. PMID:27223431

Zoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing.

PubMed

Cui, Pingping; Liu, Hongrui; Sun, Jing; Amizuka, Norio; Sun, Qinfeng; Li, Minqi

2018-01-01

Nitrogen-containing bisphosphonates (N-BPs) are potent antiresorptive drugs and their actions on osteoclasts have been studied extensively. Recent studies have suggested that N-BPs also target bone-forming cells. However, the precise mechanism of N-BPs in osteoblasts is paradoxical, and the specific role of osteocytes is worthy of in-depth study. Here, we investigated the cellular mechanisms of N-BPs regulating bone defect healing by zoledronate (ZA). Bone histomorphometry confirmed an increase in new bone formation by systemic ZA administration. ZA induced more alkaline phosphatase-positive osteoblasts and tartrate-resistant acid phosphatase-positive osteoclasts residing on the bone surface. Inexplicably, ZA increased SOST expression in osteocytes embedded in the bone matrix, which was not compatible with the intense osteoblast activity on the bone surface. ZA induced heterogeneous osteocytes and disturbed the distribution of the osteocytic-canalicular system (OLCS). Furthermore, according to the degree of OLCS regularity, dentin matrix protein 1 reactivity had accumulated around osteocytes in the ZA group, but it was distributed evenly in the OLCS of the control group. The control group showed a dense array of the gap junction protein connexin 43. However, connexin 43 was extremely sparse after ZA administration. In summary, ZA treatment reduces gap junction connections and blocks cellular communication between osteocytes and osteoblasts. Retaining SOST expression in osteocytes leads to activation of the Wnt signaling pathway and subsequent bone formation.

Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions

NASA Astrophysics Data System (ADS)

Qiu, Yongzhi; Tong, Sheng; Zhang, Linlin; Sakurai, Yumiko; Myers, David R.; Hong, Lin; Lam, Wilbur A.; Bao, Gang

2017-06-01

The vascular endothelium presents a major transport barrier to drug delivery by only allowing selective extravasation of solutes and small molecules. Therefore, enhancing drug transport across the endothelial barrier has to rely on leaky vessels arising from disease states such as pathological angiogenesis and inflammatory response. Here we show that the permeability of vascular endothelium can be increased using an external magnetic field to temporarily disrupt endothelial adherens junctions through internalized iron oxide nanoparticles, activating the paracellular transport pathway and facilitating the local extravasation of circulating substances. This approach provides a physically controlled drug delivery method harnessing the biology of endothelial adherens junction and opens a new avenue for drug delivery in a broad range of biomedical research and therapeutic applications.

78 FR 23617 - Self-Regulatory Organizations; EDGX Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-19

... Exchange introduced new Flags ZA (Retail Order, adds liquidity) and ZR (Retail Order, removes liquidity... will enable Members, and in turn, their retail customers, to benefit from the enhanced rebate (Flag ZA... able to benefit from the rebate (Flag ZA) for utilizing Retail Orders without regards to whether the...

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro.

PubMed

Gschwantler-Kaulich, Daphne; Weingartshofer, Sigrid; Grunt, Thomas W; Mairhofer, Mario; Tan, Yen; Gamper, Jutta; Singer, Christian F

2017-01-01

Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.

Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts.

PubMed

Zafar, S; Coates, D E; Cullinan, M P; Drummond, B K; Milne, T; Seymour, G J

2016-11-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication of bisphosphonate therapy. The mechanism underlying BRONJ pathogenesis is poorly understood. To determine the effects of zoledronic acid (ZA) and geranylgeraniol (GGOH) on the mevalonate pathway (MVP) in osteoblasts generated from the human mandibular alveolar bone in terms of cell viability/proliferation, migration, apoptosis and gene expression. Primary human osteoblasts (HOBs) isolated from the mandibular alveolar bone were phenotyped. HOBs were cultured with or without ZA and GGOH for up to 72 h. Cellular behaviour was examined using a CellTiter-Blue® viability assay, an Ibidi culture-insert migration assay, an Apo-ONE® Homogeneous Caspase-3/7 apoptosis assay and transmission electron microscopy (TEM). Quantitative real-time reverse transcriptase polymerase chain reaction (qRT 2 -PCR) was used to determine the simultaneous expression of 168 osteogenic and angiogenic genes modulated in the presence of ZA and GGOH. ZA decreased cell viability and migration and induced apoptosis in HOBs. TEM revealed signs of apoptosis in ZA-treated HOBs. However, the co-addition of GGOH ameliorated the effect of ZA and partially restored the cells to the control state. Twenty-eight genes in the osteogenic array and 27 genes in the angiogenic array were significantly regulated in the presence of ZA compared with those in the controls at one or more time points. The cytotoxic effect of ZA on HOBs and its reversal by the addition of GGOH suggests that the effect of ZA on HOBs is mediated via the MVP. The results suggest that GGOH could be used as a possible therapeutic/preventive strategy for BRONJ.

Zoledronic acid induces micronuclei formation, mitochondrial-mediated apoptosis and cytostasis in kidney cells.

PubMed

Singireesu, Soma Shiva Nageswara Rao; Mondal, Sujan Kumar; Yerramsetty, Suresh; Misra, Sunil

2018-06-15

Zoledronic acid (ZA), a FDA approved drug has used widely in the treatment of bone metastasis complications, has been linked to renal toxicity with unclear mechanism. The present study is aimed at investigating the genotoxic and cytotoxic effects of ZA in renal epithelial cells. The genotoxic effect of ZA in Vero and MDCK cells determined by cytokinesis block micronucleus (CBMN) assay. The cytotoxic effect assessed by analysing cell cycle profile, cell death and mitochondrial membrane potential by flow cytometry using propidium iodide, AnnexinV-FITC/PI and JC1 dye staining, respectively, BAX and Bcl-2 expression by Western blotting and caspase activity by spectrofluorimetry. The cytotoxic effect of ZA based on MTT assay revealed variable sensitivities of Vero and MDCK cells, with IC 50 values of 7.41 and 109.58 μM, respectively. The CBMN assay has shown prominent dose-dependent (IC 10-50 ) induction of micronuclei formation in both cells, indicating ZA's clastogenic and aneugenic potential. Further, the ZA treatment led the cells to apoptosis, evident from dose-dependent increase in the percentage of cells in subG1 phase and display of membranous phosphatidylserine translocation. Studies also confirmed apoptosis through mitochondria, evident from the prominent increase in BAX/Bcl-2 ratio, mitochondrial membrane depolarization and caspase-3/7 activity. In addition, ZA reduces cytokinetic activity of renal cells, evident from dose-wise lowered replicative indices. The study depict ZA's potential genotoxic effect along with cytotoxic effect in renal epithelial cells, could be key factors for the development of renal complications associated with it, which prompts renal safety measures in lieu with ZA usage. Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical sterilisation of Bos indicus bull calves following intratesticular injection of zinc acetate: effects on semen quality and testicular changes.

PubMed

Cavalieri, J; Wang, M; Johnson, L

2015-05-01

The aim of this study was to determine the effects in Bos indicus bull calves of intratesticular administration of 1mL of either saline (n=9) or one of the two doses of zinc acetate (ZA1, 57.75mg, n=10 or ZA2, 71.75mg, n=10) on semen quality and testicular changes. Semen was collected by electroejaculation on Days 343, 524 and 783 and animals were slaughtered on Day 860. Treatment reduced median maximum number of progressively motile and morphologically normal sperm collected (P=0.001) and the percentage of animals in which sperm were recovered (saline: 100%, 9/9; ZA1: 44.9%, 4/9 and ZA2: 40.0%, 4/10; P=0.013). Compared to saline treated controls, treatment with ZA reduced the mean diameter of the testes after Day 34 of treatment (treatment×time, P=0.013) and total testicular weight at slaughter (treatment: mean±SEM; saline: 569.4±59.0g, ZA1: 249.3±72.9g, ZA2: 247.5±68.1g; P=0.004). Histological changes in testes of bulls treated with ZA were characterized by germ cell depletion, vacuolation of Sertoli cells, interstitial fibrosis, epididymal duct atrophy with variable remnants of testicular tissue and degeneration. We conclude that intratesticular administration of two doses of ZA in B. indicus calves is able to severely impair spermatogenesis and cause varying degrees of testicular degeneration and a reduction in testicular diameter and mass. Further investigation is required to determine ways of obtaining more consistent results from treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Molecular identification and functional characterisation of uncoupling protein 4 in larva and pupa fat body mitochondria from the beetle Zophobas atratus.

PubMed

Slocinska, Malgorzata; Antos-Krzeminska, Nina; Rosinski, Grzegorz; Jarmuszkiewicz, Wieslawa

2012-08-01

Uncoupling protein 4 (UCP4) is a member of the UCP subfamily that mediates mitochondrial uncoupling, and sequence alignment predicts the existence of UCP4 in several insects. The present study demonstrates the first molecular identification of a partial Zophobas atratus UCP4-coding sequence and the functional characterisation of ZaUCP4 in the mitochondria of larval and pupal fat bodies of the beetle. ZaUCP4 shows a high similarity to predicted insect UCP4 isoforms and known mammalian UCP4s, both at the nucleotide and amino acid sequence levels. Bioenergetic studies clearly demonstrate UCP function in mitochondria from larval and pupal fat bodies. In non-phosphorylating mitochondria, ZaUCP activity was stimulated by palmitic acid and inhibited by the purine nucleotide GTP. In phosphorylating mitochondria, ZaUCP4 activity decreased the yield of oxidative phosphorylation. ZaUCP4 was immunodetected with antibodies raised against human UCP4 as a single 36-kDa band. A lower expression of ZaUCP4 at the level of mRNA and protein and a decreased ZaUCP4 activity were observed in the Z. atratus pupal fat body compared with the larval fat body. The different expression patterns and activity of ZaUCP4 during the larval-pupal transformation indicates an important physiological role for UCP4 in insect fat body development and function during insect metamorphosis. Copyright © 2012 Elsevier Inc. All rights reserved.

Preventive Effect of Phosphodiesterase Inhibitor Pentoxifylline Against Medication-Related Osteonecrosis of the Jaw: An Animal Study.

PubMed

Yalcin-Ulker, Gül Merve; Cumbul, Alev; Duygu-Capar, Gonca; Uslu, Ünal; Sencift, Kemal

2017-11-01

The aim of this experimental study was to investigate the prophylactic effect of pentoxifylline (PTX) on medication-related osteonecrosis of the jaw (MRONJ). Female Sprague-Dawley rats (n = 33) received zoledronic acid (ZA) for 8 weeks to create an osteonecrosis model. The left mandibular second molars were extracted and the recovery period lasted 8 weeks before sacrifice. PTX was intraperitoneally administered to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated. Histomorphometrically, between the control and ZA groups, there was no statistically significant difference in total bone volume (P = .999), but there was a statistically significant difference in bone ratio in the extraction sockets (P < .001). A comparison of the bone ratio of the ZA group with the ZA/PTX group (PTX administered after extraction) showed no statistically significant difference (P = .69), but there was a statistically significant difference with the ZA/PTX/PTX group (PTX administered before and after extraction; P = .008). Histopathologically, between the control and ZA groups, there were statistically significant differences for inflammation (P = .013), vascularization (P = .022), hemorrhage (P = .025), and regeneration (P = .008). Between the ZA and ZA/PTX groups, there were no statistically significant differences for inflammation (P = .536), vascularization (P = .642), hemorrhage (P = .765), and regeneration (P = .127). Between the ZA and ZA/PTX/PTX groups, there were statistically significant differences for inflammation (P = .017), vascularization (P = .04), hemorrhage (P = .044), and regeneration (P = .04). In this experimental model of MRONJ, it might be concluded that although PTX, given after tooth extraction, improves new bone formation that positively affects bone healing, it is not prophylactic. However, PTX given before tooth extraction is prophylactic. Therefore, PTX might affect healing in a

Differential Effect of Zoledronic Acid on Human Vascular Smooth Muscle Cells

PubMed Central

Albadawi, Hassan; Haurani, Mounir J.; Oklu, Rahmi; Trubiano, Jordan P.; Laub, Peter J.; Yoo, Hyung-Jin; Watkins, Michael T.

2012-01-01

Introduction The activation of human vascular smooth muscle cell proliferation, adhesion and migration is essential for intimal hyperplasia formation. These experiments were designed to test whether Zoledronic Acid (ZA) would modulate indices of human smooth muscle cell activation, exert differential effects on proliferating vs. quiescent cells and determine whether these effects were dependent on GTPase binding proteins prenylation. ZA was chosen for testing in these experiments because it is clinically used in humans with cancer, and has been shown to modulate rat smooth muscle cell proliferation and migration. Methods Human aortic smooth muscle cells (HASMC) were cultured under either proliferating or growth arrest (quiescent) conditions in the presence or absence of ZA for 48 hours, whereupon the effect of ZA on HASMC proliferation, cellular viability, metabolic activity and membrane integrity were compared. In addition, the effect of ZA on adhesion and migration were assessed in proliferating cells. The effect of increased concentration of ZA on the mevalonate pathway and genomic/cellular stress related poly ADP Ribose polymerase (PARP) enzyme activity were assessed using the relative prenylation of Rap-1A/B protein and the formation of poly ADP- ribosylated proteins (PAR) respectively. Results There was a dose dependent inhibition of cellular proliferation, adhesion and migration following ZA treatment. ZA treatment decreased indices of cellular viability and significantly increased membrane injury in proliferating vs. quiescent cells. This was correlated with the appearance of unprenylated Rap-1A protein and dose dependent down regulation of PARP activity. Conclusions These data suggest that ZA is effective in inhibiting HASMC proliferation, adhesion and migration which coincide with the appearance of unprenylated RAP-1A/B protein, thereby suggesting that the mevalonate pathway may play a role in the inhibition of HASMC activation. PMID:23164362

Zoledronic acid at subtoxic dose extends osteoblastic stage span of primary human osteoblasts.

PubMed

Zara, Susi; De Colli, Marianna; di Giacomo, Viviana; Zizzari, Vincenzo Luca; Di Nisio, Chiara; Di Tore, Umberto; Salini, Vincenzo; Gallorini, Marialucia; Tetè, Stefano; Cataldi, Amelia

2015-04-01

This study aimed to check the effect of zoledronic acid (ZA) at subtoxic dose on human osteoblasts (HOs) in terms of cell viability, apoptosis occurrence, and differentiation induction. ZA belongs to the family of bisphosphonates (BPs), largely used in the clinical practice for the treatment of bone diseases, often associated with jaw osteonecrosis onset. Their pharmacological action consists in the direct block of the osteoclast-mediated bone resorption along with indirect action on osteoblasts. HOs were treated choosing the highest limit concentration (10(-5) M) which does not induce toxic effects. Live/dead staining, flow cytometry, mitochondrial membrane potential assay, osteocalcin western blotting, gp38 RT-PCR, collagen type I, PGE2, and IL-6 ELISA assays were performed. Similar viability level between control and ZA-treated samples is found along with no significant increase of apoptotic and necrotic cells in ZA-treated sample. To establish if an early apoptotic pathway was triggered, Bax expression and mitochondrial membrane potential were evaluated finding a higher protein expression in control sample and a good integrity of mitochondrial membrane in both experimental points. Type I collagen secretion and alkaline phosphatase (ALP) activity appear increased in ZA-treated sample, osteocalcin expression level is reduced in ZA-treated cells, whereas no modifications of gp38 mRNA level are evidenced. No statistical differences are identified in PGE2 secretion level whereas IL-6 secretion is lower in ZA-treated HOs with respect to control ones. These results highlight that ZA, delaying the osteoblastic differentiation process versus the osteocytic lineage, strengthens its pharmacological activity enhancing bone density. The knowledge of ZA effects on osteoblasts at subtoxic dose allows to improve therapeutic protocols in order to strengthen drug pharmacological activity through a combined action on both osteoclastic and osteoblastic cells.

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro

PubMed Central

Weingartshofer, Sigrid; Grunt, Thomas W.; Mairhofer, Mario; Tan, Yen; Gamper, Jutta; Singer, Christian F.

2017-01-01

Background Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. Materials and methods Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. Results In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). Conclusion We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status. PMID:28945801

Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2+ γδ T cell cytotoxicity in a perforin-dependent manner.

PubMed

Fowler, Daniel W; Copier, John; Dalgleish, Angus G; Bodman-Smith, Mark D

2017-09-01

Vδ2 + T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2 + T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2 + T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C-C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2 + T cell cytotoxicity. Vδ2 + T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive-at least in part-to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2 + T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.

The miR-21/PTEN/Akt signaling pathway is involved in the anti-tumoral effects of zoledronic acid in human breast cancer cell lines.

PubMed

Fragni, M; Bonini, S A; Bettinsoli, P; Bodei, S; Generali, D; Bottini, A; Spano, P F; Memo, M; Sigala, S

2016-05-01

Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.

The effect of a moderate zinc deficiency and dietary fat source on the activity and expression of the Δ(3)Δ (2)-enoyl-CoA isomerase in the liver of growing rats.

PubMed

Justus, Jennifer; Weigand, Edgar

2014-06-01

Auxiliary enzymes participate in β-oxidation of unsaturated fatty acids. The objective of the study was to investigate the impact of a moderate zinc deficiency and a high intake of polyunsaturated fat on Δ(3)Δ(2)-enoyl-CoA isomerase (ECI) in the liver and other tissues. Five groups of eight weanling rats each were fed moderately zinc-deficient (ZD) or zinc-adequate (ZA) semisynthetic diets (7 or 50 mg Zn/kg) enriched with 22 % cocoa butter (CB) or 22 % safflower oil (SO) for 4 weeks: (1) ZD-CB, fed free choice; (2) ZA-CBR, ZA-CB diet fed in equivalent amounts consumed by the ZD-CB group; (3) ZD-SO, fed free choice; (4) ZA-SOR, ZA-SO diet fed in equivalent amounts consumed by the ZD-SO group; and (5) ZA-SO, fed free choice. Growth and Zn status markers were markedly reduced in the ZD groups. ECI activity in the liver of the animals fed the ZD- and ZA-SO diets were significantly higher (approximately 2- and 3-fold, respectively) as compared with the CB-fed animals, whereas activities in extrahepatic tissues (kidneys, heart, skeletal muscle, testes, adipose tissue) were not altered by dietary treatments. Transcript levels of the mitochondrial Eci gene in the liver did not significantly differ between ZD and ZA rats, but were 1.6-fold higher in the ZA-SO- than in the ZD-CB-fed animals (P < 0.05). It is concluded that diets enriched with safflower oil as a source high in linoleic acid induce markedly increased hepatic ECI activities and that a moderate Zn deficiency does not affect transcription of the mitochondrial Eci gene in the liver.

Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model.

PubMed

Esser, Alison K; Schmieder, Anne H; Ross, Michael H; Xiang, Jingyu; Su, Xinming; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Allen, John S; Williams, Todd; Wickline, Samuel A; Pan, Dipanjan; Lanza, Gregory M; Weilbaecher, Katherine N

2016-01-01

Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (P<0.05) endothelial cell viability without impacting macrophage viability. ZA suppressed (P<0.05) macrophage viability at high dosages but not endothelial cell proliferation. 3D MR neovascular imaging of rabbit Vx2 tumors showed no effect with ZA, whereas αvβ3-Fum-PD NP alone and with ZA decreased angiogenesis (P<0.05). Immunohistochemistry revealed decreased (P<0.05) microvascularity with αvβ3-Fum-PD NP and ZA and further microvascular reduction (P<0.05) with dual-therapy. In vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas αvβ3-Fum-PD-NPs reduced both measures. Dual-therapy with ZA and αvβ3-Fum-PD-NP may provide enhanced neo-adjuvant utility if macrophage ZA uptake is increased. From the Clinical Editor: Although anti-angiogenesis is one of the treatment modalities in the fight against cancer, many cancers become resistant to VEGF pathway inhibitors. In this article, the authors investigated the use of dual therapy using fumagillin, integrin-targeted lipid-encapsulated nanoparticles (αvβ3- Fum-PD NP) and zoledronic acid (ZA), in both in-vitro and in-vivo experiments. This combination approach may provide an insight to the design of future drugs against cancers. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials.

PubMed

Kroep, J R; Charehbili, A; Coleman, R E; Aft, R L; Hasegawa, Y; Winter, M C; Weilbaecher, K; Akazawa, K; Hinsley, S; Putter, H; Liefers, G J; Nortier, J W R; Kohno, N

2016-02-01

The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response. Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC. pCRb and pCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase pCRb or pCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the pCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01-4.55) and a non-significant benefit of the pCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90-7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA. This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on pCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical sterilisation of Bos indicus bull calves following intratesticular injection of zinc acetate: Effects on growth and concentrations of testosterone.

PubMed

Cavalieri, J; Wang, M

2015-08-01

The aim of this study was to determine the effects in Bos indicus calves of intra-testicular injection of either saline (n=9) or one of two doses of zinc acetate ((ZA1, 57.75mg, n=10, or ZA2, 71.75mg, n=10) or surgical castration (n=9) on circulating concentrations of testostosterone and liveweight. Human chorionic gonadotrophin (hCG, 1500IU) was administered 202 and 525 days after treatment on Day 0 and animals were slaughtered on Day 860. In animals left intact treatment with ZA reduced mean serum concentrations of testosterone (Saline: 5.58±0.79ng/mL, ZA1: 1.28±0.27ng/mL, ZA2: 1.01±0.17ng/mL; P<0.001) and concentrations 48h following administration of hCG. The maximum concentration of testosterone recorded throughout the study in six out of 19 animals treated with ZA was ≤0.21ng/mL. Treatment with ZA did not significantly affect live weights or carcass weights or result in any detectable scrotal lesions. Animals with concentrations of testosterone ≥1.0ng/mL exhibited greater liveweights throughout most of the study and yielded heavier carcass weights (340.9±7.02 versus 309.3±6.17kg, P=0.002). It is concluded that a single, intra-testicular administration of either 57.75mg or 71.75mg of ZA was able to similarly reduce circulating concentrations of testosterone without significantly affecting liveweights or carcass weights. Treatment with ZA can result in variation in circulating concentrations of testosterone which could lead to differences in behaviour, liveweights and carcass characteristics. Copyright © 2015 Elsevier B.V. All rights reserved.

Connexin45 interacts with zonula occludens-1 in osteoblastic cells

NASA Technical Reports Server (NTRS)

Laing, J. G.; Manley-Markowski, R. N.; Koval, M.; Civitelli, R.; Steinberg, T. H.

2001-01-01

Connexin43 (Cx43) and Cx45 are co-expressed in a number of different tissues. Studies demonstrated that Cx45 transfected ROS (ROS/Cx45) cells, were less permeable to low molecular weight dyes than untransfected ROS cells, that have gap junctions made of Cx43. This suggests that there may be a functionally important interaction between Cx43 and Cx45 in these cells. One way in which these proteins may interact is by associating with the same set of proteins. In order to isolate connexin interacting proteins, we isolated Cx45 from Cx45 transfected ROS cells (ROS/Cx45 cells) under mild detergent conditions. These studies showed that Cx45 co-purified with the tight junction protein, ZO-1. Immunofluorescence studies of ROS/Cx45 cells simultaneously stained with polyclonal Cx45 antibody and a monoclonal ZO-1 antibody showed that Cx45 and ZO-1 colocalized in ROS/Cx45 cells. Furthermore we found that ZO-1 could bind to peptides derived from the carboxyl terminal of Cx45 that had been covalently bound to an agarose resin. These data suggests that Cx45 and ZO-1 directly interact in ROS/Cx45 cells.

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.

PubMed

James, Nicholas; Pirrie, Sarah; Pope, Ann; Barton, Darren; Andronis, Lazaros; Goranitis, Ilias; Collins, Stuart; McLaren, Duncan; O'Sullivan, Joe; Parker, Chris; Porfiri, Emilio; Staffurth, John; Stanley, Andrew; Wylie, James; Beesley, Sharon; Birtle, Alison; Brown, Janet; Chakraborti, Prabir; Russell, Martin; Billingham, Lucinda

2016-07-01

Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification

Comparison of the efficacy, adverse effects, and cost of zoledronic acid and denosumab in the treatment of osteoporosis.

PubMed

Sheedy, Kellen C; Camara, Maria I; Camacho, Pauline M

2015-03-01

Injectable osteoporosis drugs are increasing in popularity due to their efficacy and convenient administration. In this retrospective comparison of the two available treatments, denosumab (Prolia®) and zoledronic acid (ZA, Reclast®), we aimed to determine and compare the efficacy and tolerability of denosumab and ZA. The charts of patients who received denosumab and ZA at Loyola Hospital were reviewed, and adverse events were noted. Of primary interest were myalgias, flu-like symptoms, back pain, and fractures. A questionnaire regarding the efficacy, tolerability, and treatment cost supplemented this chart review in a subset of study participants. Bone mineral density (BMD) changes, bone turnover markers, and questionnaire results were also compared. The study cohort consisted of 107 patients (51 denosumab, 56 ZA). The denosumab group had a greater mean increase in spine BMD at 1 year (0.060 g/cm2) than the ZA group (0.021 g/cm2; P = .04). The change in femur and spine BMD at 1 year were not significantly different between the 2 groups. The ZA group had a significantly greater incidence of mild flu-like symptoms (29% ZA group vs. 0% denosumab group; P = .04). The denosumab group had a higher mean increase in spine BMD, and the ZA group had a higher incidence of flu-like symptoms, but the study groups were statistically similar in terms of patient satisfaction. As denosumab is still a relatively new therapy, there were a limited number of patients with posttreatment data available for comparison. As more posttherapy data become available, it can be further investigated.

The role of vitamin E in the prevention of zoledronic acid-induced nephrotoxicity in rats: a light and electron microscopy study.

PubMed

Sert, İbrahim Unal; Kilic, Ozcan; Akand, Murat; Saglik, Lutfi; Avunduk, Mustafa Cihat; Erdemli, Esra

2018-03-01

Bisphosphonates are widely used in metastatic cancer such as prostate and breast cancer, and their nephrotoxic effects have been established previously. In this study we aimed to evaluate both the nephrotoxic effects of zoledronic acid (ZA) and the protective effects of vitamin E (Vit-E) on this process under light and electron microscopy. A total of 30 male Sprague-Dawley rats were divided into 3 groups. The first group constituted the control group. The second group was given i.v. ZA of 3 mg/kg once every 3 weeks for 12 weeks from the tail vein. The third group received the same dosage of ZA with an additional i.m . injection of 15 mg Vit-E every week for 12 weeks. Tissues were taken 4 days after the last dose of ZA for histopathological and ultrastructural evaluation. Paller score, tubular epithelial thickness and basal membrane thickness were calculated for each group. For group 2, the p -values are all < 0.001 for Paller score, epitelial thickness, and basal membrane thickness. For group 3 (ZA + Vit. E), the p -values are < 0.001 for Paller score, 0.996 for epitelial thickness, and < 0.001 basal membrane thickness. Significant differences were also observed in ultrastructural changes for group 2. However, adding Vit-E to ZA administration reversed all the histopathological changes to some degree, with statistical significance. Administration of ZA had nephrotoxic effects on rat kidney observed under both light and electron microscopy. Concomitant administration of Vit-E significantly reduces toxic histopathological effects of ZA.

Bone mineralization and vascularization in bisphosphonate-related osteonecrosis of the jaw: an experimental study in the rat.

PubMed

Kün-Darbois, Jean-Daniel; Libouban, Hélène; Mabilleau, Guillaume; Pascaretti-Grizon, Florence; Chappard, Daniel

2018-02-16

Pathogenesis of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is not fully explained. An antiangiogenic effect of bisphosphonates (BPs) or an altered bone quality have been advocated. The aims of the present study were to analyze alveolar mandibular vascularization and bone quality in rats with BRONJ. Thirty-eight Sprague-Dawley rats were randomized into two groups: zoledronic acid (ZA), n = 27, and control (CTRL) n = 11. The ZA group received a weekly IV injection of ZA (100 μg/kg) during 10 weeks. The CTRL group received saline. After 6 weeks, extraction of the right mandibular molars was performed. Rats were sacrificed after 14 weeks. Microtomography characterized bone lesions and vascularization after injection of a radio-opaque material. Raman microspectroscopy evaluated bone mineralization. Fifty-five percent of ZA rats presented bone exposure and signs of BRONJ. None sign was found at the left hemimandible in the ZA group and in the CTRL group. Vascular density appeared significantly increased in the right hemimandibles of the CTRL group compared to the left hemimandibles. Vascularization was reduced in the ZA group. A significantly increased of the mineral-to-amide ratio was found in the alveolar bone of ZA rats by Raman microspectroscopy. In a rat model of BRONJ, microtomography evidenced osteonecrosis in BRONJ. Raman spectroscopy showed an increased mineralization. Vascularization after tooth extraction was impaired by ZA. Prolonged BP administration caused an increase in the mineralization and a quantitative reduction of the vascularization in the alveolar bone; both factors might be involved concomitantly in the BRONJ pathophysiology.

Apoptosis of enterocytes and nitration of junctional complex proteins promote alcohol-induced gut leakiness and liver injury.

PubMed

Cho, Young-Eun; Yu, Li-Rong; Abdelmegeed, Mohamed A; Yoo, Seong-Ho; Song, Byoung-Joon

2018-07-01

Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury, although the molecular mechanisms are still elusive. This study was aimed at investigating the roles of apoptosis of enterocytes and nitration followed by degradation of intestinal tight junction (TJ) and adherens junction (AJ) proteins in binge alcohol-induced gut leakiness. The levels of intestinal (ileum) junctional complex proteins, oxidative stress markers and apoptosis-related proteins in rodents, T84 colonic cells and autopsied human ileums were determined by immunoblot, immunoprecipitation, immunofluorescence, and mass-spectral analyses. Binge alcohol exposure caused apoptosis of gut enterocytes with elevated serum endotoxin and liver injury. The levels of intestinal CYP2E1, iNOS, nitrated proteins and apoptosis-related marker proteins were significantly elevated in binge alcohol-exposed rodents. Differential, quantitative mass-spectral analyses of the TJ-enriched fractions of intestinal epithelial layers revealed that several TJ, AJ and desmosome proteins were decreased in binge alcohol-exposed rats compared to controls. Consistently, the levels of TJ proteins (claudin-1, claudin-4, occludin and zonula occludens-1), AJ proteins (β-catenin and E-cadherin) and desmosome plakoglobin were very low in binge alcohol-exposed rats, wild-type mice, and autopsied human ileums but not in Cyp2e1-null mice. Additionally, pretreatment with specific inhibitors of CYP2E1 and iNOS prevented disorganization and/or degradation of TJ proteins in alcohol-exposed T84 colonic cells. Furthermore, immunoprecipitation followed by immunoblot confirmed that intestinal TJ and AJ proteins were nitrated and degraded via ubiquitin-dependent proteolysis, resulting in their decreased levels. These results demonstrated for the first time the critical roles of CYP2E1, apoptosis of enterocytes, and nitration followed by ubiquitin-dependent proteolytic degradation of the

Facial-zygomatic triangle: a relationship between the extracranial portion of facial nerve and the zygomatic arch.

PubMed

Campero, A; Socolovsky, M; Martins, C; Yasuda, A; Torino, R; Rhoton, A L

2008-03-01

This study was conducted to clarify the relationships between the extracranial portion of the facial nerve (EFN) and the zygomatic arch (ZA). Four cadaveric heads (8 parotid regions), examined under 3-40x magnification, were dissected from lateral to medial to expose the EFN. In a vertical plane just anterior to the tragus, the distance from the superior edge of the ZA to the facial nerve (FN) is, on average, 26.88 mm. The FN then courses superiorly and anteriorly, crossing the ZA 18.65 mm anterior to the tragus on average. Thus, three points can be used to depict a triangle: A, at the level of the anterior border of the tragus, just above the superior edge of the ZA; B, 26 mm below A; and C, 18 mm anterior to A. This so called facial-zygomatic triangle represents the area where surgical dissection can be performed with no risk of damaging the FN. Thus, the closer one stays to the tragus, the lesser the risk of damaging the FN below the ZA. If the incision is carried out on a vertical plane closer to the tragus, the skin can be safely cut up to 2 cm below the ZA. The facial-zygomatic triangle is a very useful superficial landmark to avoid FN damage when working below the ZA.

Zoledronic acid causes γδ T cells to target monocytes and down-modulate inflammatory homing

PubMed Central

Fowler, Daniel W; Copier, John; Dalgleish, Angus G; Bodman-Smith, Mark D

2014-01-01

Zoledronic acid (ZA) is a potential immunotherapy for cancer because it can induce potent γδ T-cell-mediated anti-tumour responses. Clinical trials are testing the efficacy of intravenous ZA in cancer patients; however, the effects of systemic ZA on the activation and migration of peripheral γδ T cells remain poorly understood. We found that γδ T cells within ZA-treated peripheral blood mononuclear cells were degranulating, as shown by up-regulated expression of CD107a/b. Degranulation was monocyte dependent because CD107a/b expression was markedly reduced in the absence of CD14+ cells. Consistent with monocyte-induced degranulation, we observed γδ T-cell-dependent induction of monocyte apoptosis, as shown by phosphatidylserine expression on monocytes and decreased percentages of monocytes in culture. Despite the prevailing paradigm that ZA promotes tumour homing in γδ T cells, we observed down-modulation of their tumour homing capacity, as shown by decreased expression of the inflammatory chemokine receptors CCR5 and CXCR3, and reduced migration towards the inflammatory chemokine CCL5. Taken together our data suggest that ZA causes γδ T cells to target monocytes and down-modulate the migratory programme required for inflammatory homing. This study provides novel insight into how γδ T cells interact with monocytes and the possible implications of systemic use of ZA in cancer. PMID:24912747

Zoledronic acid overcomes chemoresistance by sensitizing cancer stem cells to apoptosis.

PubMed

Rouhrazi, H; Turgan, N; Oktem, G

2018-01-01

Unlike low tumorigenic bulk tumor cells (non-CSCs), cancer stem cells (CSCs) are a subset of tumor cells that can self-renew and differentiate into different cancer subtypes. CSCs are considered responsible for tumor recurrence, distant metastasis, angiogenesis, and drug or radiation resistance. CSCs also are resistant to apoptosis. Zoledronic acid (ZA) is a third generation bisphosphonate that reduces cell proliferation and exhibits anti-tumor effects by inducing cell death in some malignancies; however, the effects of ZA on CSCs are unclear. We investigated the anti-cancer effects of ZA on two epithelial cancer cell lines, prostate DU-145 and breast MCF7, focusing primarily on induction and activation of apoptosis. Cluster of differentiation (CD) 133 + /CD44 + prostate CSCs and CD 44 + /CD24 breast CSCs were isolated from the DU-145 human prostate cancer and MCF-7 human breast cancer cell lines, respectively, using FACSAria flow cytometry cell sorting. CSCs and non-CSCs were exposed to increasing concentrations of ZA for 24, 48 and 72 h to determine the IC 50 dose. Annexin-V assay for detecting cell death and cell cycle was performed using the Muse™ Cell Analyzer. Prostate CSCs and non-CSCs were assayed by quantitative reverse transcription PCR (qRT-PCR) array for detecting 84 key apoptosis related genes. Gene regulation at the protein level was investigated by immunofluorescence. ZA caused a dose- and time-dependent decrease in cell viability. Treatment with ZA resulted in a concomitant increase in apoptosis and cell cycle arrest at S-phase in CSCs. Significant over/under-expressions were detected in seven of the genes of ZA-treated DU-145 CSCs cells. Expressions of CASP9, CASP4, BAX and BAD genes increased, while the expressions of BIRC3, BIRC2 and BCL2 genes decreased. In the DU-145 non-CSCs, five genes exhibited changes in gene expression after ZA treatment, two exhibited increased expression (CASP7 and BAD) and three exhibited decreased expression (BIRC3

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Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-07

... the HP-API order entry protocol (HP-API) in order to qualify for the rates on Flags ZA and ZR. The... via FIX in order to qualify for the rates on Flags ZA (rebate of $0.0032 per share) and ZR (fee of $0... qualify for the rates on Flags ZA and ZR. The attestation requirement, as described above and in SR-EDGX...

Rapid assessment of crystal orientation in semi-crystalline polymer films using rotational zone annealing and impact of orientation on mechanical properties

DOE PAGES

Ye, Changhuai; Wang, Chao; Wang, Jing; ...

2017-08-17

Crystal orientation in semi-crystalline polymers tends to enhance their performance, such as increased yield strength and modulus, along the orientation direction. Zone annealing (ZA) orients the crystal lamellae through a sharp temperature gradient that effectively directs the crystal growth, but the sweep rate (V ZA) of this gradient significantly impacts the extent of crystal orientation. Here in this work, we demonstrate rotational zone annealing (RZA) as an efficient method to elucidate the influence of V ZA on the crystal morphology of thin films in a single experiment using isotactic poly(1-butene), PB-1, as a model semi-crystalline polymer. These RZA results aremore » confirmed using standard, serial linear ZA to tune the structure from an almost unidirectional oriented morphology to weakly oriented spherulites. The overall crystallinity is only modestly changed in comparison to isothermal crystallization (maximum of 55% from ZA vs. 48% for isothermal crystallization). However, the average grain size increases and the spherulites become anisotropic from ZA. Due to these structural changes, the Young's modulus of the oriented films, both parallel and perpendicular to the spherulite orientation direction, is significantly increased by ZA. The modulus does become anisotropic after ZA due to the directionality in the crystal structure, with more than a threefold increase in the modulus parallel to the orientation direction for the highest oriented film in comparison to the modulus from isothermal crystallization. Lastly, RZA enables rapid identification of conditions to maximize orientation of crystals in thin polymer films, which could find utility in determining conditions to improve crystallinity and performance in organic electronics.« less

Rapid assessment of crystal orientation in semi-crystalline polymer films using rotational zone annealing and impact of orientation on mechanical properties

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

Ye, Changhuai; Wang, Chao; Wang, Jing

Crystal orientation in semi-crystalline polymers tends to enhance their performance, such as increased yield strength and modulus, along the orientation direction. Zone annealing (ZA) orients the crystal lamellae through a sharp temperature gradient that effectively directs the crystal growth, but the sweep rate (V ZA) of this gradient significantly impacts the extent of crystal orientation. Here in this work, we demonstrate rotational zone annealing (RZA) as an efficient method to elucidate the influence of V ZA on the crystal morphology of thin films in a single experiment using isotactic poly(1-butene), PB-1, as a model semi-crystalline polymer. These RZA results aremore » confirmed using standard, serial linear ZA to tune the structure from an almost unidirectional oriented morphology to weakly oriented spherulites. The overall crystallinity is only modestly changed in comparison to isothermal crystallization (maximum of 55% from ZA vs. 48% for isothermal crystallization). However, the average grain size increases and the spherulites become anisotropic from ZA. Due to these structural changes, the Young's modulus of the oriented films, both parallel and perpendicular to the spherulite orientation direction, is significantly increased by ZA. The modulus does become anisotropic after ZA due to the directionality in the crystal structure, with more than a threefold increase in the modulus parallel to the orientation direction for the highest oriented film in comparison to the modulus from isothermal crystallization. Lastly, RZA enables rapid identification of conditions to maximize orientation of crystals in thin polymer films, which could find utility in determining conditions to improve crystallinity and performance in organic electronics.« less

Calcium Sulphate/Hydroxyapatite Carrier for Bone Formation in the Femoral Neck of Osteoporotic Rats.

PubMed

Sirka, Aurimas; Raina, Deepak Bushan; Isaksson, Hanna; Tanner, K Elizabeth; Smailys, Alfredas; Kumar, Ashok; Tarasevicius, Sarunas; Tägil, Magnus; Lidgren, Lars

2018-06-01

We investigated bone regeneration in the femoral neck canal of osteoporotic rats using a novel animal model. We used a calcium sulphate (CS)/ Hydroxyapatite (HA) carrier to locally deliver a bisphosphonate, zoledronic acid (ZA), with or without added recombinant human bone morphogenic protein-2 (rhBMP-2). Ovariectomized Sprague-Dawley rats of 28 weeks age were used. A 1 mm diameter and 8 mm long defect was created in the femoral neck by drilling from the lateral cortex in the axis of the femoral neck leaving the surrounding cortex intact. Three treatment groups and one control group were used 1) CS/HA alone, 2) CS/HA+ ZA (10 μg) 3) CS/HA+ZA (10 μg)+rhBMP-2 (4 μg) and 4) Empty defect. The bone formation was assessed at 4 weeks post-surgery using in vivo micro computed tomography (micro-CT). At 8 weeks post-surgery, the animals were sacrificed and both defect and contralateral femurs were subjected to micro-CT, mechanical testing and histology. Micro-CT results showed that the combination of CS/HA with ZA or ZA+rhBMP-2 increased the bone formation in the defect when compared to the other groups and to the contralateral hips. Evidence of new dense bone formation in CS/HA+ZA and CS/HA+ZA+rhBMP-2 groups was seen histologically. Mechanical testing results showed no differences in the load to fracture between the treatments in either of the treated or contralateral legs. The CS/HA biomaterial can be used as a carrier for ZA and rhBMP-2 to regenerate bone in the femoral neck canal of osteoporotic rats.

Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid.

PubMed

Yanae, Masashi; Fujimoto, Shinichiro; Tane, Kaori; Tanioka, Maki; Fujiwara, Kimiko; Tsubaki, Masanobu; Yamazoe, Yuzuru; Morishima, Yoshiyuki; Chiba, Yasutaka; Takao, Shintaro; Komoike, Yoshifumi; Tsurutani, Junji; Nakagawa, Kazuhiko; Nishida, Shozo

2017-09-01

Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells.

PubMed

Inoue, Sayaka; Arai, Naoya; Tomihara, Kei; Takashina, Michinori; Hattori, Yuichi; Noguchi, Makoto

2015-08-15

Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state. Copyright © 2015 Elsevier B.V. All rights reserved.

Zoledronic acid inhibits vasculogenic mimicry in murine osteosarcoma cell line in vitro.

PubMed

Fu, Dehao; He, Xianfeng; Yang, Shuhua; Xu, Weihua; Lin, Tao; Feng, Xiaobo

2011-06-30

To study the effects of zoledronic acid (ZA) on the vasculogenic mimicry of osteosarcoma cells in vitro. A Three-dimensional culture of LM8 osteosarcoma cells on a type I collagen matrix was used to investigate whether osteosarcoma cells can develop vasculogenic mimicry, and to determine the effects of ZA on this process. In addition, the cellular ultrastructural changes were observed using scanning electron microscopy and laser confocal microscopy. The effects of ZA on the translocation of RhoA protein from the cytosol to the membrane in LM8 cells were measured via immunoblotting. ZA inhibited the development of vasculogenic mimicry by the LM8 osteosarcoma cells, decreased microvilli formation on the cell surface, and disrupted the F-actin cytoskeleton. ZA prevented translocation of RhoA protein from the cytosol to the membrane in LM8 cells. ZA can impair RhoA membrane localization in LM8 cells, causing obvious changes in the ultrastructure of osteosarcoma cells and induce cell apoptosis, which may be one of the underlying mechanisms by which the agent inhibits the development of vasculogenic mimicry by the LM8 cells.

Zoledronic acid in pediatric metabolic bone disorders.

PubMed

Bowden, Sasigarn A; Mahan, John D

2017-10-01

Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted.

Zoledronic acid in pediatric metabolic bone disorders

PubMed Central

Mahan, John D.

2017-01-01

Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted. PMID:29184807

Effect of intravenous zoledronic acid infusion on electrocardiographic parameters in patients with osteoporosis.

PubMed

Aktas, I; Nazikoglu, C; Kepez, A; Ozkan, F U; Kaysin, M Y; Akpinar, P; Dogan, Z; Ileri, C; Saymaz, S; Erdogan, O

2016-12-01

We evaluated the effects of zoledronic acid (ZA) therapy on electrocardiographic (ECG) parameters for the first time in the literature. Measurements were performed on ECGs obtained before and after ZA infusion on the same day as well as 1 month after the infusion. ZA infusion did not have any short- or long-term effect on any parameter that might be associated with the tendency for atrial fibrillation or ventricular arrhythmias. The aim of the present study was to evaluate the early and late effects of ZA therapy on ECG parameters which might be associated with the tendency for atrial and ventricular arrhythmias. Consecutive patients with osteoporosis who were admitted to our clinic between December 2013 and December 2014 and who were scheduled to receive ZA infusion constituted our study population. Twelve-lead surface ECGs were obtained from all patients before and after ZA infusion on the same day as well as 1 month after the infusion. All ECG parameters were measured and compared with each other for each patient. Data of 100 patients were used in the analysis (9 male; 70.5 ± 11.6 years of age). There were no significant differences between repeated measurements regarding pmax, pmin, and p dispersion values. QT max and QT min values were significantly increased after infusion; however, there were no significant changes in QT dispersion, Tp-e interval, and Tp-e dispersion values. ZA infusion did not affect P wave dispersion both at the immediate post-infusion period and 1 month after infusion. QT values were significantly increased early after ZA infusion; however, there were no significant differences in parameters reflecting disparity of ventricular recovery times and transmural dispersion of ventricular repolarization. Based on these observations, it may be suggested that ZA infusion did not have any short- or long-term effect on any parameter that might be associated with the tendency for atrial fibrillation or ventricular arrhythmias.

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats

PubMed Central

Curtis, Ryan C.; Custis, James T.; Ehrhart, Nicole P.; Ehrhart, E. J.; Condon, Keith W.; Gookin, Sara E.; Donahue, Seth W.

2016-01-01

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma. PMID:27332712

Cytoprotective effects of melatonin on zoledronic acid-treated human mesenchymal stem cells in vitro.

PubMed

Rodríguez-Lozano, Francisco Javier; García-Bernal, David; Ros-Roca, Maria de Los Ángeles; Algueró, Maria del Carmen; Oñate-Sánchez, Ricardo Elías; Camacho-Alonso, Fabio; Moraleda, Jose María

2015-07-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a common clinical complication in patients receiving bisphosphonate therapy. Furthermore, melatonin has been proposed as a therapeutic drug for the oral cavity due to its antioxidant properties. This study aimed to evaluate the cytoprotective effects of melatonin on zoledronic acid (ZA)-treated human mesenchymal stem cells from periodontal ligament (PDLSCs) and bone marrow (BMMSCs). PDLSCs and BMMSCs were exposed to ZA, melatonin or ZA + melatonin for 72 h. Cell proliferation was measured by a colorimetric assay, whereas their mesenchymal phenotype was analyzed by flow cytometry. Proliferation assays showed that BMMSCs presented higher ZA resistance than PDLSCs, as well as a difference in response to the simultaneous treatment of ZA + melatonin. Using PDLSCs, high doses of melatonin significantly increased their proliferation, whereas lower concentrations were enough to enhance ZA-treated BMMSC proliferation. Moreover, PDLSCs displayed a CD90/CD105 downregulation and CD73 upregulation in response to ZA, which was more pronounced in response to melatonin. Furthermore, ZA or ZA + low doses of melatonin induced a decrease of expression of CD90/CD105/CD73 on BMMSCs, while a higher concentration recovered CD73 levels. These results suggest that melatonin has a cytoprotective effect on ZA-treated PDLSCs and BMMSCs. Thus, it could be used for BRONJ prevention. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Zoledronic acid induces cytogenetic toxicity in male germline cells of Swiss albino mice.

PubMed

Dasari, Ramakrishna; Misra, Sunil

2018-04-12

This study mainly focuses on the cytogenetic toxicity induction by zoledronic acid (ZA), a nitrogen containing bisphosphonate (N-BPs) in the male germline cells of Swiss albino mice. A single intraperitoneal exposure with three different doses of ZA (2, 4, and 8 mg/kg body weight), toxicity was assessed by analyzing spermatogonial metaphase chromosome aberrations at 24 h, aberrant primary spermatocytes at week 4, and abnormal spermatozoa at week 8 posttreatment. Cyclophosphamide (40 mg/kg) and 0.9% NaCl were used as positive and vehicle controls respectively in the study. The results showed that there was a significant induction in the number of chromosomal aberrations especially at two doses of ZA (4 and 8 mg/kg) after 24 h in the spermatogonial cells (p < 0.001) compared to vehicle control. The transmission genetic damages were noticed as aberrant spermatocytes with atypical bivalents (X-Y/autosomal asynapsis) at 4 mg/kg of ZA (p < 0.01) and at 8 mg/kg of ZA (p < 0.001) at week 4 posttreatment. A statistically significant higher number of abnormal spermatozoa (sperm) were also noticed at week 8 posttreatment of both at 4 and 8 mg/kg of ZA (p < 0.001). Hence, from these genotoxicity studies, it can be concluded that ZA is genotoxic in male germline cells and has the potential of transmitting the genotoxic effects from spermatogonial cells to sperm in male Swiss mice.

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

PubMed

Curtis, Ryan C; Custis, James T; Ehrhart, Nicole P; Ehrhart, E J; Condon, Keith W; Gookin, Sara E; Donahue, Seth W

2016-01-01

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

Fatigue of die cast zinc alloys

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

Schrems, K.K.; Dogan, O.N.; Goodwin, F.E.

2006-04-01

The rotating bending fatigue limit of die cast zinc alloy 2, alloy 3, alloy 5, AcuZinc 5, and ZA-8 were determined as a part of an on-going program by ILZRO into the mechanical properties of die cast zinc. The stress-life (S-N) curves of alloys 3, 5, AcuZinc 5, and ZA-8 were determined previously. This presentation reports the results of the S-N curve for Alloy 2 and the calculated fatigue limits for all five alloys. During the previous stress-life testing, the samples were stopped at 10 million cycles and the fatigue limit for alloy 3, alloy 5, and AcuZinc 5 appearedmore » to be higher and the fatigue limit for ZA-8 appeared to be lower than the values reported in the literature. This was further investigated in alloy 5 and ZA-8 by testing continuous cast bulk alloy 5 and ZA-8.« less

Effects of Dietary Supplementation with the Combination of Zeolite and Attapulgite on Growth Performance, Nutrient Digestibility, Secretion of Digestive Enzymes and Intestinal Health in Broiler Chickens

PubMed Central

Zhou, P.; Tan, Y. Q.; Zhang, L.; Zhou, Y. M.; Gao, F.; Zhou, G. H.

2014-01-01

This study was designed to investigate the effects of basal diets supplemented with a clay product consisting of zeolite and attapulgite (ZA) at 1:1 ratio on growth performance, digestibility of feed nutrients, activities of digestive enzymes in small intestine and intestinal health in broiler chickens. In experiment 1, 112 one-day-old male chickens were randomly divided into 2 groups with 8 replicates of 7 chickens each. In experiment 2, 84 one-day-old male chickens were randomly allocated into 2 groups consisting 6 replicates of 7 chickens each. The experimental diets both consisted of a maize-soybean basal control diet supplemented with 0% or 2% ZA. The diets were fed from 1 to 42 days of age. The results showed that ZA supplementation could increase body weight gain (BWG) and feed intake (FI), but had no significant effect on feed conversion ratio. The apparent digestibility values of crude protein and gross energy were significantly increased (p<0.05) by ZA from 14 to 16 d and 35 to 37 d. Dietary ZA treatment significantly increased (p<0.05) the activities of amylase, lipase and trypsin in jejunal digesta and the activities of maltase and sucrase in jejunal mucosa on days 21 and 42. The ZA supplementation also significantly increased (p<0.05) the catalase activity, reduced (p<0.05) the malondialdehyde concentration in the jejunal mucosa. In addition, a decrease of serum diamine oxidase activity and an increase (p<0.05) in concentration of secretory immunoglobulin A in jejunal mucosa were observed in birds treated with ZA on 21 and 42 days. It is concluded that ZA supplementation (2%) could partially improve the growth performance by increasing BWG and FI. This improvement was achieved through increasing the secretion of digestive enzymes, enhancing the digestibilites of nutrients, promoting intestinal health of broiler chickens. PMID:25178375

Prevalence of bisphosphonate-related osteonecrosis of the jaw-like lesions is increased in a chemotherapeutic dose-dependent manner in mice.

PubMed

Kuroshima, Shinichiro; Sasaki, Muneteru; Nakajima, Kazunori; Tamaki, Saki; Hayano, Hiroki; Sawase, Takashi

2018-07-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) worsens oral health-related quality of life. Most BRONJ occurs in multiple myeloma or metastatic breast cancer patients treated with bisphosphonate/chemotherapeutic combination therapies. Cyclophosphamide (CY), an alkylating chemotherapeutic drug, is used to treat multiple myeloma, although its use has been recently reduced. The aim of this study was to clarify the effects of CY dose on tooth extraction socket healing when CY is used with or without bisphosphonate in mice. Low-dose CY (50 mg/kg; CY-L), moderate-dose CY (100 mg/kg; CY-M), high-dose CY (150 mg/kg; CY-H), and bisphosphonate [Zometa (ZA): 0.05 mg/kg] were administered for 7 weeks. Each dose of CY and ZA in combination was also administered for 7 weeks. Both maxillary first molars were extracted at 3 weeks after the initiation of drug administration. Euthanasia was performed at 4 weeks post-extraction. Gross wound healing, microcomputed tomography analysis, histomorphometry, and immunohistochemistry were used to quantitatively evaluate osseous and soft tissue wound healing of tooth extraction sockets. ZA monotherapy induced no BRONJ-like lesions in mice. CY monotherapy rarely induced open wounds, though delayed osseous wound healing occurred in a CY dose-dependent manner. In contrast, CY/ZA combination therapy prevalently induced BRONJ-like lesions with compromised osseous and soft tissue healing in a CY dose-dependent manner. Interestingly, anti-angiogenesis was noted regardless of CY dose and ZA administration, even though only CY-M/ZA and CY-H/ZA combination therapies induced BRONJ-like lesions. Our findings suggest that high-dose CY may be associated with the development of BRONJ following tooth extraction only when CY is used together with ZA. In addition to anti-angiogenesis, other factors may contribute to the pathoetiology of BRONJ. Copyright © 2018 Elsevier Inc. All rights reserved.

Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model.

PubMed

Ersan, N; van Ruijven, L J; Bronckers, A L J J; Olgaç, V; Ilgüy, D; Everts, V

2014-01-01

The objectives of this study were to establish a bisphosphonate-related osteonecrosis of the jaw (BRONJ) rat model and to analyse the effects of teriparatide (TP) on this model. Sprague-Dawley rats were divided into three groups: I-zoledronic acid (ZA, n = 10); II-ZA and teriparatide (ZA + TP, n = 10); III-control (n = 10). Osteonecrosis was induced by administering zoledronic acid to groups ZA and ZA + TP. A week after the injections, rats underwent extraction of the first left mandibular molar. Following a four week period, TP was administered to the ZA + TP group for 28 days. Upon killing, extraction sockets were examined clinically, radiologically and histopathologically. Clinical examination revealed necrotic bone exposure in none of the animals. MicroCT (µCT) examination showed that bone mineral density of the newly formed bone in the extraction socket was lower in the ZA group than in the ZA + TP group (p < 0.05). Histopathological examination revealed that only the ZA and ZA + TP groups developed osteonecrosis, and the osteonecrotic bone area in the ZA group was larger than that in the ZA + TP group (p < 0.05). Tartrate-resistant acid phosphatase (TRAcP) enzyme histochemistry revealed that the number of detached and large osteoclasts were higher in the ZA group than in other groups, whereas the number of apoptotic osteoclasts in both ZA and ZA + TP groups were higher than in the control group (p < 0.05). Our data indicate that bisphosphonate-related osteonecrosis of the jaw model used in the present study is an attractive model to investigate treatment modalities and that TP might be an effective treatment in BRONJ.

Effect of different doses of zoledronic acid in establishing of bisphosphonate-related osteonecrosis.

PubMed

Silva, Paulo Goberlânio de Barros; Ferreira Junior, Antonio Ernando Carlos; Teófilo, Carolina Rodrigues; Barbosa, Maritza Cavalcante; Lima Júnior, Roberto César Pereira; Sousa, Fabrício Bitú; Mota, Mário Rogério Lima; Ribeiro, Ronaldo de Albuquerque; Alves, Ana Paula Negreiros Nunes

2015-09-01

To establish osteonecrosis of the jaws in rats treated with different doses of zoledronic acid (ZA). Male Wistar rats (n=6-7) received three consecutive weekly intravenous ZA infusions at doses of 0.04, 0.20 or 1.00mg/kg ZA or saline (control). Four weeks after the last administration, the animals were submitted to simple extraction of the lower left first molar. An additional dose of ZA was administered seven days later, and the animals were sacrificed 28 days after exodontia. Weight was measured and blood was collected weekly for analysis. The jaw was radiographically and microscopically examined along with the liver, spleen, kidney and stomach. All ZA doses showed a higher radiolucent area than the control (p<0.0001), but the dose of 0.04mg/kg did not show BRONJ. Doses of 0.20 and 1.00mg/kg ZA showed histological evidence of bone necrosis (p=0.0004). Anaemia (p<0.0001, r(2)=0.8073) and leucocytosis (p<0.0001, r(2)=0.9699) are seen with an increase of lymphocytes (p<0.0001, r(2)=0.6431) and neutrophils and monocytes (p=0.0218, r(2)=0.8724) in all the animals treated with an increasing dose of ZA. Haemorrhage and ectasia were observed in the spleen (p=0.0004) and stomach (p=0.0168) in a dose-dependent manner, and the animals treated with ZA showed a lower rate of weight gain (p<0.0001). We designed a bisphosphonate-related osteonecrosis of the jaw model that reproduces radiographic and histological parameters and mimics clinical alterations such as leucocytosis, anaemia and idiosyncratic inflammatory post infusion reactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Utility of 18F-fluorodeoxy glucose and 18F-sodium fluoride positron emission tomography/computed tomography in the diagnosis of medication-related osteonecrosis of the jaw: A preclinical study in a rat model.

PubMed

Kim, Yemi; Lee, Ho-Young; Yoon, Hai-Jeon; Kim, Bom Sahn

2016-04-01

The aim of this study was to determine the clinical utility of positron emission tomography/computed tomography (PET/CT) using 18F-FDG and 18F-NaF for the diagnosis of osteonecrosis of the jaw (ONJ), by observing characteristics in rat models treated with zoledronic acid (ZA) and/or dexamethasone (DX) followed by tooth extraction. A total of 48 rats were divided randomly into four groups: Group 1, rats treated with ZA and DX; Group 2, rats treated with ZA; Group 3, rats treated with DX; and Group 4, rats treated with vehicle as normal controls. They underwent examinations with both 18F-FDG and 18F-NaF PET/CT at 4 weeks prior to tooth extraction (baseline) and 4 weeks after tooth extraction. Rats were then sacrificed to evaluate the histological incidence and characteristics of ONJ. Histological and radiological characteristics of all groups were compared to assess the effects of medication and tooth extraction. Baseline PET/CT studies using 18F-FDG and 18F-NaF showed no difference in uptake among the groups. However, 18F-FDG PET/CT performed at 4 weeks after tooth extraction showed increased glucose metabolism at the extraction site in both the ZA/DX and the ZA-only groups compared with that in the vehicle-treated group, in accordance with the higher incidence of histological ONJ (p < 0.05, respectively). 18F-NaF PET/CT performed at 4 weeks after tooth extraction showed decreased bone uptake in the extraction site in the ZA/DX, ZA, and DX groups versus the vehicle group (all p < 0.05), but this was not correlated with the incidence of histological ONJ. The incidence of ONJ was highest in the ZA/DX group (66.7%), followed by the ZA group, both of which were significantly higher than in the DX and vehicle groups (both p < 0.05). 18F-FDG PET/CT as an inflammatory marker appeared to be a more appropriate imaging modality than 18F-NaF PET/CT in diagnosing ONJ in a rat model including a ZA/DX group. However, the decreased bone remodeling tendency highlighted by 18F

Ultrastructural changes in cardiac myocytes from Boxer dogs with arrhythmogenic right ventricular cardiomyopathy

PubMed Central

Oxford, Eva M.; Danko, Charles G.; Kornreich, Bruce G.; Maass, Karen; Hemsley, Shari A.; Raskolnikov, Dima; Fox, Philip R.; Delmar, Mario; Moïse, N. Sydney

2011-01-01

Objectives We sought to quantify the number and length of desmosomes, gap junctions, and adherens junctions in arrhythmogenic right ventricular cardiomyopathy (ARVC) and non-ARVC dogs, and to determine if ultrastructural changes existed. Animals Hearts from 8 boxer dogs afflicted with histopathologically confirmed ARVC and 6 dogs without ARVC were studied. Methods Quantitative transmission electron microscopy (TEM) and Western blot semi-quantification of α-actinin were used to study the intercalated disc and sarcomere of the right and left ventricles. Results When ARVC dogs were compared to non-ARVC dogs reductions in the number of desmosomes (P = 0.04), adherens junctions (P = 0.04) and gap junctions (P = 0.02) were found. The number of gap junctions (P = 0.04) and adherens junctions (P = 0.04) also were reduced in the left ventricle, while the number of desmosomes was not (P = 0.88). A decrease in the length of desmosomal complexes within LV samples (P=0.04) was found. These findings suggested disruption of proteins providing attachment of the cytoskeleton to the intercalated disc. Immunoblotting did not demonstrate a quantitative reduction in the amount of α-actinin in ARVC afflicted samples. All boxers with ARVC demonstrated the presence of electron dense material originating from the Z band and extending into the sarcomere, apparently at the expense of the cytoskeletal structure. Conclusions These results emphasize the importance of structural integrity of the intercalated disc in the pathogenesis of ARVC. In addition, observed abnormalities in sarcomeric structure suggest a novel link between ARVC and the actin-myosin contractile apparatus. PMID:21636338

Dissecting the roles of ROCK isoforms in stress-induced cell detachment.

PubMed

Shi, Jianjian; Surma, Michelle; Zhang, Lumin; Wei, Lei

2013-05-15

The homologous Rho kinases, ROCK1 and ROCK2, are involved in stress fiber assembly and cell adhesion and are assumed to be functionally redundant. Using mouse embryonic fibroblasts (MEFs) derived from ROCK1(-/-) and ROCK2(-/-) mice, we have recently reported that they play different roles in regulating doxorubicin-induced stress fiber disassembly and cell detachment: ROCK1 is involved in destabilizing the actin cytoskeleton and cell detachment, whereas ROCK2 is required for stabilizing the actin cytoskeleton and cell adhesion. Here, we present additional insights into the roles of ROCK1 and ROCK2 in regulating stress-induced impairment of cell-matrix and cell-cell adhesion. In response to doxorubicin, ROCK1(-/-) MEFs showed significant preservation of both focal adhesions and adherens junctions, while ROCK2(-/-) MEFs exhibited impaired focal adhesions but preserved adherens junctions compared with the wild-type MEFs. Additionally, inhibition of focal adhesion or adherens junction formations by chemical inhibitors abolished the anti-detachment effects of ROCK1 deletion. Finally, ROCK1(-/-) MEFs, but not ROCK2(-/-) MEFs, also exhibited preserved central stress fibers and reduced cell detachment in response to serum starvation. These results add new insights into a novel mechanism underlying the anti-detachment effects of ROCK1 deletion mediated by reduced peripheral actomyosin contraction and increased actin stabilization to promote cell-cell and cell-matrix adhesion. Our studies further support the differential roles of ROCK isoforms in regulating stress-induced loss of central stress fibers and focal adhesions as well as cell detachment.

Cost-effectiveness Analysis of Denosumab in the Prevention of Skeletal-related Events in Patients with Prostate Cancer in Kazakhstan.

PubMed

Bektur, Carina; Nurgozhin, Talgat

2014-01-01

Bone mass loss (BML) is one of the adverse effects of oncological chemotherapy, especially in cases of hormonal types of cancer, such as a prostate cancer (PC). BML is strongly associated with skeletal-related events (SREs), therefore decreasing the quality of patient's life. Denosumab shows an advantage over zoledronic acid (ZA) in delaying the first onset of SREs and subsequent SREs in adults with PC in several phase III clinical trials. Since generic ZA recently became available, the purpose of the present study was to assess the cost-effectiveness of denosumab vs. brand or generic ZA in the prevention of SREs in Kazakhstani patients with PC. A Markov model was constructed in Tree-Age Pro 2013 software program with 4-week model cycles to analyze the cost-effectiveness of the treatments from the perspective of Ministry of Health (MoH) over a 10-year PC cohort. Direct costs (in Kazakhstani monetary units "tenge" in 2014) included costs of drug, SRE (pathologic fracture, surgery to bone, radiation to bone, spinal cord compression), and adverse events treatment. All costs were discounted for 3% per year. Effectiveness was appraised based on the number of SREs. Health states were defined according to SRE occurrence, SRE history, and death. The model assumed that a maximum of 1 SRE could occur in each cycle. Transition probabilities were derived from the relevant phase III trials. Results were present in the incremental total cost per SRE avoided. One-way sensitivity analyses were performed to examine the robustness of the model. Over the 10-year period, denosumab incurred 103,091 tenge higher costs than brand ZA, 677,133 tenge higher costs than generic ZA, and 0.58 fewer SREs per patient with PC. The estimated incremental total direct costs per SRE avoided with the use of denosumab were 177,743 tenge (instead of brand ZA) and 1,167,470 tenge (instead of generic ZA). Results were robust to one-way sensitivity analyses. With the assumption that brand and generic ZAs

Bone turnover and periprosthetic bone loss after cementless total hip arthroplasty can be restored by zoledronic acid: a prospective, randomized, open-label, controlled trial.

PubMed

Huang, Tsan-Wen; Wang, Chao-Jan; Shih, Hsin-Nung; Chang, Yuhan; Huang, Kuo-Chin; Peng, Kuo-Ti; Lee, Mel S

2017-05-22

Although the loss of bone mineral density (BMD) after total hip arthroplasty (THA) is a known problem, it remains unresolved. This study prospectively examined the effect of zoledronic acid (ZA) on bone turnover and BMD after cementless THA. Between January 2010 and August 2011, 60 patients who underwent cementless THA were randomly assigned to receive either ZA infusion or placebo (0.9% normal saline only) postoperatively. ZA was administered at 2 day and 1 year postoperatively. Periprosthetic BMD in seven Gruen zones was assessed preoperatively and at given time points for 2 years. Serum markers of bone turnover, functional scales, and adverse events were recorded. Each group contained 27 patients for the final analysis. The loss of BMD across all Gruen zones (significantly in zones 1 and 7) up to 2 years postoperatively was noted in the placebo group. BMD was significantly higher in the ZA group than in the placebo group in Gruen zones 1, 2, 6, and 7 at 1 year and in Gruen zones 1, 6, and 7 at 2 years (p < 0.05). Compared with baseline measures of BMD, the ZA group had increased BMD in zones 1, 2, 4, 5, 6, and 7 at 1 year and in zones 1, 4, 6, and 7 at 2 years (p < 0.05). Serum bone-specific alkaline phosphatase and N-telopeptide of procollagen I levels were significantly increased at 6 weeks in the placebo group and decreased after 3 months in the ZA group. A transient decrease in osteocalcin level was found at 6 months in the ZA group. Functional scales and adverse events were not different between the two groups. The loss of periprosthetic BMD, especially in the proximal femur (zones 1 and 7), after cementless THA could be effectively reverted using ZA. In addition, bone turnover markers were suppressed until 2 years postoperatively following ZA administration. Chang Gung Memorial Hospital Protocol Record 98-1150A3, Prevention of Periprosthetic Bone Loss After Total Hip Replacement by Annual Bisphosphonate Therapy, has been reviewed and

The anti-tumour effects of zoledronic acid

PubMed Central

Zekri, Jamal; Mansour, Maged; Karim, Syed Mustafa

2014-01-01

Bone is the most common site for metastasis in patients with solid tumours. Bisphosphonates are an effective treatment for preventing skeletal related events and preserving quality of life in these patients. Zoledronic acid (ZA) is the most potent osteoclast inhibitor and is licensed for the treatment of bone metastases. Clodronate and pamidronate are also licensed for this indication. In addition, ZA has been demonstrated to exhibit antitumour effect. Direct and indirect mechanisms of anti-tumour effect have been postulated and at many times proven. Evidence exists that ZA antitumour effect is mediated through inhibition of tumour cells proliferation, induction of apoptosis, synergistic/additive to inhibitory effect of cytotoxic agents, inhibition of angiogenesis, decrease tumour cells adhesion to bone, decrease tumour cells invasion and migration, disorganization of cell cytoskeleton and activation of specific cellular antitumour immune response. There is also clinical evidence from clinical trials that ZA improved long term survival outcome in cancer patients with and without bone metastases. In this review we highlight the preclinical and clinical studies investigating the antitumour effect of bisphosphonates with particular reference to ZA. PMID:26909294

Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.

PubMed

Komatsu, Yuko; Ibi, Miho; Chosa, Naoyuki; Kyakumoto, Seiko; Kamo, Masaharu; Shibata, Toshiyuki; Sugiyama, Yoshiki; Ishisaki, Akira

2016-07-01

Bisphosphonates (BPs) are analogues of pyrophosphate that are known to prevent bone resorption by inhibiting osteoclast activity. Nitrogen-containing BPs, such as zoledronic acid (ZA), are widely used in the treatment of osteoporosis and bone metastasis. However, despite having benefits, ZA has been reported to induce BP-related osteonecrosis of the jaw (BRONJ) in cancer patients. The molecular pathological mechanisms responsible for the development of BRONJ, including necrotic bone exposure after tooth extraction, remain to be elucidated. In this study, we examined the effects of ZA on the transforming growth factor-β (TGF‑β)-induced myofibroblast (MF) differentiation of human gingival fibroblasts (hGFs) and the migratory activity of hGFs, which are important for wound closure by fibrous tissue formation. The ZA maximum concentration in serum (Cmax) was found to be approximately 1.47 µM, which clinically, is found after the intravenous administration of 4 mg ZA, and ZA at this dose is considered appropriate for the treatment of cancer bone metastasis or bone diseases, such as Erdheim-Chester disease. At Cmax, ZA significantly suppressed i) the TGF‑β-induced promotion of cell viability, ii) the TGF‑β-induced expression of MF markers such as α-smooth muscle actin (α-SMA) and type I collagen, iii) the TGF‑β-induced migratory activity of hGFs and iv) the expression level of TGF‑β type I receptor on the surfaces of hGFs, as well as the TGF‑β-induced phosphorylation of Smad2/3. Thus, ZA suppresses TGF‑β-induced fibrous tissue formation by hGFs, possibly through the inhibition of Smad‑dependent signal transduction. Our findings partly elucidate the molecular mechanisms underlying BRONJ and may prove to be beneficial to the identification of drug targets for the treatment of this symptom at the molecular level.

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

PubMed

Andronis, Lazaros; Goranitis, Ilias; Pirrie, Sarah; Pope, Ann; Barton, Darren; Collins, Stuart; Daunton, Adam; McLaren, Duncan; O'Sullivan, Joe M; Parker, Chris; Porfiri, Emilio; Staffurth, John; Stanley, Andrew; Wylie, James; Beesley, Sharon; Birtle, Alison; Brown, Janet E; Chakraborti, Prabir; Hussain, Syed A; Russell, J Martin; Billingham, Lucinda J; James, Nicholas D

2017-04-01

To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC). Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the National Health Service in the UK and included expenditures for trial treatments, concomitant medications, and use of related hospital and primary care services. Quality-adjusted life-years (QALYs) were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument, which evaluates health status. Results are expressed as incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. The per-patient cost for ZA was £12 667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group had on average 0.03 QALYs more than their counterparts in no ZA group. The ICER for this comparison was £8 005. Sr89 was associated with a cost of £13 230, £1365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16 884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively. The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources. © 2016 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.

How to Prune Trees, Jinsi Kupogoa Mti, Swahili version

Treesearch

Peter Bedker; Joseph O' Brien; Manfred Mielke

1995-01-01

Utangulizi-Lengo la kupogoa miti ni kupata mimea yenye afya, nguvu, na ya kuvutia. Lengo hilo litafikiwa kwa kufuata taratibu za kupogoa, na kwa kuelewa namna gani, wakati gani, na sababu za kupogoa miti.

Design of small-scale gradient coils in magnetic resonance imaging by using the topology optimization method

NASA Astrophysics Data System (ADS)

Pan, Hui; Jia, Feng; Liu, Zhen-Yu; Zaitsev, Maxim; Hennig, Juergen; Korvink, Jan G.

2018-05-01

Not Available Project supported by the National Natural Science Foundation of China (Grant Nos. 51675506 and 51275504) and the German Research Foundation (DFG) (Grant Nos. #ZA 422/5-1 and #ZA 422/6-1).

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.

PubMed

James, Nicholas D; Pirrie, Sarah J; Pope, Ann M; Barton, Darren; Andronis, Lazaros; Goranitis, Ilias; Collins, Stuart; Daunton, Adam; McLaren, Duncan; O'Sullivan, Joe; Parker, Christopher; Porfiri, Emilio; Staffurth, John; Stanley, Andrew; Wylie, James; Beesley, Sharon; Birtle, Alison; Brown, Janet; Chakraborti, Prabir; Hussain, Syed; Russell, Martin; Billingham, Lucinda J

2016-04-01

Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression-free interval, total SREs, and overall survival (OS). Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect

Fine structure of the ependyma and intercellular junctions in the area postrema of the rat.

PubMed

Gotow, T; Hashimoto, P H

1979-09-03

Ependymal cells and their junctional complexes in the area postrema of the rat were studied in detail by tracer experiments using horseradish peroxidase (HRP) and colloidal lanthanum and by freeze-etch techniques, in addition to routine electron microscopy. The ependyma of the area postrema is characterized as flattened cells possessing very few cilia, a moderate amount of microvilli, a well-developed Golgi apparatus and rough endoplasmic reticulum. Numerous vesicles or tubular formations with internal dense content were found to accumulate in the basal processes of ependymal cells; the basal process makes contact with the perivascular basal lamina. It is suggested that the dense material in the tubulovesicular formations is synthesized within the ependymal cell and discharged into the perivascular space. The apical junctions between adjacent ependymal cells display very close apposition, with a gap of 2--3 nm, but no fusion of adjacent plasma membranes; they thus represent a transitional form between the zonulae adhaerentes present in the ordinary mural ependyma and the zonulae occludentes in the choroidal epithelium. A direct intercommunication between the ventricular cerebrospinal fluid (CSF) and the blood vascular system indicates that a region exists lacking a blood-ventricular CSF barrier.

The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species.

PubMed

Monaghan-Benson, Elizabeth; Burridge, Keith

2009-09-18

Vascular permeability is a complex process involving the coordinated regulation of multiple signaling pathways in the endothelial cell. It has long been documented that vascular endothelial growth factor (VEGF) greatly enhances microvascular permeability; however, the molecular mechanisms controlling VEGF-induced permeability remain unknown. Treatment of microvascular endothelial cells with VEGF led to an increase in reactive oxygen species (ROS) production. ROS are required for VEGF-induced permeability as treatment with the free radical scavenger, N-acetylcysteine, inhibited this effect. Additionally, treatment with VEGF caused ROS-dependent tyrosine phosphorylation of both vascular-endothelial (VE)-cadherin and beta-catenin. Rac1 was required for the VEGF-induced increase in permeability and adherens junction protein phosphorylation. Knockdown of Rac1 inhibited VEGF-induced ROS production consistent with Rac lying upstream of ROS in this pathway. Collectively, these data suggest that VEGF leads to a Rac-mediated generation of ROS, which, in turn, elevates the tyrosine phosphorylation of VE-cadherin and beta-catenin, ultimately regulating adherens junction integrity.

Connexins and Cadherin Crosstalk in the Pathogenesis of Prostate Cancer

DTIC Science & Technology

2014-09-01

not morphological changes during an epithelium -to-mesenchyme transition . J Cell Sci 118, 873-887 30. Cotrina, M. L., and Nedergaard, M. (2009...Rhett, J. M., Jourdan, J., and Gourdie, R. G. (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Molecular...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Gap junctions are conglomerations of cell-cell channels that are

Effect of zoledronic acid on lumbar spinal fusion in osteoporotic patients.

PubMed

Ding, Qirui; Chen, Jian; Fan, Jin; Li, Qingqing; Yin, Guoyong; Yu, Lipeng

2017-11-01

To investigate the effect of zoledronic acid (ZA) on lumbar spinal fusion in patients with osteoporosis. This retrospective study includes 94 osteoporotic patients suffering from lumbar degenerative diseases or lumbar fracture who underwent lumbar spinal fusion in our institution from January 2013 to August 2014. They were divided into ZA group and control group according to whether the patient received ZA infusion or not. The patients in ZA group were given 5 mg intravenous ZA at the 3rd-5th days after operation. All patients took daily oral supplement of 600 mg calcium carbonate and 800 IU vitamin D during the follow-up after operation. The Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Short Form 36 (SF-36) scores were recorded preoperatively and post-operatively to evaluate the clinic outcomes; the spinal fusion was assessed by X-ray or CT Scan. 64 patients finished the final follow-up, including 30 patients in ZA group and 34 patients in control group. No significant difference was observed in gender, age, and preoperative BMI VAS, ODI, and SF-36 scores between the two groups (P > 0.05). The post-operative VAS and ODI scores decreased rapidly at 3 and 6 months, but rose back slightly at 12 and 24 months in both groups. On the contrary, post-operative SF-36 scores increased rapidly at 3 and 6 months, while fell back slightly at 12 and 24 months, with a statistically significant difference between the two groups at 12 months, but not at 3 and 6 month post-operation. The spinal fusion rate in ZA group was 90% at 6 months, 92% at 12 months, while it was 75% at 6 months, 92.86% at 12 months in control group, significantly different between the two groups at 12 months, but not at 6 months. In the whole follow-up period, adjacent vertebral compressing fracture occurred in five patients in control group, none in ZA group. No pedicle screw loosening was observed in ZA group, with six in control group. Zoledronic acid accelerates

Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

PubMed Central

2014-01-01

Background Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Methods Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. Results ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. Conclusion These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs. PMID:24612486

Site Specific Effects of Zoledronic Acid during Tibial and Mandibular Fracture Repair

PubMed Central

Yu, Yan Yiu; Lieu, Shirley; Hu, Diane; Miclau, Theodore; Colnot, Céline

2012-01-01

Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading, inflammation and exogenous molecules. Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of metabolic bone diseases. Zoledronate (ZA), a nitrogen-containing bisphosphonate (N-BP), is the most potent bisphosphonate among the clinically approved bisphosphonates. Cases of bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet, osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized tibial fractures and a new model of mandibular fracture repair. Contrary to tibial fractures, which heal mainly through endochondral ossification, mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones. PMID:22359627

Enhanced repellency of binary mixtures of Zanthoxylum armatum seed oil, vanillin, and their aerosols to mosquitoes under laboratory and field conditions.

PubMed

Kwon, Hyung Wook; Kim, Soon-Il; Chang, Kyu-Sik; Clark, J Marshall; Ahn, Young-Joon

2011-01-01

The repellency of Zanthoxylum armatum seed oil (ZA-SO), alone or in combination with vanillin (VA), its six major constituents, and another four major previously known Zanthoxylum piperitum fruit oil constituents, as well as aerosol products containing 5 or 10% ZA-SO and 5% VA, was evaluated against female Aedes aegypti in laboratory and field studies. Results were then compared with those of N,N-diethyl-3-methylbenzamide (DEET) as a standard. Hand in cage laboratory tests showed that 0.2, 0.1, and 0.05 mg/cm2 ZA-SO resulted in > 92% protection through 30-min postexposure and was not significantly different than 0.05 mg/cm2 DEET. Skin treated with linalool and limonene (from Z. armatum) provided > 80% repellency to female Ae. aegypti at 10-min exposure, whereas cuminaldehyde, citronellal, geranyl acetate, and cuminyl alcohol (from Zanthoxylum piperitum) provided > 90% protection during this same time period. Only cuminaldehyde and citronellal provided complete protection comparable to DEET at 10-min postexposure. After that time, repellency of all plant constituents to mosquitoes was considerably decreased (< approximately 65%). An increase in repellency and duration of effectiveness was produced by a binary 1:4 mixture of ZA-SO and VA (0.05:0.2 mg/cm2) that was significantly more effective than 0.05 mg/cm2 DEET through 90 min. In field tests, an aerosol formulation containing 5 or 10% ZA-SO plus 5% VA gave 100% repellency at 60-min postexposure. Although these formulations were equal to the level of protection afforded by 10% DEET, repellency to the binary ZA-SO aerosol formulations at 90 min was significantly less effective than DEET. However, mixtures formulated from ZA-SO and VA merit further study as potential repellents for protection of humans and domestic animals from biting and nuisance caused by mosquitoes.

Zoledronic Acid Inhibits Aromatase Activity and Phosphorylation: Potential Mechanism for Additive Zoledronic Acid and Letrozole Drug Interaction

PubMed Central

Schech, Amanda J.; Nemieboka, Brandon E.; Brodie, Angela H.

2012-01-01

Zoledronic acid (ZA), a bisphosphonate originally indicated for use in osteoporosis, has been reported to exert a direct effect on breast cancer cells, although the mechanism of this effect is currently unknown. Data from the ABCSG-12 and ZO-FAST clinical trials suggest that treatment with the combination of ZA and aromatase inhibitors (AI) result in increased disease free survival in breast cancer patients over AI alone. To determine whether the mechanism of this combination involved inhibition of aromatase, AC-1 cells (MCF-7 human breast cancer cells transfected with an aromatase construct) were treated simultaneously with combinations of ZA and AI letrozole for 72 hours. This combination significantly increased inhibition of aromatase activity of AC-1 cells by compared to letrozole alone. Combination treatment of 1nM letrozole and 1μM and 10μM zoledronic acid resulted in an additive drug interaction on inhibiting cell viability, as measured by MTT assay. Treatment with ZA was found to inhibit phosphorylation of aromatase on serine 473. Zoledronic acid was also shown to be more effective in inhibiting cell viability in aromatase transfected AC-1 cells when compared to inhibition of cell viability observed in non-transfected MCF-7. Estradiol was able to partially rescue the effect of 1μM and 10μM ZA on cell viability following treatment for 72 hours, as shown by a shift to the right in the estradiol dose response curve. In conclusion, these results indicate that the combination of ZA and letrozole results in an additive inhibition of cell viability. Furthermore, ZA alone can inhibit aromatase activity through inhibition of serine phosphorylation events important for aromatase enzymatic activity and contributes to inhibition of cell viability. PMID:22659283

Characterization of a siberian virus isolated from a patient with progressive chronic tick-borne encephalitis.

PubMed

Gritsun, T S; Frolova, T V; Zhankov, A I; Armesto, M; Turner, S L; Frolova, M P; Pogodina, V V; Lashkevich, V A; Gould, E A

2003-01-01

A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in Siberia from a patient who died of a progressive (2-year) form of tick-borne encephalitis 10 years after being bitten by a tick. The complete genomic sequence of this virus was determined, and an attempt was made to correlate the sequence with the biological characteristics of the virus. Phylogenetic analysis demonstrated that this virus belongs to the Siberian subtype of Tick-borne encephalitis virus. Comparison of Za virus with two related viruses, a Far Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed differences among the three viruses in pathogenicity for Syrian hamsters, cytopathogenicity for PS cells, plaque morphology, and the electrophoretic profiles of virus-specific nonstructural proteins. Comparative amino acid alignments revealed 10 individual amino acid substitutions in the Za virus polyprotein sequence that were different from those of other tick-borne flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in polyacrylamide gels as a heterogeneous group of molecules with a significantly higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses. Two amino acid substitutions, T(277)-->V and E(279)-->G, within the NS1 dimerization domain are probably responsible for the altered oligomerization of Za virus NS1. These studies suggest that the patient from whom Za virus was isolated died due to increased pathogenicity of the latent virus following spontaneous mutagenesis.

Characterization of a Siberian Virus Isolated from a Patient with Progressive Chronic Tick-Borne Encephalitis

PubMed Central

Gritsun, T. S.; Frolova, T. V.; Zhankov, A. I.; Armesto, M.; Turner, S. L.; Frolova, M. P.; Pogodina, V. V.; Lashkevich, V. A.; Gould, E. A.

2003-01-01

A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in Siberia from a patient who died of a progressive (2-year) form of tick-borne encephalitis 10 years after being bitten by a tick. The complete genomic sequence of this virus was determined, and an attempt was made to correlate the sequence with the biological characteristics of the virus. Phylogenetic analysis demonstrated that this virus belongs to the Siberian subtype of Tick-borne encephalitis virus. Comparison of Za virus with two related viruses, a Far Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed differences among the three viruses in pathogenicity for Syrian hamsters, cytopathogenicity for PS cells, plaque morphology, and the electrophoretic profiles of virus-specific nonstructural proteins. Comparative amino acid alignments revealed 10 individual amino acid substitutions in the Za virus polyprotein sequence that were different from those of other tick-borne flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in polyacrylamide gels as a heterogeneous group of molecules with a significantly higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses. Two amino acid substitutions, T277→V and E279→G, within the NS1 dimerization domain are probably responsible for the altered oligomerization of Za virus NS1. These studies suggest that the patient from whom Za virus was isolated died due to increased pathogenicity of the latent virus following spontaneous mutagenesis. PMID:12477807

N-cadherin expression in palisade nerve endings of rat vellus hairs.

PubMed

Kaidoh, Toshiyuki; Inoué, Takao

2008-02-01

Palisade nerve endings (PNs) are mechanoreceptors around vellus hairs of mammals. Each lanceolate nerve ending (LN) of the PN is characterized by a sensory nerve ending symmetrically sandwiched by two processes of type II terminal Schwann cells (tSCIIs). However, the molecular mechanisms underlying the structural organization of the PN are poorly understood. Electron microscopy showed that adherens junctions appeared to adhere to the sensory nerve ending and tSCII processes, so we examined the location of the N-cadherin adhesion system in PNs of rat vellus hairs by using immunoelectron microscopy. N-cadherin localized near both ends of the cell boundary between sensory nerve ending and tSCII processes, which corresponded to the sites of adherens junctions. We further found cadherin-associated proteins, alpha- and beta-catenins, at the linings of adherens junctions. Three-dimensional reconstruction of immunoelectron microscopic serial thin sections showed four linear arrays of N-cadherin arranged longitudinally along the LN beneath the four longitudinal borders of two tSCII processes. In contrast, sensory nerve fibers just proximal to the LNs formed common unmyelinated nerve fibers, in which N-cadherin was located mainly at the mesaxon of type I terminal Schwann cells (tSCIs). These results suggest that the four linear arrays of N-cadherin-mediated junctions adhere the sensory nerve ending and tSCII processes side by side to form the characteristic structure of the LN, and the structural differences between the LNs and the proximal unmyelinated nerve fibers possibly are due to the difference in the pattern of N-cadherin expression between sensory nerve endings and tSCII or tSCI processes. (c) 2007 Wiley-Liss, Inc.

Glutamine Supplementation Attenuates Ethanol-Induced Disruption of Apical Junctional Complexes in Colonic Epithelium and Ameliorates Gut Barrier Dysfunction and Fatty Liver in Mice

PubMed Central

Chaudhry, Kamaljit K.; Shukla, Pradeep K.; Mir, Hina; Manda, Bhargavi; Gangwar, Ruchika; Yadav, Nikki; McMullen, Megan; Nagy, Laura E.; Rao, RadhaKrishna

2015-01-01

Previous in vitro studies showed that glutamine (Gln) prevents acetaldehyde-induced disruption of tight junctions and adherens junctions in Caco-2 cell monolayers and human colonic mucosa. In the present study, we evaluated the effect of Gln supplementation on ethanol-induced gut barrier dysfunction and liver injury in mice in vivo. Ethanol feeding caused a significant increase in inulin permeability in distal colon. Elevated permeability was associated with a redistribution of tight junction and adherens junction proteins and depletion of detergent-insoluble fractions of these proteins, suggesting that ethanol disrupts apical junctional complexes in colonic epithelium and increases paracellular permeability. Ethanol-induced increase in colonic mucosal permeability and disruption of junctional complexes were most severe in mice fed Gln-free diet. Gln supplementation attenuated ethanol-induced mucosal permeability and disruption of tight junctions and adherens junctions in a dose-dependent manner, indicating the potential role of glutamine in nutritional intervention to alcoholic tissue injury. Gln supplementation dose-dependently elevated reduced-protein thiols in colon without affecting the level of oxidized-protein thiols. Ethanol feeding depleted reduced protein thiols and elevated oxidized protein thiols. Ethanol-induced protein thiol oxidation was most severe in mice fed Gln-free diet and absent in mice fed Gln-supplemented diet, suggesting that antioxidant effect is one of the likely mechanisms involved in Gln-mediated amelioration of ethanol-induced gut barrier dysfunction. Ethanol feeding elevated plasma transaminase and liver triglyceride, which was accompanied by histopathologic lesions in the liver; ethanol-induced liver damage was attenuated by Gln supplementation. These results indicate that Gln supplementation ameliorates alcohol-induced gut and liver injury. PMID:26365579

Assessing Global Transcriptome Changes in Response to South African Cassava Mosaic Virus [ZA-99] Infection in Susceptible Arabidopsis thaliana.

PubMed

Pierce, Erica J; Rey, M E Chrissie

2013-01-01

In susceptible plant hosts, co-evolution has favoured viral strategies to evade host defenses and utilize resources to their own benefit. The degree of manipulation of host gene expression is dependent on host-virus specificity and certain abiotic factors. In order to gain insight into global transcriptome changes for a geminivirus pathosystem, South African cassava mosaic virus [ZA:99] and Arabidopsis thaliana, 4×44K Agilent microarrays were adopted. After normalization, a log2 fold change filtering of data (p<0.05) identified 1,743 differentially expressed genes in apical leaf tissue. A significant increase in differential gene expression over time correlated with an increase in SACMV accumulation, as virus copies were 5-fold higher at 24 dpi and 6-fold higher at 36 dpi than at 14 dpi. Many altered transcripts were primarily involved in stress and defense responses, phytohormone signalling pathways, cellular transport, cell-cycle regulation, transcription, oxidation-reduction, and other metabolic processes. Only forty-one genes (2.3%) were shown to be continuously expressed across the infection period, indicating that the majority of genes were transient and unique to a particular time point during infection. A significant number of pathogen-responsive genes were suppressed during the late stages of pathogenesis, while during active systemic infection (14 to 24 dpi), there was an increase in up-regulated genes in several GO functional categories. An adaptive response was initiated to divert energy from growth-related processes to defense, leading to disruption of normal biological host processes. Similarities in cell-cycle regulation correlated between SACMV and Cabbage leaf curl virus (CaLCuV), but differences were also evident. Differences in gene expression between the two geminiviruses clearly demonstrated that, while some global transcriptome responses are generally common in plant virus infections, temporal host-specific interactions are required for

Assessing Global Transcriptome Changes in Response to South African Cassava Mosaic Virus [ZA-99] Infection in Susceptible Arabidopsis thaliana

PubMed Central

Pierce, Erica J.; Rey, M. E. Chrissie

2013-01-01

In susceptible plant hosts, co-evolution has favoured viral strategies to evade host defenses and utilize resources to their own benefit. The degree of manipulation of host gene expression is dependent on host-virus specificity and certain abiotic factors. In order to gain insight into global transcriptome changes for a geminivirus pathosystem, South African cassava mosaic virus [ZA:99] and Arabidopsis thaliana, 4×44K Agilent microarrays were adopted. After normalization, a log2 fold change filtering of data (p<0.05) identified 1,743 differentially expressed genes in apical leaf tissue. A significant increase in differential gene expression over time correlated with an increase in SACMV accumulation, as virus copies were 5-fold higher at 24 dpi and 6-fold higher at 36 dpi than at 14 dpi. Many altered transcripts were primarily involved in stress and defense responses, phytohormone signalling pathways, cellular transport, cell-cycle regulation, transcription, oxidation-reduction, and other metabolic processes. Only forty-one genes (2.3%) were shown to be continuously expressed across the infection period, indicating that the majority of genes were transient and unique to a particular time point during infection. A significant number of pathogen-responsive genes were suppressed during the late stages of pathogenesis, while during active systemic infection (14 to 24 dpi), there was an increase in up-regulated genes in several GO functional categories. An adaptive response was initiated to divert energy from growth-related processes to defense, leading to disruption of normal biological host processes. Similarities in cell-cycle regulation correlated between SACMV and Cabbage leaf curl virus (CaLCuV), but differences were also evident. Differences in gene expression between the two geminiviruses clearly demonstrated that, while some global transcriptome responses are generally common in plant virus infections, temporal host-specific interactions are required for

Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathway.

PubMed

Wang, Ming; Chen, Dan-Qian; Wang, Min-Chang; Chen, Hua; Chen, Lin; Liu, Dan; Zhao, Hui; Zhao, Ying-Yong

2017-12-01

The pathogenesis of tubulo-interstitial fibrosis and glomerulosclerosisis was characterized by cellular hypertrophy, extracellular matrix accumulation and podocyte detachment. Poricoic acid ZA (PZA) is a tetracyclic triterpenoid compound extracted from the surface layer of Poria cocos (LPC), which have been used extensively for diuretic and renoprotective effects. The anti-fibrotic effect of PZA is investigated in HK-2 cells and podocytes induced by TGF-β1 and angiotensin II (ANGII). qRT-PCR, siRNA, immunofluorescence staining, co-immunoprecipitation and Western blot analyses are used to evaluate the expression of RAS signaling, TGF-β/Smad pathway, epithelial-to-mesenchymal transition (EMT) and podocyte markers. PZA restores the mRNA and protein expression of EMT in HK-2 cells. Specific TGF-β1-siRNA efficiently blocks ANGII-induced protein expression of TGF-β1 and further inhibits activated Smad signaling. PZA significantly attenuates up-regulation of angiotensinogen, renin, ACE and AT1. Further, PZA reverses up-regulation of TGFβRII and suppresses Smad proteins. Simultaneously, PZA inhibits the protein interaction of TGF-β receptor and Smads and PZA also inhibits activated RAS and TGF-β/Smad signaling cascade and up-regulates protein expression of podocyte markers and mitigates podocyte injury. This study demonstrated the beneficial role of PZA in renal fibrosis and podocyte injury. Our study highlighted that PZA inhibits RAS and further suppresses TGF-β/Smad pathway through inhibiting Smad2/3 phosphorylation via blocking Smad2/3-TGFβRI protein interaction. PZA is implicated in activation of RAS/TGF-β/Smad axis in HK-2 cells and podocytes. PZA could be considered as a novel RAS inhibitor for treating CKD. Copyright © 2017 Elsevier GmbH. All rights reserved.

Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein.

PubMed

Gerard, David A; Carlson, Eric R; Gotcher, Jack E; Pickett, David O

2014-01-01

This study was conducted with 2 purposes. The first was to determine the effect of a single dose of zoledronic acid (ZA) on the healing of a tooth extraction socket in dogs. The second was to determine if placement of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge (ACS) - INFUSE, (Medtronic, Memphis, TN) into these extraction sockets would inhibit the inhibition on bone healing and remodeling by ZA. Nine adult female beagle dogs (2 to 3 yr old) were placed into 3 groups of 3 dogs each. Group I received 15 mL of sterile saline intravenously; group II received 2.5 mg of ZA intravenously; and group III received 5 mg of ZA intravenously. Forty-five days after treatment, all dogs underwent extraction of noncontiguous right and left mandibular first molars and second premolars. In group I, the right mandibular extraction sockets had nothing placed in them, whereas the left mandibular sockets had only ACS placed in them. In groups II and III, the right mandibular sockets had rhBMP-2/ACS placed in them, whereas the left mandibular sockets had only ACS placed. All extraction sockets were surgically closed. Tetracycline was given intravenously 5 and 12 days later, and all animals were euthanized 15 days after tooth extraction. The extraction sockets and rib and femur samples were harvested immediately after euthanasia, processed, and studied microscopically. A single dose of ZA significantly inhibited healing and bone remodeling in the area of the tooth extractions. The combination of rhBMP-2/ACS appeared to over-ride some of the bone remodeling inhibition of the ZA and increased bone fill in the extraction sites, and remodeling activity in the area was noted. The effects of rhBMP-2/ACS were confined to the area of the extraction sockets because bone activity at distant sites was not influenced. A single dose of ZA administered intravenously inhibits early healing of tooth extraction sockets and bone remodeling in this animal model. The

Zoledronic Acid Induces Site-Specific Structural Changes and Decreases Vascular Area in the Alveolar Bone.

PubMed

Soares, Mariana Quirino Silveira; Van Dessel, Jeroen; Jacobs, Reinhilde; da Silva Santos, Paulo Sérgio; Cestari, Tania Mary; Garlet, Gustavo Pompermaier; Duarte, Marco Antonio Hungaro; Imada, Thaís Sumie Nozu; Lambrichts, Ivo; Rubira-Bullen, Izabel Regina Fischer

2018-03-15

The aim was to assess the effect of a relevant regimen of zoledronic acid (ZA) treatment for the study of bisphosphonate-related osteonecrosis of the jaw on alveolar bone microstructure and vasculature. A sub-objective was to use 3-dimensional imaging to describe site-specific changes induced by ZA in the alveolar bone. Five Wistar rats received ZA (0.6 mg/kg) and five (controls) received saline solution in the same volume. The compounds were administered intraperitoneally in 5 doses every 28 days. The rats were euthanized 150 days after therapy onset. The mandibles were scanned using high-resolution (14-μm) micro-computed tomography (micro-CT), decalcified, cut into slices for histologic analysis (5 μm), and stained with hematoxylin-eosin. Bone quality parameters were calculated using CT-Analyser software (Bruker, Kontich, Belgium) in 2 different volumes of interest (VOIs): the region between the first molar roots (VOI-1) and the periapical region under the first and second molars' apex (VOI-2). Blood vessel density and bone histomorphometric parameters were calculated only for the region between the roots of the first molar using AxioVision Imaging software (version 4.8; Carl Zeiss, Gottingen, Germany). ZA-treated rats showed a significant increase in percentage of bone volume and density (P < .05), with thicker and more connected trabeculae. Furthermore, the ZA group showed a significant decrease in the size of the marrow spaces and nutritive canals and in blood vessel density (P < .05). In the micro-CT evaluation, VOI-2 showed better outcomes in measuring the effect of ZA on alveolar bone. ZA treatment induced bone corticalization and decreased alveolar bone vascularization. VOI-2 should be preferred for micro-CT evaluation of the effect of bisphosphonates on alveolar bone. This analysis allowed the effect of ZA on alveolar bone and its vascularization to be characterized. The results of this analysis may add further knowledge to the understanding of

Connexins and Cadherin Cross-talk in the Pathogenesis of Prostate Cancer

DTIC Science & Technology

2014-09-01

switching: essential for behavioral but not morphological changes during an epithelium -to-mesenchyme transition . J Cell Sci 118, 873-887 30. Cotrina, M...Jourdan, J., and Gourdie, R. G. (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Molecular biology of the cell...Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Gap junctions are conglomerations of cell-cell channels that are formed

* Composite Biomaterial as a Carrier for Bone-Active Substances for Metaphyseal Tibial Bone Defect Reconstruction in Rats.

PubMed

Horstmann, Peter Frederik; Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner; Lidgren, Lars; Petersen, Michael Mørk; Tägil, Magnus

2017-12-01

Restoring lost bone is a major challenge in orthopedic surgery. Currently available treatment strategies have shortcomings, such as risk of infection, nonunion, and excessive resorption. Our primary aim was to study if a commercially available gentamicin-containing composite calcium sulfate/hydroxyapatite biomaterial (GBM) could serve as a carrier for local delivery of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA) in a tibia defect model in rats. Empty and allograft-filled defects were used as controls. A 3 × 4-mm metaphyseal bone defect was created in the proximal tibia, and the rats were grouped according to defect filling: (1) Empty, (2) Allograft, (3) GBM, (4) GBM + ZA, and (5) GBM + ZA + BMP-2. In vivo microcomputed tomography (micro-CT) images at 4 weeks showed significantly higher mineralized tissue volume (MV) in the intramedullary defect region and the neocortical/callus region in all GBM-treated groups. After euthanization at 8 weeks, ex vivo micro-CT showed that addition of ZA (GBM + ZA) and BMP-2 (GBM + ZA + BMP-2) mainly increased the neocortical and callus formation, with the highest MV in the combined ZA and BMP-2-treated group. Qualitative histological analysis, verifying the increased neocortical/callus thickness and finding of trabecular bone in all GBM-treated groups, supported that the differences in MV measured with micro-CT in fact represented bone tissue. In conclusion, GBM can serve as a carrier for ZA and BMP-2 leading to increased MV in the neocortex and callus of a metaphyseal bone defect in rats.

Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta.

PubMed

Little, David G; Peacock, Lauren; Mikulec, Kathy; Kneissel, Michaela; Kramer, Ina; Cheng, Tegan L; Schindeler, Aaron; Munns, Craig

2017-08-01

In this study, we examined the therapeutic potential of anti-Sclerostin Antibody (Scl-Ab) and bisphosphonate treatments for the bone fragility disorder Osteogenesis Imperfecta (OI). Mice with the Amish OI mutation (Col1a2 G610C mice) and control wild type littermates (WT) were treated from week 5 to week 9 of life with (1) saline (control), (2) zoledronic acid given 0.025mg/kg s.c. weekly (ZA), (3) Scl-Ab given 50mg/kg IV weekly (Scl-Ab), or (4) a combination of both (Scl-Ab/ZA). Functional outcomes were prioritized and included bone mineral density (BMD), bone microarchitecture, long bone bending strength, and vertebral compression strength. By dual-energy absorptiometry, Scl-Ab treatment alone had no effect on tibial BMD, while ZA and Scl-Ab/ZA significantly enhanced BMD by week 4 (+16% and +27% respectively, P<0.05). Scl-Ab/ZA treatment also led to increases in cortical thickness and tissue mineral density, and restored the tibial 4-point bending strength to that of control WT mice. In the spine, all treatments increased compression strength over controls, but only the combined group reached the strength of WT controls. Scl-Ab showed greater anabolic effects in the trabecular bone than in cortical bone. In summary, the Scl-Ab/ZA intervention was superior to either treatment alone in this OI mouse model, however further studies are required to establish its efficacy in other preclinical and clinical scenarios. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer

PubMed Central

Murray, Shannon; Witt, Kristina; Seitz, Christina; Wallerius, Majken; Xie, Hanjing; Ullén, Anders; Harmenberg, Ulrika; Lidbrink, Elisabet; Rolny, Charlotte; Andersson, John

2017-01-01

ABSTRACT Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer. PMID:28920001

DoD Manual for Standard Data Elements

DTIC Science & Technology

1989-07-01

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Gelatin- hydroxyapatite- calcium sulphate based biomaterial for long term sustained delivery of bone morphogenic protein-2 and zoledronic acid for increased bone formation: In-vitro and in-vivo carrier properties.

PubMed

Raina, Deepak Bushan; Larsson, David; Mrkonjic, Filip; Isaksson, Hanna; Kumar, Ashok; Lidgren, Lars; Tägil, Magnus

2018-02-28

In this study, a novel macroporous composite biomaterial consisting of gelatin-hydroxyapatite-calcium sulphate for delivery of bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) has been developed. The biomaterial scaffold has a porous structure and functionalization of the scaffold with rhBMP-2 induces osteogenic differentiation of MC3T3-e1 cells seen by a significant increase in biochemical and genetic markers of osteoblastic differentiation. In-vivo muscle pouch experiments showed higher mineralization using scaffold+rhBMP-2 when compared to an approved absorbable collagen sponge (ACS)+rhBMP-2 as verified by micro-CT. Co-delivery of rhBMP-2+ZA via the novel scaffold enabled a reduction in the effective rhBMP-2 doses. The presence of tartrate resistant acid phosphatase staining in the rhBMP-2 group indicates osteoclastic resorption, which could be stalled by adding ZA, which by speculation could explain the net increase in mineralization. The new scaffold allowed for slow release of rhBMP-2 in-vitro (3.3±0.1%) after 4weeks. Using single photon emission computed tomography (SPECT), the release kinetics of 125 I-rhBMP-2 in-vivo was followed for 4weeks and a total of 65.3±15.2% 125 I-rhBMP-2 was released from the scaffolds. In-vitro 14 C-ZA release curve shows an initial burst release on day 1 (8.8±0.7%) followed by a slow release during the following 4weeks (13±0.1%). In-vivo, an initial release of 43.2±7.6% of 14 C-ZA was detected after 1day, after which the scaffold retained the remaining ZA during 4-weeks. Taken together, our results show that the developed biomaterial is an efficient carrier for spatio-temporal delivery of rhBMP-2 and ZA leading to increased bone formation compared to commercially available carrier for rhBMP-2. Copyright © 2018 Elsevier B.V. All rights reserved.

Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein

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

Li, Changzhao; Srivastava, Ritesh K.; Elmets, Craig A.

2013-09-06

Highlights: •Arsenic activates canonical Hippo signaling pathway and up-regulates αCatenin in the skin. •Arsenic activates transcriptional activity of Yap by its nuclear translocation. •Yap is involved in the disruption of tight/adherens junctions in arsenic-exposed animals. -- Abstract: Arsenic exposure in humans causes a number of toxic manifestations in the skin including cutaneous neoplasm. However, the mechanism of these alterations remains elusive. Here, we provide novel observations that arsenic induced Hippo signaling pathway in the murine skin. This pathway plays crucial roles in determining organ size during the embryonic development and if aberrantly activated in adults, contributes to the pathogenesis ofmore » epithelial neoplasm. Arsenic treatment enhanced phosphorylation-dependent activation of LATS1 kinase and other Hippo signaling regulatory proteins Sav1 and MOB1. Phospho-LATS kinase is known to catalyze the inactivation of a transcriptional co-activator, Yap. However, in arsenic-treated epidermis, we did not observed its inactivation. Thus, as expected, unphosphorylated-Yap was translocated to the nucleus in arsenic-treated epidermis. Yap by binding to the transcription factors TEADs induces transcription of its target genes. Consistently, an up-regulation of Yap-dependent target genes Cyr61, Gli2, Ankrd1 and Ctgf was observed in the skin of arsenic-treated mice. Phosphorylated Yap is important in regulating tight and adherens junctions through its binding to αCatenin. We found disruption of these junctions in the arsenic-treated mouse skin despite an increase in αCatenin. These data provide evidence that arsenic-induced canonical Hippo signaling pathway and Yap-mediated disruption of tight and adherens junctions are independently regulated. These effects together may contribute to the carcinogenic effects of arsenic in the skin.« less

Modulation of Sonic hedgehog-induced mouse embryonic stem cell behaviors through E-cadherin expression and Integrin β1-dependent F-actin formation.

PubMed

Oh, Ji Young; Suh, Han Na; Choi, Gee Euhn; Lee, Hyun Jik; Jung, Young Hyun; Ko, So Hee; Kim, Jun Sung; Chae, Chang Woo; Lee, Chang-Kyu; Han, Ho Jae

2018-06-22

Sonic hedgehog pathway (Shh) plays a central role in maintaining stem cell function and behavior in various processes related to self-renewal and tissue regeneration. However, the therapeutic effect of Shh on mouse embryonic stem cells (mESCs) has not yet been clearly described. Thus, we investigated the effect of Shh on the regulation of mESC behaviors as well as the effect of Shh-pretreated mESCs in skin wound healing. The present study investigated the underlying mechanisms of Shh signaling pathway in growth and motility of mESCs using western blot analysis, cell proliferation assay, and cell migration assay. In addition, the effect of Shh-pretreated mESCs in skin wound healing was determined using mouse excisional wound splinting model. Shh induced adherens junction disruption through proteolysis by activating matrix metallopeptidases. In addition, the release of β-catenin from adherens junctions mediated by Shh led to cell cycle-dependent mESC proliferation. Shh-mediated Gli1 expression led to integrin β1 upregulation, followed by FAK and Src phosphorylation. Furthermore, among the Rho-GTPases, Rac1 and Cdc42 were activated in a Shh-dependent manner while F-actin expression was suppressed by Rac1 and Cdc42 siRNA transfection. Consistent with the in vitro results, skin wound healing assay revealed that Shh-treated mESCs induced angiogenesis and skin wound repair compared to that in Shh-treated mESCs transfected with integrin β1 siRNA in vivo. Our results imply that Shh induces adherens junction disruption and integrin β1-dependent F-actin formation involving FAK/Src and Rac1/Cdc42 signaling pathways in mESCs. This article is protected by copyright. All rights reserved.

The retained placenta.

PubMed

Weeks, Andrew D

2008-12-01

The incidence and importance of retained placenta (RP) varies greatly around the world. In less developed countries, it affects about 0.1% of deliveries but has up to 10% case fatality rate. In more developed countries, it is more common (about 3% of vaginal deliveries) but very rarely associated with mortality. There are three main types of retained placenta following the vagina delivery: placenta adherens (when there is failed contraction of the myometrium behind the placenta), trapped placenta (a detached placenta trapped behind a closed cervix) and partial accreta (when there is a small area of accreta preventing detachment). All can be treated by manual removal of placenta, which should be carried out at 30-60 minutes postpartum. Medical management is also an option for placenta adherens and trapped placenta. The need for manual removal can be reduced by 20% by the use of intraumbilical oxytocin (30 i.u. in 30 mL saline). A trapped placenta may respond to glyceryl trinitrate (500 mcg sublingually) or gentle, persistent, controlled cord traction.

Iterative tensor voting for perceptual grouping of ill-defined curvilinear structures.

PubMed

Loss, Leandro A; Bebis, George; Parvin, Bahram

2011-08-01

In this paper, a novel approach is proposed for perceptual grouping and localization of ill-defined curvilinear structures. Our approach builds upon the tensor voting and the iterative voting frameworks. Its efficacy lies on iterative refinements of curvilinear structures by gradually shifting from an exploratory to an exploitative mode. Such a mode shifting is achieved by reducing the aperture of the tensor voting fields, which is shown to improve curve grouping and inference by enhancing the concentration of the votes over promising, salient structures. The proposed technique is validated on delineating adherens junctions that are imaged through fluorescence microscopy. However, the method is also applicable for screening other organisms based on characteristics of their cell wall structures. Adherens junctions maintain tissue structural integrity and cell-cell interactions. Visually, they exhibit fibrous patterns that may be diffused, heterogeneous in fluorescence intensity, or punctate and frequently perceptual. Besides the application to real data, the proposed method is compared to prior methods on synthetic and annotated real data, showing high precision rates.

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms.

PubMed

Lechuga, Susana; Ivanov, Andrei I

2017-07-01

The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Unravelling the Structural and Molecular Basis Responsible for the Anti-Biofilm Activity of Zosteric Acid

PubMed Central

Cattò, Cristina; Dell’Orto, Silvia; Villa, Federica; Villa, Stefania; Gelain, Arianna; Vitali, Alberto; Marzano, Valeria; Baroni, Sara; Forlani, Fabio; Cappitelli, Francesca

2015-01-01

The natural compound zosteric acid, or p-(sulfoxy)cinnamic acid (ZA), is proposed as an alternative biocide-free agent suitable for preventive or integrative anti-biofilm approaches. Despite its potential, the lack of information concerning the structural and molecular mechanism of action involved in its anti-biofilm activity has limited efforts to generate more potent anti-biofilm strategies. In this study a 43-member library of small molecules based on ZA scaffold diversity was designed and screened against Escherichia coli to understand the structural requirements necessary for biofilm inhibition at sub-lethal concentrations. Considerations concerning the relationship between structure and anti-biofilm activity revealed that i) the para-sulfoxy ester group is not needed to exploit the anti-biofilm activity of the molecule, it is the cinnamic acid scaffold that is responsible for anti-biofilm performance; ii) the anti-biofilm activity of ZA derivatives depends on the presence of a carboxylate anion and, consequently, on its hydrogen-donating ability; iii) the conjugated aromatic system is instrumental to the anti-biofilm activities of ZA and its analogues. Using a protein pull-down approach, combined with mass spectrometry, the herein-defined active structure of ZA was matrix-immobilized, and was proved to interact with the E. coli NADH:quinone reductase, WrbA, suggesting a possible role of this protein in the biofilm formation process. PMID:26132116

OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice

PubMed Central

de Molon, Rafael Scaf; Shimamoto, Hiroaki; Bezouglaia, Olga; Pirih, Flavia Q; Dry, Sarah M; Kostenuik, Paul; Boyce, Rogely W; Dwyer, Denise; Aghaloo, Tara L; Tetradis, Sotirios

2016-01-01

Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF-κB ligand (RANKL) inhibitor OPG-Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG-Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by µCT imaging and histologically. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG-Fc but not ZA. Full recovery of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers occurred after discontinuing OPG-Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal-related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a “drug holiday” in managing the ONJ patient. PMID:25727550

Impact of Actinomyces naeslundii on bisphosphonate-related osteonecrosis of the jaws in ovariectomized rats with periodontitis.

PubMed

Li, Chun Lei; Seneviratne, Chaminda Jayampath; Huo, Lei; Lu, Weijia William; Zheng, Li Wu

2015-10-01

Bisphosphonates-related osteonecrosis of the jaws (BRONJ) is a severe complication of BPs therapy with unknown pathogenesis. This study aimed to evaluate the impact of Actinomyces naeslundii (A. naeslundii) on the progression of BRONJ in ovariectomized (OVX) rat model with periodontal diseases. Sixty rats were randomly assigned into four groups. All rats underwent bilateral ovariectomy. Six weeks after surgery, animals with periodontitis induced by ligature placement were administrated with normal saline (NS), NS &A. naeslundii inoculation, zolecdronic acid (ZA) and ZA &A. naeslundii inoculation for 12 weeks, respectively. Loads of total bacteria and A. naeslundii in the mouth were assessed by real time PCR. After sacrifice, the mandibles were harvested for micro-computed tomography (micro-CT) and histological examination. Real-time PCR demonstrated that A. naeslundii was not routinely found in the rats and ZA treatment did not promote its accumulation. Micro-CT examination disclosed that ligature placement induced significant alveolar bone loss, which was greatly attenuated by ZA treatment and aggravated by A. naeslundii. Histological assessment demonstrated that ZA treatment increased the risk of developing BRONJ-like disease but this condition was not worsen with the presence of A. naeslundii. Our study suggested that oral A. naeslundii inoculation aggravated periodontal disease but not BRONJ in our animal model. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Phenomenological Constitutive Modeling of High-Temperature Flow Behavior Incorporating Individual and Coupled Effects of Processing Parameters in Super-austenitic Stainless Steel

NASA Astrophysics Data System (ADS)

Roy, Swagata; Biswas, Srija; Babu, K. Arun; Mandal, Sumantra

2018-05-01

A novel constitutive model has been developed for predicting flow responses of super-austenitic stainless steel over a wide range of strains (0.05-0.6), temperatures (1173-1423 K) and strain rates (0.001-1 s-1). Further, the predictability of this new model has been compared with the existing Johnson-Cook (JC) and modified Zerilli-Armstrong (M-ZA) model. The JC model is not befitted for flow prediction as it is found to be exhibiting very high ( 36%) average absolute error (δ) and low ( 0.92) correlation coefficient (R). On the contrary, the M-ZA model has demonstrated relatively lower δ ( 13%) and higher R ( 0.96) for flow prediction. The incorporation of couplings of processing parameters in M-ZA model has led to exhibit better prediction than JC model. However, the flow analyses of the studied alloy have revealed the additional synergistic influences of strain and strain rate as well as strain, temperature, and strain rate apart from those considered in M-ZA model. Hence, the new phenomenological model has been formulated incorporating all the individual and synergistic effects of processing parameters and a `strain-shifting' parameter. The proposed model predicted the flow behavior of the alloy with much better correlation and generalization than M-ZA model as substantiated by its lower δ ( 7.9%) and higher R ( 0.99) of prediction.

Cost per patient and potential budget implications of denosumab compared with zoledronic acid in adults with bone metastases from solid tumours who are at risk of skeletal-related events: an analysis for Austria, Sweden and Switzerland

PubMed Central

Lothgren, Mickael; Ribnicsek, Erna; Schmidt, Louise; Habacher, Wolfgang; Lundkvist, Jonas; Pfeil, Alena M; Biteeva, Irina; Vrouchou, Polina; Bracco, Andrea

2013-01-01

Objectives To assess cost implications per patient, per year, and to predict the potential annual budget impact when patients with bone metastases secondary to solid tumours at risk of skeletal-related events (SREs) transition from zoledronic acid (ZA; 4 mg every 3–4 weeks) to denosumab (120 mg every 4 weeks) in Austria, Sweden and Switzerland. Methods Country specific costs for medication and administration, patient management and SREs (defined as pathologic fracture, radiation to bone, surgery to bone and spinal cord compression) were assessed over a 1-year time horizon. Drug administration and patient management costs were taken from available public sources. SRE costs were based on local unit costs applied to country specific healthcare resources obtained from a multinational retrospective chart review study. Due to lack of real world data for the included countries, SRE rates were derived from phase III clinical trials in patients with advanced cancer and bone metastases. These trials demonstrated that denosumab was superior to ZA in the reduction of SREs. Results Estimated total annual cost savings for each patient transitioned from ZA to denosumab varied by country and cancer type, ranging from €1583 to €2375 in Austria, from €1980 to €2319 in Sweden (9.1 SEK/€) and from €3408 to €3857 in Switzerland (1.2 CHF/€). Cost savings were mainly driven by the lower SRE related costs and lower administration costs of denosumab compared with ZA. Conclusions Denosumab offers superior efficacy compared with ZA in patients with solid tumours and bone metastases. Cost savings are predicted in the Austrian, Swedish and Swiss healthcare systems following treatment transition from ZA to denosumab. PMID:23888248

Zhibitai and low-dose atorvastatin reduce blood lipids and inflammation in patients with coronary artery disease.

PubMed

Zhao, Yuhong; Peng, Ran; Zhao, Wang; Liu, Qiong; Guo, Yuan; Zhao, Shuiping; Xu, Danyan

2017-02-01

Atorvastatin decreases blood lipids but is associated with side effects. Zhibitai is a traditional Chinese medicine used to treat blood lipid disorders. The objective of this study is to evaluate the lipid-lowering effect, antiinflammatory effect, and adverse events of zhibitai combined to atorvastatin in patients with coronary heart diseases (CHDs). Patients with CHD (n = 150) were randomized to: zhibitai 480 mg + atorvastatin 10 mg (ZA10 group), atorvastatin 20 mg (A20 group), and atorvastatin 40 mg (A40 group). Lipid profile, cardiotrophin-1 (CT-1), and C-reactive protein (CRP) were measured after 4 and 8 weeks of treatment. Self-reported side effects, liver function, kidney function, and creatine kinase levels were monitored. After 8 weeks, triglycerides, total cholesterol (TC), LDL-cholesterol (LDL-C), and apolipoprotein B100 (ApoB100) levels were decreased in the ZA10 group (-64%, -37%, -46%, and -54%, respectively, compared with baseline), and these changes were similar to those of the A40 group (P > 0.05). CT-1 and high sensitivity-C reactive protein (hs-CRP) levels were significantly decreased in the ZA10 group after 4 and 8 weeks (4 weeks: -73% and 96%; 8 weeks: -89% and -98%; all P < 0.01), without differences among the 3 groups (P > 0.05). After 8 weeks of treatment, adverse events (abdominal distention, nausea, vomiting, and hunger) were found in 4, 5, and 7 patients in the ZA10, A20, and A40 groups, respectively. ZA10 significantly reduced triglycerides, TC, LDL-C, ApoB, CT-1, and hs-CRP levels in patients with CHD, similar to the effects of A40 and A20, but ZA10 lead to fewer adverse events.

Constitutive Behavior and Modeling of Al-Cu Alloy Systems

DTIC Science & Technology

2013-05-01

Mechanical Threshold of Dynamically Deformed Copper and Nitronic 40 ." Journal de Physique, 1985: 25- 34. Gama, B. A., S. L. Lopatnikov, and J. W. G...38 3. MODIFIED ZERILLI-ARMSTRONG MODEL .................................... 40 3.1 Introduction... 40 3.2 Former Modifications to ZA Model by Zerilli and Armstrong .. 42 3.3 Modifications to ZA Model

Imaging of pH in vivo using hyperpolarized 13C-labelled zymonic acid

PubMed Central

Düwel, Stephan; Hundshammer, Christian; Gersch, Malte; Feuerecker, Benedikt; Steiger, Katja; Buck, Achim; Walch, Axel; Haase, Axel; Glaser, Steffen J.; Schwaiger, Markus; Schilling, Franz

2017-01-01

Natural pH regulatory mechanisms can be overruled during several pathologies such as cancer, inflammation and ischaemia, leading to local pH changes in the human body. Here we demonstrate that 13C-labelled zymonic acid (ZA) can be used as hyperpolarized magnetic resonance pH imaging sensor. ZA is synthesized from [1-13C]pyruvic acid and its 13C resonance frequencies shift up to 3.0 p.p.m. per pH unit in the physiological pH range. The long lifetime of the hyperpolarized signal enhancement enables monitoring of pH, independent of concentration, temperature, ionic strength and protein concentration. We show in vivo pH maps within rat kidneys and subcutaneously inoculated tumours derived from a mammary adenocarcinoma cell line and characterize ZA as non-toxic compound predominantly present in the extracellular space. We suggest that ZA represents a reliable and non-invasive extracellular imaging sensor to localize and quantify pH, with the potential to improve understanding, diagnosis and therapy of diseases characterized by aberrant acid-base balance. PMID:28492229

Ab initio phonon point defect scattering and thermal transport in graphene

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

Polanco, Carlos A.; Lindsay, Lucas R.

Here, we study the scattering of phonons from point defects and their effect on lattice thermal conductivity κ using a parameter-free ab initio Green's function methodology. Specifically, we focus on the scattering of phonons by boron (B), nitrogen (N), and phosphorus substitutions as well as single- and double-carbon vacancies in graphene. We show that changes of the atomic structure and harmonic interatomic force constants locally near defects govern the strength and frequency trends of the scattering of out-of-plane acoustic (ZA) phonons, the dominant heat carriers in graphene. ZA scattering rates due to N substitutions are nearly an order of magnitudemore » smaller than those for B defects despite having similar mass perturbations. Furthermore, ZA phonon scattering rates from N defects decrease with increasing frequency in the lower-frequency spectrum in stark contrast to expected trends from simple models. ZA phonon-vacancy scattering rates are found to have a significantly softer frequency dependence (~ω 0) in graphene than typically employed in phenomenological models. The rigorous Green's function calculations demonstrate that typical mass-defect models do not adequately describe ZA phonon-defect scattering rates. Our ab initio calculations capture well the trend of κ vs vacancy density from experiments, though not the magnitudes. In conclusion, this work elucidates important insights into phonon-defect scattering and thermal transport in graphene, and demonstrates the applicability of first-principles methods toward describing these properties in imperfect materials.« less

Ab initio phonon point defect scattering and thermal transport in graphene

DOE PAGES

Polanco, Carlos A.; Lindsay, Lucas R.

2018-01-04

Here, we study the scattering of phonons from point defects and their effect on lattice thermal conductivity κ using a parameter-free ab initio Green's function methodology. Specifically, we focus on the scattering of phonons by boron (B), nitrogen (N), and phosphorus substitutions as well as single- and double-carbon vacancies in graphene. We show that changes of the atomic structure and harmonic interatomic force constants locally near defects govern the strength and frequency trends of the scattering of out-of-plane acoustic (ZA) phonons, the dominant heat carriers in graphene. ZA scattering rates due to N substitutions are nearly an order of magnitudemore » smaller than those for B defects despite having similar mass perturbations. Furthermore, ZA phonon scattering rates from N defects decrease with increasing frequency in the lower-frequency spectrum in stark contrast to expected trends from simple models. ZA phonon-vacancy scattering rates are found to have a significantly softer frequency dependence (~ω 0) in graphene than typically employed in phenomenological models. The rigorous Green's function calculations demonstrate that typical mass-defect models do not adequately describe ZA phonon-defect scattering rates. Our ab initio calculations capture well the trend of κ vs vacancy density from experiments, though not the magnitudes. In conclusion, this work elucidates important insights into phonon-defect scattering and thermal transport in graphene, and demonstrates the applicability of first-principles methods toward describing these properties in imperfect materials.« less

Simulating Eastern- and Central-Pacific Type ENSO Using a Simple Coupled Model

NASA Astrophysics Data System (ADS)

Fang, Xianghui; Zheng, Fei

2018-06-01

Severe biases exist in state-of-the-art general circulation models (GCMs) in capturing realistic central-Pacific (CP) El Niño structures. At the same time, many observational analyses have emphasized that thermocline (TH) feedback and zonal advective (ZA) feedback play dominant roles in the development of eastern-Pacific (EP) and CP El Niño-Southern Oscillation (ENSO), respectively. In this work, a simple linear air-sea coupled model, which can accurately depict the strength distribution of the TH and ZA feedbacks in the equatorial Pacific, is used to investigate these two types of El Niño. The results indicate that the model can reproduce the main characteristics of CP ENSO if the TH feedback is switched off and the ZA feedback is retained as the only positive feedback, confirming the dominant role played by ZA feedback in the development of CP ENSO. Further experiments indicate that, through a simple nonlinear control approach, many ENSO characteristics, including the existence of both CP and EP El Niño and the asymmetries between El Niño and La Niña, can be successfully captured using the simple linear air-sea coupled model. These analyses indicate that an accurate depiction of the climatological sea surface temperature distribution and the related ZA feedback, which are the subject of severe biases in GCMs, is very important in simulating a realistic CP El Niño.

Manganese soil and foliar fertilization of olive plantlets: the effect on leaf mineral and phenolic content and root mycorrhizal colonization.

PubMed

Pasković, Igor; Ćustić, Mirjana Herak; Pecina, Marija; Bronić, Josip; Ban, Dean; Radić, Tomislav; Pošćić, Filip; Jukić Špika, Maja; Soldo, Barbara; Palčić, Igor; Goreta Ban, Smiljana

2018-06-08

The aim of this study was to examine the effect of foliar (Mn_fol) and soil Zeolite-Mn (Mn_ZA) application on leaf mineral, total phenolic and oleuropein content, and mycorrhizae colonization of self-rooted cv. Leccino plantlets grown on calcareous soil. The dissolution of zeolite was 97% when citric acid was applied at 0.05 mM dm -3 , suggesting that organic acids excreted by roots can dissolve modified zeolite (Mn_ZA) making Mn available for plant uptake. The leaf Mn concentration was the highest for Mn_fol treatment at 90 DAT (172 mg kg -1 ) and 150 DAT (70 mg kg -1 ) compared to other treatments. Mn_ZA soil application increased leaf Mn concentration at 150 DAT compared to control and NPK treatment. The oleuropein leaf content was highest for Mn_fol compared to other treatments at 90 DAT and lowest at 150 DAT. Arbuscular mycorrhizal colonization was higher for Mn_fol treatment at 150 DAT compared to all other treatments. Changes in the arbuscular colonization percentage and oleuropein content may be connected to stress conditions provoked by high leaf Mn concentration in Mn_fol treatment at 90 DAT. Mn_ZA application increased leaf Mn concentration at 150 DAT compared to control and NPK treatments. It can be assumed that the dominant mechanism in Mn uptake from modified zeolite is Mn_ZA dissolution through root exudates. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Ab initio phonon point defect scattering and thermal transport in graphene

NASA Astrophysics Data System (ADS)

Polanco, Carlos A.; Lindsay, Lucas

2018-01-01

We study the scattering of phonons from point defects and their effect on lattice thermal conductivity κ using a parameter-free ab initio Green's function methodology. Specifically, we focus on the scattering of phonons by boron (B), nitrogen (N), and phosphorus substitutions as well as single- and double-carbon vacancies in graphene. We show that changes of the atomic structure and harmonic interatomic force constants locally near defects govern the strength and frequency trends of the scattering of out-of-plane acoustic (ZA) phonons, the dominant heat carriers in graphene. ZA scattering rates due to N substitutions are nearly an order of magnitude smaller than those for B defects despite having similar mass perturbations. Furthermore, ZA phonon scattering rates from N defects decrease with increasing frequency in the lower-frequency spectrum in stark contrast to expected trends from simple models. ZA phonon-vacancy scattering rates are found to have a significantly softer frequency dependence (˜ω0 ) in graphene than typically employed in phenomenological models. The rigorous Green's function calculations demonstrate that typical mass-defect models do not adequately describe ZA phonon-defect scattering rates. Our ab initio calculations capture well the trend of κ vs vacancy density from experiments, though not the magnitudes. This work elucidates important insights into phonon-defect scattering and thermal transport in graphene, and demonstrates the applicability of first-principles methods toward describing these properties in imperfect materials.

A Biphasic Calcium Sulphate/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone

PubMed Central

Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner; Kumar, Ashok; Lidgren, Lars; Tägil, Magnus

2016-01-01

In orthopedic surgery, large amount of diseased or injured bone routinely needs to be replaced. Autografts are mainly used but their availability is limited. Commercially available bone substitutes allow bone ingrowth but lack the capacity to induce bone formation. Thus, off-the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone, and zoledronic acid (ZA) to delay early resorption. In-vitro, the biphasic material released 90% of rhBMP-2 and 10% of ZA in the first week. No major changes were found in the surface structure using scanning electron microscopy (SEM) or in the mechanical properties after adding rhBMP-2 or ZA. In-vivo bone formation was studied in an abdominal muscle pouch model in rats (n = 6/group). The mineralized volume was significantly higher when the biphasic material was combined with both rhBMP-2 and ZA (21.4 ± 5.5 mm3) as compared to rhBMP-2 alone (10.9 ± 2.1 mm3) when analyzed using micro computed tomography (μ-CT) (p < 0.01). In the clinical setting, the biphasic material combined with both rhBMP-2 and ZA can potentially regenerate large volumes of bone. PMID:27189411

Dynamics between actin and the VE-cadherin/catenin complex

PubMed Central

Abu Taha, Abdallah; Schnittler, Hans-J

2014-01-01

Endothelial adherens junctions are critical for physiological and pathological processes such as differentiation, maintenance of entire monolayer integrity, and the remodeling. The endothelial-specific VE-cadherin/catenin complex provides the backbone of adherens junctions and acts in close interaction with actin filaments and actin/myosin-mediated contractility to fulfill the junction demands. The functional connection between the cadherin/catenin complex and actin filaments might be either directly through α-catenins, or indirectly e.g., via linker proteins such as vinculin, p120ctn, α-actinin, or EPLIN. However, both junction integrity and dynamic remodeling have to be contemporarily coordinated. The actin-related protein complex ARP2/3 and its activating molecules, such as N-WASP and WAVE, have been shown to regulate the lammellipodia-mediated formation of cell junctions in both epithelium and endothelium. Recent reports now demonstrate a novel aspect of the ARP2/3 complex and the nucleating-promoting factors in the maintenance of endothelial barrier function and junction remodeling of established endothelial cell junctions. Those mechanisms open novel possibilities; not only in fulfilling physiological demands but obtained information may be of critical importance in pathologies such as wound healing, angiogenesis, inflammation, and cell diapedesis. PMID:24621569

Changes in the distribution of type II transmembrane serine protease, TMPRSS2 and in paracellular permeability in IPEC-J2 cells exposed to oxidative stress.

PubMed

Paszti-Gere, Erzsebet; Barna, Reka Fanni; Kovago, Csaba; Szauder, Ipoly; Ujhelyi, Gabriella; Jakab, Csaba; Meggyesházi, Nóra; Szekacs, Andras

2015-04-01

The effect of oxidative stress on barrier integrity and localization of transmembrane serine proteinase 2 (TMPRSS2) were studied using porcine epithelial IPEC-J2 cells on membrane inserts. Increased paracellular permeability of FITC-dextran 4 kDa (fluorescence intensity 43,508 ± 2,391 versus 3,550 ± 759) and that of gentamicin (3.41 ± 0.06 % increase to controls) were measured parallel with the reduced transepithelial electrical resistance (23.3 ± 4.06 % decrease) of cell layers 6 h after 1 h 1 mM H2O2 treatment. The immunohistochemical localization of adherens junctional β-catenin was not affected by reactive oxygen species (ROS) up to 4 mM H2O2. Peroxide-triggered enhanced paracellular permeability of IPEC-J2 cell layer was accompanied by predominantly cytoplasmic occurrence of TMPRSS2 embedded in cell membrane under physiological conditions. These results support that ROS can influence paracellular gate opening via multifaceted mode of action without involvement of β-catenin redistribution in adherens junction. Altered distribution pattern of TMPRSS2 and relocalized transmembrane serine protease activity may contribute to weakening of epithelial barrier integrity under acute oxidative stress.

Projecting impacts of climate change on water availability using artificial neural network techniques

USGS Publications Warehouse

Swain, Eric D.; Gomez-Fragoso, Julieta; Torres-Gonzalez, Sigfredo

2017-01-01

Lago Loíza reservoir in east-central Puerto Rico is one of the primary sources of public water supply for the San Juan metropolitan area. To evaluate and predict the Lago Loíza water budget, an artificial neural network (ANN) technique is trained to predict river inflows. A method is developed to combine ANN-predicted daily flows with ANN-predicted 30-day cumulative flows to improve flow estimates. The ANN application trains well for representing 2007–2012 and the drier 1994–1997 periods. Rainfall data downscaled from global circulation model (GCM) simulations are used to predict 2050–2055 conditions. Evapotranspiration is estimated with the Hargreaves equation using minimum and maximum air temperatures from the downscaled GCM data. These simulated 2050–2055 river flows are input to a water budget formulation for the Lago Loíza reservoir for comparison with 2007–2012. The ANN scenarios require far less computational effort than a numerical model application, yet produce results with sufficient accuracy to evaluate and compare hydrologic scenarios. This hydrologic tool will be useful for future evaluations of the Lago Loíza reservoir and water supply to the San Juan metropolitan area.

Reactive oxygen species are required for zoledronic acid-induced apoptosis in osteoclast precursors and mature osteoclast-like cells

PubMed Central

Tai, Ta-Wei; Chen, Ching-Yu; Su, Fong-Chin; Tu, Yuan-Kun; Tsai, Tsung-Ting; Lin, Chiou-Feng; Jou, I.-Ming

2017-01-01

Inhibiting osteoclasts and osteoclast precursors to reduce bone resorption is an important strategy to treat osteoclast-related diseases, such as osteoporosis, inflammatory bone loss, and malignant bone metastasis. However, the mechanism by which apoptosis is induced in the osteoclasts and their precursors are not completely understood. Here, we used nitrogen-containing bisphosphonate zoledronic acid (ZA) to induce cell apoptosis in human and murine osteoclast precursors and mature osteoclast-like cells. Caspase-3-mediated cell apoptosis occurred following the ZA (100 μM) treatment. Reactive oxygen species (ROS) were also generated in a time-dependent manner. Following knock-down of the p47phox expression, which is required for ROS activation, or co-treatment with the ROS inhibitor, N-acetyl-L-cysteine, ZA-induced apoptosis was significantly suppressed in both osteoclast precursors and mature osteoclast-like cells. The ROS-activated mitogen-activated protein kinases pathways did not trigger cell apoptosis. However, a ROS-regulated Mcl-1 decrease simultaneously with glycogen synthase kinase (GSK)-3β promoted cell apoptosis. These findings show that ZA induces apoptosis in osteoclast precursors and mature osteoclast-like cells by triggering ROS- and GSK-3β-mediated Mcl-1 down-regulation. PMID:28281643

A 5-year retrospective longitudinal study on the incidence and the risk factors of osteonecrosis of the jaws in patients treated with zoledronic acid for bone metastases from solid tumors.

PubMed

Manfredi, M; Mergoni, G; Goldoni, M; Salvagni, S; Merigo, E; Meleti, M; Vescovi, P

2017-05-01

The aim of this study was to evaluate the incidence and the risk factors of osteonecrosis of the jaw (ONJ) in a group of patients treated with zoledronic acid (ZA) for bone metastases from solid tumors and enrolled in a preventive dental program. This 5-year retrospective longitudinal study included all consecutive oncological patients who underwent at least one infusion with ZA between 2004 and 2011 for bone metastases due to solid neoplasms. Of the 156 patients enrolled in the study, 17 developed ONJ (10.89%). At the multivariate analysis, severe periodontal disease (P=0.025), tooth extraction (P<0.0001) and starting the preventive dental program after the beginning of ZA therapy (P=0.02) were the only factors which showed a significant association with the occurrence of ONJ. This study demonstrated the importance of beginning dental prevention before zoledronic acid exposure in reducing ONJ occurrence, especially in the long term. The results of this research show that control of periodontal disease and an increase in the time between tooth extraction and the first ZA administration are recommended in order to reduce the risk of ONJ development.

PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells.

PubMed

Anitua, Eduardo; Zalduendo, Mar; Troya, María; Orive, Gorka

2016-04-01

Bisphosphonates-related osteonecrosis of the jaw (BRONJ) is a common problem in patients undergoing long-term administration of highly potent nitrogen-containing bisphosphonates (N-BPs). This pathology occurs via bone and soft tissue mechanism. Zoledronic acid (ZA) is the most potent intravenous N-BP used to prevent bone loss in patients with bone dysfunction. The objective of this in vitro study was to evaluate the role of different ZA concentrations on the cells from human oral cavity, as well as the potential of plasma rich in growth factors (PRGF) to overcome the negative effects of this BP. Primary human gingival fibroblasts and primary human alveolar osteoblasts were used. Cell proliferation was evaluated by means of a fluorescence-based method. A colorimetric assay to detect DNA fragmentation undergoing apoptosis was used to determine cell death, and the expression of both NF-κB and pNF-κB were quantified by Western blot analysis. ZA had a cytotoxic effect on both human gingival fibroblasts and human alveolar osteoblasts. This BP inhibits cell proliferation, stimulates apoptosis, and induces inflammation. However, the addition of PRGF suppresses all these negative effects of the ZA. PRGF shows a cytoprotective role against the negative effects of ZA on primary oral cells. At present, there is no definitive treatment for bisphosphonates-related osteonecrosis of the jaw (BRONJ), being mainly palliatives. Our results revealed that PRGF has a cytoprotective role in cells exposed to zoledronic acid, thus providing a reliable adjunctive therapy for the treatment of BRONJ pathology.

Transverse zones controlling the structural evolution of the Zipaquira Anticline (Eastern Cordillera, Colombia): Regional implications

NASA Astrophysics Data System (ADS)

García, Helbert; Jiménez, Giovanny

2016-08-01

We report paleomagnetic, magnetic fabric and structural results from 21 sites collected in Cretaceous marine mudstones and Paleogene continental sandstones from the limbs, hinge and transverse zones of the Zipaquira Anticline (ZA). The ZA is an asymmetrical fold with one limb completely overturned by processes like gravity and salt tectonics, and marked by several axis curvatures. The ZA is controlled by at least two (2) transverse zones known as the Neusa and Zipaquira Transverse Zones (NTZ and ZTZ, respectively). Magnetic mineralogy methods were applied at different sites and the main carriers of the magnetic properties are paramagnetic components with some sites being controlled by hematite and magnetite. Magnetic fabric analysis shows rigid-body rotation for the back-limb in the ZA, while the forelimb is subjected to internal deformation. Structural and paleomagnetic data shows the influence of the NTZ and ZTZ in the evolution of the different structures like the ZA and the Zipaquira, Carupa, Rio Guandoque, Las Margaritas and Neusa faults, controlling several factors as vergence, extension, fold axis curvature and stratigraphic detatchment. Clockwise rotations unraveled a block segmentation following a discontinuos model caused by transverse zones and one site reported a counter clockwise rotation associated with a left-lateral strike slip component for transverse faults (e.g. the Neusa Fault). We propose that diverse transverse zones have been active since Paleogene times, playing an important role in the tectonic evolution of the Cundinamarca sub-basin and controlling the structural evolution of folds and faults with block segmentation and rotations.

Osteoclasts but not osteoblasts are affected by a calcified surface treated with zoledronic acid in vitro

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

Schindeler, Aaron; Little, David G.; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney

2005-12-16

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. Recent interest has centered on the effects of bisphosphonates on osteoblasts. Chronic dosing of osteoblasts with solubilized bisphosphonates has been reported to enhance osteogenesis and mineralization in vitro. However, this methodology poorly reflects the in vivo situation, where free bisphosphonate becomes rapidly bound to mineralized bone surfaces. To establish a more clinically relevant cell culture model, we cultured bone cells on calcium phosphate coated quartz discs pre-treated with the potent nitrogen-containing bisphosphonate, zoledronic acid (ZA). Binding studies utilizing [{sup 14}C]-labeled ZA confirmed that the bisphosphonate bound in a concentration-dependent manner over themore » 1-50 {mu}M dose range. When grown on ZA-treated discs, the viability of bone-marrow derived osteoclasts was greatly reduced, while the viability and mineralization of the osteoblastic MC3T3-E1 cell line were largely unaffected. This suggests that only bone resorbing cells are affected by bound bisphosphonate. However, this system does not account for transient exposure to unbound bisphosphonate in the hours following a clinical dosing. To model this event, we transiently treated osteoblasts with ZA in the absence of a calcified surface. Osteoblasts proved highly resistant to all transitory treatment regimes, even when utilizing ZA concentrations that prevented mineralization and/or induced cell death when dosed chronically. This study represents a pharmacologically more relevant approach to modeling bisphosphonate treatment on cultured bone cells and implies that bisphosphonate therapies may not directly affect osteoblasts at bone surfaces.« less

Protocol for a randomised control trial of bisphosphonate (zoledronic acid) treatment in childhood femoral head avascular necrosis due to Perthes disease

PubMed Central

Zacharin, Margaret; Foster, Bruce; Donald, Geoffrey; Hassall, Timothy; Siafarikas, Aris; Johnson, Michael; Tham, Elaine; Whitewood, Colin; Gebski, Val; Cowell, Chris T; Little, David Graham; Munns, Craig Frank

2017-01-01

Introduction Perthes disease (PD) is an idiopathic disorder presenting with avascular necrosis to the femoral head, which frequently results in flattening. Long-term function is directly related to the subsequent femoral head sphericity. Current treatment includes mechanical modalities and surgical procedures, which are therapeutic but are not uniformly able to prevent collapse. The use of the nitrogen-containing bisphosphonate zoledronic acid (ZA) to inhibit osteoclastic bone resorption is aimed at preserving femoral head strength, reducing collapse and thus maintaining shape. The proposed multicentre, prospective, randomised controlled trial intends to evaluate the efficacy of ZA treatment in PD. Methods and analysis An open-label randomised control trial recruiting 100 children (50 each treatment arm) 5 to 16 years old with unilateral PD. Subjects are randomly assigned to either (a) ZA and standard care or (b) Standard care. The primary outcome measure is deformity index (DI), a radiographic parameter of femoral head roundness assessed at 24 months, following 12 months of ZA treatment (3-monthly doses of ZA 0.025 mg/kg at baseline, 3, 6, 9 and 12 months) plus 12 months observation (group A) or 24 months of observation (group B). Secondary outcome measures are femoral head subluxation, Faces Pain scale, Harris hip score and quality of life. Assessments are made at baseline, 3 monthly during the first year of follow-up and then 6 monthly, until the 24th month. Ethics and dissemination The study commenced following the written approval from the Human Research Ethics Committee. Safety considerations regarding the effects of ZA are monitored which include the subject’s symptomatology, mineral status, bone mass and turnover activity, and metaphyseal modelling. Data handling plan requires that all documents, clinical information, biological samples and investigation results will be held in strict confidence by study investigators to preserve its safety and

A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

PubMed

Clive, Amelia O; Hooper, Clare E; Edey, Anthony J; Morley, Anna J; Zahan-Evans, Natalie; Hall, David; Lyburn, Iain; White, Paul; Braybrooke, Jeremy P; Sequeiros, Iara; Lyen, Stephen M; Milton, Tim; Kahan, Brennan C; Maskell, Nick A

2015-01-01

Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans. We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated. Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI -4.7 to 13.0)) or change in DCE-MRI iAUC (AMD -15.4 (95%CI -58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates. This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further. UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.

Concentration, sources and risk assessment of PAHs in bottom sediments.

PubMed

Baran, Agnieszka; Tarnawski, Marek; Urbański, Krzysztof; Klimkowicz-Pawlas, Agnieszka; Spałek, Iwona

2017-10-01

The aims of the study were to investigate the concentration, sources and ecological risk of PAHs (polycyclic aromatic hydrocarbons) in bottom sediments collected from nine reservoirs located in south-eastern Poland. The concentration of ∑PAHs in sediments ranged from 150 to 33,900 μg kg -1 . The total PAH concentration in the bottom sediments was arranged in the following order: Rybnik > Rzeszów > Brzóza Królewska > Brzóza Stadnicka > Besko > Chechło > Ożanna > Głuchów > Narożniki. BAP was the major compound in sediments from the Besko, Brzóza Stadnicka and Rzeszów reservoirs; FLT in the sediments from the Rybnik, Narożniki, Ożanna and Brzóza Królewska reservoirs; and FLN from the Głuchów and Chechło reservoirs. The major inputs of PAHs were of pyrolytic origin. However, petrogenic sources of PAHs occurred especially in the Chechło and Głuchów reservoirs. The ecological risk assessment indicated that non-adverse effects on the benthic fauna may occur for sediments from the Głuchów, Narozniki and Ożanna reservoirs, while slightly adverse effects were found for sediments from the Brzóza Królewska, Besko, Brzóza Stadnicka and Chechło reservoirs. The other sediments showed moderate (Rzeszów reservoirs) and strong effect (Rybnik reservoir) on biological communities. Individual PAHs such as NAP, PHE, FLT, PYR, BAA, CHR and BAP in sediments from the Rybnik reservoir and BAP in sediments from the Rzeszów reservoirs indicated a higher possibility of occurrence of an adverse ecological effect. PCA analysis found slight difference between the reservoirs in the profile of variable PAHs. Only the sediments from the Rybnik and Chechło reservoirs differ considerably from this grouping.

Scribble is required for normal epithelial cell–cell contacts and lumen morphogenesis in the mammalian lung

PubMed Central

Yates, Laura L.; Schnatwinkel, Carsten; Hazelwood, Lee; Chessum, Lauren; Paudyal, Anju; Hilton, Helen; Romero, M. Rosario; Wilde, Jonathan; Bogani, Debora; Sanderson, Jeremy; Formstone, Caroline; Murdoch, Jennifer N.; Niswander, Lee A.; Greenfield, Andy; Dean, Charlotte H.

2013-01-01

During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in ScribCrc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen

Measuring rare and exclusive Higgs boson decays into light resonances

NASA Astrophysics Data System (ADS)

Chisholm, Andrew S.; Kuttimalai, Silvan; Nikolopoulos, Konstantinos; Spannowsky, Michael

2016-09-01

We evaluate the LHC's potential of observing Higgs boson decays into light elementary or composite resonances through their hadronic decay channels. We focus on the Higgs boson production processes with the largest cross sections, pp → h and pp → h+{jet}, with subsequent decays h → ZA or h → Z η _c, and comment on the production process pp → hZ. By exploiting track-based jet substructure observables and extrapolating to 3000 {fb}^{-1} we find {BR}(h → ZA) ≃ {BR}(h → Z η _c) ≲ 0.02 at 95 % CL. We interpret this limit in terms of the 2HDM Type 1. We find that searches for h→ ZA are complementary to existing measurements and can constrain large parts of the currently allowed parameter space.

The effect of zoledronic acid on type and volume of Modic changes among patients with low back pain.

PubMed

Koivisto, Katri; Järvinen, Jyri; Karppinen, Jaro; Haapea, Marianne; Paananen, Markus; Kyllönen, Eero; Tervonen, Osmo; Niinimäki, Jaakko

2017-06-23

Modic changes (MC) are associated with low back pain (LBP). In this study, we compared changes in size and type of MC, after a single intravenous infusion of 5 mg zoledronic acid (ZA) or placebo, among chronic LBP patients with MC on magnetic resonance imaging (MRI), and evaluated whether the MRI changes correlate with symptoms. All patients (N = 19 in ZA, 20 in placebo) had MRI at baseline (0.23-1.5 T) and at one year (1.5-3 T). We evaluated the level, type and volume of all the MC. The MC were classified into M1 (M1 (100%)), predominating M1 (M1/2 (65:35%)) or predominating M2 (M1/2 (35:65%)), and M2 (M2 (100%)). The first two were considered M1-dominant, and the latter two M2-dominant. Volumes of M1 and M2 were calculated separately for the primary MC, which was assumed to cause the symptoms, and the other MC. We analysed the one-year treatment differences in M1 and M2 volumes using analysis of covariance with adjustments for age, sex, body mass index, and smoking. The correlations between the MRI changes and the changes in LBP symptoms were analysed using Pearson correlations. In the ZA group, 84.2% of patients had M1-dominant primary MC at baseline, compared to 50% in the placebo group (p = 0.041). The primary MC in the ZA group converted more likely to M2-dominant (42.1% ZA, 15% placebo; p = 0.0119). The other MC (15 ZA, 8 placebo) were on average 42% smaller and remained largely M2-dominant. The M1 volume of the primary MC decreased in the ZA group, but increased in the placebo group (-0.83 cm 3 vs 0.91 cm 3 ; p = 0.21). The adjusted treatment difference for M1 volume was -1.9 cm 3 (95% CI -5.0 to 1.2; p = 0.22) and for M2 volume 0.23 cm 3 (p = 0.86). In the MC that remained M1-dominant, volume change correlated positively with increased symptoms in the placebo group, whereas the correlations were negative and weak in the ZA group. Zoledronic acid tended to speed up the conversion of M1-dominant into M2-dominant MC and decrease the volume

Centrifugal casting of ZA8 zinc alloy and composite A356/silicon carbide: Study and modeling of phases' and particles' segregation

NASA Astrophysics Data System (ADS)

Balout, Bahaa

Centrifugation is a casting technology that allows the production of cylindrical and graduated parts with different mechanical properties through the section. The need for materials with good quality and specific mechanical properties has been driven this technology in order to produce different types of materials such as zinc alloys and graduated metal matrix composites reinforced by hard and wear resistant particles. The goal of this research project is to study and model the eutectic macrosegregation, the solidification speed, and the speeds of solidification fronts during centrifugal casting of ZA8 zinc-aluminum alloy in order to improve the part quality and increase its strength and field reliability. Moreover, the segregation of the particles during centrifugal casting of an aluminum matrix composite reinforced by silicon carbide particles (A356/SiC) is also studied to improve and control the graduation of the parts. The cooling rate, the speed, acceleration/deceleration, displacement, and segregation of the particles across the section will be modeled by discretization of Stokes' law in time in order to take into consideration the change in the centrifugal radius and melt viscosity during cooling process. This study will allow the control of the graduation degree of particles across the section in order to improve the properties and wear resistance of the composite. This composite can be used in systems where friction is critical and load is high (reinforcements of parts for the cylinders of pneumatic systems). The results show that the maximum macrosegregation zone of the eutectic across the casting section corresponds to the last point of solidification. The eutectic macrosegregation produced during centrifugal casting of thin walled part is a normal segregation which varies depending on the solidification speed and the ratio between the speeds of solidification fronts. On the other hand, it was found that the position and volume fraction of the particles

Effect of local injection of Zolena, zoledronic acid made in Iran, on orthodontic tooth movement and root and bone resorption in rats.

PubMed

Seifi, Massoud; Asefi, Sohrab; Hatamifard, Ghazal; Lotfi, Ali

2017-01-01

Background. Anchorage control is an essential part of orthodontic treatment planning, especially in adult patients who demand a more convenient treatment. Zoledronic acid (ZA) is an effective choice to address this problem. It is the most potent member of the bisphosphonates family that has an inhibitory effect on bone resorption by suppressing osteoclast function. Therefore, ZA might be a good option for orthodontic anchorage control. The current study evaluated the effect of local administration of Zolena (ZA made in Iran) on orthodontic tooth movement (OTM) and root and bone resorption. Methods. The experimental group consisted of 30 rats in 3 subgroups (n=10). Anesthesia was induced, and one closed NiTi coil spring was installed between the first molar and central incisor unilaterally, except for the negative control group. The positive control group received vestibular injection of 0.01 mL of saline next to the maxillary first molar, and 0.01 mL of the solution was injected at the same site in the ZA group. After 21 days, the rats were sacrificed and the distance between the first and second molars was measured with a leaf gauge. Histological analysis was conducted by a blind pathologist for the number of Howship's lacunae, blood vessels, osteoclast-like cells and root resorption lacunae. Data were analyzed with ANOVA, Tukey test and t-test. Results. There were no significant differences in OTM between the force-applied groups. ZA significantly inhibited bone/root resorption and angiogenesis compared to the positive control group. Conclusion. Zolena did not decrease OTM but significantly inhibited bone and root resorption. Zolena might be less potent than its foreign counterparts.

Effects of dexamethasone and nimesulide on bisphosphonate-related osteonecrosis of the jaw: An experimental study.

PubMed

Oliveira, Camila Carvalho de; Barros Silva, Paulo Goberlânio de; Ferreira, Antonio Ernando Carlos; Gonçalves, Romélia Pinheiro; Sousa, Fabrício Bitu de; Mota, Mário Rogério Lima; Alves, Ana Paula Negreiros Nunes

2017-11-01

To evaluate the effects of dexamethasone (DEX) and nimesulide (NIM) on Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ) in rats. BRONJ was induced by zoledronic acid (ZA) infusion (0.2mg/kg) in Wistar rats (n=8), followed by extraction of the left lower first molar (BRONJ groups). Control groups (n=40) received saline (IV). For eight weeks, DEX (0.04, 0.4, 4mg/kg) or saline (SAL) were administered by gavage 24h before each infusion of ZA or saline (IV), or NIM (10.3mg/kg) was administered 24h and 12h before each infusion of ZA or saline (IV). The haematological analyses were conducted weekly. After euthanasia (day 70), the jaws were submitted to radiographic and microscopic analysis. Kidney, liver, spleen and stomach were analysed histopathologically. The BRONJ groups showed a higher radiolucent area compared with the control groups (p<0.05). Histomorphometric analysis revealed healing and new bone formation in the control groups, while the BRONJ groups exhibited devitalized bone with bacterial colonies and inflammatory infiltrate. The BRONJ-DEX 0.4 and 4mg/kg groups had a greater number of bacterial colonies (p<0.05) and an increased polymorphonuclear cell count compared to the saline-BRONJ group, while the BRONJ-NIM group had a lower polymorphonuclear count (p<0.05). The BRONJ groups had leucocytosis, which was reduced by DEX administration. Treatments with DEX with or without ZA caused white pulp atrophy. Thus, DEX or NIM therapy was not effective in preventing radiographic and histopathologic events associated with BRONJ. Treatment with DEX attenuated leucocytosis post-infusion with ZA. Copyright © 2017 Elsevier Ltd. All rights reserved.

L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer

PubMed Central

Biteau, Kevin; Guiho, Romain; Chatelais, Mathias; Taurelle, Julien; Chesneau, Julie; Corradini, Nadège; Heymann, Dominique; Redini, Françoise

2016-01-01

Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients. PMID:27152244

Synergistic Phytochemicals Fail to Protect Against Ovariectomy Induced Bone Loss in Rats.

PubMed

Ambati, Suresh; Miller, Colette N; Bass, Erica F; Hohos, Natalie M; Hartzell, Diane L; Kelso, Emily W; Trunnell, Emily R; Yang, Jeong-Yeh; Della-Fera, Mary Anne; Baile, Clifton A; Rayalam, Srujana

2018-05-24

Menopause induces a loss of bone as a result of estrogen deficiency. Despite pharmaceutical options for the treatment of osteopenia and osteoporosis, many aging women use dietary supplements with estrogenic activity to prevent bone loss and other menopausal-related symptoms. Such supplements are yet to be tested for efficacy against a Food and Drug Administration (FDA) approved medication for menopausal bone loss such as zoledronic acid (ZA). The postmenopausal rat model was used to investigate the efficacy of various synergistic phytochemical blends mixed into the diet for 16 weeks. Retired-breeder, Fischer 344 rats were randomly assigned to sham or ovariectomy surgery and 4 treatment groups: ZA; genistein supplementation; and a low dose and high dose blend of genistein, resveratrol, and quercetin. Ovariectomy resulted in a loss of both trabecular and cortical bone which was prevented with ZA. The phytochemical blends tested were unable to reverse these losses. Despite the lack of effectiveness in preventing bone loss, a significant dose-response trend was observed in the phytochemical-rich diets in bone adipocyte number compared to ovariectomized control rats. Data from this study indicate that estrogenic phytochemicals are not as efficacious as ZA in preventing menopausal-related bone loss but may have beneficial effects on bone marrow adiposity in rats.

ERM proteins of the lens.

PubMed

Bagchi, M; Katar, M; Lo, W-K; Yost, R; Hill, C; Maisel, H

2004-06-01

Ezrin and radixin and protein 4.1 were detected in the lens of the eye. These proteins were mainly present in the young elongating cortical fiber cells and localized to the plasma membranes. Moesin was not detected. Ezrin, radixin, and protein 4.1 provide another means whereby actin is linked to the plasma membrane in addition to the known adherens junctions in the lens. Copyright 2004 Wiley-Liss, Inc.

Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1–induced collective directional migration and angiogenic sprouting

PubMed Central

Oubaha, Malika; Lin, Michelle I.; Margaron, Yoran; Filion, Dominic; Price, Emily N.; Zon, Leonard I.; Côté, Jean-François

2012-01-01

Angiogenic sprouting requires that cell-cell contacts be maintained during migration of endothelial cells. Angiopoietin-1 (Ang-1) and vascular endothelial growth factor act oppositely on endothelial cell junctions. We found that Ang-1 promotes collective and directional migration and, in contrast to VEGF, induces the formation of a complex formed of atypical protein kinase C (PKC)-ζ and β-catenin at cell-cell junctions and at the leading edge of migrating endothelial cells. This complex brings Par3, Par6, and adherens junction proteins at the front of migrating cells to locally activate Rac1 in response to Ang-1. The colocalization of PKCζ and β-catenin at leading edge along with PKCζ-dependent stabilization of cell-cell contacts promotes directed and collective endothelial cell migration. Consistent with these results, down-regulation of PKCζ in endothelial cells alters Ang-1–induced sprouting in vitro and knockdown in developing zebrafish results in intersegmental vessel defects caused by a perturbed directionality of tip cells and by loss of cell contacts between tip and stalk cells. These results reveal that PKCζ and β-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis. PMID:22936663

The atypical mitogen-activated protein kinase ERK3 is essential for establishment of epithelial architecture.

PubMed

Takahashi, Chika; Miyatake, Koichi; Kusakabe, Morioh; Nishida, Eisuke

2018-06-01

Epithelia contribute to physical barriers that protect internal tissues from the external environment and also support organ structure. Accordingly, establishment and maintenance of epithelial architecture are essential for both embryonic development and adult physiology. Here, using gene knockout and knockdown techniques along with gene profiling, we show that extracellular signal-regulated kinase 3 (ERK3), a poorly characterized atypical mitogen-activated protein kinase (MAPK), regulates the epithelial architecture in vertebrates. We found that in Xenopus embryonic epidermal epithelia, ERK3 knockdown impairs adherens and tight-junction protein distribution, as well as tight-junction barrier function, resulting in epidermal breakdown. Moreover, in human epithelial breast cancer cells, inhibition of ERK3 expression induced thickened epithelia with aberrant adherens and tight junctions. Results from microarray analyses suggested that transcription factor AP-2α (TFAP2A), a transcriptional regulator important for epithelial gene expression, is involved in ERK3-dependent changes in gene expression. Of note, TFAP2A knockdown phenocopied ERK3 knockdown in both Xenopus embryos and human cells, and ERK3 was required for full activation of TFAP2A-dependent transcription. Our findings reveal that ERK3 regulates epithelial architecture, possibly together with TFAP2A. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability.

PubMed

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R

2007-03-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication.

Clostridium sordellii Lethal Toxin Kills Mice by Inducing a Major Increase in Lung Vascular Permeability

PubMed Central

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R.

2007-01-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication. PMID:17322384

Effect of zoledronic acid in an L6-L7 rabbit spine fusion model.

PubMed

Bransford, Rick; Goergens, Elisabeth; Briody, Julie; Amanat, Negin; Cree, Andrew; Little, David

2007-04-01

Previous studies have shown that zoledronic acid administration can increase mineral content and strength in distraction osteogenesis. Of the few studies that have examined the use of bisphosphonates in spinal arthrodesis, none have assessed the effect of single dose treatment. The objective of this study was to evaluate the feasibility of enhancing spinal fusion rate using single dose zoledronic acid (ZA) to increase fusion-mass size and mineral density. Forty-eight New Zealand white rabbits underwent an L6-L7 intertransverse process fusion. The L6-L7 model is more challenging than the more commonly used level of L5-L6. Animals were randomly allocated to one of three groups, one received iliac crest bone graft alone, one group received iliac crest bone graft with locally administered zoledronic acid, 20 microg, and one group received iliac crest bone graft with a single dose of systemically administered zoledronic acid, 0.1 mg/kg. ZA doses were administered at the time of surgery. Twenty-four rabbits were culled at 6 weeks and 24 rabbits were culled at 12 weeks. Success of spinal fusion was determined by manual palpation. Specimens were evaluated radiographically, underwent quantitative computerised tomography analysis and were tested biomechanically in flexion and extension. In the six-week group, only five of the 24 spines fused with no noticeable trend with respect to treatment. In the 12-week group there was a trend toward increased fusion in the systemically administered ZA group (63%) versus the other two groups (25%) but was not statistically significant (p = 0.15). Radiographically, the local ZA treatment group showed a delay in remodelling with the presence of unremodelled bone chips. The 12-week systemic ZA group exhibited an 86% increase in BMC, a 31% increase in vBMD and a 41% increase in the volume of the fusion-mass (p < 0.05). The 12-week local ZA group also showed significant increases in BMC (69%), vBMD (31%) and total fusion-mass volume (29%) (p

Prime Contract Awards Alphabetically by Contractor, by State or Country, and Place. Part 4. (Campbell and Parts Engineers-Comstron Corporation)

DTIC Science & Technology

1989-01-01

0 -l W( I * 0 0 ( < 5 ZZZZZZZ ZZZZZZZZZZZZaZaZaaZaZZZZ00ZaZZZ (.u -4 1 NNNNNNJNNNNN N N NNN NNN N NNN N NNN1 4N NNN IN NNNN N 111 U-40 1 NNNNI -NNN...qf4L) 1 m mmmmmmmmm mmmmmm OMMIXM m ca m Do mm 55 -4(,)(01 oI 000o0 0 0 00o0 000000aoa0 0 00 00 0 0o 000 0 00000000 ’ 5 0 -4-! -4 - 4 0 4- 40 4o-40 4-440...4-4-4 -4-14 14-14 - 4- --4N NN4 4-4N(’J (14 C4-.4C4 I N N -4N " J-4N-4N’.Ji (t4 01 L) -* 1 0 LA-000WUL-000~-J4z00 4

Seismic analyses of equipment in 2736-Z complex. Revision 1

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

Ocoma, E.C.

1995-04-01

This report documents the structural qualification for the existing equipment when subjected to seismic loading in the Plutonium Storage Complex. It replaces in entirety Revision 0 and reconciles the U.S. Department of Energy (DOE) comments on Revision 0. The Complex consists of 2736-Z Building (plutonium storage vault), 2736-ZA Building (vault ventilation equipment building), and 2736-ZB Building (shipping/receiving, repackaging activities). The existing equipment structurally qualified in this report are the metal storage racks for 7 inch and lard cans in room 2 of Building 2736-Z; the cubicles, can holders and pedestals in rooms 1, 3, and 4 of Building 2736-Z; themore » ventilation duct including exhaust fans/motors, emergency diesel generator, and HEPA filter housing in Building 2736-ZA; the repackaging glovebox in Building 2736-ZB; and the interface duct between Buildings 2736-Z and 2736-ZA.« less

5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

PubMed

Wagner-Johnston, Nina D; Sloan, Jeff A; Liu, Heshan; Kearns, Ann E; Hines, Stephanie L; Puttabasavaiah, Suneetha; Dakhil, Shaker R; Lafky, Jacqueline M; Perez, Edith A; Loprinzi, Charles L

2015-08-01

Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. © 2015 American Cancer Society.

Effect of Zoledronic Acid and Denosumab in Patients With Low Back Pain and Modic Change: A Proof-of-Principle Trial.

PubMed

Cai, Guoqi; Laslett, Laura L; Aitken, Dawn; Halliday, Andrew; Pan, Feng; Otahal, Petr; Speden, Deborah; Winzenberg, Tania M; Jones, Graeme

2018-05-01

The aim of this study was to evaluate the effect of zoledronic acid (ZA) and denosumab on low back pain (LBP) and Modic change (MC) over 6 months. Adults aged ≥40 years with significant LBP for at least 6 months duration and MC (type 1, 2, or mixed) were randomized to receive ZA (5 mg/100 mL), denosumab (60 mg), or placebo. LBP was measured monthly by visual analogue scale (VAS) and the LBP Rating Scale (RS). MC was measured from MRIs of T 12 -S 1 vertebrae at screening and 6 months. A total of 103 participants with moderate/severe LBP (mean VAS = 57 mm; mean RS = 18) and median total MC area 538 mm 2 were enrolled. Compared to placebo, LBP reduced significantly at 6 months in the ZA group for RS (-3.3; 95% CI, -5.9 to -0.7) but not VAS (-8.2; 95% CI, -18.8 to +2.4) with similar findings for denosumab (RS, -3.0; 95% CI, -5.7 to -0.3; VAS, -10.7; 95% CI, -21.7 to +0.2). There was little change in areal MC size overall and no difference between groups with the exception of denosumab in those with type 1 Modic change (-22.1 mm 2 ; 95% CI, -41.5 to -2.7). In post hoc analyses, both medications significantly reduced VAS LBP in participants with milder disc degeneration and non-neuropathic pain, and denosumab reduced VAS LBP in those with type 1 MC over 6 months, compared to placebo. Adverse events were more frequent in the ZA group. These results suggests a potential therapeutic role for ZA and denosumab in MC-associated LBP. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research.

Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia.

PubMed

Yishake, Mumingjiang; Yasen, Miersalijiang; Jiang, Libo; Liu, Wangmi; Xing, Rong; Chen, Qian; Lin, Hong; Dong, Jian

2018-03-01

There has been no study regarding the effect of a combination of teriparatide (TPTD) and zoledronic acid (ZA) on vertebral fusion. In this study, we investigate the effect of single and combined TPTD and ZA treatment on lumbar vertebral fusion in aged ovariectomized (OVX) rats. Sixty two-month-old female Sprague-Dawley rats were ovariectomized and underwent bilateral L4-L5 posterolateral intertransverse fusion after 10 months. The OVX rats received vehicle (control) treatment, or ZA (100 µg/kg, once), or TPTD (60 µg/kg/2 d for 42 d), or ZA + TPTD until they were euthanized at 6 weeks following lumbar vertebral fusion. The lumbar spine was harvested. Bone mineral density (BMD), bone fusion, bone volume (BV), and bone formation rate (BFR)were analyzed by dual-energy X-ray absorptiometry (DXA), radiography, micro-computed tomography, and histomorphometry. Compared with vehicle (control) treatment, ZA and TPTD monotherapy increased bone volume (BV) at fusion site, and ZA + TPTD combined therapy had an additive effect. Treatment with TPTD and ZA + TPTD increased the bone fusion rate when compared with the control group. ZA monotherapy did not alter the rate of bone fusion. The TPTD and ZA + TPTD treatment groups had increased mineral apposition rate (MAR), mineralizing surfaces/bone surface ((MS/BS), and BFR/BS compared with the OVX group. Our experiment confirm that the monotherapy with TPTD and combination therapy with ZA + TPTD in an OVX rat model of osteopenia following lumbar vertebral fusion surgery increased bone fusion mass and bone fusion rate, and ZA + TPTD combined therapy had an additive effect on bone fusion mass. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:937-944, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Relationship between zinc malnutrition and alterations in murine peripheral blood leukocytes

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

King, L.E.; Morford, L.A.; Fraker, P.J.

1991-03-15

Studies using a murine model have shown that the immune system responds rapidly and adversely to zinc deficiency. The extent of alteration of peripheral blood leukocytes (PBL) and immunoglobulin levels were investigated in four zinc dietary groups: zinc adequate (ZA); restricted fed zinc adequate (RZA); marginal zinc deficient (MZD, 72-76% of ZA mouse weight); and severely zinc deficient. The peripheral white blood cell count was 3.66 {plus minus} 1.08 {times} 10{sup 6} cells/ml for ZA mice decreasing by 21%, 28% and 54% for RZA, MZD and SZD mice respectively. An equally dramatic change in the flow cytometric light scatter profilemore » was found. ZA mice had 66% lymphocytes and 21% polymorphonuclear granulocytes (PMN) in their peripheral blood while MZD and SZD mice contained 43% and 30% lymphocytes and 40% and 60% PMNs respectively. Analysis of the phenotypic distribution of specific classes of lymphocytes revealed ZA blood contained 25% B-cells and 40% T-cells (CD5{sup +}). B-cells decreased 40-50% for RZA and MZD mice and 60-70% for SZD mice. The decline in CD5{sup +} T-cells was more modest at 30% and 45% for MZD and SZD mice. A nearly 40% decline in both T{sub h} and T{sub c/s} cells was noted for both MZD and SZD mice. Radioimmunoassay of serum for changes in IgM and IgG content revealed no change among dietary groups while serum zinc decreased 10% for RZA mice and 50% for both MZD and SZD mice. The authors conclude that peripheral blood differential counts in concert with total B and T-cell phenotype may serve as indicators of zinc status while serum zinc and Ig will not.« less

Structural simulation of adenosine phosphate via plumbagin and zoledronic acid competitively targets JNK/Erk to synergistically attenuate osteoclastogenesis in a breast cancer model

PubMed Central

Qiao, H; Wang, T-y; Yu, Z-f; Han, X-g; Liu, X-q; Wang, Y-g; Fan, Q-m; Qin, A; Tang, T-t

2016-01-01

The treatment of breast cancer-induced osteolysis remains a challenge in clinical settings. Here, we explored the effect and mechanism of combined treatment with zoledronic acid (ZA) and plumbagin (PL), a widely investigated component derived from Plumbago zeylanica, against breast cancer-induced osteoclastogenesis. We found that the combined treatment with PL and ZA suppressed cell viability of precursor osteoclasts and synergistically inhibited MDA-MB-231-induced osteoclast formation (combination index=0.28) with the abrogation of recombinant mouse receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of NF-κB/MAPK (nuclear factor-κB/mitogen-activated protein kinase) pathways. Molecular docking suggested a putative binding area within c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk) protease active sites through the structural mimicking of adenosine phosphate (ANP) by the spatial combination of PL with ZA. A homogeneous time-resolved fluorescence assay further illustrated the direct competitiveness of the dual drugs against ANP docking to phosphorylated JNK/Erk, contributing to the inhibited downstream expression of c-Jun/c-Fos/NFATc-1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1). Then, in vivo testing demonstrated that the combined administration of PL and ZA attenuated breast cancer growth in the bone microenvironment. Additionally, these molecules prevented the destruction of proximal tibia, with significant reduction of tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast cells and potentiation of apoptotic cancer cells, to a greater extent when combined than when the drugs were applied independently. Altogether, the combination treatment with PL and ZA could significantly and synergistically suppress osteoclastogenesis and inhibit tumorigenesis both in vitro and in vivo by simulating the spatial structure of ANP to inhibit competitively phosphorylation of c-Jun N

Nutrients content and quality of liquid fertilizer made from goat manure

NASA Astrophysics Data System (ADS)

Sunaryo, Yacobus; Purnomo, Djoko; Theresia Darini, Maria; Ratri Cahyani, Vita

2018-05-01

Quality of liquid fertilizer is determined by the content of nutrients and other chemical factors such as pH and EC. This research aimed to examine nutrient contents and dynamic of pH and EC of liquid fertilizer made from goat manure in combination with sugar and ammonium sulfate (ZA) and using Effective Microorganisms (EM) as the decomposer. This research was conducted by employing 3 x 3 factorial experiment with three replications. Each treatment combination was applied in 20 L of water. The first factor was the quantity of sugar which consisted of 3 levels: 12.5, 25, and 50 g L-1 of water. The second factor was the quantity of ZA which consisted of 3 levels: 25, 37.5, and 50 g L-1 of water. All combinations were added by 100 g of air dried goat manure L-1 of water and EM solution 1 ml L-1 of water, and incubated for five months. Results of the experiment indicated that the increasing concentration of ZA resulted in the significantly increase of N total and S total. Increasing concentration of sugar resulted in decreasing pH and increasing lactic acid; whereas, increasing concentration of ZA followed by increasing Electrical Conductivity (EC). There was no significantly change of pH and EC of the liquid fertilizer during five months incubation.

Effect of cytokinins and auxins on the growth of free-living conchocelis of Porphyra yezoensis

NASA Astrophysics Data System (ADS)

de-Lin, Duan; Xiu-Geng, Fei; Hong-Xu, Ren; Xiong, Chen; Ying, Zhu

1995-09-01

IAA 3-Indolylacetic acid, NAA a-Naphthylacetic acid and cytokinins in PESI culture medium were used in a study on the effects of plant hormones on the growth of free-living conchocelis of Porphyra yezoensis which showed that its growth in medium with cytokinins, IAA and NAA was more rapid than that in medium with non—phytohormones; that the optimal concentrations for promoting growth were 10 μg/L for IAA and ZA (Zeatin), and 0.1 μg/L for BA 6-Benzyl amino purine and KIN 6-Furfurylamino- purine. Mix use of NAA, IAA and cytokinins, NAA/ZA 1-1000/1 μg/L, NAA/BA 10/1-1000 μg/L, NAA/KIN 1/1-1000 μg/L promoted growth. IAA/ZA 0.1-1/0.1-1 μg/L; IAA/BA 0.1-1/0.1-10 μg/L IAA/KIN 1/0.1-1000 μg/L also promoted growth.

Signaling through the PI 3-K, Akt and SGK Pathway in Breast Cancer Progression

DTIC Science & Technology

2013-12-01

Cancer Cell Migration The Adherens Junction Protein Afadin is an Akt substrate that Updated version 10.1158/1541-7786. MCR -13-0398doi: Access...the most recent version of this article at: Material Supplementary http://mcr.aacrjournals.org/content/suppl/2013/11/22/1541-7786. MCR -13-0398.DC1...accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 22, 2013; DOI: 10.1158/1541-7786. MCR -13-0398

The Usefulness of Bone Biomarkers for Monitoring Treatment Disease: A Comparative Study in Osteolytic and Osteosclerotic Bone Metastasis Models.

PubMed

Martín-Fernández, Marta; Valencia, Karmele; Zandueta, Carolina; Ormazábal, Cristina; Martínez-Canarias, Susana; Lecanda, Fernando; de la Piedra, Concepción

2017-04-01

The skeleton is the most common site of colonization by metastatic cancers. Zoledronic acid (ZA) has been shown to be effective for the treatment of bone metastases regardless of whether the bone lesions are osteolytic or osteoblastic. Biochemical markers of bone turnover may be useful tools to quantify the degree of bone remodeling in the presence of bone metastases. The aim of this work was to establish the correlation between tumor dispersion (bioluminescence) and biochemical markers of bone turnover in two osteolytic and osteoblastic metastasis models in mice. The A549M1 cell line that produces osteolytic metastases and the LADOB cell line extracted from a patient with a lung carcinoma and osteoblastic metastases cells were retrovirally transduced with a luciferase reporter gene for in vivo image analysis. Forty-four-week-old mice were inoculated in the left cardiac ventricle with A549M1 or LADOB cells. Twenty mouse of each group were treated with a single dose of ZA (70 μg/kg) 5 days after i.c. Ten animals of each group were sacrificed at 21 and 28 days postinoculation in A549M1 and 60 and 75 days in the LADOB assay. Bioluminescence analysis was quantified 7, 14, 21 ,and 28 days postinoculation in A549M1 mice and 33, 45, 60, and 75 days after inoculation in LADOB mice. Osteocalcin (BGP), aminoterminal propeptide of procollagen I (PINP), carboxiterminal telopeptide of type I collagen (CTX), and 5b isoenzyme of tartrate-resistant acid phosphatase were measured by ELISA (IDS, UK). Bioluminescence imaging revealed a significant increase of tumor burden on time in both osteolytic and osteoblastic mice models. ZA administration resulted in a significant decrease in tumor burden at 21 and 28 days in the A549M1 animals and 60 and 70 days postinoculation in the LADOB line. Biomarkers levels were significantly increased in the untreated group at every point in the osteolytic model. In the osteoblastic model, 2 months after inoculation, all biomarkers were significantly

Blood-Brain Barrier Disruption and Oxidative Stress in Guinea Pig after Systemic Exposure to Modified Cell-Free Hemoglobin

PubMed Central

Butt, Omer I.; Buehler, Paul W.; D'Agnillo, Felice

2011-01-01

Systemic exposure to cell-free hemoglobin (Hb) or its breakdown products after hemolysis or with the use of Hb-based oxygen therapeutics may alter the function and integrity of the blood-brain barrier. Using a guinea pig exchange transfusion model, we investigated the effect of a polymerized cell-free Hb (HbG) on the expression of endothelial tight junction proteins (zonula occludens 1, claudin-5, and occludin), astrocyte activation, IgG extravasation, heme oxygenase (HO), iron deposition, oxidative end products (4-hydroxynonenal adducts and 8-hydroxydeoxyguanosine), and apoptosis (cleaved caspase 3). Reduced zonula occludens 1 expression was observed after HbG transfusion as evidenced by Western blot and confocal microscopy. Claudin-5 distribution was altered in small- to medium-sized vessels. However, total expression of claudin-5 and occludin remained unchanged except for a notable increase in occludin 72 hours after HbG transfusion. HbG-transfused animals also showed increased astrocytic glial fibrillary acidic protein expression and IgG extravasation after 72 hours. Increased HO activity and HO-1 expression with prominent enhancement of HO-1 immunoreactivity in CD163-expressing perivascular cells and infiltrating monocytes/macrophages were also observed. Consistent with oxidative stress, HbG increased iron deposition, 4-hydroxynonenal and 8-hydroxydeoxyguanosine immunoreactivity, and cleaved caspase-3 expression. Systemic exposure to an extracellular Hb triggers blood-brain barrier disruption and oxidative stress, which may have important implications for the use of Hb-based therapeutics and may provide indirect insight on the central nervous system vasculopathies associated with excessive hemolysis. PMID:21356382

Hydroquinone Strongly Alleviates Focal Ischemic Brain Injury via Blockage of Blood-Brain Barrier Disruption in Rats.

PubMed

Ha Park, Joon; Yoo, Ki-Yeon; Hye Kim, In; Cho, Jeong-Hwi; Lee, Jae-Chul; Hyeon Ahn, Ji; Jin Tae, Hyun; Chun Yan, Bing; Won Kim, Dae; Kyu Park, Ok; Kwon, Seung-Hae; Her, Song; Su Kim, Jin; Hoon Choi, Jung; Hyun Lee, Choong; Koo Hwang, In; Youl Cho, Jae; Hwi Cho, Jun; Kwon, Young-Guen; Ryoo, Sungwoo; Kim, Young-Myeong; Won, Moo-Ho; Jun Kang, Il

2016-12-01

Hydroquinone (HQ), a major benzene metabolite, occurs naturally in various plants and is manufactured for commercial use. Although HQ displays various biological effects, its neuroprotective effects following ischemic insults have not been investigated. In this study, we first examined neuroprotective effects of HQ in a rat model of transient focal cerebral ischemia. Animals were subjected to transient middle cerebral artery occlusion for 120 min. HQ (50 or 100 mg/kg) or vehicle was intraperitoneally administered once at 30 min after ischemia-reperfusion. Neuroprotection by treatment with 100 mg/kg of HQ was shown using evaluation of neurological deficits, positron-emission tomography (PET) and 2,3,5-triphenyltetrazoliumchloride (TTC) staining. In addition, HQ treatment significantly attenuated ischemia-induced Evans blue dye extravasation from blood vessels and significantly increased immunoreactivities of SMI-71 (an endothelial BBB marker) and glucose transporter-1 (GLUT-1, an endothelial cell marker) in ischemic cortex compared to the vehicle-treated ischemia-operated group. Confocal microscopy and western blot analysis also showed that HQ treatment maintained expressions of tight junction proteins (zonula occludens-1 and occludin) in the ischemic cortex. Post-treatment with HQ protected neurons from transient focal cerebral ischemic injury and the neuroprotective effect of HQ might be closely associated with prevention of BBB disruption via maintaining SMI-71 and GLUT-1 expressions as well as prevention of the degradation of zonula occludens-1 and occludin proteins. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice.

PubMed

Long, Y; Du, L; Kim, J J; Chen, B; Zhu, Y; Zhang, Y; Yao, S; He, H; Zheng, X; Huang, Z; Dai, N

2018-04-11

Alterations in intestinal permeability regulated by tight junctions (TJs) are associated with immune activation and visceral hypersensitivity in irritable bowel syndrome (IBS). Myosin light chain kinase (MLCK) is an important mediator of epithelial TJ. The aim of this study is to investigate the role of MLCK in the pathogenesis of IBS using a post infectious IBS (PI-IBS) mouse model. Trichinella spiralis-infected PI-IBS mouse model was used. Urine lactulose/mannitol ratio was measured to assess intestinal epithelial permeability. Western blotting was used to evaluate intestinal TJ protein (zonula occludens-1) and MLCK-associated protein expressions. Immune profile was assessed by measuring Th (T helper) 1/Th2 cytokine expression. Visceral sensitivity was determined by abdominal withdrawal reflex in response to colorectal distension. Eight weeks after inoculation with T. spiralis, PI-IBS mice developed decreased pain and volume thresholds during colorectal distention, increased urine lactulose/mannitol ratio, elevated colonic Th1/Th2 cytokine ratio, and decreased zonula occludens-1 expression compared to the control mice. MLCK expression was dramatically elevated in the colonic mucosa of PI-IBS mice compared to the control mice, alongside increased pMLC/MLC and decreased MLCP expression. Administration of MLCK inhibitor and TJ blocker both reversed the increased intestinal permeability, visceral hypersensitivity, and Th1-dominant immune profile in PI-IBS mice. MLCK is a pivotal step in inducing increased intestinal permeability promoting low-grade intestinal immune activation and visceral hypersensitivity in PI-IBS mice. MLCK inhibitor may provide a potential therapeutic option in the treatment of IBS. © 2018 John Wiley & Sons Ltd.

Biostimulatory effects of low-level laser therapy on epithelial cells and gingival fibroblasts treated with zoledronic acid

NASA Astrophysics Data System (ADS)

Basso, F. G.; Pansani, T. N.; Turrioni, A. P. S.; Kurachi, C.; Bagnato, V. S.; Hebling, J.; de Souza Costa, C. A.

2013-05-01

Low-level laser therapy (LLLT) has been considered as an adjuvant treatment for bisphosphonate-related osteonecrosis, presenting positive clinical outcomes. However, there are no data regarding the effect of LLLT on oral tissue cells exposed to bisphosphonates. This study aimed to evaluate the effects of LLLT on epithelial cells and gingival fibroblasts exposed to a nitrogen-containing bisphosphonate—zoledronic acid (ZA). Cells were seeded in wells of 24-well plates, incubated for 48 h and then exposed to ZA at 5 μM for an additional 48 h. LLLT was performed with a diode laser prototype—LaserTABLE (InGaAsP—780 nm ± 3 nm, 25 mW), at selected energy doses of 0.5, 1.5, 3, 5, and 7 J cm-2 in three irradiation sessions, every 24 h. Cell metabolism, total protein production, gene expression of vascular endothelial growth factor (VEGF) and collagen type I (Col-I), and cell morphology were evaluated 24 h after the last irradiation. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests at 5% significance. Selected LLLT parameters increased the functions of epithelial cells and gingival fibroblasts treated with ZA. Gene expression of VEGF and Col-I was also increased. Specific parameters of LLLT biostimulated fibroblasts and epithelial cells treated with ZA. Analysis of these in vitro data may explain the positive in vivo effects of LLLT applied to osteonecrosis lesions.

Fabrication of novel metal ion imprinted xanthan gum-layered double hydroxide nanocomposite for adsorption of rare earth elements.

PubMed

Iftekhar, Sidra; Srivastava, Varsha; Hammouda, Samia Ben; Sillanpää, Mika

2018-08-15

The work focus to enhance the properties of xanthan gum (XG) by anchoring metal ions (Fe, Zr) and encapsulating inorganic matrix (M@XG-ZA). The fabricated nanocomposite was characterized by Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDX), Fourier Transform Infrared Spectroscopy (FTIR), surface area (BET) and zeta potential analysis. The adsorption of Sc, Nd, Tm and Yb was investigated after screening of synthesized materials in detail to understand the influence of pH, contact time, temperature and initial REE (rare earth element) concentration both in single and multicomponent system via batch adsorption. The adsorption mechanism was verified by FTIR, SEM and elemental mapping. The SEM images of Zr@XG-ZA demonstrate scutes structure, which disappeared after adsorption of REEs. The maximum adsorption capacities were 132.30, 14.01, 18.15 and 25.73 mg/g for Sc, Nd, Tm and Yb, respectively. The adsorption efficiency over Zr@XG-ZA in multicomponent system was higher than single system and the REEs followed the order: Sc > Yb > Tm > Nd. The Zr@XG-ZA demonstrate good adsorption behavior for REEs up to five cycles and then it can be used as photocatalyst for the degradation of tetracycline. Thus, the work adds a new insight to design and preparation of efficient bifunctional adsorbents from sustainable materials for water purification. Copyright © 2018 Elsevier Ltd. All rights reserved.

Infra Red Dye and Endostar Loaded Poly Lactic Acid Nano Particles as a Novel Theranostic Nanomedicine for Breast Cancer.

PubMed

Zhang, Qian; Du, Yang; Jing, Lijia; Liang, Xiaolong; Li, Yaqian; Li, Xiaofeng; Dai, Zhifei; Tian, Jie

2016-03-01

Endostar, a novel recombinant human endostatin, has been proven to inhibit tumor angiogenesis and is utilized as an anticancer drug. While free drugs can display limited efficacy, nanoscaled anticancer drugs have been fabricated and proven to possess superior therapeutic effects. Poly(lactic acid) (PLA) is a FDA-approved biomaterial displaying excellent biocompatibility and low toxicity. In this study, Endostar-loaded PLA nanoparticles (EPNPs) were first prepared, and a near-infrared (NIR) dye, IRDye 800CW, was conjugated to the surface for detecting nanoparticle biodistribution through fluorescence molecular imaging (FMI) using an orthotopic breast tumor mouse model. The antitumor efficacy of EPNPs was examined using bioluminescence imaging (BLI) and immunohistology. To further improve the antitumor effects, we combined EPNPs with zoledronic acid monohydrate (ZA), which is known to decrease the tumor-associated macrophages (TAM) and inhibit tumor progression. We found that EPNPs decreased human umbilical vein endothelial cell (HUVEC) viability by inhibiting tumor growth gene expression more significantly than free Endostar in vitro. In vivo, EPNPs displayed better tumor growth inhibitory effects compared with free Endostar, and the combination of EPNPs with ZA exhibited more significant antitumor effects. As confirmed by CD31 and CD11b immunohistochemistry, the combination of EPNPs and ZA showed synergistic effects in reducing tumor angiogenesis and TAM accumulation in tumor regions. Taken together, this study presents a novel and effective form of nanoscaled Endostar for the treatment of breast cancer that displays synergistic antitumor effects in combination with ZA.

The force-sensing device region of α-catenin is an intrinsically disordered segment in the absence of intramolecular stabilization of the autoinhibitory form.

PubMed

Hirano, Yoshinori; Amano, Yu; Yonemura, Shigenobu; Hakoshima, Toshio

2018-05-01

Mechanotransduction by α-catenin facilitates the force-dependent development of adherens junctions (AJs) by recruiting vinculin to reinforce actin anchoring of AJs. The α-catenin mechanotransducing action is facilitated by its force-sensing device region that autoinhibits the vinculin-binding site 1 (VBS1). Here, we report the high-resolution structure of the force-sensing device region of α-catenin, which shows the autoinhibited form comprised of helix bundles E, F and G. The cryptic VBS1 is embedded into helix bundle E stabilized by direct interactions with the autoinhibitory region forming helix bundles F and G. Our molecular dissection study showed that helix bundles F and G are stable in solution in each isolated form, whereas helix bundle E that contains VBS1 is unstable and intrinsically disordered in solution in the isolated form. We successfully identified key residues mediating the autoinhibition and produced mutated α-catenins that display variable force sensitivity and autoinhibition. Using these mutants, we demonstrate both in vitro and in vivo that, in the absence of this stabilization, the helix bundle containing VBS1 would adopt an unfolded form, thus exposing VBS for vinculin binding. We provide evidence for importance of mechanotransduction with the intrinsic force sensitivity for vinculin recruitment to adherens junctions of epithelial cell sheets with mutated α-catenins. © 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

PubMed Central

Sankapal, Soni; Gupta, Phalguni; Ratner, Deena; Ding, Ming; Shen, Chengli; Sanyal, Anwesha; Stolz, Donna; Cu-Uvin, Susan; Ramratnam, Bharat

2016-01-01

Abstract Epithelial cells in human cervical and colonic mucosa do not express HIV receptor. However, HIV transmission occurs across the unbreached epithelia by an unknown mechanism. In this study, the effect of HIV exposure on tight junction (TJ) and cytokine production in ectocervical and colon mucosal epithelia in tissue biopsies was investigated in an organ culture model. After HIV exposure, the distribution patterns and quantities of epithelial TJ and adherens proteins were evaluated by immunofluorescence staining followed by confocal microscopy. Cytokine mRNA in the mucosal epithelia was also evaluated by real-time reverse transcription–polymerase chain reaction (RT-PCR). HIV transmission was evaluated by measuring p24 production in culture supernatant. Our results showed there were no significant changes in the distribution and quantities of epithelial TJ/adherens junction (AJ) proteins after exposure to HIV. However, higher levels of CXCL10 and CXCL11 mRNA expression were detected in HIV-exposed ectocervical epithelia. In case of colon mucosa, higher levels of CXCL10 and IL-6 mRNA expression were detected in HIV-exposed colon mucosa. Our study suggests that HIV induces cytokine production in epithelial cells, which may facilitate HIV transmission by recruiting HIV target cells in the submucosal region. Furthermore, HIV transmission may not occur through epithelial TJ/AJ disruption. PMID:27153934

Rap1 and Canoe/afadin are essential for establishment of apical–basal polarity in the Drosophila embryo

PubMed Central

Choi, Wangsun; Harris, Nathan J.; Sumigray, Kaelyn D.; Peifer, Mark

2013-01-01

The establishment and maintenance of apical–basal cell polarity is critical for assembling epithelia and maintaining organ architecture. Drosophila embryos provide a superb model. In the current view, apically positioned Bazooka/Par3 is the initial polarity cue as cells form during cellularization. Bazooka then helps to position both adherens junctions and atypical protein kinase C (aPKC). Although a polarized cytoskeleton is critical for Bazooka positioning, proteins mediating this remained unknown. We found that the small GTPase Rap1 and the actin-junctional linker Canoe/afadin are essential for polarity establishment, as both adherens junctions and Bazooka are mispositioned in their absence. Rap1 and Canoe do not simply organize the cytoskeleton, as actin and microtubules become properly polarized in their absence. Canoe can recruit Bazooka when ectopically expressed, but they do not obligatorily colocalize. Rap1 and Canoe play continuing roles in Bazooka localization during gastrulation, but other polarity cues partially restore apical Bazooka in the absence of Rap1 or Canoe. We next tested the current linear model for polarity establishment. Both Bazooka and aPKC regulate Canoe localization despite being “downstream” of Canoe. Further, Rap1, Bazooka, and aPKC, but not Canoe, regulate columnar cell shape. These data reshape our view, suggesting that polarity establishment is regulated by a protein network rather than a linear pathway. PMID:23363604

Meta-Analysis of Integrity Tests: A Critical Examination of Validity Generalization and Moderator Variables

DTIC Science & Technology

1992-06-01

AVA LABLLTY OF PEPOR’ 2b DECLASSfFiCATION DOWNGRADING SCHEDULE UnI imiited 4 PERFORMING ORGANZAT ON REPORT NUMBER(S) 5 MON’TORzNG ORGA% ZA C% RPEOR...8217 " S 92- 1 6a NAME OF PERFORMING ORGANIZATION 6b OFFPCE SYMBOL 7a NAME OF V0’O0R ’C OCGAz) ZA- %I University of Iowa (Ifappicable) Defense Personnel...data points. Results indicate that integrity test validities are positive and in many cases substantial for predicting both job performance and

High energy density Z-pinch plasmas using flow stabilization

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

Shumlak, U., E-mail: shumlak@uw.edu; Golingo, R. P., E-mail: shumlak@uw.edu; Nelson, B. A., E-mail: shumlak@uw.edu

The ZaP Flow Z-Pinch research project[1] at the University of Washington investigates the effect of sheared flows on MHD instabilities. Axially flowing Z-pinch plasmas are produced that are 100 cm long with a 1 cm radius. The plasma remains quiescent for many radial Alfvén times and axial flow times. The quiescent periods are characterized by low magnetic mode activity measured at several locations along the plasma column and by stationary visible plasma emission. Plasma evolution is modeled with high-resolution simulation codes – Mach2, WARPX, NIMROD, and HiFi. Plasma flow profiles are experimentally measured with a multi-chord ion Doppler spectrometer. Amore » sheared flow profile is observed to be coincident with the quiescent period, and is consistent with classical plasma viscosity. Equilibrium is determined by diagnostic measurements: interferometry for density; spectroscopy for ion temperature, plasma flow, and density[2]; Thomson scattering for electron temperature; Zeeman splitting for internal magnetic field measurements[3]; and fast framing photography for global structure. Wall stabilization has been investigated computationally and experimentally by removing 70% of the surrounding conducting wall to demonstrate no change in stability behavior.[4] Experimental evidence suggests that the plasma lifetime is only limited by plasma supply and current waveform. The flow Z-pinch concept provides an approach to achieve high energy density plasmas,[5] which are large, easy to diagnose, and persist for extended durations. A new experiment, ZaP-HD, has been built to investigate this approach by separating the flow Z-pinch formation from the radial compression using a triaxial-electrode configuration. This innovation allows more detailed investigations of the sheared flow stabilizing effect, and it allows compression to much higher densities than previously achieved on ZaP by reducing the linear density and increasing the pinch current. Experimental results

A test of the adhesion approximation for gravitational clustering

NASA Technical Reports Server (NTRS)

Melott, Adrian L.; Shandarin, Sergei; Weinberg, David H.

1993-01-01

We quantitatively compare a particle implementation of the adhesion approximation to fully non-linear, numerical 'N-body' simulations. Our primary tool, cross-correlation of N-body simulations with the adhesion approximation, indicates good agreement, better than that found by the same test performed with the Zel-dovich approximation (hereafter ZA). However, the cross-correlation is not as good as that of the truncated Zel-dovich approximation (TZA), obtained by applying the Zel'dovich approximation after smoothing the initial density field with a Gaussian filter. We confirm that the adhesion approximation produces an excessively filamentary distribution. Relative to the N-body results, we also find that: (a) the power spectrum obtained from the adhesion approximation is more accurate than that from ZA or TZA, (b) the error in the phase angle of Fourier components is worse than that from TZA, and (c) the mass distribution function is more accurate than that from ZA or TZA. It appears that adhesion performs well statistically, but that TZA is more accurate dynamically, in the sense of moving mass to the right place.

A test of the adhesion approximation for gravitational clustering

NASA Technical Reports Server (NTRS)

Melott, Adrian L.; Shandarin, Sergei F.; Weinberg, David H.

1994-01-01

We quantitatively compare a particle implementation of the adhesion approximation to fully nonlinear, numerical 'N-body' simulations. Our primary tool, cross-correlation of N-body simulations with the adhesion approximation, indicates good agreement, better than that found by the same test performed with the Zel'dovich approximation (hereafter ZA). However, the cross-correlation is not as good as that of the truncated Zel'dovich approximation (TZA), obtained by applying the Zel'dovich approximation after smoothing the initial density field with a Gaussian filter. We confirm that the adhesion approximation produces an excessively filamentary distribution. Relative to the N-body results, we also find that: (a) the power spectrum obtained from the adhesion approximation is more accurate that that from ZA to TZA, (b) the error in the phase angle of Fourier components is worse that that from TZA, and (c) the mass distribution function is more accurate than that from ZA or TZA. It appears that adhesion performs well statistically, but that TZA is more accurate dynamically, in the sense of moving mass to the right place.

Multiple Reaction Monitoring Mode Based Liquid Chromatography-Mass Spectrometry Method for Simultaneous Quantification of Brassinolide and Other Plant Hormones Involved in Abiotic Stresses.

PubMed

Kasote, Deepak M; Ghosh, Ritesh; Chung, Jun Young; Kim, Jonggeun; Bae, Inhwan; Bae, Hanhong

2016-01-01

Plant hormones are the key regulators of adaptive stress response. Abiotic stresses such as drought and salt are known to affect the growth and productivity of plants. It is well known that the levels of plant hormones such as zeatin (ZA), abscisic acid (ABA), salicylic acid (SA), jasmonic acid (JA), and brassinolide (BR) fluctuate upon abiotic stress exposure. At present, there is not any single suitable liquid chromatography-mass spectrometry (LC-MS) method for simultaneous analysis of BR and other plant hormones involved in abiotic stresses. In the present study, we developed a simple, sensitive, and rapid method for simultaneous analysis of five major plant hormones, ZA, ABA, JA, SA, and BR, which are directly or indirectly involved in drought and salt stresses. The optimized extraction procedure was simple and easy to use for simultaneous measurement of these plant hormones in Arabidopsis thaliana. The developed method is highly reproducible and can be adapted for simultaneous measurement of changes in plant hormones (ZA, ABA, JA, SA, and BR) in response to abiotic stresses in plants like A. thaliana and tomato.

A figure of merit for AMTEC electrodes

NASA Technical Reports Server (NTRS)

Underwood, M. L.; Williams, R. M.; Jeffries-Nakamura, B.; Ryan, M. A.

1991-01-01

As a method to compare the results of alkali metal thermoelectric converter (AMTEC) electrode performance measured under different conditions, an AMTEC figure of merit called ZA is proposed. This figure of merit is the ratio of the experimental maximum power for an electrode to a calculated maximum power density as determined from a recently published electrode performance model. The calculation of a maximum power density assumes that certain loss terms in the electrode can be reduced to essentially zero by improved cell design and construction, and that the electrochemical exchange current is determined from a standard value. Other losses in the electrode are considered inherent to the electrode performance. Thus, these terms remain in the determination of the calculated maximum power. A value of ZA near one, then, indicates an electrode performance near the maximum possible performance. The primary limitation of this calculation is that the small electrode effect cannot be included. This effect leads to anomalously high values of ZA. Thus, the electrode area should be reported along with the figure of merit.

Metal Matrix Composites Directionally Solidified

NASA Astrophysics Data System (ADS)

Ares, Alicia Esther; Schvezov, Carlos Enrique

The present work is focus on studying the dendritic solidification of metal matrix composites, MMCs, (using zinc-aluminum, ZA, alloys as matrix and the addition of SiC and Al2O3 particles). The compounds were obtained by as-cast solidification, under continuous stirring and in a second stage were directionally solidified in order to obtain different dendritic growth (columnar, equiaxed and columnar-to-equiaxed transition (CET)). The results in MMCs were compared with those obtained in directional solidification of ZA alloys, primarily with regard to structural parameters. The size and evolution of microstructure, according to the size of the MMCs particles and the variation of the thermal parameters was analyzing. In general it was found that the size of the microstructure (secondary dendritic spacing) decreases with the increase of particles in the matrix. When cooling rate increases, particle size decreases, and a higher cooling rate causes finer and more homogeneous dendrites Also, the segregation which was found in the matrix of the composites was significantly less than in the case of ZA alloys.

Low-loss Z-type barium hexaferrite composites from nanoscale ZnAl2O4 addition for high-frequency applications

NASA Astrophysics Data System (ADS)

Zheng, Zongliang; Feng, Quanyuan; Harris, Vincent G.

2018-05-01

In this study, nanocrystalline ZnAl2O4 (ZA) were introduced to Z-type barium hexaferrite (Co2Z) and the effects of ZA addition upon the crystal-phase composition, microstructure, permeability and permittivity as well as losses characteristics over a wide frequency range of 10 MHz-1 GHz have been systematically investigated. With increasing ZA content (x) from 0 to 15 wt%, the permeability μ' at low frequencies decreased from 12.0 to 4.3, while the permittivity ɛ' was decreased from 27.4 to 10.7. Correspondingly, the frequency stability of permeability and permittivity were improved and the losses were effectively reduced. When x is in the range of 5-10 wt%, the magnetic loss tan δμ is in the order of 10-2 and the dielectric loss tan δɛ is in the order of 10-3 at 300 MHz, which is lower by one order of magnitude compared with that of undoped Co2Z. The modified magnetic and dielectric properties are closely related to the changing phase composition and microstructure.

Modulation of Tumor Cell Metabolism by Laser Photochemotherapy with Cisplatin or Zoledronic Acid In Vitro.

PubMed

Heymann, Paul Günther Baptist; Henkenius, Katharina Sabine Elisabeth; Ziebart, Thomas; Braun, Andreas; Hirthammer, Klara; Halling, Frank; Neff, Andreas; Mandic, Robert

2018-03-01

Laser photochemotherapy is a new approach in cancer treatment using low-level laser therapy (LLLT) to enhance the effect of chemotherapy. In order to evaluate the effect of LLLT on tumor cells, HeLa cells were treated with cisplatin or zoledronic acid (ZA) followed by LLLT. Cell viability was evaluated with 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Oxidative phosphorylation and glycolysis were measured using extracellular flux analysis. Immunocytochemistry of heat-shock protein 70 (HSP70) and western blot analysis were performed. LLLT alone increased viability and was associated with lower oxidative phosphorylation but higher glycolysis rates. Cisplatin and ZA alone lowered cell viability, glycolysis and oxidative phosphorylation. This effect was significantly enhanced in conjunction with LLLT and was accompanied by reduced oxidative phosphorylation and collapse of glycolysis. Our observations indicate that LLLT may raise the cytotoxicity of cisplatin and ZA by modulating cellular metabolism, pointing to a possible application in cancer treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

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

Xie, Fan; Li, Pengcheng; Gong, Jianhua

Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer)more » augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. - Highlights: • Zoledronic acid (ZA) is effectively against lung cancer cells in vitro and in vivo. • ZA acts on lung cancer cells through inhibition of protein prenylation. • ZA suppresses global downstream phosphorylation of Ras signalling. • ZA enhances the effects of chemotherapeutic drugs in lung cancer cells.« less

Changes in cortical bone channels network and osteocyte organization after the use of zoledronic acid.

PubMed

Rabelo, Gustavo Davi; Travençolo, Bruno Augusto Nassif; Oliveira, Marcio Augusto; Beletti, Marcelo Emílio; Gallottini, Marina; Silveira, Fernando Ricardo Xavier da

2015-12-01

The aim of this study was to evaluate the effects of zoledronic acid (ZA) on the cortical bone channels network (CBCN) and osteocyte organization in relation to the bone channels. Eighteen male Wistar rats were divided into control (CG) and test groups (TG). Twelve animals from TG received 3 ZA doses (7.5 µg/kg), and 6 animals from CG did not receive any medication. TG animals were euthanized at 14 (n = 6) and 75 (n = 6) dadys after drug injection. CBCN was analyzed in mandibles and tibias using computational routines. The osteocyte organization was qualitatively evaluated in tibias using a three-dimensional reconstruction of images from serial histological sections. Significant differences in CBCN of tibia were found between the treated and untreated rats, with a wider range of sizes and shapes of the channels after the use of ZA (channels area p = 0.0063, channels area SD p = 0.0276) and less bone matrix (bone volume p = 0.0388). The alterations in the channels' morphology were more evident at 75 days after the drug injection (channels perimeter p = 0.0286). No differences were found in mandibles CBCN. The osteocyte distribution revealed more variable patterns of cell distribution in ZA groups, with non-homogeneous distribution of cells in relation to the bone channels. Zoledronic acid induces structural changes in CBCN and modifies the osteocyte arrangement in cortical bone in the tibia; also, the variability in the morphology of bone channels became more evident after a certain time of the use of the drug.

Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study.

PubMed

De Colli, Marianna; Tortorella, Paolo; Agamennone, Mariangela; Campestre, Cristina; Loiodice, Fulvio; Cataldi, Amelia; Zara, Susi

2018-07-01

Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)‑stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2 and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS‑induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis.

The Zeldovich & Adhesion approximations and applications to the local universe

NASA Astrophysics Data System (ADS)

Hidding, Johan; van de Weygaert, Rien; Shandarin, Sergei

2016-10-01

The Zeldovich approximation (ZA) predicts the formation of a web of singularities. While these singularities may only exist in the most formal interpretation of the ZA, they provide a powerful tool for the analysis of initial conditions. We present a novel method to find the skeleton of the resulting cosmic web based on singularities in the primordial deformation tensor and its higher order derivatives. We show that the A 3 lines predict the formation of filaments in a two-dimensional model. We continue with applications of the adhesion model to visualise structures in the local (z < 0.03) universe.

Helicopter Blade Analysis

DTIC Science & Technology

1947-01-01

9, 9^ + 9, ) • sin (*-©„)- 0 za ^ yf Neglecting the gravity forces and using the above assumptions, ( jt- 8o ) reduces to U-ßZ) i pcV2 C...ez ), by dropping subscript "f" and setting 0 = Q , d* = 0 , becomes (iC-84) Tg pcV2 C1 dx - mx (0 9^ + 9 ) dx + dS = 0 Subtracting {a-&4...from (ff-ɝ£ ): (x-a^-) | pcV2 (C, - C,) dx - mx Of (<t> - 8 ) dx f za y - mx (9 - 9 ) dx + dS„ - dS H- P do = 0 Integrating (z-83

Perfluorohexadecanoic acid increases paracellular permeability in endothelial cells through the activation of plasma kallikrein-kinin system.

PubMed

Liu, Qian S; Hao, Fang; Sun, Zhendong; Long, Yanmin; Zhou, Qunfang; Jiang, Guibin

2018-01-01

Per- and polyfluoroalkyl substances (PFASs) are ubiquitous and high persistent in human blood, thus potentially inducing a myriad of deleterious consequences. Plasma kallikrein-kinin system (KKS), which physiologically regulates vascular permeability, is vulnerable to exogenous stimulators, like PFASs with long-chain alkyl backbone substituted by electronegative fluorine. The study on the interactions of PFASs with the KKS and the subsequent effects on vascular permeability would be helpful to illustrate how the chemicals penetrate the biological vascular barriers to reach different tissues. In present study, three representative PFASs, including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexadecanoic acid (PFHxDA), were investigated for their effects on the activation of the KKS, paracellular permeability in human retina endothelial cells (HRECs) and integrity of the adherens junctions. In contrast to either PFOS or PFOA, PFHxDA efficiently triggered KKS activation in a concentration-dependent manner based on protease activity assays. The plasma activated by PFHxDA significantly increased paracellular permeability of HRECs through the degradation of adherens junctions. As evidenced by the antagonistic effect of aprotinin, PFHxDA-involved effects on vascular permeability were mediated by KKS activation. The results herein firstly revealed the mechanistic pathway for PFHxDA induced effects on vascular endothelial cells. Regarding the possible structure-related activities of the chemicals, this finding would be of great help in the risk assessment of PFASs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Occludin confers adhesiveness when expressed in fibroblasts.

PubMed

Van Itallie, C M; Anderson, J M

1997-05-01

Occludin is an integral membrane protein specifically associated with tight junctions. Previous studies suggest it is likely to function in forming the intercellular seal. In the present study, we expressed occludin under an inducible promotor in occludin-null fibroblasts to determine whether this protein confers intercellular adhesion. When human occludin is stably expressed in NRK and Rat-1 fibroblasts, which lack endogenous occludin and tight junctions but do have well developed ZO-1-containing adherens-like junctions, occludin colocalizes with ZO-1 to points of cell-cell contact. In contrast, L-cell fibroblasts which lack cadherin-based adherens junctions, target neither ZO-1 nor occludin to sites of cell contact. Occludin-induced adhesion was next quantified using a suspended cell assay. In NRK and Rat-1 cells, occludin expression induces adhesion in the absence of calcium, thus independent of cadherin-cadherin contacts. In contrast, L-cells are nonadhesive in this assay and show no increase in adhesion after induction of occludin expression. Binding of an antibody to the first of the putative extracellular loops of occludin confirmed that this sequence was exposed on the cell surface, and synthetic peptides containing the amino acid sequence of this loop inhibit adhesion induced by occludin expression. These results suggest that the extracellular surface of occludin is directly involved in cell-cell adhesion and the ability to confer adhesiveness correlates with the ability to colocalize with its cytoplasmic binding protein, ZO-1.

Smooth muscle-protein translocation and tissue function.

PubMed

Eddinger, Thomas J

2014-09-01

Smooth muscle (SM) tissue is a complex organization of multiple cell types and is regulated by numerous signaling molecules (neurotransmitters, hormones, cytokines, etc.). SM contractile function can be regulated via expression and distribution of the contractile and cytoskeletal proteins, and activation of any of the second messenger pathways that regulate them. Spatial-temporal changes in the contractile, cytoskeletal or regulatory components of SM cells (SMCs) have been proposed to alter SM contractile activity. Ca(2+) sensitization/desensitization can occur as a result of changes at any of these levels, and specific pathways have been identified at all of these levels. Understanding when and how proteins can translocate within the cytoplasm, or to-and-from the plasmalemma and the cytoplasm to alter contractile activity is critical. Numerous studies have reported translocation of proteins associated with the adherens junction and G protein-coupled receptor activation pathways in isolated SMC systems. Specific examples of translocation of vinculin to and from the adherens junction and protein kinase C (PKC) and 17 kDa PKC-potentiated inhibitor of myosin light chain phosphatase (CPI-17) to and from the plasmalemma in isolated SMC systems but not in intact SM tissues are discussed. Using both isolated SMC systems and SM tissues in parallel to pursue these studies will advance our understanding of both the role and mechanism of these pathways as well as their possible significance for Ca(2+) sensitization in intact SM tissues and organ systems. © 2014 Wiley Periodicals, Inc.

Epithelial-mesenchymal transition abolishes the susceptibility of polarized epithelial cell lines to measles virus.

PubMed

Shirogane, Yuta; Takeda, Makoto; Tahara, Maino; Ikegame, Satoshi; Nakamura, Takanori; Yanagi, Yusuke

2010-07-02

Measles virus (MV), an enveloped negative-strand RNA virus, remains a major cause of morbidity and mortality in developing countries. MV predominantly infects immune cells by using signaling lymphocyte activation molecule (SLAM; also called CD150) as a receptor, but it also infects polarized epithelial cells, forming tight junctions in a SLAM-independent manner. Although the ability of MV to infect polarized epithelial cells is thought to be important for its transmission, the epithelial cell receptor for MV has not been identified. A transcriptional repressor, Snail, induces epithelial-mesenchymal transition (EMT), in which epithelial cells lose epithelial cell phenotypes, such as adherens and tight junctions. In this study, EMT was induced by expressing Snail in a lung adenocarcinoma cell line, II-18, which is highly susceptible to wild-type MV. Snail-expressing II-18 cells lost adherens and tight junctions. Microarray analysis confirmed the induction of EMT in II-18 cells and suggested a novel function of Snail in protein degradation and distribution. Importantly, wild-type MV no longer entered EMT-induced II-18 cells, suggesting that the epithelial cell receptor is down-regulated by the induction of EMT. Other polarized cell lines, NCI-H358 and HT-29, also lost susceptibility to wild-type MV when EMT was induced. However, the complete formation of tight junctions rather reduced MV entry into HT-29 cells. Taken together, these data suggest that the unidentified epithelial cell receptor for MV is involved in the formation of epithelial intercellular junctions.

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial

PubMed Central

Mason, Malcolm D.; Clarke, Noel W.; James, Nicholas D.; Dearnaley, David P.; Spears, Melissa R.; Ritchie, Alastair W.S.; Attard, Gerhardt; Cross, William; Jones, Rob J.; Parker, Christopher C.; Russell, J. Martin; Thalmann, George N.; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A.; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D.; O’Sullivan, Joe M.; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K.B.; Sydes, Matthew R.

2017-01-01

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial.

PubMed

Mason, Malcolm D; Clarke, Noel W; James, Nicholas D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Attard, Gerhardt; Cross, William; Jones, Rob J; Parker, Christopher C; Russell, J Martin; Thalmann, George N; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D; O'Sullivan, Joe M; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K B; Sydes, Matthew R

2017-05-10

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned

Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study.

PubMed

Otaify, G A; Aglan, M S; Ibrahim, M M; Elnashar, M; El Banna, R A S; Temtamy, S A

2016-01-01

Treatment with zoledronic acid (ZA) over 2 years, among 33 children with osteogenesis imperfecta (OI) and five Bruck syndrome cases, showed reduction in fracture rates, pain, and improvement in bone mineral density (BMD) and motor milestones of development. This is the first study reporting the use of bisphosphonates in patients with Bruck syndrome (BS). OI and BS are genetic disorders that result in bone fragility and reduced BMD. There is little literature describing the efficacy and safety of ZA in this population. In this study, we assess the response to treatment with ZA at six monthly intervals in Egyptian children with OI and BS for a period of 2 years. Thirty-three patients with OI and five patients with BS were treated with 0.1 mg/kg ZA intravenously every 6 months for 2 years during which they were followed up using different parameters. A clinical severity score (CSS) was applied to the patients before and 2 years after the start of therapy. Comparison of disease severity and response to ZA treatment between autosomal-dominant (AD) and autosomal-recessive (AR) OI patients was also done. After 6 months of treatment, OI and BS patients showed a significant increase in BMD Z-scores (P < 0.003 in the spine and P < 0.004 in the hip), together with a significant drop in fracture rate (P < 0.001), relief of pain (P < 0.001), and improvement in ambulation (P < 0.001). CSS was significantly reduced after 2 years of treatment in both OI and BS patients. AR-OI patients were more severely affected than AD-OI patients and showed more significant improvement. Zoledronic acid proved to be safe and effective in the treatment of OI and BS. The biannual infusion protocol was convenient to patients. There was a positive correlation between disease severity and benefits of the treatment. The use of the CSS proved to be of value in the assessment of the degree of severity in OI, and with some modifications, it was a valuable tool for the assessment of

On observation of neutron quantum states in the Earth's gravitational field

NASA Astrophysics Data System (ADS)

Vankov, Anatoli Andrei

2010-03-01

Observation of neutron gravitational quantum states En=mgzn in the peV energy range (z1 is about 10μm in the vertical direction) in the experiment conducted at Laue-Langevin Institute, Grenoble, with ultracold neutrons was recently reported in a series of publications. The purpose of the present work is to analyze the experiment. The experimental apparatus is designed to measure a transmission function T(za), namely, a horizontal flux of relatively fast neutrons (k≫kz in wavelength terms) passing through a slit of variable height za of upper absorbing wall. The quantum states in question are defined by the so-called Airy functions, which are solutions to the stationary 1D equation for a neutron “bouncing” above the perfect mirror in a linear potential field. The Airy functions describe the quantum bouncer (QB), the concept of which is subject to theoretical study of toy 1D models of gravitationally bound particles in nonrelativistic quantum mechanics (QM). This is essentially different from the 3D nonstationary QM object, “the running QB,” investigated in the experiment. The authors assume that there is a connection between T(za) and the probability density distribution P(z,za) for QB states. They devised the “phenomenological model,” in which the quantum pattern should be visible in the transmission curve. We argue, however, that the measured curve T(za) is not sensitive to QB states. Instead, it is sensitive to dynamics of neutron horizontal transport inside the absorbing slit for neutrons of energy values about 105 times greater than eigenvalues En. The latter are related to the neutron transverse mode kz and cannot be termed “energies of neutron gravitational quantum states.” We conclude that the experiment setup and real conditions are not adequate to the claimed objective, and the methodology of measured data treatment is flawed. The authors’ claim that “neutron gravitational quantum states are observed” is neither theoretically nor

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

Schuermann, Karl; Vorwerk, Dierk; Buecker, Arno

Purpose: To compare nonferromagnetic iliac artery prostheses in their suitability for patency monitoring with magnetic resonance angiography (MRA) using conventional angiography as a reference. Methods: In experiment 1, three Memotherm stents were inserted into the iliac arteries of each of six sheep: two 'tandem' stents on one side and a single stent on the other side. In experiment 2, four prostheses (normal and low-porosity Corvita stent-grafts, Memotherm, ZA-stent) were inserted in each of 11 sheep. Patency was monitored before and 1, 3, and 6 months after insertion with 3D phase-contrast and two 2D time-of-flight sequences (TOF-1: TR/TE = 18/6.9, TOF-2:more » 13/2.5) with and without contrast at 1.5 T. On 206 coronal MIP images (72 pre-, 134 post-stenting), three readers analyzed 824 iliac segments (206 x 4) for patency and artifacts. Results: There was no difference in the number of artifacts between tandem and single iliac Memotherm stents. The ZA-stent induced significantly fewer artifacts than the other prostheses (p < 0.00001). With MRA, patency of the ZA-stent was correctly diagnosed in 88% of cases, which was almost comparable to nonstented iliac segments (95%), patency of the Memotherm stent in 59%, and of the Corvita stent-grafts in 57% and 55%. The TOF-2 sequence with contrast yielded the best images. Conclusion: MRA compatibility of nonferromagnetic prostheses depends strongly on the design of the device. MRA may be used to monitor the patency of iliac ZA-stents, whereas iliac Memotherm stents and Corvita stent-grafts appear to be less suited for follow-up with MRA.« less

Human immunodeficiency virus-associated disruption of mucosal barriers and its role in HIV transmission and pathogenesis of HIV/AIDS disease

PubMed Central

Tugizov, Sharof

2016-01-01

Abstract Oral, intestinal and genital mucosal epithelia have a barrier function to prevent paracellular penetration by viral, bacterial and other pathogens, including human immunodeficiency virus (HIV). HIV can overcome these barriers by disrupting the tight and adherens junctions of mucosal epithelia. HIV-associated disruption of epithelial junctions may also facilitate paracellular penetration and dissemination of other viral pathogens. This review focuses on possible molecular mechanisms of HIV-associated disruption of mucosal epithelial junctions and its role in HIV transmission and pathogenesis of HIV and acquired immune deficiency syndrome (AIDS). PMID:27583187

E-cadherin in contact inhibition and cancer.

PubMed

Mendonsa, Alisha M; Na, Tae-Young; Gumbiner, Barry M

2018-05-21

E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding between cells is important in mediating contact inhibition of proliferation when cells reach confluence. Loss of E-cadherin expression results in loss of contact inhibition and is associated with increased cell motility and advanced stages of cancer. In this review we discuss the role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer.

A-DaGO-Fun: an adaptable Gene Ontology semantic similarity-based functional analysis tool.

PubMed

Mazandu, Gaston K; Chimusa, Emile R; Mbiyavanga, Mamana; Mulder, Nicola J

2016-02-01

Gene Ontology (GO) semantic similarity measures are being used for biological knowledge discovery based on GO annotations by integrating biological information contained in the GO structure into data analyses. To empower users to quickly compute, manipulate and explore these measures, we introduce A-DaGO-Fun (ADaptable Gene Ontology semantic similarity-based Functional analysis). It is a portable software package integrating all known GO information content-based semantic similarity measures and relevant biological applications associated with these measures. A-DaGO-Fun has the advantage not only of handling datasets from the current high-throughput genome-wide applications, but also allowing users to choose the most relevant semantic similarity approach for their biological applications and to adapt a given module to their needs. A-DaGO-Fun is freely available to the research community at http://web.cbio.uct.ac.za/ITGOM/adagofun. It is implemented in Linux using Python under free software (GNU General Public Licence). gmazandu@cbio.uct.ac.za or Nicola.Mulder@uct.ac.za Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Phonon-assisted indirect transitions in angle-resolved photoemission spectra of graphite and graphene

NASA Astrophysics Data System (ADS)

Ayria, Pourya; Tanaka, Shin-ichiro; Nugraha, Ahmad R. T.; Dresselhaus, Mildred S.; Saito, Riichiro

2016-08-01

Indirect transitions of electrons in graphene and graphite are investigated by means of angle-resolved photoemission spectroscopy (ARPES) with several different incident photon energies and light polarizations. The theoretical calculations of the indirect transition for graphene and for a single crystal of graphite are compared with the experimental measurements for highly-oriented pyrolytic graphite and a single crystal of graphite. The dispersion relations for the transverse optical (TO) and the out-of-plane longitudinal acoustic (ZA) phonon modes of graphite and the TO phonon mode of graphene can be extracted from the inelastic ARPES intensity. We find that the TO phonon mode for k points along the Γ -K and K -M -K' directions in the Brillouin zone can be observed in the ARPES spectra of graphite and graphene by using a photon energy ≈11.1 eV. The relevant mechanism in the ARPES process for this case is the resonant indirect transition. On the other hand, the ZA phonon mode of graphite can be observed by using a photon energy ≈6.3 eV through a nonresonant indirect transition, while the ZA phonon mode of graphene within the same mechanism should not be observed.

Heat conductivity in graphene and related materials: A time-domain modal analysis

NASA Astrophysics Data System (ADS)

Gill-Comeau, Maxime; Lewis, Laurent J.

2015-11-01

We use molecular dynamics (MD) simulations to study heat conductivity in single-layer graphene and graphite. We analyze the MD trajectories through a time-domain modal analysis and show that this is essential for obtaining a reliable representation of the heat flow in graphene and graphite as it permits the proper treatment of collective vibrational excitations, in contrast to a frequency-domain formulation. Our temperature-dependent results are in very good agreement with experiment and, for temperatures in the range 300-1200 K, we find that the ZA branch allows more heat flow than all other branches combined while the contributions of the TA, LA, and ZO branches are comparable at all temperatures. Conductivity mappings reveal strong collective excitations associated with low-frequency ZA modes. We demonstrate that these collective effects are a consequence of the quadratic nature of the ZA branch as they also show up in graphite but are reduced in strained graphene, where the dispersion becomes linear, and are absent in diamond, where acoustic branches are linear. In general, neglecting collective excitations yields errors similar to those from the single-mode relaxation-time approximation.

Non Linear Internal Waves: Modeling of Their Influence on Acoustic Mode Energy Fluctuations and Characterization Using SAR Systems

DTIC Science & Technology

2007-12-01

mik R i t m s m m s p z t za z e e dz z ω ω φ ωω φ ω ρ−∞ = = ∫ . (2.21) For a pulse, the pressure will be given by: 0 0 1... mik R m s m m s m D p z t za z e dz F t z ω φ ωω φ ω ρ− = ≈ ∫ (2.25) where 0 0 ( )( ) mi t tmF t e d ω ω ω ω ω ω +∆ − − −∆ = ∫ . From these...43 D. SENSITIVITY OF THE MODEL................................................................50 E

United States Air Force Statistical Digest, Fiscal Year 1968. Twenty Third Edition

DTIC Science & Technology

1968-09-30

Tac1l1calMter - Total. f::Jiti. •• • • • •--;-:- • F-4Il •••• F-4.B•• F-l00fJ/F. F-IO$D/F. F- Uti • a:-W’aallteaopna1ssanae -1’otal • -40...Quarter Aircraft Quarter Hours On Hand uti 11- HOurs On Hand UU11- ANDS!RIIS, FlOlll1 During zaUon nown During zat10n ’. Quarter Rate Quarter Bate...8217MISSION :na.. DESIGN. AGE c . Uti - AVlm- ~ti-SERIES, ~ FLYING HOURS AGE FLYING HOURS WITHIN CoJllo. 11-. AIR- COJllo. 11-’ SortiesBASES u: bat za

Structural Technology Evaluation Analysis Program (STEAP). Delivery Order 0025: Laser Peening for Reliable Fatigue Life

DTIC Science & Technology

2010-12-01

6 ]. Shot peening is a cold working process in which the surface of the 4 Approved for public release; distribution unlimited...for the ZA Model Parameter Value σa 945.1961MPa B 246.6467MPa β0 1.1636×10− 6 β1 0.1065 B0 1481.249 MPa εr 0.0538 α0 10− 6 α1 3.1564×10− 4 Figures 15 and...16 show the strain rate dependence curves at different strains for the JC and ZA models. 10 − 6 10 − 4 10 −2 10 0 10 2 10 4 10 6 1000 1100 1200

Second-moment equality and the structural chemistry of the main-group intermetallic compounds

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

Lee, S.

1991-01-02

The authors determine electron counting rules for ZA{sub 2{minus}x}B{sub x} compounds, where Z is an electropositive atoms and A and B are main-group atoms. These rules are derived from a Huckel-type theory. Agreement between theory and experiment for all the major ZA{sub 2{minus}x}B{sub x} families, which include the MgCu{sub 2}, MoSi{sub 2}, CeCd{sub 2}, CeCu{sub 2}, MgAgAs, CaIn{sub 2}, AlB{sub 2}, ThSi{sub 2}, and Cu{sub 2}Sb structure types, is excellent. The results are interpreted by use of the method of moments.

Intestinal barrier analysis by assessment of mucins, tight junctions, and α-defensins in healthy C57BL/6J and BALB/cJ mice

PubMed Central

Volynets, Valentina; Rings, Andreas; Bárdos, Gyöngyi; Ostaff, Maureen J.; Wehkamp, Jan; Bischoff, Stephan C.

2016-01-01

ABSTRACT The intestinal barrier is gaining increasing attention because it is related to intestinal homeostasis and disease. Different parameters have been used in the past to assess intestinal barrier functions in experimental studies; however most of them are poorly defined in healthy mice. Here, we compared a number of barrier markers in healthy mice, established normal values and correlations. In 48 mice (24 C57BL/6J, 24 BALB/cJ background), we measured mucus thickness, and expression of mucin-2, α-defensin-1 and -4, zonula occludens-1, occludin, junctional adhesion molecule-A, claudin-1, 2 and -5. We also analyzed claudin-3 and fatty acid binding protein-2 in urine and plasma, respectively. A higher expression of mucin-2 protein was found in the colon compared to the ileum. In contrast, the α-defensins-1 and -4 were expressed almost exclusively in the ileum. The protein expression of the tight junction molecules claudin-1, occludin and zonula occludens-1 did not differ between colon and ileum, although some differences occurred at the mRNA level. No age- or gender-related differences were found. Differences between C57BL/6J and BALB/cJ mice were found for α-defensin-1 and -4 mRNA expression, and for urine and plasma marker concentrations. The α-defensin-1 mRNA correlated with claudin-5 mRNA, whereas α-defensin-4 mRNA correlated with claudin-3 concentrations in urine. In conclusion, we identified a number of murine intestinal barrier markers requiring tissue analyses or measurable in urine or plasma. We provide normal values for these markers in mice of different genetic background. Such data might be helpful for future animal studies in which the intestinal barrier is of interest. PMID:27583194

Intestinal barrier analysis by assessment of mucins, tight junctions, and α-defensins in healthy C57BL/6J and BALB/cJ mice.

PubMed

Volynets, Valentina; Rings, Andreas; Bárdos, Gyöngyi; Ostaff, Maureen J; Wehkamp, Jan; Bischoff, Stephan C

2016-01-01

The intestinal barrier is gaining increasing attention because it is related to intestinal homeostasis and disease. Different parameters have been used in the past to assess intestinal barrier functions in experimental studies; however most of them are poorly defined in healthy mice. Here, we compared a number of barrier markers in healthy mice, established normal values and correlations. In 48 mice (24 C57BL/6J, 24 BALB/cJ background), we measured mucus thickness, and expression of mucin-2, α-defensin-1 and -4, zonula occludens-1, occludin, junctional adhesion molecule-A, claudin-1, 2 and -5. We also analyzed claudin-3 and fatty acid binding protein-2 in urine and plasma, respectively. A higher expression of mucin-2 protein was found in the colon compared to the ileum. In contrast, the α-defensins-1 and -4 were expressed almost exclusively in the ileum. The protein expression of the tight junction molecules claudin-1, occludin and zonula occludens-1 did not differ between colon and ileum, although some differences occurred at the mRNA level. No age- or gender-related differences were found. Differences between C57BL/6J and BALB/cJ mice were found for α-defensin-1 and -4 mRNA expression, and for urine and plasma marker concentrations. The α-defensin-1 mRNA correlated with claudin-5 mRNA, whereas α-defensin-4 mRNA correlated with claudin-3 concentrations in urine. In conclusion, we identified a number of murine intestinal barrier markers requiring tissue analyses or measurable in urine or plasma. We provide normal values for these markers in mice of different genetic background. Such data might be helpful for future animal studies in which the intestinal barrier is of interest.

Digital holographic interferometry employing Fresnel transform reconstruction for the study of flow shear stabilized Z-pinch plasmas.

PubMed

Ross, M P; Shumlak, U

2016-10-01

The ZaP-HD flow Z-pinch project provides a platform to explore how shear flow stabilized Z-pinches could scale to high-energy-density plasma (plasma with pressures exceeding 1 Mbar) and fusion reactor conditions. The Z-pinch is a linear plasma confinement geometry in which the plasma carries axial electric current and is confined by its self-induced magnetic field. ZaP-HD generates shear stabilized, axisymmetric Z-pinches with stable lifetimes approaching 60 μs. The goal of the project is to increase the plasma density and temperature compared to the previous ZaP project by compressing the plasma to smaller radii (≈1 mm). Radial and axial plasma electron density structure is measured using digital holographic interferometry (DHI), which provides the necessary fine spatial resolution. ZaP-HD's DHI system uses a 2 ns Nd:YAG laser pulse with a second harmonic generator (λ = 532 nm) to produce holograms recorded by a Nikon D3200 digital camera. The holograms are numerically reconstructed with the Fresnel transform reconstruction method to obtain the phase shift caused by the interaction of the laser beam with the plasma. This provides a two-dimensional map of line-integrated electron density, which can be Abel inverted to determine the local number density. The DHI resolves line-integrated densities down to 3 × 10 20 m -2 with spatial resolution near 10 μm. This paper presents the first application of Fresnel transform reconstruction as an analysis technique for a plasma diagnostic, and it analyzes the method's accuracy through study of synthetic data. It then presents an Abel inversion procedure that utilizes data on both sides of a Z-pinch local number density profile to maximize profile symmetry. Error estimation and Abel inversion are applied to the measured data.

Acute oral toxicity and biodistribution study of zinc-aluminium-levodopa nanocomposite

NASA Astrophysics Data System (ADS)

Kura, Aminu Umar; Saifullah, Bullo; Cheah, Pike-See; Hussein, Mohd Zobir; Azmi, Norazrina; Fakurazi, Sharida

2015-03-01

Layered double hydroxide (LDH) is an inorganic-organic nano-layered material that harbours drug between its two-layered sheets, forming a sandwich-like structure. It is attracting a great deal of attention as an alternative drug delivery (nanodelivery) system in the field of pharmacology due to their relative low toxic potential. The production of these nanodelivery systems, aimed at improving human health through decrease toxicity, targeted delivery of the active compound to areas of interest with sustained release ability. In this study, we administered zinc-aluminium-LDH-levodopa nanocomposite (ZAL) and zinc-aluminium nanocomposite (ZA) to Sprague Dawley rats to evaluate for acute oral toxicity following OECD guidelines. The oral administration of ZAL and ZA at a limit dose of 2,000 mg/kg produced neither mortality nor acute toxic signs throughout 14 days of the observation. The percentage of body weight gain of the animals showed no significant difference between control and treatment groups. Animal from the two treated groups gained weight continuously over the study period, which was shown to be significantly higher than the weight at the beginning of the study ( P < 0.05). Biochemical analysis of animal serum showed no significant difference between rats treated with ZAL, ZA and controls. There was no gross lesion or histopathological changes observed in vital organs of the rats. The results suggested that ZAL and ZA at 2,000 mg/kg body weight in rats do not induce acute toxicity in the animals. Elemental analysis of tissues of treated animals demonstrated the wider distribution of the nanocomposite including the brain. In summary, findings of acute toxicity tests in this study suggest that zinc-aluminium nanocomposite intercalated with and the un-intercalated were safe when administered orally in animal models for short periods of time. It also highlighted the potential distribution ability of Tween-80 coated nanocomposite after oral administration.

Catalog of Space Shuttle Earth Observations Handheld Photography. Space Transportation System 37 (STS-37) Mission Dates: April 5 Through 11, 1991

DTIC Science & Technology

1991-08-01

mC3* o 0 Im IOOm cy1Y C~~-3 )C) tUN o( -PNr - oG 1-4 o oGo c do oo GoO a m.w o , " 00 0OD 0 0ooom a @ a 4m0)4m4 C M m0)ahm0)cmm ao4m4 OC C N-N^A Nm " N...L303113 31393B3131 3N3131M393133 383 10 ~ ~ ~ ~ ~ ~~G 10110 0 400 (100 01100 I.- .atmza a af tz z zaW 2aU 2cM Zz za aaa aa a a cn cc Oo (0 to in 410

Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock.

PubMed

Pati, Shibani; Peng, Zhanglong; Wataha, Katherine; Miyazawa, Byron; Potter, Daniel R; Kozar, Rosemary A

2018-01-01

In severe trauma and hemorrhage the early and empiric use of fresh frozen plasma (FFP) is associated with decreased morbidity and mortality. However, utilization of FFP comes with the significant burden of shipping and storage of frozen blood products. Dried or lyophilized plasma (LP) can be stored at room temperature, transported easily, reconstituted rapidly with ready availability in remote and austere environments. We have previously demonstrated that FFP mitigates the endothelial injury that ensues after hemorrhagic shock (HS). In the current study, we sought to determine whether LP has similar properties to FFP in its ability to modulate endothelial dysfunction in vitro and in vivo. Single donor LP was compared to single donor FFP using the following measures of endothelial cell (EC) function in vitro: permeability and transendothelial monolayer resistance; adherens junction preservation; and leukocyte-EC adhesion. In vivo, using a model of murine HS, LP and FFP were compared in measures of HS- induced pulmonary vascular inflammation and edema. Both in vitro and in vivo in all measures of EC function, LP demonstrated similar effects to FFP. Both FFP and LP similarly reduced EC permeability, increased transendothelial resistance, decreased leukocyte-EC binding and persevered adherens junctions. In vivo, LP and FFP both comparably reduced pulmonary injury, inflammation and vascular leak. Both FFP and LP have similar potent protective effects on the vascular endothelium in vitro and in lung function in vivo following hemorrhagic shock. These data support the further development of LP as an effective plasma product for human use after trauma and hemorrhagic shock.

Saccharomyces boulardii CNCM I-745 Restores intestinal Barrier Integrity by Regulation of E-cadherin Recycling.

PubMed

Terciolo, Chloé; Dobric, Aurélie; Ouaissi, Mehdi; Siret, Carole; Breuzard, Gilles; Silvy, Françoise; Marchiori, Bastien; Germain, Sébastien; Bonier, Renaté; Hama, Adel; Owens, Roisin; Lombardo, Dominique; Rigot, Véronique; André, Frédéric

2017-08-01

Alteration in intestinal permeability is the main factor underlying the pathogenesis of many diseases affecting the gut, such as inflammatory bowel disease [IBD]. Characterization of molecules targeting the restoration of intestinal barrier integrity is therefore vital for the development of alternative therapies. The yeast Saccharomyces boulardii CNCM I-745 [Sb], used to prevent and treat antibiotic-associated infectious and functional diarrhea, may have a beneficial effect in the treatment of IBD. We analyzed the impact of Sb supernatant on tissue integrity and components of adherens junctions using cultured explants of colon from both IBD and healthy patients. To evaluate the pathways by which Sb regulates the expression of E-cadherin at the cell surface, we developed in vitro assays using human colonic cell lines, including cell aggregation, a calcium switch assay, real-time measurement of transepithelial electrical resistance [TEER] and pulse-chase experiments. We showed that Sb supernatant treatment of colonic explants protects the epithelial morphology and maintains E-cadherin expression at the cell surface. In vitro experiments revealed that Sb supernatant enhances E-cadherin delivery to the cell surface by re-routing endocytosed E-cadherin back to the plasma membrane. This process, involving Rab11A-dependent recycling endosome, leads to restoration of enterocyte adherens junctions, in addition to the overall restoration and strengthening of intestinal barrier function. These findings open new possibilities of discovering novel options for prevention and therapy of diseases that affect intestinal permeability. Copyright © 2017 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells

PubMed Central

Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M.; Tian, Lin; Zhao, Hong; Zhao, Zhen; Du, Shiyu; Tao, Jianning; Lee, Brendan; Westbrook, Thomas F.; Wong, Stephen T. C.; Jin, Xin; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H.-F.

2014-01-01

Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases. PMID:25600338

Tonic regulation of vascular permeability

PubMed Central

Curry, Fitz-Roy E.; Adamson, Roger H.

2014-01-01

Our major theme is that the layered structure of the endothelial barrier requires continuous activation of signaling pathways regulated by S1P and intracellular cAMP. These pathways modulate the adherens junction, continuity of tight junction strands, and the balance of synthesis and degradation of glycocalyx components. We evaluate recent evidence that baseline permeability is maintained by constant activity of mechanisms involving the small GTPases Rap1 and Rac1. In the basal state, the barrier is compromised when activities of the small GTPases are reduced by low S1P supply or delivery. With inflammatory stimulus, increased permeability can be understood in part as the action of signaling to reduce Rap1 and Rac1 activation. With the hypothesis that microvessel permeability and selectivity under both normal and inflammatory conditions are regulated by mechanisms that are continuously active it follows that when S1P or intracellular cAMP are elevated at the time of inflammatory stimulus, they can buffer changes induced by inflammatory agents and maintain normal barrier stability. When endothelium is exposed to inflammatory conditions and subsequently exposed to elevated S1P or intracellular cAMP, the same processes restore the functional barrier by first reestablishing the adherens junction, then modulating tight junctions and glycocalyx. In more extreme inflammatory conditions, loss of the inhibitory actions of Rac1 dependent mechanisms may promote expression of more inflammatory endothelial phenotypes by contributing to the up-regulation of RhoA dependent contractile mechanisms and the sustained loss of surface glycocalyx allowing access of inflammatory cells to the endothelium. PMID:23374222

A Reactor Development Scenario for the FuZE Sheared-Flow Stabilized Z-pinch

NASA Astrophysics Data System (ADS)

McLean, Harry S.; Higginson, D. P.; Schmidt, A.; Tummel, K. K.; Shumlak, U.; Nelson, B. A.; Claveau, E. L.; Forbes, E. G.; Golingo, R. P.; Stepanov, A. D.; Weber, T. R.; Zhang, Y.

2017-10-01

We present a conceptual design, scaling calculations, and development path for a pulsed fusion reactor based on a flow-stabilized Z-pinch. Experiments performed on the ZaP and ZaP-HD devices have largely demonstrated the basic physics of sheared-flow stabilization at pinch currents up to 100 kA. Initial experiments on the FuZE device, a high-power upgrade of ZaP, have achieved 20 usec of stability at pinch current 100-200 kA and pinch diameter few mm for a pinch length of 50 cm. Scaling calculations based on a quasi-steady-state power balance show that extending stable duration to 100 usec at a pinch current of 1.5 MA and pinch length of 50 cm, results in a reactor plant Q 5. Future performance milestones are proposed for pinch currents of: 300 kA, where Te and Ti are calculated to exceed 1-2 keV; 700 kA, where DT fusion power would be expected to exceed pinch input power; and 1 MA, where fusion energy per pulse exceeds input energy per pulse. This work funded by USDOE ARPA-E and performed under the auspices of Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. LLNL-ABS-734770.

Land-use effects on erosion, sediment yields, and reservoir sedimentation: a case study in the Lago Loiza Basin, Puerto Rico

USGS Publications Warehouse

Gellis, A.C.; Webb, R.M.T.; McIntyre, S.C.; Wolfe, W.J.

2006-01-01

 Lago Loíza impounded in 1953 to supply San Juan, Puerto Rico, with drinking water; by 1994, it had lost 47% of its capacity. To characterize sedimentation in Lago Loíza, a study combining land-use history, hillslope erosion rates, and subbasin sediment yields was conducted. Sedimentation rates during the early part of the reservoir’s operation (1953– 1963) were slightly higher than the rates during 1964–1990. In the early history of the reservoir, cropland comprised 48% of the basin and erosion rates were high. Following economic shifts during the 1960s, cropland was abandoned and replaced by forest, which increased from 7.6% in 1950 to 20.6% in 1987. These land-use changes follow a pattern similar to the northeastern United States. Population in the Lago Loíza Basin increased 77% from 1950 to 1990, and housing units increased 194%. Sheetwash erosion measured from 1991 to 1993 showed construction sites had the highest sediment concentration (61,400 ppm), followed by cropland (47,400 ppm), pasture (3510 ppm), and forest (2050 ppm). This study illustrates how a variety of tools and approaches can be used to understand the complex interaction between land use, upland erosion, fluvial sediment transport and storage, and reservoir sedimentation. 

A Comparative Study on Johnson Cook, Modified Zerilli-Armstrong and Arrhenius-Type Constitutive Models to Predict High-Temperature Flow Behavior of Ti-6Al-4V Alloy in α + β Phase

NASA Astrophysics Data System (ADS)

Cai, Jun; Wang, Kuaishe; Han, Yingying

2016-03-01

True stress and true strain values obtained from isothermal compression tests over a wide temperature range from 1,073 to 1,323 K and a strain rate range from 0.001 to 1 s-1 were employed to establish the constitutive equations based on Johnson Cook, modified Zerilli-Armstrong (ZA) and strain-compensated Arrhenius-type models, respectively, to predict the high-temperature flow behavior of Ti-6Al-4V alloy in α + β phase. Furthermore, a comparative study has been made on the capability of the three models to represent the elevated temperature flow behavior of Ti-6Al-4V alloy. Suitability of the three models was evaluated by comparing both the correlation coefficient R and the average absolute relative error (AARE). The results showed that the Johnson Cook model is inadequate to provide good description of flow behavior of Ti-6Al-4V alloy in α + β phase domain, while the predicted values of modified ZA model and the strain-compensated Arrhenius-type model could agree well with the experimental values except under some deformation conditions. Meanwhile, the modified ZA model could track the deformation behavior more accurately than other model throughout the entire temperature and strain rate range.

zeldovich-PLT: Zel'dovich approximation initial conditions generator

NASA Astrophysics Data System (ADS)

Eisenstein, Daniel; Garrison, Lehman

2016-05-01

zeldovich-PLT generates Zel'dovich approximation (ZA) initial conditions (i.e. first-order Lagrangian perturbation theory) for cosmological N-body simulations, optionally applying particle linear theory (PLT) corrections.

Force transmission in epithelial tissues.

PubMed

Vasquez, Claudia G; Martin, Adam C

2016-03-01

In epithelial tissues, cells constantly generate and transmit forces between each other. Forces generated by the actomyosin cytoskeleton regulate tissue shape and structure and also provide signals that influence cells' decisions to divide, die, or differentiate. Forces are transmitted across epithelia because cells are mechanically linked through junctional complexes, and forces can propagate through the cell cytoplasm. Here, we review some of the molecular mechanisms responsible for force generation, with a specific focus on the actomyosin cortex and adherens junctions. We then discuss evidence for how these mechanisms promote cell shape changes and force transmission in tissues. © 2016 Wiley Periodicals, Inc.

The Interaction of Two Complex Loci, Zeste and Bithorax in DROSOPHILA MELANOGASTER

PubMed Central

Kaufman, T. C.; Tasaka, S. E.; Suzuki, D. T.

1973-01-01

It has been found that certain alleles of the zeste locus (za 1-1.0) have no phenotype of their own, but interact with certain alleles at the bithorax locus (bx 3-58.8). This interaction takes the form of an enhancement of the homeotic bx phenotype to a more extreme form—i.e., the metathorax is transformed into mesothorax in varying degrees depending on the bx allele used. This enhancement is somewhat reminiscent of the transvection effect described by Lewis (1954). The characterization of the interaction thus far has shown that the enhancement only effects bx alleles which arise spontaneously, whereas the origin of the za allele is unimportant. The gene claret nondisjunctional was used for the production of gynandromorphs which showed that the enhancing ability of za, like the eye pigment change caused by z, is autonomous. The enhancement of one specific allele (bx34e), which is temperature-sensitive, has allowed a delineation of the temperature-sensitive period of the bithorax locus to a period extending from the middle of the second larval instar to the middle of the third larval instar. These results, as well as those of other enhancer and suppressor systems in Drosophila, have revealed the possibility of the involvement of heterocyclic compounds in the control of cell determination and fate in Drosophila melanogaster. PMID:4203579

Preventive dental management of osteonecrosis of the jaws related to zoledronic acid treatment.

PubMed

Coello-Suanzes, J A; Rollon-Ugalde, V; Castaño-Seiquer, A; Lledo-Villar, E; Herce-Lopez, J; Infante-Cossio, P; Rollon-Mayordomo, A

2018-02-07

To evaluate the effect of preventive dental management on reducing the incidence and delaying the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients treated with intravenous zoledronic acid (ZA). This single-center clinical study included 255 cancer patients monitored over a 6-year period. Patients received dental treatment prior (Group A) or after (Group B) the initiation of ZA therapy. Dental treatments performed, incidence proportion (IP) and incidence rate (IR) in both groups were analyzed using significance tests. BRONJ onset were estimated using the Kaplan-Meier estimator and log-rank test. Independent risk factors to develop BRONJ were evaluated using Cox regression analysis models. 37 patients suffered from BRONJ (IP=14.5%), 7.3% in group A and 36.5% in group B (p=0.000). The IR was 0.007 patients/month in group B and 0.004 in group A. BRONJ free survival at 3 years were 97% in group A and 66% in group B. Survival curves were significant (p=0.056) according to log-rank test. Multivariate Cox models showed that dental extractions (p=0.000) were significant. BRONJ occurred significantly in patients who underwent dental extractions after the initiation of ZA and did not accomplish a preventive dental program. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

In situ X-ray diffraction study of reduction processes of Fe{sub 3}O{sub 4}- and Fe{sub 1-x}O-based ammonia-synthesis catalysts

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

Zheng Yifan, E-mail: zhengyifan@zjut.edu.c; Catalysis Institute, Zhejiang University of Technology, Hangzhou 310014; Liu Huazhang

2009-09-15

The temperature-programmed reduction process of two types of industrial ammonia-synthesis catalysts, A110 and ZA-5, which are, respectively, based on Fe{sub 3}O{sub 4} and Fe{sub 1-x}O precursors, were studied by in situ X-ray power diffraction (XRD). It has been found that the ZA-5 has lower reduction temperature and faster reduction rate, and its active phase alpha-Fe possesses a higher value of lattice microstrain than A110. The simulation based on Rietveld refinement has also shown that the shape of alpha-Fe grain of ZA-5 has a mixed shape of cube and sphere with more exposing (111) and (211) planes, while that of A110more » looks like a concave cube with more exposing (110) planes. Based on the results obtained, a growth model of alpha-Fe during the reduction of Fe{sub 3}O{sub 4}- and Fe{sub 1-x}O-based ammonia-synthesis catalysts is proposed, and the origins for the activity difference has been also discussed. - Graphical Abstract: A proposed growth model of active phase alpha-Fe during reduction. Due to H{sub 2} diffusing easily into the pores, reduction starts on outside and inside surface simultaneously to form 'microcrystalline film', and the particles shrink during reduction which results in breaking of the aggregated oxide particle.« less

Evaluating Changes In the Elemental Composition of Micrometeorites During Entry into the Earth’s Atmosphere

NASA Astrophysics Data System (ADS)

Rudraswami, N. G.; Shyam Prasad, M.; Dey, S.; Plane, J. M. C.; Feng, W.; Taylor, S.

2015-11-01

We evaluate the heating of extraterrestrial particles entering the atmosphere using the comprehensive chemical ablation model (CABMOD). This model predicts the ablation rates of individual elements in a particle with a defined size, composition, entry velocity, and entry angle with respect to the zenith (ZA). In the present study, bulk chemical analyses of 1133 Antarctica micrometeorites (collected from the south pole water well) are interpreted using CABMOD. The marked spread in Fe/Si values in unmelted, partially melted, and melted micrometeorites is explained by the loss of relatively volatile Fe during atmospheric entry. The combined theoretical modeling and elemental composition of the micrometeorites (Mg/Si ratios) suggest that ˜85% of particles have a provenance of carbonaceous chondrites, the remaining ˜15% are either ordinary or enstatite chondrites. About 65% of the micrometeorites have undergone <20% ablation, while a further 20% have lost between 20% and 60% of their original mass. This has implications for understanding the micrometeorite flux that reaches the Earth's surface, as well as estimating the pre-atmospheric size of the particles. Our work shows that the unmelted particles that contribute ˜50% to the total micrometeorite collection on Earth's surface have a small entry zone: ZA = 60°-90° if the entry velocity is ˜11 km s-1, and ZA = 80°-90° for >11-21 km s-1.

YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

PubMed Central

Neto, Filipa; Klaus-Bergmann, Alexandra; Ong, Yu Ting; Alt, Silvanus; Vion, Anne-Clémence; Szymborska, Anna; Carvalho, Joana R; Hollfinger, Irene; Bartels-Klein, Eireen; Franco, Claudio A

2018-01-01

Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels. PMID:29400648

Gene expression of human lung cancer cell line CL1-5 in response to a direct current electric field.

PubMed

Huang, Ching-Wen; Chen, Huai-Yi; Yen, Meng-Hua; Chen, Jeremy J W; Young, Tai-Horng; Cheng, Ji-Yen

2011-01-01

Electrotaxis is the movement of adherent living cells in response to a direct current (dc) electric field (EF) of physiological strength. Highly metastatic human lung cancer cells, CL1-5, exhibit directional migration and orientation under dcEFs. To understand the transcriptional response of CL1-5 cells to a dcEF, microarray analysis was performed in this study. A large electric-field chip (LEFC) was designed, fabricated, and used in this study. CL1-5 cells were treated with the EF strength of 0 mV/mm (the control group) and 300 mV/mm (the EF-treated group) for two hours. Signaling pathways involving the genes that expressed differently between the two groups were revealed. It was shown that the EF-regulated genes highly correlated to adherens junction, telomerase RNA component gene regulation, and tight junction. Some up-regulated genes such as ACVR1B and CTTN, and some down-regulated genes such as PTEN, are known to be positively and negatively correlated to cell migration, respectively. The protein-protein interactions of adherens junction-associated EF-regulated genes suggested that platelet-derived growth factor (PDGF) receptors and ephrin receptors may participate in sensing extracellular electrical stimuli. We further observed a high percentage of significantly regulated genes which encode cell membrane proteins, suggesting that dcEF may directly influence the activity of cell membrane proteins in signal transduction. In this study, some of the EF-regulated genes have been reported to be essential whereas others are novel for electrotaxis. Our result confirms that the regulation of gene expression is involved in the mechanism of electrotactic response.

CUB domain-containing protein 1 and the epidermal growth factor receptor cooperate to induce cell detachment.

PubMed

Law, Mary E; Ferreira, Renan B; Davis, Bradley J; Higgins, Paul J; Kim, Jae-Sung; Castellano, Ronald K; Chen, Sixue; Luesch, Hendrik; Law, Brian K

2016-08-05

While localized malignancies often respond to available therapies, most disseminated cancers are refractory. Novel approaches, therefore, are needed for the treatment of metastatic disease. CUB domain-containing protein1 (CDCP1) plays an important role in metastasis and drug resistance; the mechanism however, is poorly understood. Breast cancer cell lines were engineered to stably express EGFR, CDCP1 or phosphorylation site mutants of CDCP1. These cell lines were used for immunoblot analysis or affinity purification followed by immunoblot analysis to assess protein phosphorylation and/or protein complex formation with CDCP1. Kinase activity was evaluated using phosphorylation site-specific antibodies and immunoblot analysis in in vitro kinase assays. Protein band excision and mass spectrometry was utilized to further identify proteins complexed with CDCP1 or ΔCDCP1, which is a mimetic of the cleaved form of CDCP1. Cell detachment was assessed using cell counting. This paper reports that CDCP1 forms ternary protein complexes with Src and EGFR, facilitating Src activation and Src-dependent EGFR transactivation. Importantly, we have discovered that a class of compounds termed Disulfide bond Disrupting Agents (DDAs) blocks CDCP1/EGFR/Src ternary complex formation and downstream signaling. CDCP1 and EGFR cooperate to induce detachment of breast cancer cells from the substratum and to disrupt adherens junctions. Analysis of CDCP1-containing complexes using proteomics techniques reveals that CDCP1 associates with several proteins involved in cell adhesion, including adherens junction and desmosomal cadherins, and cytoskeletal elements. Together, these results suggest that CDCP1 may facilitate loss of adhesion by promoting activation of EGFR and Src at sites of cell-cell and cell-substratum contact.

Rac1 and Cdc42 Differentially Modulate Cigarette Smoke–Induced Airway Cell Migration through p120-Catenin–Dependent and –Independent Pathways

PubMed Central

Zhang, Lili; Gallup, Marianne; Zlock, Lorna; Finkbeiner, Walter E.; McNamara, Nancy A.

2014-01-01

The adherens junction protein p120-catenin (p120ctn) shuttles between E-cadherin–bound and cytoplasmic pools to regulate E-cadherin/catenin complex stability and cell migration, respectively. When released from the adherens junction, p120ctn promotes cell migration through modulation of the Rho GTPases Rac1, Cdc42, and RhoA. Accordingly, the down-regulation and cytoplasmic mislocalization of p120ctn has been reported in all subtypes of lung cancers and is associated with grave prognosis. Previously, we reported that cigarette smoke induced cytoplasmic translocation of p120ctn and cell migration, but the underlying mechanism was unclear. Using primary human bronchial epithelial cells exposed to smoke-concentrated medium (Smk), we observed the translocation of Rac1 and Cdc42, but not RhoA, to the leading edge of polarized and migrating human bronchial epithelial cells. Rac1 and Cdc42 were robustly activated by smoke, whereas RhoA was inhibited. Accordingly, siRNA knockdown of Rac1 or Cdc42 completely abolished Smk-induced cell migration, whereas knockdown of RhoA had no effect. p120ctn/Rac1 double knockdown completely abolished Smk-induced cell migration, whereas p120ctn/Cdc42 double knockdown did not. These data suggested that Rac1 and Cdc42 coactivation was essential to smoke-promoted cell migration in the presence of p120ctn, whereas migration proceeded via Rac1 alone in the absence of p120ctn. Thus, Rac1 may provide an omnipotent therapeutic target in reversing cell migration during the early (intact p120ctn) and late (loss of p120ctn) stages of lung carcinogenesis. PMID:23562274

The Structure of the Statocyst of the Freshwater Snail Biomphalaria Glabrata (Pulmonata, Basommatophora)

NASA Technical Reports Server (NTRS)

Gao, Wenyuan; Wiederhold, Michael L.

1997-01-01

The structure of the statocyst of the freshwater snail Biomphalaria glabrata has been examined by light and electron microscopy. The two statocysts are located on the dorsal-lateral side of the left and right pedal ganglion. The statocysts are spherical, fluid-filled capsules with a diameter of approximately 60 microns for young and 110 microns for adult snails. The wall of the cyst is composed of large receptor cells and many smaller supporting cells. The receptor cells bear cilia which are evenly distributed on the apical surface. The cilia have the typical 9+2 internal tubule configuration. Striate rootlets originate from the base of the basal body and run downward into the cytoplasm. Side-roots arise from one side of the basal body and a basal foot from the other. For each receptor cell, the basal foot always points to the periphery of the surface, indicating that the receptor cell is non-polarized. The receptor cells contain cytoplasmic organelles such as mitochondria, ribosomes, rough and smooth endoplasmic reticulum, compact Golgi bodies and multivesicular bodies. Supporting cells bearing microvilli are interposed between the receptor cells. The junction complex between the supporting cells and the receptor cells is composed of adherens and septate junctions, while between supporting cells only the adherens junctions are present. The static nerve arises from the lateral side of the cyst and contains axons in which parallel neurotubules and mitochondria are found. The axons arise directly from the base of the receptor cells without synapse. In the cyst lumen there are unattached statoconia. The statoconia have a plate-like or concentric membranous ring structure. Based on the morphology, the function of the statocyst in Biomphalaria is discussed.

Prevention of neutrophil extravasation by α2-adrenoceptor-mediated endothelial stabilization.

PubMed

Herrera-García, Ada María; Domínguez-Luis, María Jesús; Arce-Franco, María; Armas-González, Estefanía; Álvarez de La Rosa, Diego; Machado, José David; Pec, Martina K; Feria, Manuel; Barreiro, Olga; Sánchez-Madrid, Francisco; Díaz-González, Federico

2014-09-15

Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α-mediated decrease in expression of the adherens junctional molecules, VE-cadherin, β-catenin, and plakoglobin, and reduced the ICAM-1-mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans. Copyright © 2014 by The American Association of Immunologists, Inc.

Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy.

PubMed

Monickaraj, Finny; McGuire, Paul; Das, Arup

2018-05-01

Inflammation plays an important role in the pathogenesis of diabetic retinopathy. We have previously demonstrated the effect of cathepsin D (CD) on the mechanical disruption of retinal endothelial cell junctions and increased vasopermeability, as well as increased levels of CD in retinas of diabetic mice. Here, we have also examined the effect of CD on endothelial-pericyte interactions, as well as the effect of dipeptidyl peptidase-4 (DPP4) inhibitor on CD in endothelial-pericyte interactions in vitro and in vivo. Cocultured cells that were treated with pro-CD demonstrated a significant decrease in the expression of platelet-derived growth factor receptor-β, a tyrosine kinase receptor that is required for pericyte cell survival; N-cadherin, the key adherens junction protein between endothelium and pericytes; and increases in the vessel destabilizing agent, angiopoietin-2. The effect was reversed in cells that were treated with DPP4 inhibitor along with pro-CD. With pro-CD treatment, there was a significant increase in the phosphorylation of the downstream signaling protein, PKC-α, and Ca 2+ /calmodulin-dependent protein kinase II in endothelial cells and pericytes, which disrupts adherens junction structure and function, and this was significantly reduced with DPP4 inhibitor treatment. Increased CD levels, vasopermeability, and alteration in junctional-related proteins were observed in the retinas of diabetic rats, which were significantly changed with DPP4 inhibitor treatment. Thus, DPP4 inhibitors may be used as potential adjuvant therapeutic agents to treat increased vascular leakage observed in patients with diabetic macular edema.-Monickaraj, F., McGuire, P., Das, A. Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy.

Ultrastructural analysis of bone nodules formed in vitro by isolated fetal rat calvaria cells

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

Bhargava, U.; Bar-Lev, M.; Bellows, C.G.

When cells enzymatically digested from 21 d fetal rat calvaria are grown in ascorbic acid and Na beta-glycerophosphate, they form discrete three-dimensional nodular structures with the histological and immunohistochemical appearance of woven bone. The present investigation was undertaken to verify that bone-like features were identifiable at the ultrastructural level. The nodules formed on top of a fibroblast-like multilayer of cells. The upper surface of the nodules was lined by a continuous layer of cuboidal osteoblastic cells often seen to be joined by adherens junctions. Numerous microvilli, membrane protrusions, and coated pits could be seen on the upper surface of thesemore » cells, their cytoplasm contained prominent RER and Golgi membranes, and processes extended from their lower surfaces into a dense, highly organized collagenous matrix. Some osteocyte-like cells were completely embedded within this matrix; they also displayed RER and prominent processes which extended through the matrix and often made both adherens and gap junctional contacts with the processes of other cells. The fibroblastic cells not participating in nodule formation were surrounded by a less dense collagenous matrix and, in contrast to the matrix of the nodules, it did not mineralize. An unmineralized osteoid-like layer was seen directly below the cuboidal top layer of cells. A mineralization front was detectable below this in which small, discrete structures resembling matrix vesicles and feathery mineral crystals were evident and frequently associated with the collagen fibrils. More heavily mineralized areas were seen further into the nodule. Electron microprobe and electron and X-ray diffraction analysis confirmed the mineral to be hydroxyapatite.« less

The cognitive impairment induced by zinc deficiency in rats aged 0∼2 months related to BDNF DNA methylation changes in the hippocampus.

PubMed

Hu, Yan-Dan; Pang, Wei; He, Cong-Cong; Lu, Hao; Liu, Wei; Wang, Zi-Yu; Liu, Yan-Qiang; Huang, Cheng-Yu; Jiang, Yu-Gang

2017-11-01

This study was carried out to understand the effects of zinc deficiency in rats aged 0∼2 months on learning and memory, and the brain-derived neurotrophic factor (BDNF) gene methylation status in the hippocampus. The lactating mother rats were randomly divided into three groups (n = 12): zinc-adequate group (ZA: zinc 30 mg/kg diet), zinc-deprived group (ZD: zinc 1 mg/kg diet), and a pair-fed group (PF: zinc 30 mg/kg diet), in which the rats were pair-fed to those in the ZD group. After weaning (on day 23), offspring were fed the same diets as their mothers. After 37 days, the zinc concentrations in the plasma and hippocampus were measured, and the behavioral function of the offspring rats was measured using the passive avoidance performance test. We then assessed the DNA methylation patterns of the exon IX of BDNF by methylation-specific quantitative real-time PCR and the mRNA expression of BDNF in the hippocampus by RT-PCR. Compared with the ZA and PF groups, rats in the ZD group had shorter latency period, lower zinc concentrations in the plasma and hippocampus (P < 0.05). Interestingly, the DNA methylation of the BDNF exon IX was significantly increased in the ZD group, compared with the ZA and PF groups, whereas the expression of the BDNF mRNA was decreased. In addition, the DNMT1 mRNA expression was significantly upregulated and DNMT3A was downregulated in the ZD group, but not in the ZA and PF groups. The learning and memory damage in offspring may be a result of the epigenetic changes of the BDNF genes in response to the zinc-deficient diet during 0∼2 month period. Furthermore, this work supports the speculative notion that altered DNA methylation of BDNF in the hippocampus is one of the main causes of cognitive impairment by zinc deficiency.

Arrhythmia

MedlinePlus

... cardiologists who specialize in arrhythmias. Medical and Family Histories To diagnose an arrhythmia, your doctor may ask ... your doctor will use a procedure called cardiac catheterization (KATH-e-ter-ih-ZA-shun). A thin, ...

N-point statistics of large-scale structure in the Zel'dovich approximation

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

Tassev, Svetlin, E-mail: tassev@astro.princeton.edu

2014-06-01

Motivated by the results presented in a companion paper, here we give a simple analytical expression for the matter n-point functions in the Zel'dovich approximation (ZA) both in real and in redshift space (including the angular case). We present numerical results for the 2-dimensional redshift-space correlation function, as well as for the equilateral configuration for the real-space 3-point function. We compare those to the tree-level results. Our analysis is easily extendable to include Lagrangian bias, as well as higher-order perturbative corrections to the ZA. The results should be especially useful for modelling probes of large-scale structure in the linear regime,more » such as the Baryon Acoustic Oscillations. We make the numerical code used in this paper freely available.« less

Notched bar Izod impact properties of zinc die castings

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

Schrems, K.K.; Dogan, O.N.; Goodwin, F.E.

2007-03-01

Notched bar Izod impact testing of zinc die cast Alloy 3, Alloy 5, ZA-8, and AcuZinc 5 was performed at five temperatures between -40\\mDC and room temperature in accordance with ASTM E23 for impact testing of metallic materials. A direct comparison between ASTM D256 for impact testing of plastics and ASTM E23 was performed using continuously cast zinc specimens of Alloy 5 and ZA-8 at -40\\mDC and room temperature. There are differences in sample sizes, impact velocity, and striker geometry between the two tests. Bulk zinc tested according to ASTM E23 resulted in higher impact energies at -40\\mDC and lowermore » impact energies at room temperature then did the same alloys when tested according to ASTM D256.« less

E-cadherin roles in animal biology: A perspective on thyroid hormone-influence.

PubMed

Izaguirre, María Fernanda; Casco, Victor Hugo

2016-11-04

The establishment, remodeling and maintenance of tissular architecture during animal development, and even across juvenile to adult life, are deeply regulated by a delicate interplay of extracellular signals, cell membrane receptors and intracellular signal messengers. It is well known that cell adhesion molecules (cell-cell and cell-extracellular matrix) play a critical role in these processes. Particularly, adherens junctions (AJs) mediated by E-cadherin and catenins determine cell-cell contact survival and epithelia function. Consequently, this review seeks to encompass the complex and prolific knowledge about E-cadherin roles during physiological and pathological states, particularly focusing on the influence exerted by the thyroid hormone (TH).

75 FR 6627 - Broadband Technology Opportunities Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-10

... DEPARTMENT OF COMMERCE National Telecommunications and Information Administration [Docket No. 0907141137-0079-07] RIN 0660-ZA28 Broadband Technology Opportunities Program AGENCY: National... policy and application procedures for the Broadband Technology Opportunities Program (BTOP) established...

Viral gastroenteritis (stomach flu)

MedlinePlus

... Nelson Textbook of Pediatrics . 20th ed. Philadelphia, PA: Elsevier; 2016:chap 265. Bhutta ZA. Acute gastroenteritis in ... Nelson Textbook of Pediatrics . 20th ed. Philadelphia, PA: Elsevier; 2016:chap 340. Dupont HL. Acute infectious diarrhea ...

Oo-Za-We-Kwun Centre Incorporated

ERIC Educational Resources Information Center

Findlay, P. R.; And Others

1976-01-01

The Centre is described as being designed to help native people participate more effectively in a modern Canadian environment. The residential family program includes a five-week Life Skills course followed by a two-year transfer of learning period during which counseling, paid employment, and community activities are available. (Author/MS)

Berberrubine attenuates mucosal lesions and inflammation in dextran sodium sulfate-induced colitis in mice

PubMed Central

Huang, Yan-Feng; Qu, Chang; Xu, Lie-Qiang; Su, Zi-Ren; Zeng, Hui-Fang; Zheng, Lin; Yi, Tie-Gang; Li, Hui-Lin; Chen, Jian-Ping

2018-01-01

Ulcerative colitis (UC) is a chronic relapsing disease without satisfactory treatments, in which intestinal inflammation and disrupted intestinal epithelial barrier are two main pathogeneses triggering UC. Berberrubine (BB) is deemed as one of the major active metabolite of berberine (BBR), a naturally-occurring isoquinoline alkaloid with appreciable anti-UC effect. This study aimed to comparatively investigate the therapeutic effects of BB and BBR on dextran sodium sulfate (DSS)-induced mouse colitis model, and explore the potential underlying mechanism. Results revealed that BB (20 mg/kg) produced a comparable therapeutic effect as BBR (50 mg/kg) and positive control sulfasalazine (200 mg/kg) by significantly reducing the disease activity index (DAI) with prolonged colon length and increased bodyweight as compared with the DSS group. BB treatment was shown to significantly ameliorate the DSS-induced colonic pathological alternations and decreased histological scores. In addition, BB markedly attenuated colonic inflammation by alleviating inflammatory cell infiltration and inhibiting myeloperoxidase (MPO) and cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10) productions in DSS mice. Furthermore, BB treatment substantially upregulated the expression of tight junction (TJ) proteins (zonula occludens-1, zonula occludens-2, claudin-1, occludin) and mRNA expression of mucins (mucin-1 and mucin-2), and decreased the Bax/Bcl-2 ratio. In summary, BB exerted similar effect to its analogue BBR and positive control in attenuating DSS-induced UC with much lower dosage and similar mechanism. The protective effect observed may be intimately associated with maintaining the integrity of the intestinal mucosal barrier and mitigating intestinal inflammation, which were mediated at least partially, via favorable modulation of TJ proteins and mucins and inhibition of inflammatory mediators productions in the colonic tissue. This is the first report to demonstrate that BB

Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms.

PubMed

Wang, Dong; Xu, Xin; Wu, Yin-Gang; Lyu, Li; Zhou, Zi-Wei; Zhang, Jian-Ning

2018-05-01

Traumatic brain injury induces potent inflammatory responses that can exacerbate secondary blood-brain barrier (BBB) disruption, neuronal injury, and neurological dysfunction. Dexmedetomidine is a novel α2-adrenergic receptor agonist that exert protective effects in various central nervous system diseases. The present study was designed to investigate the neuroprotective action of dexmedetomidine in a mouse traumatic brain injury model, and to explore the possible mechanisms. Adult male C57BL/6J mice were subjected to controlled cortical impact. After injury, animals received 3 days of consecutive dexmedetomidine therapy (25 µg/kg per day). The modified neurological severity score was used to assess neurological deficits. The rotarod test was used to evaluate accurate motor coordination and balance. Immunofluorescence was used to determine expression of ionized calcium binding adapter molecule-1, myeloperoxidase, and zonula occluden-1 at the injury site. An enzyme linked immunosorbent assay was used to measure the concentration of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6. The dry-wet weight method was used to measure brain water content. The Evans blue dye extravasation assay was used to measure BBB disruption. Western blot assay was used to measure protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1 p20, IL-1β, nuclear factor kappa B (NF-κB) p65, occluding, and zonula occluden-1. Flow cytometry was used to measure cellular apoptosis. Results showed that dexmedetomidine treatment attenuated early neurological dysfunction and brain edema. Further, dexmedetomidine attenuated post-traumatic inflammation, up-regulated tight junction protein expression, and reduced secondary BBB damage and apoptosis. These protective effects were accompanied by down-regulation of the NF-κB and NLRP3 inflammasome pathways. These findings suggest that dexmedetomidine exhibits

76 FR 62 - Interpretive Standards for Systemic Compensation Discrimination and Voluntary Guidelines for Self...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-03

... 1250-ZA00 Interpretive Standards for Systemic Compensation Discrimination and Voluntary Guidelines for... Order 11246 with respect to Systemic Compensation Discrimination (Standards) and Voluntary Guidelines... to Systemic Compensation Discrimination (Voluntary Guidelines). OFCCP is proposing to rescind the...

Campylobacter infection

MedlinePlus

... eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2015:chap 303. Bhutta ZA. Acute gastroenteritis ... Nelson Textbook of Pediatrics . 20th ed. Philadelphia, PA: Elsevier; 2016:chap 340. DuPont HL. Approach to the ...

75 FR 27984 - Broadband Technology Opportunities Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-19

....: 0907141137-0222-10] RIN 0660-ZA28 Broadband Technology Opportunities Program AGENCY: National...; Reopening of Application Filing Window for Broadband Technology Opportunities Program Comprehensive... filing window for the Broadband Technology Opportunities Program (BTOP) that the agency established...

75 FR 3791 - Broadband Technology Opportunities Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-22

... Department of Agriculture Rural Utilities Service Broadband Technology Opportunities Program; Notices #0;#0... 0660-ZA28 Broadband Technology Opportunities Program AGENCY: National Telecommunications and... for the Broadband Technology Opportunities Program (BTOP or Program) that the agency established...

Use of zinc as a treatment for traumatic brain injury in the rat: effects on cognitive and behavioral outcomes.

PubMed

Cope, Elise C; Morris, Deborah R; Scrimgeour, Angus G; Levenson, Cathy W

2012-09-01

While treatments for the behavioral deficits associated with traumatic brain injury (TBI) are currently limited, animal models suggest that zinc supplementation may increase resilience to TBI. This work tests the hypothesis that zinc supplementation after TBI can be used as treatment to improve behavioral outcomes such as anxiety, depression, and learning and memory. TBI was induced by controlled cortical impact to the medial frontal cortex. After TBI, rats were fed either a zinc adequate (ZA, 30 ppm) or zinc supplemented (ZS, 180 ppm) diet. Additional rats in each dietary group (ZA or ZS) were given a single intraperitoneal (ip) injection of zinc (30 mg/kg) 1 hour following injury. Brain injury resulted in significant increases in anxiety-like and depression-like behaviors as well as impairments in learning and memory. None of the zinc treatments (dietary or ip zinc) improved TBI-induced anxiety. The 2-bottle saccharin preference test for anhedonia revealed that dietary ZS also did not improve depression-like behaviors. However, dietary ZS combined with an early ip zinc injection significantly reduced anhedonia (P < .001). Dietary supplementation after injury, but not zinc injection, significantly improved (P < .05) cognitive behavior as measured by the time spent finding the hidden platform in the Morris water maze test compared with injured rats fed a ZA diet. These data suggest that zinc supplementation may be an effective treatment option for improving behavioral deficits such as cognitive impairment and depression following TBI.

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover.

PubMed

De Colli, Marianna; Tortorella, Paolo; Marconi, Guya Diletta; Agamennone, Mariangela; Campestre, Cristina; Tauro, Marilena; Cataldi, Amelia; Zara, Susi

2016-11-01

Bisphosphonates (BPs) are drugs clinically used in resorptive diseases. It was already proved that some clinically relevant BPs can inhibit a class of enzymes called matrix metalloproteinases (MMPs), required during tissue remodelling. Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present study was to compare the effect of zoledronic acid (ZA), the most potent bisphosphonate available as therapy, with new sulfonamide containing BPs in an in vitro model of human gingival fibroblasts (HGFs). Western blot was used to measure procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability; L-lactate-dehydrogenase (LDH) measurement was performed for toxicity evaluation and ELISA for prostaglandin E 2 (PGE 2 ) secretion assessment. When compared with ZA, the treatment with the newly synthesized compounds shows increasing viability, procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE 2 and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthesized compounds-treated samples. These findings allowed to conclude that new tested BPs did not affect HGFs viability and adhesion, did not induce cellular toxicity, were not responsible for inflammatory event induction and could preserve the physiological matrix turnover. It could be hypothesized that the new molecules were better tolerated by soft tissues, resulting in lesser side effects.

SPIDER: A new tool for measuring fission yields

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

Meierbachtol, Krista C.

2014-03-27

The goals of this project are to measure fission-fragment yields as a function of (En, Z,A, TKE); develop theory in order to evaluate fission yield data; and provide an evaluation of the Pu-239 fission yields.

75 FR 10464 - Broadband Technology Opportunities Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-08

... DEPARTMENT OF COMMERCE National Telecommunications and Information Administration [Docket Number 0907141137-0119-08] RIN 0660-ZA28 Broadband Technology Opportunities Program AGENCY: National... Infrastructure (CCI) projects under the Broadband Technology Opportunities Program (BTOP) is extended until 5:00...

75 FR 14131 - Broadband Technology Opportunities Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-24

... DEPARTMENT OF COMMERCE National Telecommunications and Information Administration [Docket Number: 0907141137-0154-09] RIN 0660-ZA28 Broadband Technology Opportunities Program AGENCY: National... under the Broadband Technology Opportunities Program (BTOP) is extended until 10 p.m. Eastern Daylight...

Application of Multidimensional Data Visualization by Means of Self-Organizing Kohonen Maps to Evaluate Classification Possibilities of Various Coal Types / Zastosowanie Wizualizacji Wielowymiarowych Danych Za Pomocą Sieci Kohonena Do Oceny Możliwości Klasyfikacji Różnych Typów Węgla

NASA Astrophysics Data System (ADS)

Jamróz, Dariusz; Niedoba, Tomasz

2015-03-01

Multidimensional data visualization methods are a modern tool allowing to classify some analysed objects. In the case of grained materials e.g. coal, many characteristics have an influence on the material quality. The paper presents the possibility of applying visualization techniques for coal type identification and determination of significant differences between various types of coal. To achieve this purpose, the method of Kohonen maps was applied by means of which three types of coal - 31, 34.2 and 35 (according to Polish classification of coal types) were investigated. It was stated that the applied methodology allows to identify certain coal types efficiently and can be used as a qualitative criterion for grained materials. Metody wizualizacji wielowymiarowych danych są nowoczesnym narzędziem umożliwającym klasyfikację analizowanych obiektów, którymi mogą być różnego typu dane opisujące wybrane zjawisko lub materiał. W przypadku materiałów uziarnionych, jakim jest np. węgiel, wiele cech ma wpływ na jakość materiału, tj. np. gęstość, wielkość ziaren, ciepło spalania, zawartość popiołu, zawartość siarki itp. Na potrzeby artykułu przeprowadzono rozdział węgli z trzech wybranych kopalni węgla kamiennego, zlokalizowanych w Górnośląskim Okręgu Przemysłowym. Każda z tych kopalni pracuje na innego typu węglu. W tym przypadku były to węgle o typach 31, 34.2 oraz 35 (według polskiej klasyfikacji typów węgla). Najpierw, materiał został podzielony na klasy ziarnowe a następnie za pomocą rozdziale w cieczy ciężkiej (roztwór chlorku cynku) na frakcje gęstościowe. Dla tak przygotowanego materiału przeprowadzono następnie analizy chemiczne mające na celu określenie takich parametrów, jak zawartość siarki, zawartość popiołu, zawartość części lotnych, ciepło spalania oraz wilgotność analityczną. W ten sposób, dla każdej klaso-frakcji uzyskano bogate charakterystyki badanego

Thermal transport and anharmonic phonons in strained monolayer hexagonal boron nitride

NASA Astrophysics Data System (ADS)

Li, Shasha; Chen, Yue

2017-03-01

Thermal transport and phonon-phonon coupling in monolayer hexagonal boron nitride (h-BN) under equibiaxial strains are investigated from first principles. Phonon spectra at elevated temperatures have been calculated from perturbation theory using the third-order anharmonic force constants. The stiffening of the out-of-plane transverse acoustic mode (ZA) near the Brillouin zone center and the increase of acoustic phonon lifetimes are found to contribute to the dramatic increase of thermal transport in strained h-BN. The transverse optical mode (TO) at the K point, which was predicted to lead to mechanical failure of h-BN, is found to shift to lower frequencies at elevated temperatures under equibiaxial strains. The longitudinal and transverse acoustic modes exhibit broad phonon spectra under large strains in sharp contrast to the ZA mode, indicating strong in-plane phonon-phonon coupling.

PSI-Center Validation Studies

NASA Astrophysics Data System (ADS)

Nelson, B. A.; Akcay, C.; Glasser, A. H.; Hansen, C. J.; Jarboe, T. R.; Marklin, G. J.; Milroy, R. D.; Morgan, K. D.; Norgaard, P. C.; Shumlak, U.; Sutherland, D. A.; Victor, B. S.; Sovinec, C. R.; O'Bryan, J. B.; Held, E. D.; Ji, J.-Y.; Lukin, V. S.

2014-10-01

The Plasma Science and Innovation Center (PSI-Center - http://www.psicenter.org) supports collaborating validation platform experiments with 3D extended MHD simulations using the NIMROD, HiFi, and PSI-TET codes. Collaborators include the Bellan Plasma Group (Caltech), CTH (Auburn U), HBT-EP (Columbia), HIT-SI (U Wash-UW), LTX (PPPL), MAST (Culham), Pegasus (U Wisc-Madison), SSX (Swarthmore College), TCSU (UW), and ZaP/ZaP-HD (UW). The PSI-Center is exploring application of validation metrics between experimental data and simulations results. Biorthogonal decomposition (BOD) is used to compare experiments with simulations. BOD separates data sets into spatial and temporal structures, giving greater weight to dominant structures. Several BOD metrics are being formulated with the goal of quantitive validation. Results from these simulation and validation studies, as well as an overview of the PSI-Center status will be presented.

40 CFR 430.00 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-07-01

... semi-chemical mills using an ammonia base or a sodium base (Ba). G Mechanical Pulp Pulp and paper at... nonintegrated mills (Za). a This subpart is contained in the 40 CFR parts 425 through 699, edition revised as of...

40 CFR 430.00 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... semi-chemical mills using an ammonia base or a sodium base (Ba). G Mechanical Pulp Pulp and paper at... nonintegrated mills (Za). a This subpart is contained in the 40 CFR parts 425 through 699, edition revised as of...

IL-4 and IL-13 Compromise the Sinonasal Epithelial Barrier and Perturb Intercellular Junction Protein Expression

PubMed Central

Wise, Sarah K.; Laury, Adrienne M.; Katz, Elizabeth H.; Den Beste, Kyle A.; Parkos, Charles A.; Nusrat, Asma

2014-01-01

Introduction Altered expression of epithelial intercellular junction proteins has been observed in sinonasal biopsies from nasal polyps and epithelial layers cultured from nasal polyp patients. These alterations comprise a “leaky” epithelial barrier phenotype. We hypothesize that Th2 cytokines IL-4 and IL-13 modulate epithelial junction proteins thereby contributing to the leaky epithelial barrier. Methods Differentiated primary sinonasal epithelial layers cultured at the air-liquid interface were exposed to IL-4, IL-13, and controls for 24 hours at 37°C. Epithelial resistance measurements were taken every 4 hours during cytokine exposure. Western blot and immunofluorescence staining/confocal microscopy were used to assess changes in a panel of tight and adherens junction proteins. Western blot densitometry was quantified with image analysis. Results IL-4 and IL-13 exposure resulted in a mean decrease in transepithelial resistance at 24 hours to 51.6% (n=6) and 68.6% (n=8) of baseline, respectively. Tight junction protein JAM-A expression decreased 42.2% with IL-4 exposure (n=9) and 37.5% with IL-13 exposure (n=9). Adherens junction protein E-cadherin expression decreased 35.3% with IL-4 exposure (n=9) and 32.9% with IL-13 exposure (n=9). Tight junction protein claudin-2 showed more variability but had a trend toward higher expression with Th2 cytokine exposure. There were no appreciable changes in claudin-1, occludin, or ZO-1 with IL-4 or IL-13 exposure. Conclusion Sinonasal epithelial exposure to Th2 cytokines IL-4 and IL-13 results in alterations in intercellular junction proteins, reflecting increased epithelial permeability. Such changes may explain some of the phenotypic manifestations of Th2-mediated sinonasal disease, such as edema, nasal discharge, and environmental reactivity. PMID:24510479

Direct Ca2+-dependent Heterophilic Interaction between Desmosomal Cadherins, Desmoglein and Desmocollin, Contributes to Cell–Cell Adhesion

PubMed Central

Chitaev, Nikolai A.; Troyanovsky, Sergey M.

1997-01-01

Human fibrosarcoma cells, HT-1080, feature extensive adherens junctions, lack mature desmosomes, and express a single known desmosomal protein, Desmoglein 2 (Dsg2). Transfection of these cells with bovine Desmocollin 1a (Dsc1a) caused dramatic changes in the subcellular distribution of endogenous Dsg2. Both cadherins clustered in the areas of the adherens junctions, whereas only a minor portion of Dsg2 was seen in these areas in the parental cells. Deletion mapping showed that intact extracellular cadherin-like repeats of Dsc1a (Arg1-Thr170) are required for the translocation of Dsg2. Deletion of the intracellular C-domain that mediates the interaction of Dsc1a with plakoglobin, or the CSI region that is involved in the binding to desmoplakin, had no effect. Coimmunoprecipitation experiments of cell lysates stably expressing Dsc1a with anti-Dsc or -Dsg antibodies demonstrate that the desmosomal cadherins, Dsg2 and Dsc1a, are involved in a direct Ca2+-dependent interaction. This conclusion was further supported by the results of solid phase binding experiments. These showed that the Dsc1a fragment containing cadherin-like repeats 1 and 2 binds directly to the extracellular portion of Dsg in a Ca2+-dependent manner. The contribution of the Dsg/ Dsc interaction to cell–cell adhesion was tested by coculturing HT-1080 cells expressing Dsc1a with HT-1080 cells lacking Dsc but expressing myc-tagged plakoglobin (MPg). In the latter cells, MPg and the endogenous Dsg form stable complexes. The observed specific coimmunoprecipitation of MPg by anti-Dsc antibodies in coculture indicates that an intercellular interaction between Dsc1 and Dsg is involved in cell–cell adhesion. PMID:9214392

Expression pattern of adhesion molecules in junctional epithelium differs from that in other gingival epithelia.

PubMed

Hatakeyama, S; Yaegashi, T; Oikawa, Y; Fujiwara, H; Mikami, T; Takeda, Y; Satoh, M

2006-08-01

The gingival epithelium is the physiologically important interface between the bacterially colonized gingival sulcus and periodontal soft and mineralized connective tissues, requiring protection from exposure to bacteria and their products. However, of the three epithelia comprising the gingival epithelium, the junctional epithelium has much wider intercellular spaces than the sulcular epithelium and oral gingival epithelium. Hence, the aim of the present study was to characterize the cell adhesion structure in the junctional epithelium compared with the other two epithelia. Gingival epithelia excised at therapeutic flap surgery from patients with periodontitis were examined for expression of adhesion molecules by immunofluorescence. In the oral gingival epithelium and sulcular epithelium, but not in the junctional epithelium, desmoglein 1 and 2 in cell-cell contact sites were more abundant in the upper than the suprabasal layers. E-cadherin, the main transmembranous molecule of adherens junctions, was present in spinous layers of the oral gingival epithelium and sulcular epithelium, but was scarce in the junctional epithelium. In contrast, desmoglein 3 and P-cadherin were present in all layers of the junctional epithelium as well as the oral gingival epithelium and sulcular epithelium. Connexin 43 was clearly localized to spinous layers of the oral gingival epithelium, sulcular epithelium and parts of the junctional epithelium. Claudin-1 and occludin were expressed in the cell membranes of a few superficial layers of the oral gingival epithelium. These findings indicated that the junctional epithelium contains only a few desmosomes, composed of only desmoglein 3; adherens junctions are probably absent because of defective E-cadherin. Thus, the anchoring junctions connecting junctional epithelium cells are lax, causing widened intercellular spaces. In contrast, the oral gingival epithelium, which has a few tight junctions, functions as a barrier.

Ultrastructural and biochemical localization of N-RAP at the interface between myofibrils and intercalated disks in the mouse heart.

PubMed

Zhang, J Q; Elzey, B; Williams, G; Lu, S; Law, D J; Horowits, R

2001-12-11

N-RAP is a recently discovered muscle-specific protein found at cardiac intercalated disks. Double immunogold labeling of mouse cardiac muscle reveals that vinculin is located immediately adjacent to the fascia adherens region of the intercalated disk membrane, while N-RAP extends approximately 100 nm further toward the interior of the cell. We partially purified cardiac intercalated disks using low- and high-salt extractions followed by density gradient centrifugation. Immunoblots show that this preparation is highly enriched in desmin and junctional proteins, including N-RAP, talin, vinculin, beta1-integrin, N-cadherin, and connexin 43. Electron microscopy and immunolabeling demonstrate that N-RAP and vinculin are associated with the large fragments of intercalated disks that are present in this preparation, which also contains numerous membrane vesicles. Detergent treatment of the partially purified intercalated disks removed the membrane vesicles and extracted vinculin and beta1-integrin. Further separation on a sucrose gradient removed residual actin and myosin and yielded a fraction morphologically similar to fasciae adherentes that was highly enriched in N-RAP, N-cadherin, connexin 43, talin, desmin, and alpha-actinin. The finding that N-RAP copurifies with detergent-extracted intercalated disk fragments even though beta-integrin and vinculin have been completely removed suggests that N-RAP association with the adherens junction region is mediated by the cadherin system. Consistent with this hypothesis, we found that recombinant N-RAP fragments bind alpha-actinin in a gel overlay assay. In addition, immunofluorescence shows that N-RAP remains bound at the ends of isolated, detergent-treated cardiac myofibrils. These results demonstrate that N-RAP remains tightly bound to myofibrils and fasciae adherentes during biochemical purification and may be a key constituent in the mechanical link between these two structures.

Expression of TM4SF10, a Claudin/EMP/PMP22 family cell junction protein, during mouse kidney development and podocyte differentiation.

PubMed

Bruggeman, Leslie A; Martinka, Scott; Simske, Jeffrey S

2007-02-01

Cell junctions in the nephron are highly specialized to perform specific and distinct filtration and reabsorption functions. The mature kidney forms complex cell junctions including slit diaphragms that prevent the passage of serum proteins into the filtrate, and tubule cell junctions that regulate specific paracellular ion reuptake. We have investigated the expression of TM4SF10 (Trans-Membrane tetra(4)-Span Family 10) in mouse kidneys. TM4SF10 is the vertebrate orthologue of Caenorhabditis elegans VAB-9, a tetraspan adherens junction protein in the PMP22/EMP/Claudin family of proteins. We found that TM4SF10 localizes at the basal-most region of podocyte precursors before the capillary loop stage, at some tubule precursors, and at the ureteric bud junction with S-shaped bodies. Overall expression of TM4SF10 peaked at postnatal day 4 and was virtually absent in adult kidneys. The very limited expression of TM4SF10 protein that persisted into adulthood was restricted to a few tubule segments but remained localized to the basal region of lateral membranes. In undifferentiated cultured podocytes, TM4SF10 localized to the perinuclear region and translocated to the cell membrane after Cadherin appearance at cell-cell contacts. TM4SF10 colocalized with ZO1 and p120ctn in undifferentiated confluent podocytes and also colocalized with the tips of actin filaments at cell contacts. Upon differentiation of cultured podocytes, TM4SF10 protein disappeared from cell contacts and expression ceased. These results suggest that TM4SF10 functions during differentiation of podocytes and may participate in the maturation of cell junctions from simple adherens junctions to elaborate slit diaphragms. TM4SF10 may define a new class of Claudin-like proteins that function during junctional development.

Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin.

PubMed

Chichger, Havovi; Braza, Julie; Duong, Huetran; Boni, Geraldine; Harrington, Elizabeth O

2016-06-01

Pulmonary edema occurs in settings of acute lung injury, in diseases, such as pneumonia, and in acute respiratory distress syndrome. The lung interendothelial junctions are maintained in part by vascular endothelial (VE)-cadherin, an adherens junction protein, and its surface expression is regulated by endocytic trafficking. The Rab family of small GTPases are regulators of endocytic trafficking. The key trafficking pathways are regulated by Rab4, -7, and -9. Rab4 regulates the recycling of endosomes to the cell surface through a rapid-shuttle process, whereas Rab7 and -9 regulate trafficking to the late endosome/lysosome for degradation or from the trans-Golgi network to the late endosome, respectively. We recently demonstrated a role for the endosomal adaptor protein, p18, in regulation of the pulmonary endothelium through enhanced recycling of VE-cadherin to adherens junction. Thus, we hypothesized that Rab4, -7, and -9 regulate pulmonary endothelial barrier function through modulating trafficking of VE-cadherin-positive endosomes. We used Rab mutants with varying activities and associations to the endosome to study endothelial barrier function in vitro and in vivo. Our study demonstrates a key role for Rab4 activation and Rab9 inhibition in regulation of vascular permeability through enhanced VE-cadherin expression at the interendothelial junction. We further showed that endothelial barrier function mediated through Rab4 is dependent on extracellular signal-regulated kinase phosphorylation and activity. Thus, we demonstrate that Rab4 and -9 regulate VE-cadherin levels at the cell surface to modulate the pulmonary endothelium through extracellular signal-regulated kinase-dependent and -independent pathways, respectively. We propose that regulating select Rab GTPases represents novel therapeutic strategies for patients suffering with acute respiratory distress syndrome.

75 FR 50884 - Navigation and Navigable Waters; Technical, Organizational, and Conforming Amendments, Sector...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

... 3 and 165 to reflect changes in Coast Guard internal organizational structure. Sector Portland and... 1625-ZA25 Navigation and Navigable Waters; Technical, Organizational, and Conforming Amendments, Sector... Waters; Technical, Organizational, and Conforming Amendments, Sector Columbia River.'' 2. On page 48564...

What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

PubMed

Vale, C L; Fisher, D J; White, I R; Carpenter, J R; Burdett, S; Clarke, N W; Fizazi, K; Gravis, G; James, N D; Mason, M D; Parmar, M K B; Rydzewska, L H; Sweeney, C J; Spears, M R; Sydes, M R; Tierney, J F

2018-05-01

Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Uniquely, we have included all available

NE VIII lambda 774 and time variable associated absorption in the QSO UM 675

NASA Astrophysics Data System (ADS)

Hamann, Fred; Barlow, Thomas A.; Beaver, E. A.; Burbidge, E. M.; Cohen, Ross D.; Junkkarinen, Vesa; Lyons, R.

1995-04-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the za approximately equal ze absorption system of the ze = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at za = 2.1340 (shifted approximately 1500 km/s from ze strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other za approximately equal ze absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 1018/sq cm in the low-ionization gas to approximately 1020/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link za approximately equal to ze systems with X-ray 'wamr absorbers. We show that the Ne VIII absorbing gas would itself produce measurable warm

Maize pathogens suppress inducible phytoalexin production to thwart innate plant immunity

USDA-ARS?s Scientific Manuscript database

Kauralexins (KA) and zealexins (ZA) are newly described secondary metabolites in maize that serve as inducible chemical defenses against insects and pathogens. In contrast to the abundance of terpene volatiles in leaves, these non-volatile terpenoid phytoalexins are only mildly produced in response ...

75 FR 3820 - Broadband Initiatives Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-22

... DEPARTMENT OF AGRICULTURE Rural Utilities Service RIN 0572-ZA01 Broadband Initiatives Program... policy and application procedures for the second round of funding under the broadband initiatives (the... Act) for the Broadband Initiatives Program (BIP) which provides loans, grants, and loan/grant...

75 FR 44172 - Neurological and Physical Medicine Devices; Designation of Special Controls for Certain Class II...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-28

... [Docket No. FDA-2009-N-0493] RIN 0910-ZA37 Neurological and Physical Medicine Devices; Designation of... document proposed to amend certain neurological and physical medicine device regulations to establish... to amend certain neurological device and physical medicine device regulations to establish special...

Electron-positron pair production in ion collisions at low velocity beyond Born approximation

NASA Astrophysics Data System (ADS)

Lee, R. N.; Milstein, A. I.

2016-10-01

We derive the spectrum and the total cross section of electromagnetic e+e- pair production in the collisions of two nuclei at low relative velocity β. Both free-free and bound-free e+e- pair production is considered. The parameters ηA,B =ZA,B α are assumed to be small compared to unity but arbitrary compared to β (ZA,B are the charge numbers of the nuclei and α is the fine structure constant). Due to a suppression of the Born term by high power of β, the first Coulomb correction to the amplitude appears to be important at ηA,B ≳ β. The effect of a finite nuclear mass is discussed. In contrast to the result obtained in the infinite nuclear mass limit, the terms ∝M-2 are not suppressed by the high power of β and may easily dominate at sufficiently small velocities.

MGMRES: A generalization of GMRES for solving large sparse nonsymmetric linear systems

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

Young, D.M.; Chen, J.Y.

1994-12-31

The authors are concerned with the solution of the linear system (1): Au = b, where A is a real square nonsingular matrix which is large, sparse and non-symmetric. They consider the use of Krylov subspace methods. They first choose an initial approximation u{sup (0)} to the solution {bar u} = A{sup {minus}1}B of (1). They also choose an auxiliary matrix Z which is nonsingular. For n = 1,2,{hor_ellipsis} they determine u{sup (n)} such that u{sup (n)} {minus} u{sup (0)}{epsilon}K{sub n}(r{sup (0)},A) where K{sub n}(r{sup (0)},A) is the (Krylov) subspace spanned by the Krylov vectors r{sup (0)}, Ar{sup (0)}, {hor_ellipsis},more » A{sup n{minus}1}r{sup 0} and where r{sup (0)} = b{minus}Au{sup (0)}. If ZA is SPD they also require that (u{sup (n)}{minus}{bar u}, ZA(u{sup (n)}{minus}{bar u})) be minimized. If, on the other hand, ZA is not SPD, then they require that the Galerkin condition, (Zr{sup n}, v) = 0, be satisfied for all v{epsilon}K{sub n}(r{sup (0)}, A) where r{sup n} = b{minus}Au{sup (n)}. In this paper the authors consider a generalization of GMRES. This generalized method, which they refer to as `MGMRES`, is very similar to GMRES except that they let Z = A{sup T}Y where Y is a nonsingular matrix which is symmetric by not necessarily SPD.« less

First-principles prediction of phononic thermal conductivity of silicene: A comparison with graphene

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

Gu, Xiaokun; Yang, Ronggui, E-mail: Ronggui.Yang@Colorado.Edu

2015-01-14

There has been great interest in two-dimensional materials, beyond graphene, for both fundamental sciences and technological applications. Silicene, a silicon counterpart of graphene, has been shown to possess some better electronic properties than graphene. However, its thermal transport properties have not been fully studied. In this paper, we apply the first-principles-based phonon Boltzmann transport equation to investigate the thermal conductivity of silicene as well as the phonon scattering mechanisms. Although both graphene and silicene are two-dimensional crystals with similar crystal structure, we find that phonon transport in silicene is quite different from that in graphene. The thermal conductivity of silicenemore » shows a logarithmic increase with respect to the sample size due to the small scattering rates of acoustic in-plane phonon modes, while that of graphene is finite. Detailed analysis of phonon scattering channels shows that the linear dispersion of the acoustic out-of-plane (ZA) phonon modes, which is induced by the buckled structure, makes the long-wavelength longitudinal acoustic phonon modes in silicene not as efficiently scattered as that in graphene. Compared with graphene, where most of the heat is carried by the acoustic out-of-plane (ZA) phonon modes, the ZA phonon modes in silicene only have ∼10% contribution to the total thermal conductivity, which can also be attributed to the buckled structure. This systematic comparison of phonon transport and thermal conductivity of silicene and graphene using the first-principle-based calculations shed some light on other two-dimensional materials, such as two-dimensional transition metal dichalcogenides.« less

Length divergence of the lattice thermal conductivity in suspended graphene nanoribbons

NASA Astrophysics Data System (ADS)

Majee, Arnab K.; Aksamija, Zlatan

2016-06-01

Thermal properties of graphene have attracted much attention, culminating in a recent measurement of its length dependence in ribbons up to 9 μ m long. In this paper, we use the improved Callaway model to solve the phonon Boltzmann transport equation while capturing both the resistive (umklapp, isotope, and edge roughness) and nonresistive (normal) contributions. We show that for lengths smaller than 100 μ m , scaling the ribbon length while keeping the width constant leads to a logarithmic divergence of thermal conductivity. The length dependence is driven primarily by a ballistic-to-diffusive transition in the in-plane (LA and TA) branches, while in the hydrodynamic regime when 10 μ m ZA) branch shows a clear logarithmic trend, driven by the nonresistive normal contribution. We find that thermal conductivity converges beyond L >100 μ m due to the coupling between in-plane and flexural modes. This coupling leads to renormalization of ZA phonon dispersion in the long-wavelength range, preventing further divergence of thermal conductivity. We also uncover a strong dependence on sample width, which we attribute to the interplay between nonresistive normal and diffusive edge scattering in the Poisseuille flow regime. We conclude that normal processes play a crucial role in the length and width dependence of thermal transport in graphene in the hydrodynamic regime and dictate the relative in-plane (LA+TA) to out-of-plane (ZA) contribution to transport.

75 FR 7591 - Guidance on Recommended Interim Preliminary Remediation Goals for Dioxin in Soil at CERCLA and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-22

... ENVIRONMENTAL PROTECTION AGENCY [EPA-HQ-SFUND-2009-0907; FRL-9114-6] RIN 2050-ZA05 Guidance on Recommended Interim Preliminary Remediation Goals for Dioxin in Soil at CERCLA and RCRA Sites; Extension of... Interim Preliminary Remediation Goals for Dioxin in Soil at Comprehensive Environmental Response...

Evaluation of Proposed Dredged Material Disposal Alternatives for New York/New Jersey Harbor. Phase 1

DTIC Science & Technology

1988-08-01

following initial incubation of the inoculum in lactose broth. The presence of Vibrio parahemolyticus was determined using trypticase citrate 0 bile salts...SaZmonella (enteritis), SalmonelZa typhosa (typhoid fever), ShigeZla (dysentery), and Vibrio cholerae (cholera). The organisms causing these diseases do not

75 FR 28778 - Broadband Initiatives Program

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-24

... DEPARTMENT OF AGRICULTURE Rural Utilities Service RIN 0572-ZA01 Broadband Initiatives Program AGENCY: Rural Utilities Service, Department of Agriculture. ACTION: Notice of Extension of filing Public... Initiatives Program (BIP), published in the Federal Register at 75 FR 3820 (January 22, 2010). Such technical...

77 FR 28536 - Representation Procedures and Rulemaking Authority

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-15

... NATIONAL MEDIATION BOARD 29 CFR Part 1206 [Docket No. C-7034] RIN 3140-ZA01 Representation Procedures and Rulemaking Authority AGENCY: National Mediation Board. ACTION: Proposed rule with request for comments. SUMMARY: This proposal amends the National Mediation Board's (NMB or Board) existing rules for...

77 FR 33701 - Representation Procedures and Rulemaking Authority; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-07

... NATIONAL MEDIATION BOARD 29 CFR Parts 1206 [Docket No. C-7034] RIN 3140-ZA01 Representation Procedures and Rulemaking Authority; Correction AGENCY: National Mediation Board. ACTION: Proposed rule... May 15, 2012. The proposed rule changes the National Mediation Board's (NMB or Board) existing rules...

75 FR 58329 - Federal Travel Regulation (FTR); Relocation Expenses Test Programs

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-24

...; Docket 2010-0016; Sequence 1] RIN 3090-ZA01 Federal Travel Regulation (FTR); Relocation Expenses Test... extended the authority for relocation expenses test programs for Federal employees, made by the passage of..., permits the Administrator of General Services to authorize Federal agencies to test new and innovative...

75 FR 32273 - Representation Election Procedure

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-08

... NATIONAL MEDIATION BOARD 29 CFR Parts 1202 and 1206 [Docket No. C-6964] RIN 3140-ZA00 Representation Election Procedure AGENCY: National Mediation Board. ACTION: Final rule; delay of effective date. SUMMARY: The National Mediation Board (NMB) is delaying the effective date of its rule regarding...

78 FR 73438 - Reorganization of Sector Baltimore and Hampton Roads; Conforming Amendments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-06

... Assawoman Bay, Fenwick Island--Ocean City, MD, Safety Zone, from the Coast Guard Sector Hampton Roads--COTP...-0251] RIN 1625-ZA32 Reorganization of Sector Baltimore and Hampton Roads; Conforming Amendments AGENCY... Roads' Marine Inspection Zone and Captain of the Port Zones. These conforming amendments are necessary...

Analysis of Solar Potential of Roofs Based on Digital Terrain Model

NASA Astrophysics Data System (ADS)

Gorički, M.; Poslončec-Petrić, V.; Frangeš, S.; Bačić, Ž.

2017-09-01

One of the basic goals of the smart city concept is to create a high-quality environment that is long sustainable and economically justifiable. The priority and concrete goal today is to promote and provide sustainable sources of energy (SSE). Croatia is rich with sun energy and as one of the sunniest European countries, it has a huge insufficiently used solar potential at its disposal. The paper describes the procedure of analysing the solar potential of a pilot area Sveti Križ Začretje by means of digital surface model (DSM) and based on the data available in the Meteorological and Hydrological Service of the Republic of Croatia. Although a more detailed analysis would require some additional factors, it is clear that the installation of 19,6m2 of solar panels in each household could cover annual requirements of the household in the analysed area, the locality Sveti Križ Začretje.

Overview of the FuZE Fusion Z-Pinch Experiment

NASA Astrophysics Data System (ADS)

Shumlak, U.; Nelson, B. A.; Claveau, E. L.; Forbes, E. G.; Golingo, R. P.; Stepanov, A. D.; Weber, T. R.; Zhang, Y.; McLean, H. S.; Higginson, D. P.; Schmidt, A.; Tummel, K. K.

2017-10-01

Successful results of the sheared flow stabilized (SFS) Z-pinch from ZaP and ZaP-HD have motivated the new FuZE project to scale the plasma performance to fusion conditions. The SFS Z-pinch is immune to the instabilities that plague the conventional Z-pinch yet maintains the same favorable radial scaling. The plasma density and temperature increase rapidly with decreasing plasma radius, which naturally leads to a compact configuration at fusion conditions. The SFS Z-pinch is being investigated as a novel approach to a compact fusion device in a collaborative ARPA-E ALPHA project with the University of Washington and Lawrence Livermore National Laboratory. The project includes an experimental effort coupled with high-fidelity physics modeling using kinetic and fluid simulations. Along with scaling law analysis, computational and experimental results from the FuZE device are presented. This work is supported by an award from US ARPA-E.

First-Principles Determination of Ultralow Thermal Conductivity of monolayer WSe2

NASA Astrophysics Data System (ADS)

Zhou, Wu-Xing; Chen, Ke-Qiu

2015-10-01

By using first-principles calculations combined with the phonon Boltzmann transport equation, we systematically investigate the phonon transport of monolayer WSe2. Compared with other 2D materials, the monolayer WSe2 is found to have an ultralow thermal conductivity due to the ultralow Debye frequency and heavy atom mass. The room temperature thermal conductivity for a typical sample size of 1 μm is 3.935  W/m K, which is one order of magnitude lower than that of MoS2. And the room temperature thermal conductivity can be further decreased by about 95% in 10 nm sized samples. Moreover, we also find the ZA phonons have the dominant contribution to the thermal conductivity, and the relative contribution is almost 80% at room temperature, which is remarkably higher than that for monolayer MoS2. This is because the ZA phonons have longer lifetime than that of LA and TA phonons in monolayer WSe2.

The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells

PubMed Central

Castella, Barbara; Kopecka, Joanna; Sciancalepore, Patrizia; Mandili, Giorgia; Foglietta, Myriam; Mitro, Nico; Caruso, Donatella; Novelli, Francesco; Riganti, Chiara; Massaia, Massimo

2017-01-01

Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. PMID:28580927

Structure and properties of stir-cast zinc alloys

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

LeHuy, H.; Blain J.; Masounave, J.

Stir casting (or rheocasting) of ZA-27 zinc alloys was investigated experimentally. By vigorously agitating the alloys during cooling, the dendrites that were forming were fragmented giving a unique structure composed of spherical and rosette shaped particles suspended in the remaining liquid. Under high shear rates ({center dot}{gamma} = 300s{sup {minus}1} or more) the slurries with primary particle concentrations as high as 60% displayed viscosities as low as 20 poises and could easily be casted. The effects of processing variables such as shearing and cooling rates and casting temperatures were studied. Their relative importance on the rheological and microstructural behavior ofmore » the stir cast alloys are discussed. Results from viscosity measurements on slurries show that non-dendritical ZA-27 alloys obey a power law fluid model. Finally, results from mechanical and compressive studies carried out on solidified slurries are discussed and compared to conventional casted and wrought alloy properties.« less

Ca II and Na I absorption in the QSO S4 0248 + 430 due to an intervening galaxy

NASA Technical Reports Server (NTRS)

Womble, Donna S.; Junkkarinen, Vesa T.; Cohen, Ross D.; Burbidge, E. Margaret

1990-01-01

Observations of the QSO S4 0248 + 430 and a nearby anonymous galaxy are presented. Two absorption components are found in both Ca II H and K and Na I D1 and D2 at z(a) = 0.0515, 0.0523. Column densities of log N(Ca II) = 13.29, 13.50, and log N(Na I) = 13.79, 14.18 are found for z(a) = 0.0515, 0.0523 absorption systems, respectively. The column density ratios imply considerable calcium depletion and disk-type absorbing gas. At least one and possibly both absorption components are produced by high-velocity gas. A broadband image of the field shows an asymmetrical armlike feature or possible tidal tail covering and extending past the position of the QSO. The presence of this extended feature and the apparent difference between the absorption velocities and galaxy rotation velocity suggest that the absorbing gas is not ordinary disk gas, but rather is a result of tidal disruption.

PSI-Center Simulations of Validation Platform Experiments

NASA Astrophysics Data System (ADS)

Nelson, B. A.; Akcay, C.; Glasser, A. H.; Hansen, C. J.; Jarboe, T. R.; Marklin, G. J.; Milroy, R. D.; Morgan, K. D.; Norgaard, P. C.; Shumlak, U.; Victor, B. S.; Sovinec, C. R.; O'Bryan, J. B.; Held, E. D.; Ji, J.-Y.; Lukin, V. S.

2013-10-01

The Plasma Science and Innovation Center (PSI-Center - http://www.psicenter.org) supports collaborating validation platform experiments with extended MHD simulations. Collaborators include the Bellan Plasma Group (Caltech), CTH (Auburn U), FRX-L (Los Alamos National Laboratory), HIT-SI (U Wash - UW), LTX (PPPL), MAST (Culham), Pegasus (U Wisc-Madison), PHD/ELF (UW/MSNW), SSX (Swarthmore College), TCSU (UW), and ZaP/ZaP-HD (UW). Modifications have been made to the NIMROD, HiFi, and PSI-Tet codes to specifically model these experiments, including mesh generation/refinement, non-local closures, appropriate boundary conditions (external fields, insulating BCs, etc.), and kinetic and neutral particle interactions. The PSI-Center is exploring application of validation metrics between experimental data and simulations results. Biorthogonal decomposition is proving to be a powerful method to compare global temporal and spatial structures for validation. Results from these simulation and validation studies, as well as an overview of the PSI-Center status will be presented.

Zakon za srednoto obrazovanie (Secondary Education Act).

ERIC Educational Resources Information Center

1971

This document is an English-language abstract (approximately 1,500 words) of the Macedonian Secondary Education Act of 1970. Secondary Education is an integral part of the consolidated system of education and training. All citizens have an equal right to acquire the knowledge and skills they need in any type of secondary level institution.…

CD82 and Cell-Cell Adhesion in Metastatic Prostate Cancer

DTIC Science & Technology

2013-07-01

in our laboratory that previously was mentored on this project as  a summer intern by the PI.  Amanda and Alexis will also perform  flow   cytometry ...restoration using surface biotin labeling, immunofluorescent staining and flow cytometry for CD82 and E-cadherin in DU145.CD82 cells. 4. Assess the...Factor Receptor and  Hepatocyte  Growth Factor Receptor) and E‐ cadherin (2‐6).  E‐cadherin is responsible for the formation of adherens junctions in the

SILAC-Based Quantitative Proteomic Analysis of Human Lung Cell Response to Copper Oxide Nanoparticles

PubMed Central

Edelmann, Mariola J.; Shack, Leslie A.; Naske, Caitlin D.; Walters, Keisha B.; Nanduri, Bindu

2014-01-01

Copper (II) oxide (CuO) nanoparticles (NP) are widely used in industry and medicine. In our study we evaluated the response of BEAS-2B human lung cells to CuO NP, using Stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics and phosphoproteomics. Pathway modeling of the protein differential expression showed that CuO NP affect proteins relevant in cellular function and maintenance, protein synthesis, cell death and survival, cell cycle and cell morphology. Some of the signaling pathways represented by BEAS-2B proteins responsive to the NP included mTOR signaling, protein ubiquitination pathway, actin cytoskeleton signaling and epithelial adherens junction signaling. Follow-up experiments showed that CuO NP altered actin cytoskeleton, protein phosphorylation and protein ubiquitination level. PMID:25470785

77 FR 71860 - Self-Regulatory Organizations; EDGX Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-04

... RLP Approval Order, which account for the difference of assumed information and sophistication level... Members that utilize Retail Orders. Flag ZA is proposed to be yielded for those Members that use Retail... is proposed to be yielded for those Members that use Retail Orders that remove liquidity from EDGX...

Topical Treatment of Cutaneous Leishmaniasis W/WR279396 Phase II Study. Addendum

DTIC Science & Technology

2006-07-01

France) g. Tape so seal plates h. Sterile flat-bottom 96-well plates i. Inverted microscope with trail (France) j . Cryomarkers 2. Check list 2...Subinvestigators: Nathalie Messaoud Amor Zaâtour Abdelkarim El Fahem Nabil Haj Hmida OBJECTIVE To collaborate with the monitoring visit SUNDAY 19/02

75 FR 17093 - Neurological and Physical Medicine Devices; Designation of Special Controls for Certain Class II...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-05

... [Docket No. FDA-2009-N-0493] RIN 0910-ZA37 Neurological and Physical Medicine Devices; Designation of... proposing to amend certain neurological device and physical medicine device regulations to establish special..., FDA is proposing to amend the physical medicine devices regulation at Sec. 890.5850 (21 CFR 890.5850...

78 FR 77601 - Adjustment of Monetary Threshold for Reporting Rail Equipment Accidents/Incidents for Calendar...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-24

..., Notice No. 6] RIN 2130-ZA12 Adjustment of Monetary Threshold for Reporting Rail Equipment Accidents... threshold from $9,900 to $10,500 for certain railroad accidents/incidents involving property damage that... reflect cost increases that have occurred since the reporting threshold was last published in November of...

Interdecadal Change in the Tropical Pacific Precipitation Anomaly Pattern around the Late 1990s during Boreal Spring

NASA Astrophysics Data System (ADS)

Wen, Zhiping; Guo, Yuanyuan; Wu, Renguang

2017-04-01

The leading mode of boreal spring precipitation variability over the tropical Pacific experienced a pronounced interdecadal change around the late 1990s. The pattern before 1998 features positive precipitation anomalies over the equatorial eastern Pacific (EP) with positive principle component years. The counterpart after 1998 exhibits a westward shift of the positive center to the equatorial central Pacific (CP). Observational evidence shows that this interdecadal change in the leading mode of precipitation variability is closely associated with a distinctive sea surface temperature (SST) anomaly pattern. The westward shift of the anomalous precipitation center after 1998 is in tandem with a similar shift of maximum warming from the EP to CP. Diagnostic analyses based on a linear equation of the mixed layer temperature anomaly exhibit that an interdecadal enhancement of zonal advection (ZA) feedback process plays a vital role in the shift in the leading mode of both the tropical Pacific SST and the precipitation anomaly during spring. Moreover, the variability of the anomalous zonal current at the upper ocean dominates the ZA feedback change, while the mean zonal SST gradient associated with a La Niña-like pattern of the mean state only accounts for a relatively trivial proportion of the ZA feedback change. It was found that both the relatively rapid decaying of the SST anomalies in the EP and the La Niña-like mean state make it conceivable that the shift of the leading mode of the tropical precipitation anomaly only occurs in spring. In addition, the largest variance of the anomalous zonal current in spring might contribute to the unique interdecadal change in the tropical spring precipitation anomaly pattern.

Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.

PubMed

Tsutsumi, Ryosuke; Hock, Colleen; Bechtold, C Dustin; Proulx, Steven T; Bukata, Susan V; Ito, Hiromu; Awad, Hani A; Nakamura, Takashi; O'Keefe, Regis J; Schwarz, Edward M

2008-10-01

Aseptic loosening of total joint replacements is caused by wear debris-induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP-induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro-CT and traditional histology. Although micro-CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 +/- 0.23 mm(3) versus 0.15 +/- 0.067 mm(3); p < 0.01). Although OPG and high-dose ZA completely inhibited this PE-induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE-treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti- and PE-treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001). (c) 2008 Orthopaedic Research Society.

A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy.

PubMed

Ugaonkar, Shweta R; Wesenberg, Asa; Wilk, Jolanta; Seidor, Samantha; Mizenina, Olga; Kizima, Larisa; Rodriguez, Aixa; Zhang, Shimin; Levendosky, Keith; Kenney, Jessica; Aravantinou, Meropi; Derby, Nina; Grasperge, Brooke; Gettie, Agegnehu; Blanchard, James; Kumar, Narender; Roberts, Kevin; Robbiani, Melissa; Fernández-Romero, José A; Zydowsky, Thomas M

2015-09-10

Women urgently need a self-initiated, multipurpose prevention technology (MPT) that simultaneously reduces their risk of acquiring HIV-1, HSV-2, and HPV (latter two associated with increased risk of HIV-1 acquisition) and prevents unintended pregnancy. Here, we describe a novel core-matrix intravaginal ring (IVR), the MZCL IVR, which effectively delivered the MZC combination microbicide and a contraceptive. The MZCL IVR contains four active pharmaceutical ingredients (APIs): MIV-150 (targets HIV-1), zinc acetate (ZA; targets HIV-1 and HSV-2), carrageenan (CG; targets HPV and HSV-2), and levonorgestrel (LNG; targets unintended pregnancy). The elastomeric IVR body (matrix) was produced by hot melt extrusion of the non-water swellable elastomer, ethylene vinyl acetate (EVA-28), containing the hydrophobic small molecules, MIV-150 and LNG. The solid hydrophilic core, embedded within the IVR by compression, contained the small molecule ZA and the macromolecule CG. Hydrated ZA/CG from the core was released by diffusion via a pore on the IVR while the MIV-150/LNG diffused from the matrix continuously for 94 days (d) in vitro and up to 28 d (study period) in macaques. The APIs released in vitro and in vivo were active against HIV-1ADA-M, HSV-2, and HPV16 PsV in cell-based assays. Serum LNG was at levels associated with local contraceptive effects. The results demonstrate proof-of-concept of a novel core-matrix IVR for sustained and simultaneous delivery of diverse molecules for the prevention of HIV, HSV-2 and HPV acquisition, as well as unintended pregnancy. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Modeling Tight Junction Dynamics and Oscillations

PubMed Central

Kassab, Fuad; Marques, Ricardo Paulino; Lacaz-Vieira, Francisco

2002-01-01

Tight junction (TJ) permeability responds to changes of extracellular Ca2+ concentration. This can be gauged through changes of the transepithelial electrical conductance (G) determined in the absence of apical Na+. The early events of TJ dynamics were evaluated by the fast Ca2+ switch assay (FCSA) (Lacaz-Vieira, 2000), which consists of opening the TJs by removing basal calcium (Ca2+ bl) and closing by returning Ca2+ bl to normal values. Oscillations of TJ permeability were observed when Ca2+ bl is removed in the presence of apical calcium (Ca2+ ap) and were interpreted as resulting from oscillations of a feedback control loop which involves: (a) a sensor (the Ca2+ binding sites of zonula adhaerens), (b) a control unit (the cell signaling machinery), and (c) an effector (the TJs). A mathematical model to explain the dynamical behavior of the TJs and oscillations was developed. The extracellular route (ER), which comprises the paracellular space in series with the submucosal interstitial fluid, was modeled as a continuous aqueous medium having the TJ as a controlled barrier located at its apical end. The ER was approximated as a linear array of cells. The most apical cell is separated from the apical solution by the TJ and this cell bears the Ca2+ binding sites of zonula adhaerens that control the TJs. According to the model, the control unit receives information from the Ca2+ binding sites and delivers a signal that regulates the TJ barrier. Ca2+ moves along the ER according to one-dimensional diffusion following Fick's second law. Across the TJ, Ca2+ diffusion follows Fick's first law. Our first approach was to simulate the experimental results in a semiquantitative way. The model tested against experiment results performed in the frog urinary bladder adequately predicts the responses obtained in different experimental conditions, such as: (a) TJ opening and closing in a FCSA, (b) opening by the presence of apical Ca2+ and attainment of a new steady-state, (c

Turbulent Sensible Heat Flux in Łódź Obtained from Scintillometer Measuerments - Comparison of Free and Mix Algorithms

NASA Astrophysics Data System (ADS)

Zieliński, Mariusz; Fortuniak, Krzysztof; Pawlak, Włodzimierz

2012-01-01

The primary aim of this paper was to present the results of turbulent sensible heat flux (QH) measurements with Scintillometer Scintec BLS900 (LAS). The theoretical background of scintillation method has been presented as well as two different ways of sensible heat flux computation from LAS. The measurements presented here were conducted from April to December 2011. Diurnal and partially annual variability of QH has been analyzed, moreover the mean diurnal course of QH in considered months has been prepared. In order to choose the optimal method of QH computation from LAS the results obtained with three different Monin-Obuchov similarity theory functions as well as free convection assumption has been compared. In first case it has been proved that sensible heat flux differs significantly depending on chosen universal function. In turn in case of free convection assumptions it has been revealed that it is valid only for very unstable conditions. Therefore it does not apply to long-time heat flux measurement in case of Łódź. Nevertheless, this study has shown that scintillation method is valuable and reasonable source of path-averaged QH estimates in considered city. Głównym celem pracy była prezentacja wyników pomiarów turbulencyjnego strumienia ciepła jawnego (QH) w Łodzi za pomocą scyntylometru Scintec BLS900. Przedstawione zostały założenia teoretyczne metody scyntylacyjnej, jak również metody wyznaczania strumienia ciepła jawnego za pomocą scyntylometru. Pomiary obejmowały okres od kwietnia do grudnia 2011 roku. Przeanalizowano dobową oraz częściowo roczną zmienność QH, wyznaczając przy tym średnie dobowe jego przebiegi dla poszczególnych miesięcy. W celu wyznaczenia optymalnej metody estymacji QH z pomiarów scyntylometrycznych porównano wyniki uzyskane przy wykorzystaniu trzech różnych funkcji uniwersalnych teorii podobieństwa Monina- Obuchova, jak również przybliżenia dla swobodnej konwekcji. W pierwszym przypadku wykazano

The LAOM Multidimensional Anxiety Scale for Measuring Anxiety in Children and Adolescents: Addressing the Psychometric Properties of the Scale

ERIC Educational Resources Information Center

Kozina, Ana

2012-01-01

The article introduces a new anxiety scale, called the LAOM (Lestvica anksioznosti za otroke in mladostnike [The anxiety scale for children and adolescents]) for measuring self-reported multidimensional anxiety. The scale has been developed with a special focus on the school setting, using one sample from an elementary school which is…

Integrating Language Lab Materials into Advanced Russian.

ERIC Educational Resources Information Center

Allar, Gregory

1986-01-01

Describes the use of language lab materials supplied by the pedagogical journal "Russkij Jazyk Za Rubezom" in an advanced Russian-language class. Each week students were given a relevant picture and vocabulary list prior to listening to a taped story. The story was used as the basis for conversation. (LMO)

Bisphosphonates in the Prevention of Post-Traumatic Osteoarthritis

DTIC Science & Technology

David, et al . 2017 J Ortho Res. - Histological analysis of mouse joints following DMM demonstrated rapid (within 3-day of injury), and focal (spatially...Medial Meniscus in Mice (David, et al . 2018 In Preparation) - The present study has shown that repeated i. a. injection of ZA into the murine knee

Targeting Androgen Receptor in Breast Cancer: Enzalutamide as a Novel Breast Cancer Therapeutic

DTIC Science & Technology

2014-09-01

of Medivation. JG, FG, IEA, and EMcC are employed by Fundacion Ciencia & Vida in Santiago, Chile and receive partial funding from Medivation. The...CA 94105, USA. 3Fundación Ciencia & Vida, Avda. Zañartu 1482 - Ñuñoa, Santiago 7780272, Chile. 4Department of Medicine, Division of Oncology

75 FR 39556 - Extension of the Designation of El Salvador for Temporary Protected Status and Automatic...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-09

... Docket No. USCIS 2010-0032] RIN 1615-ZA95 Extension of the Designation of El Salvador for Temporary... designation of El Salvador for temporary protected status (TPS) for 18 months from its current expiration date... nationals of El Salvador (or aliens having no nationality who last habitually resided in El Salvador) with...

SigmaPlot 2000, Version 6.00, SPSS Inc. Computer Software Project Management, Requirements, and Design Document

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

HURLBUT, S.T.

2000-10-24

SigmaPlot is a vendor software product that will be used to convert the area under an absorbance curve generated by a Fourier transform infrared spectrometer (FTIR) to a relative area. SigmaPlot will be used in conjunction with procedure ZA-565-301, ''Determination of Moisture by Supercritical Fluid Extraction and Infrared Detection.''

Air Pollution, Climate, and Heart Disease

MedlinePlus

... CJ , Ezzati M , AlMazroa MA , Memish ZA . A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet . 2012 ; 380 : 2224 – 2260 . OpenUrl CrossRef ...

N-cadherin in adult rat cardiomyocytes in culture. II. Spatio-temporal appearance of proteins involved in cell-cell contact and communication. Formation of two distinct N-cadherin/catenin complexes.

PubMed

Hertig, C M; Butz, S; Koch, S; Eppenberger-Eberhardt, M; Kemler, R; Eppenberger, H M

1996-01-01

The spatio-temporal appearance and distribution of proteins forming the intercalated disc were investigated in adult rat cardiomyocytes (ARC). The 'redifferentiation model' of ARC involves extensive remodelling of the plasma membrane and of the myofibrillar apparatus. It represents a valuable system to elucidate the formation of cell-cell contact between cardiomyocytes and to assess the mechanisms by which different proteins involved in the cell-cell adhesion process are sorted in a precise manner to the sites of function. Appearance of N-cadherin, the catenins and connexin43 within newly formed adherens and gap junctions was studied. Here first evidence is provided for a formation of two distinct and separable N-cadherin/catenin complexes in cardiomyocytes. Both complexes are composed of N-cadherin and alpha-catenin which bind to either beta-catenin or plakoglobin in a mutually exclusive manner. The two N-cadherin/catenin complexes are assumed to be functionally involved in the formation of cell-cell contacts in ARC; however, the differential appearance and localization of the two types of complexes may also point to a specific role during ARC differentiation. The newly synthesized beta-catenin containing complex is more abundant during the first stages in culture after ARC isolation, while the newly synthesized plakoglobin containing complex progressively accumulates during the morphological changes of ARC. ARC formed a tissue-like pattern in culture whereby the new cell-cell contacts could be dissolved through Ca2+ depletion. Presence of cAMP and replenishment of Ca2+ content in the culture medium not only allowed reformation of cell-cell contacts but also affected the relative protein ratio between the two N-cadherin/catenin complexes, increasing the relative amount of newly synthesized beta-catenin over plakoglobin at a particular stage of ARC differentiation. The clustered N-cadherin/catenin complexes at the plasma membrane appear to be a prerequisite for the

The inner CSF–brain barrier: developmentally controlled access to the brain via intercellular junctions

PubMed Central

Whish, Sophie; Dziegielewska, Katarzyna M.; Møllgård, Kjeld; Noor, Natassya M.; Liddelow, Shane A.; Habgood, Mark D.; Richardson, Samantha J.; Saunders, Norman R.

2015-01-01

In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially consisting of neuroepithelial cells and later radial glial cells, is characterized by “strap” junctions, which limit the exchange of different sized molecules between cerebrospinal fluid and the brain parenchyma. Here we provide a systematic study of permeability properties of this inner cerebrospinal fluid-brain barrier during mouse development from embryonic day, E17 until adult. Results show that at fetal stages exchange across this barrier is restricted to the smallest molecules (286Da) and the diffusional restraint is progressively removed as the brain develops. By postnatal day P20, molecules the size of plasma proteins (70 kDa) diffuse freely. Transcriptomic analysis of junctional proteins present in the cerebrospinal fluid-brain interface showed expression of adherens junctional proteins, actins, cadherins and catenins changing in a development manner consistent with the observed changes in the permeability studies. Gap junction proteins were only identified in the adult as was claudin-11. Immunohistochemistry was used to localize at the cellular level some of the adherens junctional proteins of genes identified from transcriptomic analysis. N-cadherin, β - and α-catenin immunoreactivity was detected outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11 was only immunopositive in the adult, consistent with results obtained from transcriptomic analysis. These results provide information about physiological, molecular

Rapamycin regulates autophagy and cell adhesion in induced pluripotent stem cells.

PubMed

Sotthibundhu, Areechun; McDonagh, Katya; von Kriegsheim, Alexander; Garcia-Munoz, Amaya; Klawiter, Agnieszka; Thompson, Kerry; Chauhan, Kapil Dev; Krawczyk, Janusz; McInerney, Veronica; Dockery, Peter; Devine, Michael J; Kunath, Tilo; Barry, Frank; O'Brien, Timothy; Shen, Sanbing

2016-11-15

Cellular reprogramming is a stressful process, which requires cells to engulf somatic features and produce and maintain stemness machineries. Autophagy is a process to degrade unwanted proteins and is required for the derivation of induced pluripotent stem cells (iPSCs). However, the role of autophagy during iPSC maintenance remains undefined. Human iPSCs were investigated by microscopy, immunofluorescence, and immunoblotting to detect autophagy machinery. Cells were treated with rapamycin to activate autophagy and with bafilomycin to block autophagy during iPSC maintenance. High concentrations of rapamycin treatment unexpectedly resulted in spontaneous formation of round floating spheres of uniform size, which were analyzed for differentiation into three germ layers. Mass spectrometry was deployed to reveal altered protein expression and pathways associated with rapamycin treatment. We demonstrate that human iPSCs express high basal levels of autophagy, including key components of APMKα, ULK1/2, BECLIN-1, ATG13, ATG101, ATG12, ATG3, ATG5, and LC3B. Block of autophagy by bafilomycin induces iPSC death and rapamycin attenuates the bafilomycin effect. Rapamycin treatment upregulates autophagy in iPSCs in a dose/time-dependent manner. High concentration of rapamycin reduces NANOG expression and induces spontaneous formation of round and uniformly sized embryoid bodies (EBs) with accelerated differentiation into three germ layers. Mass spectrometry analysis identifies actin cytoskeleton and adherens junctions as the major targets of rapamycin in mediating iPSC detachment and differentiation. High levels of basal autophagy activity are present during iPSC derivation and maintenance. Rapamycin alters expression of actin cytoskeleton and adherens junctions, induces uniform EB formation, and accelerates differentiation. IPSCs are sensitive to enzyme dissociation and require a lengthy differentiation time. The shape and size of EBs also play a role in the heterogeneity of

Lagrangian or Eulerian; real or Fourier? Not all approaches to large-scale structure are created equal

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

Tassev, Svetlin, E-mail: tassev@astro.princeton.edu

We present a pedagogical systematic investigation of the accuracy of Eulerian and Lagrangian perturbation theories of large-scale structure. We show that significant differences exist between them especially when trying to model the Baryon Acoustic Oscillations (BAO). We find that the best available model of the BAO in real space is the Zel'dovich Approximation (ZA), giving an accuracy of ∼<3% at redshift of z = 0 in modelling the matter 2-pt function around the acoustic peak. All corrections to the ZA around the BAO scale are perfectly perturbative in real space. Any attempt to achieve better precision requires calibrating the theorymore » to simulations because of the need to renormalize those corrections. In contrast, theories which do not fully preserve the ZA as their solution, receive O(1) corrections around the acoustic peak in real space at z = 0, and are thus of suspicious convergence at low redshift around the BAO. As an example, we find that a similar accuracy of 3% for the acoustic peak is achieved by Eulerian Standard Perturbation Theory (SPT) at linear order only at z ≈ 4. Thus even when SPT is perturbative, one needs to include loop corrections for z∼<4 in real space. In Fourier space, all models perform similarly, and are controlled by the overdensity amplitude, thus recovering standard results. However, that comes at a price. Real space cleanly separates the BAO signal from non-linear dynamics. In contrast, Fourier space mixes signal from short mildly non-linear scales with the linear signal from the BAO to the level that non-linear contributions from short scales dominate. Therefore, one has little hope in constructing a systematic theory for the BAO in Fourier space.« less

Second moment scaling and the relationship of geometric and electronic structure

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

Hoistad, L.M.

1993-01-01

Extended Hueckel band calculations were used to show the ditellurides in the CdI[sub 2] structure type with more than 16 valence electrons/MTe[sub 2] unit should have an instability due to their electronic structure. Single crystal X-ray diffraction studies of the electron rich Ta[sub 1[minus]x]Ti[sub x]Te[sub 2] (x = 0.2, 0.3, 0.4 and 0.5) show that a statistical distortion of the CdI[sub 2] structure type has indeed occurred for these compounds confirming the theoretical calculations. Second Moment Scaled Hueckel theory was used to examine the basis of the Hume-Rothery phases are face centered cubic, hexagonal closest packed ([zeta], [epsilon] and [eta]-hcp),more » body centered cubic, [beta]-Mn and [gamma]-brass structures. Good agreement between the experimental and theoretically predicted electron concentration ranges was achieved when an s, p and contracted d orbital model was used. The results presented in this thesis were the first theoretical calculations that corroborate the entire set of Hume-Rothery electron concentration rules. Second Moment Scaled Hueckel energies were used for constructing structure maps for intermetallic compounds with stoichiometry ZA[sub 2], ZA[sub 3] and ZA[sub 6]. Calculations were performed only on the covalent network of the A atoms. The structure types considered were SmSb[sub 2], ZrSi[sub 2], Cu[sub 2]Sb, AuCu[sub 3], TiNi[sub 3], TiCu[sub 3], BiF[sub 3], SnNi[sub 3], NdTe[sub 3], TiS[sub 3], SmAu[sub 6], CeCu[sub 6] and PuGa[sub 6]. The bond distance variation found for closo-borohydrides B[sub 8]H[sub 8][sup 2[minus

An experimental and theoretical investigation on the optical and photocatalytic properties of ZnS nanoparticles

NASA Astrophysics Data System (ADS)

La Porta, F. A.; Nogueira, A. E.; Gracia, Lourdes; Pereira, W. S.; Botelho, G.; Mulinari, T. A.; Andrés, Juan; Longo, E.

2017-04-01

From the viewpoints of materials chemistry and physical chemistry, crystal structure directly determines the electronic structure and furthermore their optical and photocatalytic properties. Zinc sulfide (ZnS) nanoparticles (NPs) with tunable photoluminescence (PL) emission and high photocatalytic activity have been obtained by means of a microwave-assisted solvothermal (MAS) method using different precursors (i.e., zinc nitrate (ZN), zinc chloride (ZC), or zinc acetate (ZA)). The morphologies, optical properties, and electronic structures of the as-synthesized ZnS NPs were characterized by X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDX), Brunauer-Emmett-Teller (BET) isotherms for N2 adsorption/desorption processes, diffuse reflectance spectroscopy (DRS), PL measurements and theoretical calculations. Density functional theory calculations were used to determine the geometries and electronic properties of bulk wurtzite (WZ) ZnS NPs and their (0001), (101 ̅0), (112 ̅0), (101 ̅1), and (101 ̅2) surfaces. The dependence of the PL emission behavior of ZnS NPs on the precursor was elucidated by examining the energy band structure and density of states. The method for degradation of Rhodamine B (RhB) was used as a probe reaction to investigate the photocatalytic activity of the as-Synthesised ZnS NPs under UV light irradiation. The PL behavior as well as photocatalytic activities of ZnS NPs were attributed to specific features of the structural and electronic structures. Increased photocatalytic degradation was observed for samples synthesized using different precursors in the following order: ZAZA. Furthermore, the possible photodegradation mechanism of the as-prepared ZnS NPs were also briefly discussed.

Analyzing non-LTE Kr plasmas produced in high energy density experiments: from the Z machine to the National Ignition Facility

NASA Astrophysics Data System (ADS)

Dasgupta, Arati

2015-11-01

Designing high fluence photon sources above 10 keV are a challenge for High Energy Density plasmas. This has motivated radiation source development investigations of Kr with K-shell energies around 13 keV. Recent pulsed power driven gas-puff experiments on the refurbished Z machine at Sandia have produced intense X-rays in the multi-keV photon energy range. K-shell radiative yields and efficiencies are very high for Ar, but rapidly decrease for higher atomic number (ZA) elements such as Kr. It has been suggested that an optimum exists corresponding to a trade-off between the increase of photon energy for higher ZA elements and the corresponding fall off in radiative power. However the conversion efficiency on NIF, where the drive, energy deposition process, and target dynamics are different, does not fall off with higher ZA as rapidly as on Z. We have developed detailed atomic structure and collisional data for the full K-, L- and partial M-shell of Kr using the Flexible Atomic Code (FAC). Our non-LTE atomic model includes all collisional and recombination processes, including state-specific dielectronic recombination (DR), that significantly affect ionization balance and spectra of Kr plasmas at the temperatures and densities of concern. The model couples ionization physics, radiation production and transport, and magnetohydrodynamics. In this talk, I will give a detailed description of the model and discuss 1D Kr simulations employing a multifrequency radiation transport scheme. Synthetic K- and L-shell spectra will be compared with available experimental data. This talk will analyze experimental data indicative of the differences between Z and NIF experimental data and discuss how they affect the K-shell radiative output of Kr plasma. Work supported by DOE/NNSA.

Supportability in Aircraft Systems through Technology and Acquisition Strategy Applications.

DTIC Science & Technology

1987-09-01

structures is their corrosion resistance. These integral structures are water impregnable. Also, the absence of rivet and fastener hole eliminates the...REPCRT SECURITY CLASS,F,CAT ON lb RESTR;CTIVE MARK.NGSU",CLAS S I7 F 15E Za. SECURITY CLASSiFICAT;ON AUTHORITY 3 DISTRiBUTiQN/ AVAILABILIT ’ OF REPORT

75 FR 80073 - Reasonable Break Time for Nursing Mothers

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-21

... DEPARTMENT OF LABOR Wage and Hour Division RIN 1235-ZA00 Reasonable Break Time for Nursing Mothers... and a place for nursing mothers to express breast milk for one year after their child's birth. The... the break time for nursing mothers law. The break time requirement that is now part of the FLSA is set...

A Personnel Flow Model for Predicting the Coast Guard Enlisted Force Structure.

DTIC Science & Technology

1987-09-01

nd Reader Peter Purdue, Chairman Department of Operations Research -Kneale T. Marshal--7-. Dean of Information and Policy Scie ces O,, 2 ABSTRACT The...calls a proxy for economic variables mertion-ed ~rL~ b. Average age, 7-me --n Service, >-ne -ie This data was incomplete and no- Za~ecor:: zec ’I/ month

The myosin ID pathway and left-right asymmetry in Drosophila.

PubMed

Géminard, Charles; González-Morales, Nicanor; Coutelis, Jean-Baptiste; Noselli, Stéphane

2014-06-01

Drosophila is a classical model to study body patterning, however left-right (L/R) asymmetry had remained unexplored, until recently. The discovery of the conserved myosin ID gene as a major determinant of L/R asymmetry has revealed a novel L/R pathway involving the actin cytoskeleton and the adherens junction. In this process, the HOX gene Abdominal-B plays a major role through the control of myosin ID expression and therefore symmetry breaking. In this review, we present organs and markers showing L/R asymmetry in Drosophila and discuss our current understanding of the underlying molecular genetic mechanisms. Drosophila represents a valuable model system revealing novel strategies to establish L/R asymmetry in invertebrates and providing an evolutionary perspective to the problem of laterality in bilateria. © 2014 Wiley Periodicals, Inc.

New views on the neural crest epithelial-mesenchymal transition and neuroepithelial interkinetic nuclear migration

PubMed Central

Erickson, Carol A

2009-01-01

By developing a technique for imaging the avian neural crest epithelial-mesenchymal transition (EMT), we have discovered cellular behaviors that challenge current thinking on this important developmental event, including the probability that complete disassembly of the adherens junctions may not control whether or not a neural epithelial cell undergoes an EMT. Further, neural crest cells can adopt multiple modes of cell motility in order to emigrate from the neuroepithelium. We also gained insights into interkinetic nuclear migration (INM). For example, the movement of the nucleus from the basal to apical domain may not require microtubule motors nor an intact nuclear envelope, and the nucleus does not always need to reach the apical surface in order for cytokinesis to occur. These studies illustrate the value of live-cell imaging to elucidate cellular processes. PMID:20195454

A micropatterning approach for imaging Cx43 dynamic trafficking to cell-cell borders

PubMed Central

Zhang, Shan-Shan; Hong, SoonGweon; Kléber, André G.; Lee, Luke P.; Shaw, Robin M.

2014-01-01

The precise expression and timely delivery of connexin 43 (Cx43) proteins to form gap junctions are essential for electrical coupling of cardiomyocytes. Growing evidence supports a cytoskeletal-based trafficking paradigm for Cx43 delivery directly to adherens junctions at the intercalated disc. A limitation of Cx43 localization assays in cultured cells, in which cell-cell contacts are essential, is the inability to control for cell geometry or reproducibly generate contact points. Here we present a micropatterned cell pairing system well suited for live microscopy to examine how the microtubule and actin cytoskeleton confer specificity to Cx43 trafficking to precisely defined cell-cell junctions. This system can also be adapted for other cell types and used to study dynamic intracellular movements of other proteins important for cell-cell communication‥ PMID:24444605

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics.

PubMed

Hatzfeld, Mechthild; Keil, René; Magin, Thomas M

2017-06-01

Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome-keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Damping of acoustic flexural phonons in silicene: influence on high-field electronic transport

NASA Astrophysics Data System (ADS)

Rengel, Raúl; Iglesias, José M.; Mokhtar Hamham, El; Martín, María J.

2018-06-01

Silicene is a two-dimensional buckled material with broken horizontal mirror symmetry and Dirac-like dispersion. Under such conditions, flexural acoustic (ZA) phonons play a dominant role. Consequently, it is necessary to consider some suppression mechanism for electron–phonon interactions with long wavelengths in order to reach mobilities useful for electronic applications. In this work, we analyze, by means of an ensemble Monte Carlo simulator, the influence of several possibilities for the description of the effect of ZA phonon damping on electronic transport in silicene. The results show that a hard cutoff situation (total suppression for phonons with a wavelength longer than a critical one), as it has been proposed in the literature, does not yield a realistic picture regarding the electronic distribution function, and it artificially induces a negative differential resistance at moderate and high fields. Sub-parabolic dispersions, on the other hand, may provide a more realistic description in terms of the behavior of the electron distribution in the momentum space, but need extremely short cutoff wavelengths to reach functional mobility and drift velocity values.

Design Calculations 105’ MLW Structure East Coast Air Combat Maneuvering Range Offshore Kitty Hawk, North Carolina. Volume 1.

DTIC Science & Technology

1976-09-01

of C0 Ca 0 C2 00 ao C 00 CC C3C Q0 C. -f fta -i ft z CI, av CI" O am ame m m f m fmA ’am fu CIn I a l C l Al C l C l C "l C. C lo a D Ti C 5...i 11116 .~4 U-----------V V 3P*Pf .. - 3 F F II $~~Nc~A -1C) a - e v I F. 4.9 za A All - 3. tn 1f0 ow a :Fd ’m I-. m fu 11% 0 fmd fl Ml In -f 0. C...A l -,- 󈧋 - P e- 0 V.. :p ~ AE~ 0 Z 0 u ’ -A - f 1 va- ftA ’I za - .0J2 11 1 2- 0 S1 155wk3inP63 n!N VS 2iOiI 󈧎 -01L 41 1%3 c4 In . * g 11A sraC a

Reflectance-Based Sensor Validation Over Ice Surfaces

NASA Technical Reports Server (NTRS)

Jaross, Glen; Dodge, James C. (Technical Monitor)

2003-01-01

During this period work was performed in the following areas. These areas are defined in the Work Schedule presented in the original proposal: BRDF development, Data acquisition and processing, THR Table generation and Presentations and Publications. BRDF development involves creating and/or modifying a reflectance model of the Antarctic surface. This model must, for a temporal and spatial average, be representative of the East Antarctic plateau and be expressed in terms of the three standard surface angles: solar zenith angle (SolZA), view zenith angle (SatZA), and relative azimuth angle (RelAZ). We successfully acquired a limited amount of NOAA-9 AVHRR data for radiance validation. The data were obtained from the Laboratory for Terrestrial Physics at Goddard Space Flight Center. We developed our own reading and unpacking software, which we used to select Channel 1 data (visible). We then applied geographic subsetting criteria (same as used for TOMS), and wrote only the relevant data to packed binary files. We proceeded with analysis of these data, which is not yet complete.

Multi-component lanthanide hybrids based on zeolite A/L and zeolite A/L-polymers for tunable luminescence.

PubMed

Chen, Lei; Yan, Bing

2015-02-01

Some multi-component hybrids based on zeolite L/A are prepared. Firstly, zeolite A/L is loaded with lanthanide complexes (Eu-DBM or Tb-AA (acetylacetone = AA, dibenzoylmethane = DBM)) into its channels. Secondly, 3-methacryloyloxypropyltrimethoxysilane (γ-MPS) is used to covalently graft onto the surface of functionalized zeolite A/L (Si-[ZA/L⊃Eu-DBM(Tb-AA)]). Thirdly, lanthanide ions (Eu(3+)/Tb(3+)) are coordinated to the functionalized zeolite A/L and ligands (phen(1,10-phenanthroline) or bipy (2,2'-bipyridyl)) are introduced by a ship-in-bottle method. The inside-outside double modifications of ZA/L with lanthanide complexes afford the final hybrids and these are characterized by means of XRD, FT-IR, UV-vis DRS, SEM and luminescence spectroscopy, some of which display white or near-white light emission. Furthermore, selected above-mentioned hybrids are incorporated into PEMA/PMMA (poly ethyl methylacryate/poly methyl methacrylate) hosts to prepare luminescent polymer films. These results provide abundant data that these hybrid materials can be expected to have potential application in various practical fields.

Dollar Summary of Federal Supply Classification and Service Category by Company. Part 7 (6650-9999)

DTIC Science & Technology

1991-01-01

WI WI Cw-E I 1 W ~ 1 IV) 0 - 4 1 - U 4 1 -4 L 1 . . . .4 L tun W-1 1 .4 C 0 4 1 I- *4 C 0) - 0 0 0 C 0 1 1-1 1C 1 - 1 4 1) 0 I-.4 f C ~ 4~. a (𔃾 I I...wA 01w1w Ij TL Ia cc 0 0 0 0 0 0 0 000 CL 0 0 0 0 0 (A 1- 0 L0 0- a - " C i C w 0) CA Za- CL. a > (n.> z->) > wa w w zA Zaw 0 -J 2 Zi 0 " x00 0 Z 1...82174𔃺 0 mI D’ 2 C 0 <I I 0C 0 aU C 4~ ~ X% x- 0 x- C .I . .I . MI 4 .0E 01 . . 0 m IlIE 1 .4 𔃾𔃾 0 - C E - 1’ . U - . tun MO) 0 - 11 - 0 1244-0> 0 U C

Mermin-Wagner theorem, flexural modes, and degraded carrier mobility in two-dimensional crystals with broken horizontal mirror symmetry

NASA Astrophysics Data System (ADS)

Fischetti, Massimo V.; Vandenberghe, William G.

2016-04-01

We show that the electron mobility in ideal, free-standing two-dimensional "buckled" crystals with broken horizontal mirror (σh) symmetry and Dirac-like dispersion (such as silicene and germanene) is dramatically affected by scattering with the acoustic flexural modes (ZA phonons). This is caused both by the broken σh symmetry and by the diverging number of long-wavelength ZA phonons, consistent with the Mermin-Wagner theorem. Non-σh-symmetric, "gapped" 2D crystals (such as semiconducting transition-metal dichalcogenides with a tetragonal crystal structure) are affected less severely by the broken σh symmetry, but equally seriously by the large population of the acoustic flexural modes. We speculate that reasonable long-wavelength cutoffs needed to stabilize the structure (finite sample size, grain size, wrinkles, defects) or the anharmonic coupling between flexural and in-plane acoustic modes (shown to be effective in mirror-symmetric crystals, like free-standing graphene) may not be sufficient to raise the electron mobility to satisfactory values. Additional effects (such as clamping and phonon stiffening by the substrate and/or gate insulator) may be required.

An investigation of the properties of Mg-Zn-Al alloys

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

Zhang, Z.; Couture, A.; Luo, A.

1998-06-05

During the past ten years, the use of magnesium castings in the automotive and electronics industries has been expanding at an impressive rate. Die casting is one of the most effective fabrication methods and has been extensively used to produce magnesium components, especially in the automotive industry. However, the number of available Mg-based alloys for die casting is very limited. Therefore, it is pressing to develop some new Mg die casting alloys with good creep resistance, acceptable castability and low cost. Mg-Zn-Al (ZA) is a promising alloy system which is able to meet the requirements. But up to now, onlymore » a small amount of research has been carried out on this system. The aim of the present work is to examine and evaluate the microstructural features, tensile properties and creep resistance in order to get a better overall understanding of alloys of this system and to identify the most promising compositions. The influence of small additions of Ca and Sr on the tensile and creep properties of ZA alloys was also investigated.« less

The convergence of complete active space self-consistent-field configuration interaction including all single and double excitation energies to the complete basis set limit

NASA Astrophysics Data System (ADS)

Petersson, George A.; Malick, David K.; Frisch, Michael J.; Braunstein, Matthew

2006-07-01

Examination of the convergence of full valence complete active space self-consistent-field configuration interaction including all single and double excitation (CASSCF-CISD) energies with expansion of the one-electron basis set reveals a pattern very similar to the convergence of single determinant energies. Calculations on the lowest four singlet states and the lowest four triplet states of N2 with the sequence of n-tuple-ζ augmented polarized (nZaP) basis sets (n =2, 3, 4, 5, and 6) are used to establish the complete basis set limits. Full configuration-interaction (CI) and core electron contributions must be included for very accurate potential energy surfaces. However, a simple extrapolation scheme that has no adjustable parameters and requires nothing more demanding than CAS(10e -,8orb)-CISD/3ZaP calculations gives the Re, ωe, ωeXe, Te, and De for these eight states with rms errors of 0.0006Å, 4.43cm-1, 0.35cm-1, 0.063eV, and 0.018eV, respectively.

Pre_GI: a global map of ontological links between horizontally transferred genomic islands in bacterial and archaeal genomes

PubMed Central

Pierneef, Rian; Cronje, Louis; Bezuidt, Oliver; Reva, Oleg N.

2015-01-01

Abstract The Predicted Genomic Islands database (Pre_GI) is a comprehensive repository of prokaryotic genomic islands (islands, GIs) freely accessible at http://pregi.bi.up.ac.za/index.php . Pre_GI, Version 2015, catalogues 26 744 islands identified in 2407 bacterial/archaeal chromosomes and plasmids. It provides an easy-to-use interface which allows users the ability to query against the database with a variety of fields, parameters and associations. Pre_GI is constructed to be a web-resource for the analysis of ontological roads between islands and cartographic analysis of the global fluxes of mobile genetic elements through bacterial and archaeal taxonomic borders. Comparison of newly identified islands against Pre_GI presents an alternative avenue to identify their ontology, origin and relative time of acquisition. Pre_GI aims to aid research on horizontal transfer events and materials through providing data and tools for holistic investigation of migration of genes through ecological niches and taxonomic boundaries. Database URL: http://pregi.bi.up.ac.za/index.php , Version 2015 PMID:26200753

An Empirical Analysis of the Navy Junior Reserve Officer Training Corps (NJROTC)

DTIC Science & Technology

1987-12-01

o_ _ion For NTIS GRA&I DTIC TAB 0 Ula•ncnmwood [] , ,, Juutiriou~iozl Dis !tribution/ Availability (,’ odk 3 Alra .taI / Diat ~~za V. TABLE OF CONTENTS...followingq: I. The overall total 2. The row totals 3. The column totals "Supertables" were also extensively used. A supertable is essentially a collection

T Cell Responses to Arenavirus Infections.

DTIC Science & Technology

1991-11-01

CLASSIFICATION OF THIS PAGE Form AAmWved REPORT DOCUMENTATION PAGE OMB No.O 70O1U ts. REPORT SECURITY CLASSIFICATION lb. RESTRICTIVE MARKINGS Unclassified Za...1991. J. Virol. 65.3001-3006. 23. Ahmed, R., L. D., Butler, and L. Bhatti. 1988. J. Virol. 62: 21 02-21 06. 24. Moskophidis 0, S. P. Cobbold , H. Waldmann

Corrections to hyperfine splitting and Lamb shift induced by diagrams with second order radiative insertions in the electron line

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

Eides, M.I.; Karshenboim, S.G.; Shelyuto, V.A.

1994-12-31

Contributions to HFS and to the Lamb shift intervals of order a{sup 2}(Za){sup 5} induced by gauge invariant set of nineteen topologically different graphs with two radiative photons inserted in the electron line are considered. Corrections both to HFS and Lamb shift induced by nine diagrams are calculated in the Fried-Yennie gauge.

Effect of resveratrol and zinc on intracellular zinc status in normal human prostate epithelial cells

USDA-ARS?s Scientific Manuscript database

To evaluate the influence of resveratrol on cellular zinc status, normal human prostate epithelial (NHPrE) cells were treated with 6 levels of resveratrol (0, 0.5, 1, 2.5, 5 and 10 microM) and 4 levels of zinc [0, 4, 16, and 32 microM for zinc-deficient (ZD), zinc-normal (ZN), zinc-adequate (ZA), an...

76 FR 14679 - Prevailing Wage Rates for Construction Occupations on Guam for Purposes of the H-2B Temporary...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-17

...)(v)(E) and (F). If the prevailing wage rate is too low, available U.S. workers may be dissuaded from... Docket No. USCIS-2010-0006] RIN 1615-ZA98 Prevailing Wage Rates for Construction Occupations on Guam for... the public on the system that the Governor of Guam is using to determine prevailing wage rates for...

Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins.

PubMed

Cohen, Clemens D; Klingenhoff, Andreas; Boucherot, Anissa; Nitsche, Almut; Henger, Anna; Brunner, Bodo; Schmid, Holger; Merkle, Monika; Saleem, Moin A; Koller, Klaus-Peter; Werner, Thomas; Gröne, Hermann-Josef; Nelson, Peter J; Kretzler, Matthias

2006-04-11

Shared transcription factor binding sites that are conserved in distance and orientation help control the expression of gene products that act together in the same biological context. New bioinformatics approaches allow the rapid characterization of shared promoter structures and can be used to find novel interacting molecules. Here, these principles are demonstrated by using molecules linked to the unique functional unit of the glomerular slit diaphragm. An evolutionarily conserved promoter model was generated by comparative genomics in the proximal promoter regions of the slit diaphragm-associated molecule nephrin. Phylogenetic promoter fingerprints of known elements of the slit diaphragm complex identified the nephrin model in the promoter region of zonula occludens-1 (ZO-1). Genome-wide scans using this promoter model effectively predicted a previously unrecognized slit diaphragm molecule, cadherin-5. Nephrin, ZO-1, and cadherin-5 mRNA showed stringent coexpression across a diverse set of human glomerular diseases. Comparative promoter analysis can identify regulatory pathways at work in tissue homeostasis and disease processes.

Wind-blown sand movement periods on the Nyírség alluvial fan, Hungary

NASA Astrophysics Data System (ADS)

Buró, Botond; Lóki, József; Sipos, György; Négyesi, Gábor; Andrási, Bence; Jakab, Attila; Félegyházi, Enikő; Molnár, Mihály

2017-04-01

Wind-blown sand movement periods on the Nyírség alluvial fan, Hungary The Nyírség is an alluvial fan, was built by rivers, which were flown down from the NE Carpathians. When the weather was dry, wind-blown sand was blowed out and the wind started to develop the aeolian landforms. The first significant sand movements in the Nyírség was in the Upper plenniglacial and the Late glacial. The main landforms of the Nyírség were developed at this time. The aeolic transformation of the land was not completed in the Nyírség at the end of the Pleistocene. In the Holocene the sand moved within small area, mainly by anthropogenic impact. Our aim is clarify the age of the wind-blown sand movements period, with different absolute (Radiocarbon dating method, OSL), and relative (Archaeological finds, Pollen analyses) dating methods. We have collected for the age determining charcoal from many sand quarry (Gégény, Kántorjánosi, Nyíradony, Nagyvarsány, Máriapócs and Lövőpetri) which contain fossil soil layer. For the OSL measurements samples were collected from Baktalórántháza, Gégény and Kántorjánosi sand quarries. We collected samples from 5 places for the pollen analyses (Nyírtanya, Máriapócs, Nyírbéltek-Nyírlúgos, Nyírábrány, Vámospércs), and also from an archaeological excavation (Nyíregyháza- Oros). The new age dates show us, that in the Nyírség the first significant sand movements were in the cold and drier period of the Upper pleniglacial and Late glacial (Baktalórántháza, Nyírtanya, Vámospércs). At the end of the Pleistocene the sand movements not competed in the Nyírség (Gégény, Kántorjánosi, Nyírábrány). In the Holocene there were many little sand movement periods, mainly caused by anthropogenic impact (Nyíradony, Nyíregyháza-Oros). The research was supported by the European Union and the State of Hungary, co-financed by the European Regional Development Fund in the project of GINOP-2.3.2.-15-2016-00009 'ICER

N2O and N2 emissions from contrasting soil environments - interactive effects of soil nitrogen, hydrology and microbial communities

NASA Astrophysics Data System (ADS)

Christiansen, Jesper; Elberling, Bo; Ribbons, Relena; Hedo, Javier; José Fernández Alonso, Maria; Krych, Lukasz; Sandris Nielsen, Dennis; Kitzler, Barbara

2016-04-01

Reactive nitrogen (N) in the environment has doubled relative to the natural global N cycle with consequences for biogeochemical cycling of soil N. Also, climate change is expected to alter precipitation patterns and increase soil temperatures which in Arctic environments may accelerate permafrost thawing. The combination of changes in the soil N cycle and hydrological regimes may alter microbial transformations of soil N with unknown impacts on N2O and N2 emissions from temperate and Arctic soils. We present the first results of soil N2O and N2 emissions, chemistry and microbial communities over soil hydrological gradients (upslope, intermediate and wet) across a global N deposition gradient. The global gradient covered an N-limited high Arctic tundra (Zackenberg-ZA), a pacific temperate rain forest (Vancouver Island-VI) and an N saturated forest in Austria (Klausenleopoldsdorf-KL). The N2O and N2 emissions were measured from intact cores at field moisture in a He-atmosphere system. Extractable NH4+ and NO3-, organic and microbial C and N and potential enzyme-activities were determined on soil samples. Soil genomic DNA was subjected to MiSeq-based tag-encoded 16S rRNA and ITS gene amplicon sequencing for the bacterial and fungal community structure. Similar soil moisture levels were observed for the upslope, intermediate and wet locations at ZA, VI and KL, respectively. Extractable NO3- was highest at the N rich KL and lowest at ZA and showed no trend with soil moisture similar to NH4+. At ZA and VI soil NH4+ was higher than NO3- indicating a tighter N cycling. N2O emissions increased with soil moisture at all sites. The N2O emissions for the wet locations ranked similarly to NO3- with the largest response to soil moisture at KL. N2 emissions were remarkably similar across the sites and increased with soil wetness. Microbial C and N also increased with soil moisture and were overall lowest at the N rich KL site. The potential activity of protease enzyme was site

Leading logarithmic corrections to the muonium hyperfine splitting and to the hydrogen Lamb shift

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

Karshenboim, S.G.

1994-12-31

Main leading corrections with recoil logarithm log(M/m) and low-energy logarithm log(Za) to the Muonium hyperfine splitting axe discussed. Logarithmic corrections have magnitudes of 0.1 {divided_by} 0.3 kHz. Non-leading higher order corrections axe expected to be not larger than 0.1 kHz. Leading logarithmic correction to the Hydrogen Lamb shift is also obtained.

The Role of Sequence Markers on Reading and Recall: A Comparison of Native and Nonnative English Speakers

DTIC Science & Technology

1988-12-15

ORGANIZATION PEPOPT NVBER S; 6a E O c PEPFC=V’NG CPC;% ZA " ON 6o OrFiCE SYMBOL 7a NAME OF MONITORING ORGANZA - ON 0 University of Califor-ia (If appi cable...readers. Experimental Aging Research, 7, 253-268. McLeod, B., & McLaughlin, B. (1986). Restructuring or automatization? Reading in a second language

Shear stress and the endothelial transport barrier.

PubMed

Tarbell, John M

2010-07-15

The shear stress of flowing blood on the surfaces of endothelial cells that provide the barrier to transport of solutes and water between blood and the underlying tissue modulates the permeability to solutes and the hydraulic conductivity. This review begins with a discussion of transport pathways across the endothelium and then considers the experimental evidence from both in vivo and in vitro studies that shows an influence of shear stress on endothelial transport properties after both acute (minutes to hours) and chronic (hours to days) changes in shear stress. Next, the effects of shear stress on individual transport pathways (tight junctions, adherens junctions, vesicles and leaky junctions) are described, and this information is integrated with the transport experiments to suggest mechanisms controlling both acute and chronic responses of transport properties to shear stress. The review ends with a summary of future research challenges.

The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells

PubMed Central

Shields, Alicia R.; Spence, Allyson C.; Yamashita, Yukiko M.; Davies, Erin L.; Fuller, Margaret T.

2014-01-01

Specialized microenvironments, or niches, provide signaling cues that regulate stem cell behavior. In the Drosophila testis, the JAK-STAT signaling pathway regulates germline stem cell (GSC) attachment to the apical hub and somatic cyst stem cell (CySC) identity. Here, we demonstrate that chickadee, the Drosophila gene that encodes profilin, is required cell autonomously to maintain GSCs, possibly facilitating localization or maintenance of E-cadherin to the GSC-hub cell interface. Germline specific overexpression of Adenomatous Polyposis Coli 2 (APC2) rescued GSC loss in chic hypomorphs, suggesting an additive role of APC2 and F-actin in maintaining the adherens junctions that anchor GSCs to the niche. In addition, loss of chic function in the soma resulted in failure of somatic cyst cells to maintain germ cell enclosure and overproliferation of transit-amplifying spermatogonia. PMID:24346697

Spin-Polarization in Quasi-Magnetic Tunnel Junctions

NASA Astrophysics Data System (ADS)

Xie, Zheng-Wei; Li, Ling

2017-05-01

Spin polarization in ferromagnetic metal/insulator/spin-filter barrier/nonmagnetic metal, referred to as quasi-magnetic tunnel junctions, is studied within the free-electron model. Our results show that large positive or negative spin-polarization can be obtained at high bias in quasi-magnetic tunnel junctions, and within large bias variation regions, the degree of spin-polarization can be linearly tuned by bias. These linear variation regions of spin-polarization with bias are influenced by the barrier thicknesses, barrier heights and molecular fields in the spin-filter (SF) layer. Among them, the variations of thickness and heights of the insulating and SF barrier layers have influence on the value of spin-polarization and the linear variation regions of spin-polarization with bias. However, the variations of molecular field in the SF layer only have influence on the values of the spin-polarization and the influences on the linear variation regions of spin-polarization with bias are slight. Supported by the Key Natural Science Fund of Sichuan Province Education Department under Grant Nos 13ZA0149 and 16ZA0047, and the Construction Plan for Scientific Research Innovation Team of Universities in Sichuan Province under Grant No 12TD008.

Constitutive Equations and ANN Approach to Predict the Flow Stress of Ti-6Al-4V Alloy Based on ABI Tests

NASA Astrophysics Data System (ADS)

Wang, Fuzeng; Zhao, Jun; Zhu, Ningbo

2016-11-01

The flow behavior of Ti-6Al-4V alloy was studied by automated ball indentation (ABI) tests in a wide range of temperatures (293, 493, 693, and 873 K) and strain rates (10-6, 10-5, and 10-4 s-1). Based on the experimental true stress-plastic strain data derived from the ABI tests, the Johnson-Cook (JC), Khan-Huang-Liang (KHL) and modified Zerilli-Armstrong (ZA) constitutive models, as well as artificial neural network (ANN) methods, were employed to predict the flow behavior of Ti-6Al-4V. A comparative study was made on the reliability of the four models, and their predictability was evaluated in terms of correlation coefficient ( R) and mean absolute percentage error. It is found that the flow stresses of Ti-6Al-4V alloy are more sensitive to temperature than strain rate under current experimental conditions. The predicted flow stresses obtained from JC model and KHL model show much better agreement with the experimental results than modified ZA model. Moreover, the ANN model is much more efficient and shows a higher accuracy in predicting the flow behavior of Ti-6Al-4V alloy than the constitutive equations.

The ultraviolet dayglow at solar maximum. 1 - Far UV spectroscopy at 3.5 A resolution

NASA Technical Reports Server (NTRS)

Eastes, R. W.; Feldman, P. D.; Gentieu, E. P.; Christensen, A. B.

1985-01-01

The earth's far ultraviolet dayglow (1080-1515 A) was observed at about 3.5 A resolution during a period of high solar activity near solar maximum om June 27, 1980. The observations were made at local noon by rocket-borne spectrometers viewing toward the earth's northern limb at 90 deg zenith angle (ZA) at altitudes between 100 and 245 km, and at 98 deg ZA between 245 and 260 km. The zenith angle was 8.9 deg. These spectra are compared with earlier lower-resolution dayglow data obtained during a period of lower solar activity and with auroral spectra. The brightness ratio of O I 1356 to the N2 Lyman-Birge-Hopfield (LBH) system, an indicator of the O to N2 density ratio, is lower than that previously measured at mid-latitudes and closer to the value found in aurorae. In the LBH system a depletion of the bands originating on the v-prime = 3 vibrational level of the excited state is found. Some weak N2 Birge-Hopfield bands and N I lines only marginally detected previously in the dayglow are confirmed.

Catadioptric lenses in Visible Light Communications

NASA Astrophysics Data System (ADS)

Garcia-Marquez, J.; Valencia, J. C.; Perez, H.; Topsu, S.

2015-04-01

Since few years ago, visible light communications (VLC) have experience an accelerated interest from a research point of view. The beginning of this decade has seen many improvements in VLC at an electronic level. High rates of transmission at low bit error ratios (BER) have been reported. A few numbers of start-ups have initiated activities to offer a variety of applications ranging from indoor geo-localization to internet, but in spite of these advancements, some other problems arise. Long-range transmissions mean a high BER which reduce the number of applications. In this sense, new redesigned optical collectors or in some cases, optical reflectors must be considered to ensure a low BER at higher distance transmissions. Here we also expose a preliminary design of a catadioptric and monolithical lens for a LI-FI receiver with two rotationally symmetrical main piecewise surfaces za and zb. These surfaces are represented in a system of cylindrical coordinates with an anterior surface za with a central and refractive sector surrounded by a peripheral reflective sector and a back piecewise surface zb with a central refractive sector and a reflective sector, both characterized as ideal for capturing light within large acceptance angles.

Indicated Prevention of Fetal Alcohol Spectrum Disorders in South Africa: Effectiveness of Case Management

PubMed Central

de Vries, Marlene M.; Joubert, Belinda; Cloete, Marise; Roux, Sumien; Baca, Beth A.; Hasken, Julie M.; Barnard, Ronel; Buckley, David; Kalberg, Wendy O.; Snell, Cudore L.; Marais, Anna-Susan; Seedat, Soraya; Parry, Charles D. H.; May, Philip A.

2015-01-01

In the Western Cape Province of South Africa (ZA) a subculture of binge drinking produces the highest global documented prevalence of fetal alcohol spectrum disorders (FASD). FASD prevention research activities in ZA use the Comprehensive Prevention approach from the United States Institute of Medicine. Case management (CM) was delivered as a method of indicated prevention to empower heavy drinking pregnant women to achieve cessation or a reduction in drinking. CM activities incorporated life management, Motivational Interviewing (MI) techniques and the Community Reinforcement Approach (CRA). Data were collected at baseline, 6, 12 and 18 months. Mean drinking decreases 6 months into CM; but overall alcohol consumption rose significantly over time to levels higher than baseline at 12 and 18 months. Alcohol consumption drops significantly from before pregnancy to the second and third trimesters. AUDIT scores indicate that problematic drinking decreases significantly even after the vulnerable fetus/baby was born. CM significantly increases client happiness, which correlates with reduced weekend drinking. CM was successful for women with high-risk drinking behaviour, and was effective in helping women stop drinking, or drink less, while pregnant, reducing the risk of FASD. PMID:26703708

Enhancement of Plant Establishment on Dredged Material Sites with Mycorrhizal Fungi and Clay Amendments

DTIC Science & Technology

1989-10-01

montmorillonite enhanced the growth of smooth brome grass. Topsoil, the clays attapulgite and kaolinite , and the commercial products Agrosoke anj Stawetwere...clays bentonite, attapulgite, kaolinite , and montmorillonite . Trade name and company addresses for the clays are listed in Table 1. Agrosoke and Stawet...desertcoZa, G. etunicatwn, and G. intraradice8. The clays attapulgite, ben- tonite, kaclinite,/and montmorillonite from various commercial sources were

USSR Report, Political and Sociological Affairs, No. 1437.

DTIC Science & Technology

1983-08-02

to Christian Jaak Peterson, the first Estonian lyric poet, now stands in old Vyshgorod, under the ancient lindens and oaks. Estonian poetry began...world. I. R. Grigulevich has also devoted many articles, surveys, and essays to the activity of the Catho- lic Church. These works examine such...issledovaniya za rubezhom. Kritiches- kiye ocherki" /Ethnological Studies Abroad: Critical Essays /, Moscow, 1973; "Kontseptsii zarubezhnoy etnografii

Impact properties of zinc die cast alloys

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

Schrems, Karol K.; Dogan, Omer N.; Manahan, M.P.

2005-01-01

Alloys 3, 5, AcuZinc 5, and ZA-8 were tested at five temperatures between -40 C and room temperature to determine impact properties. Izod impact energy data was obtained in accordance with ASTM D256. Unlike ASTM E23, these samples were tested with a milled notch in order to compare with plastic samples. In addition, flexural data was obtained for design use.

Biaxial tensile strain tuned up-and-down behavior on lattice thermal conductivity in β-AsP monolayer

NASA Astrophysics Data System (ADS)

Guo, San-Dong; Dong, Jun

2018-07-01

Various two-dimensional (2D) materials with a graphene-like buckled structure have emerged, and the β-phase AsP monolayer has been recently proposed to be thermodynamically stable from first-principles calculations. The studies of thermal transport are very useful for these 2D materials-based nano-electronics devices. Motivated by this, a comparative study of strain-dependent phonon transport of AsP monolayers is performed by solving the linearized phonon Boltzmann equation within the single-mode relaxation time approximation (RTA). It is found that the lattice thermal conductivity () of the AsP monolayer is very close to the one of As monolayer with a similar buckled structure, which is due to neutralization between the reduction of phonon lifetimes and group velocity enhancement from As to AsP monolayer. The corresponding room-temperature sheet thermal conductance of AsP monolayer is 152.5 . It is noted that the increasing tensile strain can harden a long wavelength out-of-plane (ZA) acoustic mode, and soften the in-plane longitudinal acoustic (LA) and transversal acoustic (TA) modes. Calculated results show that of AsP monolayer presents a nonmonotonic up-and-down behavior with increased strain. The unusual strain dependence is due to the competition among the reduction of phonon group velocities, improved phonon lifetimes of ZA mode and nonmonotonic up-and-down phonon lifetimes of TA/LA mode. It is found that acoustic branches dominate the in the considered strain range, and the contribution from ZA branch increases with increased strain, while it is opposite for TA/LA branch. By analyzing cumulative with respect to phonon mean free path, tensile strain can modulate effectively the size effects on in the AsP monolayer. Our work enriches the studies of thermal transports of 2D materials with graphene-like buckled structures, and strengthens the idea to engineer thermal transport properties by simple mechanical strain, and stimulates further experimental works

Corrosion resistance of alumina forming alloys against molten chlorides for energy production. II: Electrochemical impedance spectroscopy under thermal cycling conditions

DOE PAGES

Gomez-Vidal, Judith C.; Fernandez, A. G.; Tirawat, R.; ...

2017-04-01

Next-generation power systems require higher temperatures to increase the efficiency of electricity production in the power block. Concentrating solar power (CSP) technology is looking for high temperature thermal fluids able to work in the range of 550–750 °C. Molten chlorides containing NaCl, KCl, MgCl 2, and/or ZnCl 2 are being considered for solar receivers and/or sensible- or latent- thermal energy storage systems. Vapor pressures of chlorides are high enough that in combination with oxygen gaseous compounds will produce a harsh atmosphere that is generally very aggressive to common chromia forming alloys. Corrosion mitigations must consider a solution in which bothmore » zones (immersed in fluid and exposed to vapor phase) will be protected. This could easily be obtained using alloy surface modification approaches. Surface passivation, produced after pre-oxidation treatments, of alumina forming alloys (Inconel 702, Haynes 224 and Kanthal APMT) was evaluated in molten 35.59 wt% MgCl2 – 64.41 wt% KCl thermally cycled from 550 °C to 700 °C in flowing Ar and static zero air (ZA) atmospheres. Electrochemical impedance spectroscopy tests and metallographic characterization showed that the best performing alloy was pre-oxidized In702 in ZA at 1050 °C for 4 h due to the formation of protective, dense and continuous alumina layers. The alumina layers were unstable when flowing Ar was used as the inert atmosphere during corrosion evaluations. Corrosion results in static ZA are promising for next-generation CSP applications using molten chlorides because alumina scales were stable after 185 h of immersion in the oxygen-containing atmosphere. Alumina layers in pre-oxidized Al-FA In702 grew from 5 µm (before immersion) to 13 µm (after 185 h of immersion). As a result, the use of these alloys could be commercial feasibility and cost-effective because of the possibility of using oxygen-containing atmospheres instead of keeping enclosed systems with inert

Corrosion resistance of alumina forming alloys against molten chlorides for energy production. II: Electrochemical impedance spectroscopy under thermal cycling conditions

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

Gomez-Vidal, Judith C.; Fernandez, A. G.; Tirawat, R.

Next-generation power systems require higher temperatures to increase the efficiency of electricity production in the power block. Concentrating solar power (CSP) technology is looking for high temperature thermal fluids able to work in the range of 550–750 °C. Molten chlorides containing NaCl, KCl, MgCl 2, and/or ZnCl 2 are being considered for solar receivers and/or sensible- or latent- thermal energy storage systems. Vapor pressures of chlorides are high enough that in combination with oxygen gaseous compounds will produce a harsh atmosphere that is generally very aggressive to common chromia forming alloys. Corrosion mitigations must consider a solution in which bothmore » zones (immersed in fluid and exposed to vapor phase) will be protected. This could easily be obtained using alloy surface modification approaches. Surface passivation, produced after pre-oxidation treatments, of alumina forming alloys (Inconel 702, Haynes 224 and Kanthal APMT) was evaluated in molten 35.59 wt% MgCl2 – 64.41 wt% KCl thermally cycled from 550 °C to 700 °C in flowing Ar and static zero air (ZA) atmospheres. Electrochemical impedance spectroscopy tests and metallographic characterization showed that the best performing alloy was pre-oxidized In702 in ZA at 1050 °C for 4 h due to the formation of protective, dense and continuous alumina layers. The alumina layers were unstable when flowing Ar was used as the inert atmosphere during corrosion evaluations. Corrosion results in static ZA are promising for next-generation CSP applications using molten chlorides because alumina scales were stable after 185 h of immersion in the oxygen-containing atmosphere. Alumina layers in pre-oxidized Al-FA In702 grew from 5 µm (before immersion) to 13 µm (after 185 h of immersion). As a result, the use of these alloys could be commercial feasibility and cost-effective because of the possibility of using oxygen-containing atmospheres instead of keeping enclosed systems with inert