YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

PubMed Central

He, Chunbo; Lv, Xiangmin; Hua, Guohua; Lele, Subodh M; Remmenga, Steven; Dong, Jixin; Davis, John S; Wang, Cheng

2014-01-01

Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces expression of EGF receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, while knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression. PMID:25798835

Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle

NASA Technical Reports Server (NTRS)

Adams, Gregory R.

2002-01-01

Similar to bone, skeletal muscle responds and adapts to changes in loading state via mechanisms that appear to be intrinsic to the muscle. One of the mechanisms modulating skeletal muscle adaptation it thought to involve the autocrine and/or paracrine production of insulinlike growth factor-I. This brief review outlines components of the insulinlike growth factor-I system as it relates to skeletal muscle and provides the rationale for the theory that insulinlike growth factor-I is involved with muscle adaptation.

Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation

PubMed Central

Song, Jianwen; Guan, Ming; Zhao, Zhenwen; Zhang, Junjie

2015-01-01

Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation. PMID:26313906

PGE2 is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation

PubMed Central

Starner, Renny J.; McClelland, Lindy; Abdel-Malek, Zalfa; Fricke, Alex; Scott, Glynis

2013-01-01

Melanocyte proliferation, dendrite formation, and pigmentation are controlled by paracrine factors, particularly following exposure to ultraviolet radiation (UVR). Little is known about autocrine factors for melanocytes. Prostaglandins activate signaling pathways involved in growth, differentiation and apoptosis. Prostaglandin E2 (PGE2) is the most abundant prostaglandin released by keratinocytes following UVR, and stimulates the formation of dendrites in melanocytes. Synthesis of PGE2 is controlled by cPLA2, which releases arachidonic acid from membranes, and COX-2 and prostaglandin E2 synthases (PGES), which convert arachidonic acid to PGH2 and PGH2 to PGE2, respectively. In this report we show that multiple irradiations of human melanocytes with UVR stimulates tyrosinase activity, independent of expression of a functional melanocortin 1 receptor, suggesting the presence of a non-melanocortin autocrine factor. Irradiation of melanocytes activated cPLA2, the rate-limiting step in eicosanoid synthesis, and stimulated PGE2 secretion. PGE2 increased cAMP production, tyrosinase activity and proliferation in melanocytes. PGE2 binds to four distinct G-protein coupled receptors (EP1–4). We show that EP4 receptor signaling stimulates cAMP production in melanocytes. Conversely, stimulation of the EP3 receptor lowered basal cAMP levels. These data suggest that relative levels or activity of these receptors controls effects of PGE2 on cAMP in melanocytes. The data are the first to identify PGE2 as an UVR-inducible autocrine factor for melanocytes that stimulates tyrosinase activity and proliferation, and to show that EP3 and EP4 receptor signaling have opposing effects on cAMP production, a critical signaling pathway that regulates proliferation and melanogenesis in melanocytes. PMID:20500768

Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo

PubMed Central

Zhou, Zhen Ni; Sharma, Ved P.; Beaty, Brian T.; Roh-Johnson, Minna; Peterson, Esther A.; Van Rooijen, Nico; Kenny, Paraic A.; Wiley, H. Steven; Condeelis, John S.; Segall, Jeffrey E.

2013-01-01

Increased expression of HBEGF in ER negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulating macrophages through the secretion of CSF-1 while the tumor associated macrophages (TAMs) in turn aid in tumor cell invasion by secreting EGF. To determine how the autocrine expression of EGFR ligands by carcinoma cells would affect this paracrine loop mechanism, and in particular whether tumor cell invasion depends on spatial ligand gradients generated by TAMs, we generated cell lines with increased HBEGF expression. We find that autocrine HBEGF expression enhanced in vivo intravasation and metastasis, and resulted in a novel phenomenon in which macrophages were no longer required for in vivo invasion of breast cancer cells. In vitro studies revealed that expression of HBEGF enhanced invadopodium formation, thus providing a mechanism for cell autonomous invasion. The increased invadopodium formation was directly dependent on EGFR signaling, as demonstrated by a rapid decrease in invadopodia upon inhibition of autocrine HBEGF/EGFR signaling as well as inhibition of signaling downstream of EGFR activation. HBEGF expression also resulted in enhanced invadopodium function via upregulation of MMP2 and MMP9 expression. We conclude that high levels of HBEGF expression can short-circuit the tumor cell/macrophage paracrine invasion loop, resulting in enhanced tumor invasion that is independent of macrophage signaling. PMID:24013225

An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart

PubMed Central

Park, Eon Joo; Watanabe, Yusuke; Smyth, Graham; Miyagawa-Tomita, Sachiko; Meyers, Erik; Klingensmith, John; Camenisch, Todd; Buckingham, Margaret; Moon, Anne M.

2009-01-01

In order to understand how secreted signals regulate complex morphogenetic events, it is crucial to identify their cellular targets. By conditional inactivation of Fgfr1 and Fgfr2 and overexpression of the FGF antagonist sprouty 2 in different cell types, we have dissected the role of FGF signaling during heart outflow tract development in mouse. Contrary to expectation, cardiac neural crest and endothelial cells are not primary paracrine targets. FGF signaling within second heart field mesoderm is required for remodeling of the outflow tract: when disrupted, outflow myocardium fails to produce extracellular matrix and TGFβ and BMP signals essential for endothelial cell transformation and invasion of cardiac neural crest. We conclude that an autocrine regulatory loop, initiated by the reception of FGF signals by the mesoderm, regulates correct morphogenesis at the arterial pole of the heart. These findings provide new insight into how FGF signaling regulates context-dependent cellular responses during development. PMID:18832392

A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

PubMed

Fernández, S; Genis, L; Torres-Alemán, I

2014-08-07

Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells.

PubMed Central

Shamah, S M; Stiles, C D; Guha, A

1993-01-01

Malignant astrocytoma is the most common primary human brain tumor. Most astrocytomas express a combination of platelet-derived growth factor (PDGF) and PDGF receptor which could close an autocrine loop. It is not known whether these autocrine loops contribute to the transformed phenotype of astrocytoma cells or are incidental to that phenotype. Here we show that dominant-negative mutants of the PDGF ligand break the autocrine loop and revert the phenotype of BALB/c 3T3 cells transformed by the PDGF-A or PDGF-B (c-sis) gene. Then, we show that these mutants are selective in that they do not alter the phenotype of 3T3 cells transformed by an activated Ha-ras or v-src gene or by simian virus 40. Finally, we show that these mutants revert the transformed phenotype of two independent human astrocytoma cell lines. They have no effect on the growth of human medulloblastoma, bladder carcinoma, or colon carcinoma cell lines. These observations are consistent with the view that PDGF autocrine loops contribute to the transformed phenotype of at least some human astrocytomas. Images PMID:8246942

Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR

PubMed Central

Sahm, Felix; Rauschenbach, Katharina J.; Trump, Saskia; Winter, Marcus; Ott, Martina; Ochs, Katharina; Lutz, Christian; Liu, Xiangdong; Anastasov, Natasa; Lehmann, Irina; Höfer, Thomas; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

2014-01-01

Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR–IL-6–STAT3 signaling loop. Inhibition of the AHR–IL-6–STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients. PMID:24657910

Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer

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

Kenny, Paraic A.; Bissell, Mina J.

2005-06-15

The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop which provides an oncogenic stimulus in the absence of proto-oncogene mutation. Inhibition of this protease, TACE/ADAM17, reverts the malignant phenotype by preventing mobilization of two crucial growth factors, Amphiregulin and TGF{alpha}. We show further that the efficacy of EGFR inhibitors is overcome by physiological levels of growth factors and that successful EGFR inhibition is dependent on reducing ligand bioavailability. Using existing patient outcome data, wemore » demonstrate a strong correlation between TACE and TGF{alpha} expression in human breast cancers that is predictive of poor prognosis.« less

FGF19 functions as autocrine growth factor for hepatoblastoma

PubMed Central

Elzi, David J.; Song, Meihua; Blackman, Barron; Weintraub, Susan T.; López-Terrada, Dolores; Chen, Yidong; Tomlinson, Gail E.; Shiio, Yuzuru

2016-01-01

Hepatoblastoma is the most common liver cancer in children, accounting for over 65% of all childhood liver malignancies. Hepatoblastoma is distinct from adult liver cancer in that it is not associated with hepatitis virus infection, cirrhosis, or other underlying liver pathology. The paucity of appropriate cell and animal models has been hampering the mechanistic understanding of hepatoblastoma pathogenesis. Consequently, there is no molecularly targeted therapy for hepatoblastoma. To gain insight into cytokine signaling in hepatoblastoma, we employed mass spectrometry to analyze the proteins secreted from Hep293TT hepatoblastoma cell line we established and identified the specific secretion of fibroblast growth factor 19 (FGF19), a growth factor for liver cells. We determined that silencing FGF19 by shRNAs or neutralizing secreted FGF19 by anti-FGF19 antibody inhibits the proliferation of hepatoblastoma cells. Furthermore, blocking FGF19 signaling by an FGF receptor kinase inhibitor suppressed hepatoblastoma growth. RNA expression analysis in hepatoblastoma tumors revealed that the high expression of FGF19 signaling pathway components as well as the low expression of FGF19 signaling repression targets correlates with the aggressiveness of the tumors. These results suggest the role of FGF19 as autocrine growth factor for hepatoblastoma. PMID:27382436

Autocrine expression of the epidermal growth factor receptor ligand heparin-binding EGF-like growth factor in cervical cancer.

PubMed

Schrevel, Marlies; Osse, E Michelle; Prins, Frans A; Trimbos, J Baptist M Z; Fleuren, Gert Jan; Gorter, Arko; Jordanova, Ekaterina S

2017-06-01

In cervical cancer, the epidermal growth factor receptor (EGFR) is overexpressed in 70-90% of the cases and has been associated with poor prognosis. EGFR-based therapy is currently being explored in cervical cancer. We investigated which EGFR ligand is primarily expressed in cervical cancer and which cell type functions as the major source of this ligand. We hypothesized that macrophages are the main source of EGFR ligands and that a paracrine loop between tumor cells and macrophages is responsible for ligand expression. mRNA expression analysis was performed on 32 cervical cancer cases to determine the expression of the EGFR ligands amphiregulin, β-cellulin, epidermal growth factor (EGF), epiregulin, heparin-binding EGF-like growth factor (HB‑EGF) and transforming growth factor α (TGFα). Subsequently, protein expression was determined immunohistochemically on 36 additional cases. To assess whether macrophages are the major source of EGFR ligands, immunohistochemical double staining was performed on four representative tissue slides. Expression of the chemokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif ligand 2 (CCL2) was determined by mRNA in situ hybridization. Of the known EGFR ligands, HB‑EGF had the highest mRNA expression and HB‑EGF and EGFR protein expression were highly correlated. Tumor specimens with high EGFR expression showed higher numbers of macrophages, and higher expression of GM-CSF and CCL2, but only a small subset (9%) of macrophages was found to be HB‑EGF-positive. Strikingly, 78% of cervical cancer specimens were found to express HB‑EGF. Standardized assessment of staining intensity, using spectral imaging analysis, showed that HB‑EGF expression was higher in the tumor compartment than in the stromal compartment. These results suggest that HB‑EGF is an important EGFR ligand in cervical cancer and that cervical cancer cells are the predominant source of HB‑EGF. Therefore, we propose an autocrine

Intracellular autocrine VEGF signaling promotes EBDC cell proliferation, which can be inhibited by Apatinib.

PubMed

Peng, Sui; Zhang, Yanyan; Peng, Hong; Ke, Zunfu; Xu, Lixia; Su, Tianhong; Tsung, Allan; Tohme, Samer; Huang, Hai; Zhang, Qiuyang; Lencioni, Riccardo; Zeng, Zhirong; Peng, Baogang; Chen, Minhu; Kuang, Ming

2016-04-10

Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Activated stress response pathways within multicellular aggregates utilize an autocrine component.

PubMed

Jack, Graham D; Cabrera, M Carla; Manning, Michael L; Slaughter, Stephen M; Potts, Malcolm; Helm, Richard F

2007-04-01

Multicellular aggregates (spheroids) of primary human foreskin fibroblasts (HFF-2) and a glioblastoma cell line (T98G) entered and exited from long term (2 weeks) metabolic arrest utilizing an autocrine response. Cytokine production (specifically IFN-gamma) activated a Gadd45alpha/p38 pathway that led to increased AP-1 (c-jun and ATF3) transcription factor levels, augmenting cytokine production in an autocrine fashion. Whereas HFF-2 aggregates were capable of surviving long term arrest and recovery during NF-kappaB inhibition independent of JNK activation, T98G aggregates were not. Such endogenous processes are not easily observed with adherent monolayer cell culturing systems, strongly suggesting that more emphasis needs to be placed on determining the operational signal transduction cascades within multicellular aggregates. Extracellular inputs such as spheroid formation, arrest, and regrowth as monolayers invoke intracellular signaling responses converging at the AP-1 transcription factor level. Variations in responses are both cell type and transformation state dependent and require an autocrine cytokine component. The data are discussed in relation to the wounding response and avascular tumor growth mechanisms.

Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons.

PubMed

Wang, Liang; Chang, Xingya; She, Liang; Xu, Duo; Huang, Wei; Poo, Mu-ming

2015-06-03

Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activity-dependent autocrine BDNF secretion. Therefore, BDNF expressed in adult-born GCs plays a critical role in dendrite development by acting as an autocrine factor. Copyright © 2015 the authors 0270-6474/15/358384-10$15.00/0.

Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca(2+) signals and an IL-6 autocrine loop.

PubMed

Bustamante, Mario; Fernández-Verdejo, Rodrigo; Jaimovich, Enrique; Buvinic, Sonja

2014-04-15

Interleukin-6 (IL-6) is an important myokine that is highly expressed in skeletal muscle cells upon exercise. We assessed IL-6 expression in response to electrical stimulation (ES) or extracellular ATP as a known mediator of the excitation-transcription mechanism in skeletal muscle. We examined whether the canonical signaling cascade downstream of IL-6 (IL-6/JAK2/STAT3) also responds to muscle cell excitation, concluding that IL-6 influences its own expression through a positive loop. Either ES or exogenous ATP (100 μM) increased both IL-6 expression and p-STAT3 levels in rat myotubes, a process inhibited by 100 μM suramin and 2 U/ml apyrase. ATP also evoked IL-6 expression in both isolated skeletal fibers and extracts derived from whole FDB muscles. ATP increased IL-6 release up to 10-fold. STAT3 activation evoked by ATP was abolished by the JAK2 inhibitor HBC. Blockade of secreted IL-6 with a neutralizing antibody or preincubation with the STAT3 inhibitor VIII reduced STAT3 activation evoked by extracellular ATP by 70%. Inhibitor VIII also reduced by 70% IL-6 expression evoked by ATP, suggesting a positive IL-6 loop. In addition, ATP increased up to 60% the protein levels of SOCS3, a negative regulator of the IL-6 signaling pathway. On the other hand, intracellular calcium chelation or blockade of IP3-dependent calcium signals abolished STAT3 phosphorylation evoked by either extracellular ATP or ES. These results suggest that expression of IL-6 in stimulated skeletal muscle cells is mediated by extracellular ATP and nucleotide receptors, involving IP3-dependent calcium signals as an early step that triggers a positive IL-6 autocrine loop.

Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer.

PubMed Central

Sehgal, I; Powers, S; Huntley, B; Powis, G; Pittelkow, M; Maihle, N J

1994-01-01

After therapeutic hormone deprivation, prostate cancer cells often develop androgen-insensitive growth through mechanisms thus far undefined. Neuropeptides have been previously implicated as growth factors in some prostate cancers. Here, we demonstrate that androgen-sensitive LNCaP human prostate cancer cells produce and secrete neurotensin following androgen withdrawal. We show that while LNCaP cells express the neurotensin receptor, only androgen-deprived cells exhibit a growth response to exogenous neurotensin. We further demonstrate that androgen-stimulated cells may be refractory to exogenous neurotensin due to androgen induction of a metalloprotease active toward neurotensin. Thus, prostate cancer cells deprived of androgen develop an alternative autocrine growth mechanism involving neurotensin. Images PMID:8197117

Induction of autocrine factor inhibiting cell motility from murine B16-BL6 melanoma cells by alpha-melanocyte stimulating hormone.

PubMed

Murata, J; Ayukawa, K; Ogasawara, M; Watanabe, H; Saiki, I

1999-03-15

We have previously reported that neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) successfully inhibited Matrigel invasion and haptotactic migration of B16-BL6 melanoma cells towards both fibronectin and laminin without affecting their growth. In the present study, we investigated the inhibitory mechanism of tumor cell motility by alpha-MSH. Alpha-MSH significantly blocked the autocrine motility factor (AMF)-enhanced cell motility. However, alpha-MSH did neither prevent the secretion of AMF from B16-BL6 cells nor alter the expression level of AMF receptor (gp78). On the other hand, alpha-MSH induced the secretion of the motility inhibitory factor(s) from B16-BL6 cells in a concentration- and time-dependent manner. The induction of the motility inhibitor(s) was proportional to increasing levels of intracellular cAMP induced by alpha-MSH as well as forskolin, and the activity was abolished by an adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA). The motility-inhibiting activity in conditioned medium (CM) from alpha-MSH-treated B16-BL6 cells was found to have a m.w. below 3 kDa after fractionation. This activity was abolished by boiling but insensitive to trypsin. The treatment of tumor cells with cycloheximide reduced the activity in alpha-MSH-stimulated CM. Our results suggest that alpha-MSH inhibited the motility of B16-BL6 cells through induction of autocrine factor(s).

Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform

NASA Astrophysics Data System (ADS)

Müller, Eike; Wang, Weijia; Qiao, Wenlian; Bornhäuser, Martin; Zandstra, Peter W.; Werner, Carsten; Pompe, Tilo

2016-08-01

Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine, endocrine and metabolic cues, paracrine and autocrine signals are involved in controlling quiescence, proliferation and differentiation of HSC with strong implications on expansion and differentiation ex vivo as well as in vivo transplantation. Towards this aim, a cell culture analysis on a polymer microcavity carrier platform was combined with a partial least square analysis of a mechanistic model of cell proliferation. We could demonstrate the discrimination of specific autocrine and paracrine signals from soluble factors as stimulating and inhibitory effectors in hematopoietic stem and progenitor cell culture. From that we hypothesize autocrine signals to be predominantly involved in maintaining the quiescent state of HSC in single-cell niches and advocate our analysis platform as an unprecedented option for untangling convoluted signaling mechanisms in complex cell systems being it of juxtacrine, paracrine or autocrine origin.

Rhythmic autocrine activity in cultured insect epidermal cells.

PubMed

Mesnier, M; Partiaoglou, N; Oberlander, H; Porcheron, P

2000-05-01

It is now well established that ecdysteroids can be produced in insects in the absence of prothoracic glands. In this respect, it has been shown that cells in culture can produce ecdysteroids. Our aims were: (1) to determine whether ecdysteroid target cells of epidermal origin could also be the source of ecdysteroids; (2) to monitor more accurately the kinetics of ecdysteroid production; and (3) to check for possible relationships between this synthetic activity and dynamics of cell division. An insect cell line (IAL-PID2) established from imaginal discs of the Indian meal moth, Plodia interpunctella, with wild-type sensitivity to ecdysteroids was used in our study. Our results showed that the Plodia cell line exhibited autocrine activity. When division of IAL-PID2 cells was synchronized, a rhythmic production of ecdysteroids was observed. However, further experiments indicated that this rhythmicity could be cell autonomous. This led us to anticipate the existence of two cell subpopulations that would be able to produce ecdysteroids rhythmically, a minor one that would be cell cycle serum-independent population, and a major population that would need serum growth factors to proliferate and produce ecdysteroids. Qualitative study of the ecdysteroid content of the media clearly showed that ecdysone was the major immunoreactive product. Taken together, our findings clearly show that an insect cell line of epidermal origin is capable of rhythmic autocrine production of ecdysteroids. These results support the hypothesis that alternate sites for ecdysteroid production in vivo may exist and could play a role in local regulation of development. We now plan to determine the cellular basis of this rhythmic autocrine activity and to confirm the existence of growth factor-autonomous cells in the culture as well as the potent role played by ecdysteroids in the cross-talk between various cell subpopulations. Copyright 2000 Wiley-Liss, Inc.

Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone

PubMed Central

Mukhina, Svetlana; Mertani, Hichem C.; Guo, Ke; Lee, Kok-Onn; Gluckman, Peter D.; Lobie, Peter E.

2004-01-01

We report here that autocrine production of human growth hormone (hGH) results in a phenotypic conversion of mammary carcinoma cells such that they exhibit the morphological and molecular characteristics of a mesenchymal cell, including expression of fibronectin and vimentin. Autocrine production of hGH resulted in reduced plakoglobin expression and relocalization of E-cadherin to the cytoplasm, leading to dissolution of cell-cell contacts and decreased cell height. These phenotypic changes were accompanied by an increase in cell motility, elevated activity of specific matrix metalloproteinases, and an acquired ability to invade a reconstituted basement membrane. Forced expression of plakoglobin significantly decreased mammary carcinoma cell migration and invasion stimulated by autocrine hGH. In vivo, autocrine hGH stimulated local invasion of mammary carcinoma cells concomitant with a prominent stromal reaction in comparison with well delineated and capsulated growth of mammary carcinoma cells lacking autocrine production of hGH. Thus, autocrine production of hGH by mammary carcinoma cells is sufficient for generation of an invasive phenotype. Therapeutic targeting of autocrine hGH may provide a mechanistic approach to prevent metastatic extension of human mammary carcinoma. PMID:15353581

Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells

PubMed Central

2013-01-01

Background Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. Results We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1β, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. Conclusions These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis. PMID:23937860

CXCL1 induces senescence of cancer-associated fibroblasts via autocrine loops in oral squamous cell carcinoma

PubMed Central

Kim, Eun Kyoung; Moon, Sook; Kim, Do Kyeong; Zhang, Xianglan

2018-01-01

Cancer-associated fibroblasts (CAFs) have emerged as one of the main factors related to cancer progression, however, the conversion mechanism of normal fibroblasts (NOFs) to CAFs has not been well elucidated. The aim of this study was to investigate the underlying mechanism of CAF transformation from NOFs in oral squamous cell carcinoma (OSCC). This study found that NOFs exposed to OSCC cells transformed to senescent cells. The cytokine antibody array showed the highest secretion levels of IL-6 and CXCL1 in NOFs co-cultured with OSCC cells. Despite that both IL-6 and CXCL1 induced the senescent phenotype of CAFs, CXCL1 secretion showed a cancer-specific response to transform NOFs into CAFs in OSCC, whereas IL-6 secretion was eventuated by common co-culture condition. Further, CXCL1 was released from NOFs co-cultured with OSCC cells, however, CXCL1 was undetectable in mono-cultured NOFs or co-cultured OSCC cells with NOFs. Taken together, this study demonstrates that CXCL1 can transform NOFs into senescent CAFs via an autocrine mechanism. These data might contribute to further understanding of CAFs and to development of a potential therapeutic approach targeting cancer cells-CAFs interactions. PMID:29360827

Ableson Kinases Negatively Regulate Invadopodia Function and Invasion in Head and Neck Squamous Cell Carcinoma by Inhibiting an HB-EGF Autocrine Loop

PubMed Central

Hayes, Karen E.; Walk, Elyse L.; Ammer, Amanda Gatesman; Kelley, Laura C.; Martin, Karen H.; Weed, Scott A.

2014-01-01

Head and neck squamous cell carcinoma (HNSCC) has a proclivity for locoregional invasion. HNSCC mediates invasion in part through invadopodia-based proteolysis of the extracellular matrix (ECM). Activation of Src, Erk1/2, Abl and Arg downstream of epidermal growth factor receptor (EGFR) modulates invadopodia activity through phosphorylation of the actin regulatory protein cortactin. In MDA-MB-231 breast cancer cells, Abl and Arg function downstream of Src to phosphorylate cortactin, promoting invadopodia ECM degradation activity and thus assigning a pro-invasive role for Ableson kinases. We report that Abl kinases have an opposite, negative regulatory role in HNSCC where they suppress invadopodia and tumor invasion. Impairment of Abl expression or Abl kinase activity with imatinib mesylate enhanced HNSCC matrix degradation and 3D collagen invasion, functions that were impaired in MDA-MB-231. HNSCC lines with elevated EGFR and Src activation did not contain increased Abl or Arg kinase activity, suggesting Src could bypass Abl/Arg to phosphorylate cortactin and promote invadopodia ECM degradation. Src transformed Abl−/−/Arg−/− fibroblasts produced ECM degrading invadopodia containing pY421 cortactin, indicating that Abl/Arg are dispensable for invadopodia function in this system. Imatinib treated HNSCC cells had increased EGFR, Erk1/2 and Src activation, enhancing cortactin pY421 and pS405/418 required for invadopodia function. Imatinib stimulated shedding of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) from HNSCC cells, where soluble HB-EGF enhanced invadopodia ECM degradation in HNSCC but not in MDA-MB-231. HNSCC cells treated with inhibitors of the EGFR invadopodia pathway indicated that EGFR and Src are required for invadopodia function. Collectively our results indicate that Abl kinases negatively regulate HNSCC invasive processes through suppression of an HB-EGF autocrine loop responsible for activating a EGFR-Src-cortactin cascade

Collagen and Stretch Modulate Autocrine Secretion of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Proteins from Differentiated Skeletal Muscle Cells

NASA Technical Reports Server (NTRS)

Perrone, Carmen E.; Fenwick-Smith, Daniela; Vandenburgh, Herman H.

1995-01-01

Stretch-induced skeletal muscle growth may involve increased autocrine secretion of insulin-like growth factor-1 (IGF-1) since IGF-1 is a potent growth factor for skeletal muscle hypertrophy, and stretch elevates IGF-1 mRNA levels in vivo. In tissue cultures of differentiated avian pectoralis skeletal muscle cells, nanomolar concentrations of exogenous IGF-1 stimulated growth in mechanically stretched but not static cultures. These cultures released up to 100 pg of endogenously produced IGF-1/micro-g of protein/day, as well as three major IGF binding proteins of 31, 36, and 43 kilodaltons (kDa). IGF-1 was secreted from both myofibers and fibroblasts coexisting in the muscle cultures. Repetitive stretch/relaxation of the differentiated skeletal muscle cells stimulated the acute release of IGF-1 during the first 4 h after initiating mechanical activity, but caused no increase in the long-term secretion over 24-72 h of IGF-1, or its binding proteins. Varying the intensity and frequency of stretch had no effect on the long-term efflux of IGF-1. In contrast to stretch, embedding the differentiated muscle cells in a three-dimensional collagen (Type I) matrix resulted in a 2-5-fold increase in long-term IGF-1 efflux over 24-72 h. Collagen also caused a 2-5-fold increase in the release of the IGF binding proteins. Thus, both the extracellular matrix protein type I collagen and stretch stimulate the autocrine secretion of IGF-1, but with different time kinetics. This endogenously produced growth factor may be important for the growth response of skeletal myofibers to both types of external stimuli.

Autocrine stimulation of human hepatocytes triggers late DNA synthesis and stabilizes long-term differentiation in vitro.

PubMed

Leckel, Kerstin; Strey, Christoph; Bechstein, Wolf O; Boost, Kim A; Auth, Marcus K H; El Makhfi, Amal; Juengel, Eva; Wedel, Steffen; Jones, Jon; Jonas, Dietger; Blaheta, Roman A

2008-05-01

Isolated human hepatocytes are of great value in investigating cell transplantation, liver physiology, pathology, and drug metabolism. Though hepatocytes possess a tremendous proliferative capacity in vivo, their ability to grow in culture is severely limited. We postulated that repeated medium change, common to most in vitro systems, may prevent long-term maintenance of hepato-specific functions and growth capacity. To verify our hypotheses we compared the DNA synthesis and differentiation status of isolated human hepatocytes, cultured in medium which was renewed every day or was not changed for 3 weeks ('autocrine' setting). Daily medium change led to rapid hepatocellular de-differentiation without any signs of DNA replication. In contrast, the autocrine setting allowed hepatocytes to become highly differentiated, demonstrated by an elevated ASGPr expression level, and increased albumin and fibrinogen synthesis and release. Cytokeratin 18 filaments were stably expressed, whereas cytokeratin 19 remained undetectable. Hepatocytes growing in an autocrine fashion were activated in the presence of hepatocyte growth factor (HGF), evidenced by c-Met phosphorylation. However, HGF response was not achieved when the culture medium was renewed daily. Furthermore, the autocrine setting evoked a late but strong interleukin 6 release into the culture supernatant, reaching maximum values after a 10-day cultivation period, and intense BrdU incorporation after a further 5-day period. Our data suggest that preservation of the same medium creates environmental conditions which allow hepatocytes to control their differentiation status and DNA synthesis in an autocrine fashion. Further studies are necessary to identify the key mediators involved in autocrine communication and to design the optimal culture configuration for clinical application.

Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib

PubMed Central

Lupo, Audrey Mansuet; Mourra, Najat; Takahashi, Takashi; Fléjou, Jean François; Trédaniel, Jean; Régnard, Jean François; Damotte, Diane; Alifano, Marco; Forgez, Patricia

2014-01-01

Alterations in the signaling pathways of epidermal growth factor receptors (HERs) are associated with tumor aggressiveness. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 60% of lung cancers. In a previous clinical study, NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in a selected population of stage I lung adenocarcinomas treated by surgery alone. In a second study, shown here, the frequent and high expression of NTSR1 was correlated with a pejorative prognosis in 389 patients with stage I to III lung adenocarcinoma, and was an independent prognosis marker. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here we highlight the cellular mechanisms activated by Neurotensin (NTS) and its high affinity receptor (NTSR1) contributing to lung cancer cell aggressiveness. We show that the NTS autocrine and/or paracrine regulation causes EGFR, HER2, and HER3 over-expression and activation in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and EGF “like” ligands (HB-EGF, Neuregulin 1) release. By establishing autocrine and/or paracrine NTS regulation, we show that tumor growth is modulated according to NTS expression, with a low growth rate in those tumors that do not express NTS. Accordingly, xenografted tumors expressing NTS and NTSR1 showed a positive response to erlotinib, whereas tumors void of NTSR1 expression had no detectable response. This is consistent with the presence of a NTS autocrine loop, leading to the sustained activation of EGFR and responsible for cancer aggressiveness. We propose the use of NTS/NTSR1 tumor expression, as a biomarker for the use of EGFR tyrosine kinase inhibitors in patients lacking EGFR mutation. PMID:25249545

Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib.

PubMed

Younes, Mohamad; Wu, Zherui; Dupouy, Sandra; Lupo, Audrey Mansuet; Mourra, Najat; Takahashi, Takashi; Fléjou, Jean François; Trédaniel, Jean; Régnard, Jean François; Damotte, Diane; Alifano, Marco; Forgez, Patricia

2014-09-30

Alterations in the signaling pathways of epidermal growth factor receptors (HERs) are associated with tumor aggressiveness. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 60% of lung cancers. In a previous clinical study, NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in a selected population of stage I lung adenocarcinomas treated by surgery alone. In a second study, shown here, the frequent and high expression of NTSR1 was correlated with a pejorative prognosis in 389 patients with stage I to III lung adenocarcinoma, and was an independent prognosis marker. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here we highlight the cellular mechanisms activated by Neurotensin (NTS) and its high affinity receptor (NTSR1) contributing to lung cancer cell aggressiveness. We show that the NTS autocrine and/or paracrine regulation causes EGFR, HER2, and HER3 over-expression and activation in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and EGF "like" ligands (HB-EGF, Neuregulin 1) release. By establishing autocrine and/or paracrine NTS regulation, we show that tumor growth is modulated according to NTS expression, with a low growth rate in those tumors that do not express NTS. Accordingly, xenografted tumors expressing NTS and NTSR1 showed a positive response to erlotinib, whereas tumors void of NTSR1 expression had no detectable response. This is consistent with the presence of a NTS autocrine loop, leading to the sustained activation of EGFR and responsible for cancer aggressiveness. We propose the use of NTS/NTSR1 tumor expression, as a biomarker for the use of EGFR tyrosine kinase inhibitors in patients lacking EGFR mutation.

Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor.

PubMed

Vassbotn, F S; Havnen, O K; Heldin, C H; Holmsen, H

1994-05-13

Human platelets contain platelet-derived growth factor (PDGF) in their alpha-granules which is released during platelet exocytosis. We show by immunoprecipitation and 125I-PDGF binding experiments that human platelets have functionally active PDGF alpha-receptors, but not beta-receptors. The PDGF alpha-receptor (PDGFR-alpha) was identified as a 170-kDa glycosylated protein-tyrosine kinase as found in other cell types. Stimulation of platelets with 0.1 unit/ml thrombin resulted in a significant increase (2-5-fold) of the tyrosine phosphorylation of the PDGFR-alpha, as determined by immunoprecipitation with phosphotyrosine antiserum as well as with PDGFR-alpha antiserum. The observed thrombin-induced autophosphorylation of the PDGFR-alpha was inhibited by the addition of a neutralizing monoclonal PDGF antibody. Thus, our results suggest that the platelet PDGFR-alpha is stimulated in an autocrine manner by PDGF secreted during platelet activation. Preincubation of platelets with PDGF inhibited thrombin-induced platelet aggregation and secretion of ATP + ADP and beta-hexosaminidase. Thrombin-induced platelet aggregation was also reversed when PDGF was added 30 s after thrombin stimulation. Inhibition of the autocrine PDGF pathway during platelet activation by the PDGF antibody led to a potentiation of thrombin-induced beta-hexosaminidase secretion. Thus, the PDGFR-alpha takes part in a negative feedback regulation during platelet activation. Our demonstration of PDGF alpha-receptors on human platelets and its inhibitory function during platelet activation identifies a new possible role of PDGF in the regulation of thrombosis.

Autocrine-paracrine regulation of the mammary gland.

PubMed

Weaver, S R; Hernandez, L L

2016-01-01

The mammary gland has a remarkable capacity for regulation at a local level, particularly with respect to its main function: milk secretion. Regulation of milk synthesis has significant effects on animal and human health, at the level of both the mother and the neonate. Control by the mammary gland of its essential function, milk synthesis, is an evolutionary necessity and is therefore tightly regulated at a local level. For at least the last 60 yr, researchers have been interested in elucidating the mechanisms underpinning the mammary gland's ability to self-regulate, largely without the influence from systemic hormones or signals. By the 1960s, scientists realized the importance of milk removal in the capacity of the gland to produce milk and that the dynamics of this removal, including emptying of the alveolar spaces and frequency of milking, were controlled locally as opposed to traditional systemic hormonal regulation. Using both in vitro systems and various mammalian species, including goats, marsupials, humans, and dairy cows, it has been demonstrated that the mammary gland is largely self-regulating in its capacity to support the young, which is the evolutionary basis for milk production. Local control occurs at the level of the mammary epithelial cell through pressure and stretching negative-feedback mechanisms, and also in an autocrine fashion through bioactive factors within the milk which act as inhibitors, regulating milk secretion within the alveoli themselves. It is only within the last 20 to 30 yr that potential candidates for these bioactive factors have been examined at a molecular level. Several, including parathyroid hormone-related protein, growth factors (transforming growth factor, insulin-like growth factor, epidermal growth factor), and serotonin, are synthesized within and act upon the gland and possess dynamic receptor activity resulting in diverse effects on growth, calcium homeostasis, and milk composition. This review will focus on the

Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production.

PubMed

Baseler, Walter A; Davies, Luke C; Quigley, Laura; Ridnour, Lisa A; Weiss, Jonathan M; Hussain, S Perwez; Wink, David A; McVicar, Daniel W

2016-12-01

Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, "alternatively activated" macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes. Copyright © 2016. Published by Elsevier B.V.

Autocrine signal transmission with extracellular ligand degradation

NASA Astrophysics Data System (ADS)

Muratov, C B; Posta, F; Shvartsman, S Y

2009-03-01

Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand-receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers.

Autocrine-Derived Epidermal Growth Factor Receptor Ligands Contribute to Recruitment of Tumor-Associated Macrophage and Growth of Basal Breast Cancer Cells In Vivo

PubMed Central

Nickerson, Nicole K.; Mill, Christopher P.; Wu, Hsin-Jung; Riese, David J.; Foley, John

2014-01-01

Epidermal growth factor receptor (EGFR) expression has been linked to progression of basal breast cancers. Many breast cancer cells harbor the EGFR and produce its family of ligands, suggesting they may participate in autocrine and paracrine signaling with cells of the tumor microenvironment. EGFR ligand expression was profiled in the basal breast cancer cell line MDA-231 where AREG, TGF-α, and HBEGF were the three ligands most highly expressed. Autocrine signaling was modulated through silencing or overexpression of these three ligands using lentiviral constructs and the impact measured using motility, proliferation, and cytokine expression assays. Changes in receptor phosphorylation and receptor turnover were examined. Knockdown of AREG or TGF-α in vitro resulted in decreased motility (p < 0.05) and decreased expression of macrophage chemoattractants. Overexpression of TGF-α increased motility and chemoattractant expression, whereas AREG did not. HBEGF modulation had no effect on any cellular behaviors. All the cells with altered ligand production were inoculated into female athymic nude mice to form mammary fat pad tumors, followed by immunohistochemical analysis for necrosis, angiogenesis, and macrophage recruitment. In vivo, knockdown of AREG or TGF-α increased survival (p < 0.001) while decreasing angiogenesis (p < 0.001), tumor growth (p < 0.001), and macrophage attraction (p < 0.001). Overexpression of AREG appeared to elicit a greater effect than TGF-α on mammary fat pad tumor growth by increasing angiogenesis (p < 0.001) and macrophage attraction to the tumor (p < 0.01). We propose these changes in mammary tumor growth were the result of increased recruitment of macrophages to the tumor by cells with altered autocrine EGFR signaling. We conclude that AREG and TGF-α were somewhat interchangeable in their effects on EGFR signaling; however, TGF-α had a greater effect in vitro and AREG had a greater effect in vivo. PMID:23879171

Autocrine-derived epidermal growth factor receptor ligands contribute to recruitment of tumor-associated macrophage and growth of basal breast cancer cells in vivo.

PubMed

Nickerson, Nicole K; Mill, Christopher P; Wu, Hsin-Jung; Riese, David J; Foley, John

2013-01-01

Epidermal growth factor receptor (EGFR) expression has been linked to progression of basal breast cancers. Many breast cancer cells harbor the EGFR and produce its family of ligands, suggesting they may participate in autocrine and paracrine signaling with cells of the tumor microenvironment. EGFR ligand expression was profiled in the basal breast cancer cell line MDA-231 where AREG, TGF-alpha, and HBEGF were the three ligands most highly expressed. Autocrine signaling was modulated through silencing or overexpression of these three ligands using lentiviral constructs and the impact measured using motility, proliferation, and cytokine expression assays. Changes in receptor phosphorylation and receptor turnover were examined. Knockdown of AREG or TGF-alpha in vitro resulted in decreased motility (p < 0.05) and decreased expression of macrophage chemoattractants. Overexpression of TGF-alpha increased motility and chemoattractant expression, whereas AREG did not. HBEGF modulation had no effect on any cellular behaviors. All the cells with altered ligand production were inoculated into female athymic nude mice to form mammary fat pad tumors, followed by immunohistochemical analysis for necrosis, angiogenesis, and macrophage recruitment. In vivo, knockdown of AREG or TGF-alpha increased survival (p < 0.001) while decreasing angiogenesis (p < 0.001), tumor growth (p < 0.001), and macrophage attraction (p < 0.001). Overexpression of AREG appeared to elicit a greater effect than TGF-alpha on mammary fat pad tumor growth by increasing angiogenesis (p < 0.001) and macrophage attraction to the tumor (p < 0.01). We propose these changes in mammary tumor growth were the result of increased recruitment of macrophages to the tumor by cells with altered autocrine EGFR signaling. We conclude that AREG and TGF-alpha were somewhat interchangeable in their effects on EGFR signaling; however, TGF-alpha had a greater effect in vitro and AREG had a greater effect in vivo.

Autocrine motility factor (neuroleukin, phosphohexose isomerase) induces cell movement through 12-lipoxygenase-dependent tyrosine phosphorylation and serine dephosphorylation events.

PubMed

Timár, J; Tóth, S; Tóvári, J; Paku, S; Raz, A

1999-01-01

Autocrine motility factor (AMF) is one of the motility cytokines regulating tumor cell migration, therefore identification of the signaling pathway coupled with it has critical importance. Previous studies revealed several elements of this pathway predominated by lipoxygenase-PKC activations but the role for tyrosine kinases remained questionable. Motility cytokines frequently have mitogenic effect as well, producing activation of overlapping signaling pathways therefore we have used B16a melanoma cells as models where AMF has exclusive motility effect. Our studies revealed that in B16a cells AMF initiated rapid (1-5 min) activation of the protein tyrosine kinase (PTK) cascade inducing phosphorylation of 179, 125, 95 and 40/37 kD proteins which was mediated by upstream cyclo- and lipoxygenases. The phosphorylated proteins were localized to the cortical actin-stress fiber attachment zones in situ by confocal microscopy. On the other hand, AMF receptor activation induced significant decrease in overall serine-phosphorylation level of cellular proteins accompanied by serine phosphorylation of 200, 90, 78 and 65 kd proteins. The decrease in serine phosphorylation was independent of PTKs, PKC as well as cyclo- and lipoxygenases. However, AMF induced robust translocation of PKCalpha to the stress fibers and cortical actin suggesting a critical role for this kinase in the generation of the motility signal. Based on the significant decrease in serine phosphorylation after AMF stimulus in B16a cells we postulated the involvement of putative serine/threonine phosphatase(s) upstream lipoxygenase and activation of the protein tyrosine kinase cascade downstream cyclo- and lipoxygenase(s) in the previously identified autocrine motility signal.

Promotion of human early embryonic development and blastocyst outgrowth in vitro using autocrine/paracrine growth factors.

PubMed

Kawamura, Kazuhiro; Chen, Yuan; Shu, Yimin; Cheng, Yuan; Qiao, Jie; Behr, Barry; Pera, Renee A Reijo; Hsueh, Aaron J W

2012-01-01

Studies using animal models demonstrated the importance of autocrine/paracrine factors secreted by preimplantation embryos and reproductive tracts for embryonic development and implantation. Although in vitro fertilization-embryo transfer (IVF-ET) is an established procedure, there is no evidence that present culture conditions are optimal for human early embryonic development. In this study, key polypeptide ligands known to be important for early embryonic development in animal models were tested for their ability to improve human early embryo development and blastocyst outgrowth in vitro. We confirmed the expression of key ligand/receptor pairs in cleavage embryos derived from discarded human tri-pronuclear zygotes and in human endometrium. Combined treatment with key embryonic growth factors (brain-derived neurotrophic factor, colony-stimulating factor, epidermal growth factor, granulocyte macrophage colony-stimulating factor, insulin-like growth factor-1, glial cell-line derived neurotrophic factor, and artemin) in serum-free media promoted >2.5-fold the development of tri-pronuclear zygotes to blastocysts. For normally fertilized embryos, day 3 surplus embryos cultured individually with the key growth factors showed >3-fold increases in the development of 6-8 cell stage embryos to blastocysts and >7-fold increase in the proportion of high quality blastocysts based on Gardner's criteria. Growth factor treatment also led to a 2-fold promotion of blastocyst outgrowth in vitro when day 7 surplus hatching blastocysts were used. When failed-to-be-fertilized oocytes were used to perform somatic cell nuclear transfer (SCNT) using fibroblasts as donor karyoplasts, inclusion of growth factors increased the progression of reconstructed SCNT embryos to >4-cell stage embryos. Growth factor supplementation of serum-free cultures could promote optimal early embryonic development and implantation in IVF-ET and SCNT procedures. This approach is valuable for infertility

Autocrine and paracrine Shh signaling are necessary for tooth morphogenesis, but not tooth replacement in snakes and lizards (Squamata).

PubMed

Handrigan, Gregory R; Richman, Joy M

2010-01-01

Here we study the role of Shh signaling in tooth morphogenesis and successional tooth initiation in snakes and lizards (Squamata). By characterizing the expression of Shh pathway receptor Ptc1 in the developing dentitions of three species (Eublepharis macularius, Python regius, and Pogona vitticeps) and by performing gain- and loss-of-function experiments, we demonstrate that Shh signaling is active in the squamate tooth bud and is required for its normal morphogenesis. Shh apparently mediates tooth morphogenesis by separate paracrine- and autocrine-mediated functions. According to this model, paracrine Shh signaling induces cell proliferation in the cervical loop, outer enamel epithelium, and dental papilla. Autocrine signaling within the stellate reticulum instead appears to regulate cell survival. By treating squamate dental explants with Hh antagonist cyclopamine, we induced tooth phenotypes that closely resemble the morphological and differentiation defects of vestigial, first-generation teeth in the bearded dragon P. vitticeps. Our finding that these vestigial teeth are deficient in epithelial Shh signaling further corroborates that Shh is needed for the normal development of teeth in snakes and lizards. Finally, in this study, we definitively refute a role for Shh signaling in successional dental lamina formation and conclude that other pathways regulate tooth replacement in squamates.

Autocrine Positive Feedback Regulation of Prolactin Release From Tilapia Prolactin Cells and Its Modulation by Extracellular Osmolality.

PubMed

Yamaguchi, Yoko; Moriyama, Shunsuke; Lerner, Darren T; Grau, E Gordon; Seale, Andre P

2016-09-01

Prolactin (PRL) is a vertebrate hormone with diverse actions in osmoregulation, metabolism, reproduction, and in growth and development. Osmoregulation is fundamental to maintaining the functional structure of the macromolecules that conduct the business of life. In teleost fish, PRL plays a critical role in osmoregulation in fresh water. Appropriately, PRL cells of the tilapia are directly osmosensitive, with PRL secretion increasing as extracellular osmolality falls. Using a model system that employs dispersed PRL cells from the euryhaline teleost fish, Oreochromis mossambicus, we investigated the autocrine regulation of PRL cell function. Unknown was whether these PRL cells might also be sensitive to autocrine feedback and whether possible autocrine regulation might interact with the well-established regulation by physiologically relevant changes in extracellular osmolality. In the cell-perfusion system, ovine PRL and two isoforms of tilapia PRL (tPRL), tPRL177 and tPRL188, stimulated the release of tPRLs from the dispersed PRL cells. These effects were significant within 5-10 minutes and lasted the entire course of exposure, ceasing within 5-10 minutes of removal of tested PRLs from the perifusion medium. The magnitude of response varied between tPRL177 and tPRL188 and was modulated by extracellular osmolality. On the other hand, the gene expression of tPRLs was mainly unchanged or suppressed by static incubations of PRL cells with added PRLs. By demonstrating the regulatory complexity driven by positive autocrine feedback and its interaction with osmotic stimuli, these findings expand upon the knowledge that pituitary PRL cells are regulated complexly through multiple factors and interactions.

Autocrine IL-6 mediates pituitary tumor senescence

PubMed Central

Fuertes, Mariana; Ajler, Pablo; Carrizo, Guillermo; Cervio, Andrés; Sevlever, Gustavo; Stalla, Günter K.; Arzt, Eduardo

2017-01-01

Cellular senescence is a stable proliferative arrest state. Pituitary adenomas are frequent and mostly benign, but the mechanism for this remains unknown. IL-6 is involved in pituitary tumor progression and is produced by the tumoral cells. In a cell autonomous fashion, IL-6 participates in oncogene-induced senescence in transduced human melanocytes. Here we prove that autocrine IL-6 participates in pituitary tumor senescence. Endogenous IL-6 inhibition in somatotroph MtT/S shRNA stable clones results in decreased SA-β-gal activity and p16INK4a but increased pRb, proliferation and invasion. Nude mice injected with IL-6 silenced clones develop tumors contrary to MtT/S wild type that do not, demonstrating that clones that escape senescence are capable of becoming tumorigenic. When endogenous IL-6 is silenced, cell cultures derived from positive SA-β-gal human tumor samples decrease the expression of the senescence marker. Our results establish that IL-6 contributes to maintain senescence by its autocrine action, providing a natural model of IL-6 mediated benign adenoma senescence. PMID:27902467

Heavy quark form factors at two loops

NASA Astrophysics Data System (ADS)

Ablinger, J.; Behring, A.; Blümlein, J.; Falcioni, G.; De Freitas, A.; Marquard, P.; Rana, N.; Schneider, C.

2018-05-01

We compute the two-loop QCD corrections to the heavy quark form factors in the case of the vector, axial-vector, scalar and pseudoscalar currents up to second order in the dimensional parameter ɛ =(4 -D )/2 . These terms are required in the renormalization of the higher-order corrections to these form factors.

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice

PubMed Central

Farhang Ghahremani, Morvarid; Radaelli, Enrico; Haigh, Katharina; Bartunkova, Sonia; Haenebalcke, Lieven; Marine, Jean-Christophe; Goossens, Steven; Haigh, Jody J

2014-01-01

Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition. PMID:24626176

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice.

PubMed

Farhang Ghahremani, Morvarid; Radaelli, Enrico; Haigh, Katharina; Bartunkova, Sonia; Haenebalcke, Lieven; Marine, Jean-Christophe; Goossens, Steven; Haigh, Jody J

2014-01-01

Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition.

Theileria parva infection induces autocrine growth of bovine lymphocytes.

PubMed Central

Dobbelaere, D A; Coquerelle, T M; Roditi, I J; Eichhorn, M; Williams, R O

1988-01-01

Bovine lymphocytes infected with the parasite Theileria parva continuously secrete a growth factor that is essential for their proliferation in vitro and also constitutively express interleukin 2 receptors on their surface. Dilution of the secreted growth factor, caused by culturing cells at low density, results in retardation of culture growth. Human recombinant interleukin 2, however, effectively substitutes for the diluted growth factor by restoring normal growth rates and also allows Theileria-infected cells to be grown at low density without the use of feeder layers. Secretion of the growth factor and expression of the interleukin 2 receptor depend on the presence of the parasite in the cytoplasm of the host cell. Elimination of the parasite from the cell cytoplasm by the specific antitheilerial drug BW 720c results in the arrest of growth factor secretion and the disappearance of interleukin 2 receptors from the cell surface. This is accompanied by growth arrest and reversion of the infected cells to the morphology of resting lymphocytes. We propose that the continuous proliferation of infected cells in vitro is mediated by autocrine receptor activation. Images PMID:3133661

Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer.

PubMed

Lin, Yi; Zhai, Ertao; Liao, Bing; Xu, Lixia; Zhang, Xinhua; Peng, Sui; He, Yulong; Cai, Shirong; Zeng, Zhirong; Chen, Minhu

2017-02-14

Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment. The expression of phosphor VEGFR2 in gastric cancer cell lines was determined by real-time PCR, immunofluorescence, and Western blot. The gastric cancer cells were administrated with or without recombination human VEGF (rhVEGF), VEGFR2 neutralizing antibody, U73122, SU1498, and Apatinib. The nude mice were used for xenograft tumor model. we found that autocrine VEGF induced high VEGFR2-expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells. The autocrine VEGF was self-sustained through increasing VEGF mRNA and protein expression. It exerted pro-proliferative effect through a PLC-ERK1/2 dependent pathway. Furthermore, we demonstrated that in VEGFR2 overexpressing gastric cancer cells, Apatinib inhibited cell proliferation in vitro and delayed xenograft tumor growth in vivo. However, these effects were not observed in VEGFR2 low expressing gastric cancer cells. These results suggested that autocrine VEGF signaling promotes gastric cancer cell proliferation and enhances Apatinib treatment outcome in VEGFR2 overexpression gastric cancer cells both in vitro and in vivo. This study would enable better stratification of gastric cancer patients for clinical treatment decision.

Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer

PubMed Central

Xu, Lixia; Zhang, Xinhua; Peng, Sui; He, Yulong; Cai, Shirong; Zeng, Zhirong; Chen, Minhu

2017-01-01

Background Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment. Methods The expression of phosphor VEGFR2 in gastric cancer cell lines was determined by real-time PCR, immunofluorescence, and Western blot. The gastric cancer cells were administrated with or without recombination human VEGF (rhVEGF), VEGFR2 neutralizing antibody, U73122, SU1498, and Apatinib. The nude mice were used for xenograft tumor model. Results we found that autocrine VEGF induced high VEGFR2-expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells. The autocrine VEGF was self-sustained through increasing VEGF mRNA and protein expression. It exerted pro-proliferative effect through a PLC-ERK1/2 dependent pathway. Furthermore, we demonstrated that in VEGFR2 overexpressing gastric cancer cells, Apatinib inhibited cell proliferation in vitro and delayed xenograft tumor growth in vivo. However, these effects were not observed in VEGFR2 low expressing gastric cancer cells. Conclusion These results suggested that autocrine VEGF signaling promotes gastric cancer cell proliferation and enhances Apatinib treatment outcome in VEGFR2 overexpression gastric cancer cells both in vitro and in vivo. This study would enable better stratification of gastric cancer patients for clinical treatment decision. PMID:28061477

Ortho stops marketing Lippes Loop; cites economic factors.

PubMed

1985-11-01

Ortho Pharmaceutical Corporation has stopped marketing the Lippes Loop IUD, the only inert IUD currently available in the US. The firm cited "economic considerations" as its reason. Linda Organ, company spokeswoman, told Contraceptive Technology Update (CTU) that the number of women using IUDs has declined in the past few years and, as a result, Ortho's Lippes Loop sales dropped. Most physicians, according to Organ, currently prescribe copper-bearing IUDs. Few devices have been studied as thoroughly before marketing as the Lippes Loop, according to its developer, Dr. Jack Lippes. Lippes told CTU that the Population Council analyzed 40,000 women from 1962 to 1968 and "found no trouble with the Loop." Lippes attributes Ortho's recent decision to 2 factors: the IUD has been only "marginally profitable" and the problems of A.H. Robins with the Dalkon Shield has most likely had an effect; and the US Food and Drug Administration (FDA) published a proposed rule in August 1985 that would require any company wanting to manufacture and market IUDs like the Lippes Loop to submit a premarketing approval application to that agency. In effect, the FDA's rule would only apply to the Lippes Loop. Under the proposed rule, any company wanting to market Lippes Loops, or any nondrug IUD, would have to submit an application to the FDA with a detailed discussion and supporting clinical studies addressing the following concerns: pelvic actinomycosis; tubal infertility; duration that the IUD should remain in situ; and safety of leaving the IUD in situ when contraception is no longer indicated. According to Lillian Yin, FDA device evaluation, the clinical effectiveness and most of the safety issues regarding inert IUDs have been thoroughly covered in published data. She told CTU that "most of the information needed is straightforward, but the part that's new involves the long term use infection rate." Yin indicated that the FDA received a letter from Ortho advising the agency of the

Reversion of autocrine transformation by a dominant negative platelet-derived growth factor mutant.

PubMed

Vassbotn, F S; Andersson, M; Westermark, B; Heldin, C H; Ostman, A

1993-07-01

A non-receptor-binding mutant of the platelet-derived growth factor (PDGF) A chain, PDGF-0, was generated by exchanging 7 amino acids in the sequence. The mutant chains formed dimers that were similar to wild-type PDGF-AA with regard to stability and rate of processing to the mature 30-kDa secreted forms. Moreover, the mutant chains formed disulfide-bonded heterodimers with the PDGF B chain in NIH 3T3 cells heterodimer underwent the same processing and secretion as PDGF-AB. Transfection of c-sis-expressing 3T3 cells with PDGF-0 significantly inhibited the transformed phenotype of these cells, as determined by the following criteria. (i) Compared with PDGF-0-negative clones, PDGF-0-producing clones showed a reverted morphology. (ii) Clones producing PDGF-0 grew more slowly than PDGF-0-negative clones, with a fivefold difference in cell number after 14 days in culture. (iii) The expression of PDGF-0 completely inhibited the ability of the c-sis-expressing 3T3 cells to form colonies in soft agar; this inhibition was overcome by the addition of recombinant PDGF-BB to the culture medium, showing that the lack of colony formation of these cells was not due to a general unresponsiveness to PDGF. The specific expression of a PDGF-0/PDGF wild-type heterodimer in COS cells revealed that the affinity of the mutant heterodimer for the PDGF alpha receptor was decreased by approximately 50-fold compared with that of PDGF-AA. Thus, we show that a non-receptor-binding PDGF A-chain mutant neutralizes in a trans-dominant manner the autocrine transforming potential of the c-sis/PDGF B chain by forming low-affinity heterodimers with wild-type PDGF chains. This method of specifically antagonizing the effect of PDGF may be useful in investigations of the role of PDGF in normal and pathological conditions.

Endothelium-derived fibronectin regulates neonatal vascular morphogenesis in an autocrine fashion.

PubMed

Turner, Christopher J; Badu-Nkansah, Kwabena; Hynes, Richard O

2017-11-01

Fibronectin containing alternatively spliced EIIIA and EIIIB domains is largely absent from mature quiescent vessels in adults, but is highly expressed around blood vessels during developmental and pathological angiogenesis. The precise functions of fibronectin and its splice variants during developmental angiogenesis however remain unclear due to the presence of cardiac, somitic, mesodermal and neural defects in existing global fibronectin KO mouse models. Using a rare family of surviving EIIIA EIIIB double KO mice, as well as inducible endothelial-specific fibronectin-deficient mutant mice, we show that vascular development in the neonatal retina is regulated in an autocrine manner by endothelium-derived fibronectin, and requires both EIIIA and EIIIB domains and the RGD-binding α5 and αv integrins for its function. Exogenous sources of fibronectin do not fully substitute for the autocrine function of endothelial fibronectin, demonstrating that fibronectins from different sources contribute differentially to specific aspects of angiogenesis.

Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects.

PubMed

Granero-Moltó, Froilán; Myers, Timothy J; Weis, Jared A; Longobardi, Lara; Li, Tieshi; Yan, Yun; Case, Natasha; Rubin, Janet; Spagnoli, Anna

2011-10-01

Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC(IGF)), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC(IGF) or traceable MSC(IGF)-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1(-/-)) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC(IGF) through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC(IGF) to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1(-/-) mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1(-/-) left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC(IGF) in fracture repair and potentially to treat nonunions. Copyright © 2011 AlphaMed Press.

One-loop Parke-Taylor factors for quadratic propagators from massless scattering equations

NASA Astrophysics Data System (ADS)

Gomez, Humberto; Lopez-Arcos, Cristhiam; Talavera, Pedro

2017-10-01

In this paper we reconsider the Cachazo-He-Yuan construction (CHY) of the so called scattering amplitudes at one-loop, in order to obtain quadratic propagators. In theories with colour ordering the key ingredient is the redefinition of the Parke-Taylor factors. After classifying all the possible one-loop CHY-integrands we conjecture a new one-loop amplitude for the massless Bi-adjoint Φ3 theory. The prescription directly reproduces the quadratic propagators of the traditional Feynman approach.

Two-loop matching factors for light quark masses and three-loop mass anomalous dimensions in the RI/SMOM schemes

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

Sturm, C.; Almeida, L.

2010-04-26

Light quark masses can be determined through lattice simulations in regularization invariant momentum-subtraction (RI/MOM) schemes. Subsequently, matching factors, computed in continuum perturbation theory, are used in order to convert these quark masses from a RI/MOM scheme to the {ovr MS} scheme. We calculate the two-loop corrections in QCD to these matching factors as well as the three-loop mass anomalous dimensions for the RI/SMOM and RI/SMOM{sub {gamma}{mu}} schemes. These two schemes are characterized by a symmetric subtraction point. Providing the conversion factors in the two different schemes allows for a better understanding of the systematic uncertainties. The two-loop expansion coefficients ofmore » the matching factors for both schemes turn out to be small compared to the traditional RI/MOM schemes. For n{sub f} = 3 quark flavors they are about 0.6%-0.7% and 2%, respectively, of the leading order result at scales of about 2 GeV. Therefore, they will allow for a significant reduction of the systematic uncertainty of light quark mass determinations obtained through this approach. The determination of these matching factors requires the computation of amputated Green's functions with the insertions of quark bilinear operators. As a by-product of our calculation we also provide the corresponding results for the tensor operator.« less

Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607

PubMed Central

2012-01-01

Background The c-Met receptor tyrosine kinase is aberrantly activated in many solid tumors. In a prior study we showed that prostate cancer PC-3 cells exhibit constitutively activated c-Met without exogenous hepatocyte growth factor (HGF); however whether this characteristic is due to an endogenous HGF/c-Met autocrine loop remains controversial. In the current study we examined the response of PC-3 cells to an anti-HGF neutralizing antibody or a small molecule Met kinase inhibitor (BMS-777607). Methods Cell scattering was tested by monitoring cell morphology after HGF stimulation. Cell migration was examined by both “wound-healing” and transwell assasy and invasion was detected by Matrigel-coated transwell assay. Proliferation, survival and anoikis were determined by MTT, colony formation and trypan blue exclusion assay, respectively. Gene and protein expression were assessed by real-time PCR and Western blot, respectively. Results Although HGF mRNA could be detected in PC-3 cells, the molecular weight of secreted “HGF” protein was inconsistent with the functional recombinant HGF. Furthermore, conditioned medium from PC-3 cell cultures was ineffective at triggering either motogenic behavior or c-Met signaling in DU145, another prostate cancer cell line expressing c-Met but lacking basal c-Met activation. PC-3 cells also were not responsive to the anti-HGF neutralizing antibody in experiments assessing proliferation, migration, or c-Met signaling. BMS-777607 treatment with micromolar doses nonetheless led to significant inhibition of multiple PC-3 cell functions including proliferation, clonogenicity, migration and invasion. At the molecular level, BMS-777607 suppressed autophosphorylated c-Met and downstream c-Src and Akt pathways. Conclusions These results suggest that the constitutive c-Met activation in PC-3 is independent of autocrine stimulation. Because PC-3 cells were responsive to BMS-777607 but not the anti-HGF antibody, the findings also indicate

Non-planar one-loop Parke-Taylor factors in the CHY approach for quadratic propagators

NASA Astrophysics Data System (ADS)

Ahmadiniaz, Naser; Gomez, Humberto; Lopez-Arcos, Cristhiam

2018-05-01

In this work we have studied the Kleiss-Kuijf relations for the recently introduced Parke-Taylor factors at one-loop in the CHY approach, that reproduce quadratic Feynman propagators. By doing this, we were able to identify the non-planar one-loop Parke-Taylor factors. In order to check that, in fact, these new factors can describe non-planar amplitudes, we applied them to the bi-adjoint Φ3 theory. As a byproduct, we found a new type of graphs that we called the non-planar CHY-graphs. These graphs encode all the information for the subleading order at one-loop, and there is not an equivalent of these in the Feynman formalism.

Reversion of autocrine transformation by a dominant negative platelet-derived growth factor mutant.

PubMed Central

Vassbotn, F S; Andersson, M; Westermark, B; Heldin, C H; Ostman, A

1993-01-01

A non-receptor-binding mutant of the platelet-derived growth factor (PDGF) A chain, PDGF-0, was generated by exchanging 7 amino acids in the sequence. The mutant chains formed dimers that were similar to wild-type PDGF-AA with regard to stability and rate of processing to the mature 30-kDa secreted forms. Moreover, the mutant chains formed disulfide-bonded heterodimers with the PDGF B chain in NIH 3T3 cells heterodimer underwent the same processing and secretion as PDGF-AB. Transfection of c-sis-expressing 3T3 cells with PDGF-0 significantly inhibited the transformed phenotype of these cells, as determined by the following criteria. (i) Compared with PDGF-0-negative clones, PDGF-0-producing clones showed a reverted morphology. (ii) Clones producing PDGF-0 grew more slowly than PDGF-0-negative clones, with a fivefold difference in cell number after 14 days in culture. (iii) The expression of PDGF-0 completely inhibited the ability of the c-sis-expressing 3T3 cells to form colonies in soft agar; this inhibition was overcome by the addition of recombinant PDGF-BB to the culture medium, showing that the lack of colony formation of these cells was not due to a general unresponsiveness to PDGF. The specific expression of a PDGF-0/PDGF wild-type heterodimer in COS cells revealed that the affinity of the mutant heterodimer for the PDGF alpha receptor was decreased by approximately 50-fold compared with that of PDGF-AA. Thus, we show that a non-receptor-binding PDGF A-chain mutant neutralizes in a trans-dominant manner the autocrine transforming potential of the c-sis/PDGF B chain by forming low-affinity heterodimers with wild-type PDGF chains. This method of specifically antagonizing the effect of PDGF may be useful in investigations of the role of PDGF in normal and pathological conditions. Images PMID:8321214

Conformal anomaly of generalized form factors and finite loop integrals

NASA Astrophysics Data System (ADS)

Chicherin, Dmitry; Sokatchev, Emery

2018-04-01

We reveal a new mechanism of conformal symmetry breaking at Born level. It occurs in generalized form factors with several local operators and an on-shell state of massless particles. The effect is due to hidden singularities on collinear configurations of the momenta. This conformal anomaly is different from the holomorphic anomaly of amplitudes. We present a number of examples in four and six dimensions. We find an application of the new conformal anomaly to finite loop momentum integrals with one or more massless legs. The collinear region around a massless leg creates a contact anomaly, made visible by the loop integration. The anomalous conformal Ward identity for an ℓ-loop integral is a 2nd-order differential equation whose right-hand side is an (ℓ - 1)-loop integral. It could serve as a new useful tool to find/test analytic expressions for conformal integrals. We illustrate this point with several examples of known integrals. We propose a new differential equation for the four-dimensional scalar double box.

CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling.

PubMed

Lin, C; Liao, W; Jian, Y; Peng, Y; Zhang, X; Ye, L; Cui, Y; Wang, B; Wu, X; Xiong, Z; Wu, S; Li, J; Wang, X; Song, L

2017-06-29

Metastatic relapse remains largely incurable and a major challenge of clinical management in breast cancer, but the underlying mechanisms are poorly understood. Herein, we report that CGI-99 is overexpressed in breast cancer tissues from patients with metastatic recurrence within 5 years. High CGI-99 significantly predicts poorer 5-year metastasis-free patient survival. We find that CGI-99 increases breast cancer stem cell properties, and potentiates efficient tumor lung colonization and outgrowth in vivo. Furthermore, we demonstrate that CGI-99 activates the autocrine interleukin-6 (IL-6)/STAT3 signaling by increasing the accumulation and activity of RNA polymerase II and p300 cofactor at the proximal promoter of IL-6. Importantly, delivery of the IL-6-receptor humanized monoclonal antibody tocilizumab robustly abrogates CGI-99-induced metastasis in vivo. Finally, we find that high levels of CGI-99 are significantly correlated with STAT3 hyperactivation in breast cancer patients. These findings reveal a potential mechanism for constitutive activation of autocrine IL-6/STAT3 signaling and may suggest a novel target for clinical intervention in breast cancer.

Mucin1 mediates autocrine transforming growth factor beta signaling through activating the c-Jun N-terminal kinase/activator protein 1 pathway in human hepatocellular carcinoma cells.

PubMed

Li, Qiongshu; Liu, Guomu; Shao, Dan; Wang, Juan; Yuan, Hongyan; Chen, Tanxiu; Zhai, Ruiping; Ni, Weihua; Tai, Guixiang

2015-02-01

In a previous study, we observed by global gene expression analysis that oncogene mucin1 (MUC1) silencing decreased transforming growth factor beta (TGF-β) signaling in the human hepatocellular carcinoma (HCC) cell line SMMC-7721. In this study, we report that MUC1 overexpression enhanced the levels of phosphorylated Smad3 linker region (p-Smad3L) (Ser-213) and its target gene MMP-9 in HCC cells, suggesting that MUC1 mediates TGF-β signaling. To investigate the effect of MUC1 on TGF-β signaling, we determined TGF-β secretion in MUC1 gene silencing and overexpressing cell lines. MUC1 expression enhanced not only TGF-β1 expression at the mRNA and protein levels but also luciferase activity driven by a TGF-β promoter, as well as elevated the activation of c-Jun N-terminal kinase (JNK) and c-Jun, a member of the activation protein 1 (AP-1) transcription factor family. Furthermore, pharmacological reduction of TGF-β receptor (TβR), JNK and c-Jun activity inhibited MUC1-induced autocrine TGF-β signaling. Moreover, a co-immunoprecipitation assay showed that MUC1 directly bound and activated JNK. In addition, both MUC1-induced TGF-β secretion and exogenous TGF-β1 significantly increased Smad signaling and cell migration, which were markedly inhibited by either TβR inhibitor or small interfering RNA silencing of TGF-β1 gene in HCC cells. The high correlation between MUC1 and TGF-β1 or p-Smad3L (Ser-213) expression was shown in tumor tissues from HCC patients by immunohistochemical staining analysis. Collectively, these results indicate that MUC1 mediates autocrine TGF-β signaling by activating the JNK/AP-1 pathway in HCC cells. Therefore, MUC1 plays a key role in HCC progression and could serve as an attractive target for HCC therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

PubMed Central

Marshall, Marianne E.; Hinz, Trista K.; Kono, Scott A.; Singleton, Katherine R.; Bichon, Brady; Ware, Kathryn E.; Marek, Lindsay; Frederick, Barbara A.; Raben, David; Heasley, Lynn E.

2011-01-01

Purpose We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC). Experimental Design FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and EGFR-dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR. Results FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed while only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and ERK signaling in three HNSCC cell lines while three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR TKIs with no contribution from FGFR pathways. Conclusions FGFR signaling was dominant or co-dominant with EGFR in six HNSCC lines while three lines exhibited little or no role for FGFRs and were highly EGFR-dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC. PMID:21673064

Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration

PubMed Central

Dias, Sergio; Hattori, Koichi; Zhu, Zhenping; Heissig, Beate; Choy, Margaret; Lane, William; Wu, Yan; Chadburn, Amy; Hyjek, Elizabeth; Gill, Muhammad; Hicklin, Daniel J.; Witte, Larry; Moore, M.A.S.; Rafii, Shahin

2000-01-01

Emerging data suggest that VEGF receptors are expressed by endothelial cells as well as hematopoietic stem cells. Therefore, we hypothesized that functional VEGF receptors may also be expressed in malignant counterparts of hematopoietic stem cells such as leukemias. We demonstrate that certain leukemias not only produce VEGF but also express functional VEGFR-2 in vivo and in vitro, resulting in the generation of an autocrine loop that may support leukemic cell survival and proliferation. Approximately 50% of freshly isolated leukemias expressed mRNA and protein for VEGFR-2. VEGF165 induced phosphorylation of VEGFR-2 and increased proliferation of leukemic cells, demonstrating these receptors were functional. VEGF165 also induced the expression of MMP-9 by leukemic cells and promoted their migration through reconstituted basement membrane. The neutralizing mAb IMC-1C11, specific to human VEGFR-2, inhibited leukemic cell survival in vitro and blocked VEGF165-mediated proliferation of leukemic cells and VEGF-induced leukemic cell migration. Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant elevation of human, but not murine, VEGF in plasma and death of inoculated mice within 3 weeks. Injection of IMC-1C11 inhibited proliferation of xenotransplanted human leukemias and significantly increased the survival of inoculated mice. Interruption of signaling by VEGFRs, particularly VEGFR-2, may provide a novel strategy for inhibiting leukemic cell proliferation. PMID:10953026

Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma.

PubMed

Peng, Hong; Zhang, Qiuyang; Li, Jiali; Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

2016-03-29

Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC.

Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma

PubMed Central

Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

2016-01-01

Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID:26967384

K-RAS(V12) Induces Autocrine Production of EGFR Ligands and Mediates Radioresistance Through EGFR-Dependent Akt Signaling and Activation of DNA-PKcs

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

Minjgee, Minjmaa; Toulany, Mahmoud; Kehlbach, Rainer

2011-12-01

Purpose: It is known that postirradiation survival of tumor cells presenting mutated K-RAS is mediated through autocrine activation of epidermal growth factor receptor (EGFR). In this study the molecular mechanism of radioresistance of cells overexpressing mutated K-RAS(V12) was investigated. Methods and Materials: Head-and-neck cancer cells (FaDu) presenting wild-type K-RAS were transfected with empty vector or vector expressing mutated K-RAS(V12). The effect of K-RAS(V12) on autocrine production of EGFR ligands, activation of EGFR downstream pathways, DNA damage repair, and postirradiation survival was analyzed. Results: Conditioned medium collected from K-RAS(V12)-transfected cells enhanced activation of the phosphatidylinositol-3-kinase-Akt pathway and increased postirradiation survival ofmore » wild-type K-RAS parental cells when compared with controls. These effects were reversed by amphiregulin (AREG)-neutralizing antibody. In addition, secretion of the EGFR ligands AREG and transforming growth factor {alpha} was significantly increased upon overexpression of K-RAS(V12). Expression of mutated K-RAS(V12) resulted in an increase in radiation-induced DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation at S2056. This increase was accompanied by increased repair of DNA double-strand breaks. Abrogation of DNA-PKcs phosphorylation by serum depletion or AREG-neutralizing antibody underscored the role of autocrine production of EGFR ligands, namely, AREG, in regulating DNA-PKcs activation in K-RAS mutated cells. Conclusions: These data indicate that radioresistance of K-RAS mutated tumor cells is at least in part due to constitutive production of EGFR ligands, which mediate enhanced repair of DNA double-strand breaks through the EGFR-phosphatidylinositol-3-kinase-Akt cascade.« less

Two-loop matching factors for light quark masses and three-loop mass anomalous dimensions in the regularization invariant symmetric momentum-subtraction schemes

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

Almeida, Leandro G.; Physics Department, Brookhaven National Laboratory, Upton, New York 11973; Sturm, Christian

2010-09-01

Light quark masses can be determined through lattice simulations in regularization invariant momentum-subtraction (RI/MOM) schemes. Subsequently, matching factors, computed in continuum perturbation theory, are used in order to convert these quark masses from a RI/MOM scheme to the MS scheme. We calculate the two-loop corrections in QCD to these matching factors as well as the three-loop mass anomalous dimensions for the RI/SMOM and RI/SMOM{sub {gamma}{sub {mu}} }schemes. These two schemes are characterized by a symmetric subtraction point. Providing the conversion factors in the two different schemes allows for a better understanding of the systematic uncertainties. The two-loop expansion coefficients ofmore » the matching factors for both schemes turn out to be small compared to the traditional RI/MOM schemes. For n{sub f}=3 quark flavors they are about 0.6%-0.7% and 2%, respectively, of the leading order result at scales of about 2 GeV. Therefore, they will allow for a significant reduction of the systematic uncertainty of light quark mass determinations obtained through this approach. The determination of these matching factors requires the computation of amputated Green's functions with the insertions of quark bilinear operators. As a by-product of our calculation we also provide the corresponding results for the tensor operator.« less

Endothelin-3 production by human rhabdomyosarcoma: a possible new marker with a paracrine role.

PubMed

Palladini, Arianna; Astolfi, Annalisa; Croci, Stefania; De Giovanni, Carla; Nicoletti, Giordano; Rosolen, Angelo; Sartori, Francesca; Lollini, Pier-Luigi; Landuzzi, Lorena; Nanni, Patrizia

2006-03-01

Several autocrine and paracrine growth factor circuits have been found in human rhabdomyosarcoma cells. In this study we show that endothelin-3 (ET-3), a vasoactive peptide, is produced by human rhabdomyosarcoma cell lines, whereas it is not expressed by human sarcoma cell lines of non-muscle origin. We did not find evidence of a significant autocrine loop; nevertheless ET-3 produced by rhabdomyosarcoma cells can act as a paracrine factor, since it promotes migration of endothelial cells. Moreover ET-3 is present in plasma of mice bearing xenografts of human rhabdomyosarcoma cells, and may be potential new marker of the human rhabdomyosarcoma to be studied further.

Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGFβ3

PubMed Central

2012-01-01

Background Valvulogenesis and septation in the developing heart depend on the formation and remodeling of endocardial cushions in the atrioventricular canal (AVC) and outflow tract (OFT). These cushions are invaded by a subpopulation of endocardial cells that undergo an epithelial-mesenchymal transition in response to paracrine and autocrine transforming growth factor β (TGFβ) signals. We previously demonstrated that the RNA binding protein muscleblind-like 1 (MBNL1) is expressed specifically in the cushion endocardium, and knockdown of MBNL1 in stage 14 embryonic chicken AVC explants enhances TGFβ-dependent endocardial cell invasion. Results In this study, we demonstrate that the effect of MBNL1 knockdown on invasion remains dependent on TGFβ3 after it is no longer required to induce basal levels of invasion. TGFβ3, but not TGFβ2, levels are elevated in medium conditioned by MBNL1-depleted AVC explants. TGFβ3 is elevated even when the myocardium is removed, indicating that MBNL1 modulates autocrine TGFβ3 production in the endocardium. More TGFβ3-positive cells are observed in the endocardial monolayer following MBNL1 knockdown. Addition of exogenous TGFβ3 to AVC explants recapitulates the effects of MBNL1 knockdown. Time course experiments demonstrate that knockdown of MBNL1 induces precocious TGFβ3 secretion, and early exposure to excess TGFβ3 induces precocious invasion. MBNL1 expression precedes TGFβ3 in the AVC endocardium, consistent with a role in preventing precocious autocrine TGFβ3 signaling. The stimulatory effects of MBNL1 knockdown on invasion are lost in stage 16 AVC explants. Knockdown of MBNL1 in OFT explants similarly enhances cell invasion, but not activation. TGFβ is necessary and sufficient to mediate this effect. Conclusions Taken together, these data support a model in which MBNL1 negatively regulates cell invasion in the endocardial cushions by restricting the magnitude and timing of endocardial-derived TGFβ3 production. PMID

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

Che, Qi; Liu, Bin-Ya; Wang, Fang-Yuan

Highlights: • IL-6 could promote endometrial cancer cells proliferation. • IL-6 promotes its own production through an autocrine feedback loop. • ERK and NF-κB pathway inhibitors inhibit IL-6 production and tumor growth. • IL-6 secretion relies on the activation of ERK–NF-κB pathway axis. • An orthotopic nude endometrial carcinoma model confirms the effect of IL-6. - Abstract: Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In thismore » study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK–NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.« less

IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: evidence for a role as an autocrine growth factor.

PubMed

Nicholl, Michael B; Ledgewood, Chelsea L; Chen, Xuhui; Bai, Qian; Qin, Chenglu; Cook, Kathryn M; Herrick, Elizabeth J; Diaz-Arias, Alberto; Moore, Bradley J; Fang, Yujiang

2014-12-01

Interleukin-35 (IL-35), an IL-12 cytokine family member, mediates the immune inhibitory function of regulatory T cells (Treg). We assayed the presence of IL-35 in paraffin-embedded human pancreas cancer (PCAN) and unexpectedly found IL-35 was expressed mainly by epithelial derived PCAN cells, but not by Treg. We further examined the expression and effect of exogenous IL-35 in human PCAN cell lines and found IL-35 promoted growth and inhibited apoptosis in PCAN cell lines. IL-35 induced proliferation correlated with an increase in cyclin B, cyclin D, cdk2, and cdk4 and a decrease in p27 expression, while inhibition of apoptosis was associated with an increase in Bcl-2 and a decrease in TRAILR1. We conclude IL-35 is produced by PCAN in vivo and promotes PCAN cell line growth in vitro. These results might indicate an important new role for IL-35 as an autocrine growth factor in PCAN growth. Copyright © 2014 Elsevier Ltd. All rights reserved.

Renormalization of loop functions for all loops

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

Brandt, R.A.; Neri, F.; Sato, M.

1981-08-15

It is shown that the vacuum expectation values W(C/sub 1/,xxx, C/sub n/) of products of the traces of the path-ordered phase factors P exp(igcontour-integral/sub C/iA/sub ..mu../(x)dx/sup ..mu../) are multiplicatively renormalizable in all orders of perturbation theory. Here A/sub ..mu../(x) are the vector gauge field matrices in the non-Abelian gauge theory with gauge group U(N) or SU(N), and C/sub i/ are loops (closed paths). When the loops are smooth (i.e., differentiable) and simple (i.e., non-self-intersecting), it has been shown that the generally divergent loop functions W become finite functions W when expressed in terms of the renormalized coupling constant and multipliedmore » by the factors e/sup -K/L(C/sub i/), where K is linearly divergent and L(C/sub i/) is the length of C/sub i/. It is proved here that the loop functions remain multiplicatively renormalizable even if the curves have any finite number of cusps (points of nondifferentiability) or cross points (points of self-intersection). If C/sub ..gamma../ is a loop which is smooth and simple except for a single cusp of angle ..gamma.., then W/sub R/(C/sub ..gamma../) = Z(..gamma..)W(C/sub ..gamma../) is finite for a suitable renormalization factor Z(..gamma..) which depends on ..gamma.. but on no other characteristic of C/sub ..gamma../. This statement is made precise by introducing a regularization, or via a loop-integrand subtraction scheme specified by a normalization condition W/sub R/(C-bar/sub ..gamma../) = 1 for an arbitrary but fixed loop C-bar/sub ..gamma../. Next, if C/sub ..beta../ is a loop which is smooth and simple except for a cross point of angles ..beta.., then W(C/sub ..beta../) must be renormalized together with the loop functions of associated sets S/sup i//sub ..beta../ = )C/sup i//sub 1/,xxx, C/sup i//sub p/i) (i = 2,xxx,I) of loops C/sup i//sub q/ which coincide with certain parts of C/sub ..beta../equivalentC/sup 1//sub 1/. Then W/sub R/(S/sup i//sub ..beta../) = Z/sup i

Reactive Oxygen Species Alter Autocrine and Paracrine Signaling

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

Zangar, Richard C.; Bollinger, Nikki; Weber, Thomas J.

2011-12-01

Cytochrome P450 (P450) 3A4 (CYP3A4) is the most abundant P450 protein in human liver and intestine and is highly inducible by a variety of drugs and other compounds. The P450 catalytic cycle is known to uncouple and release reactive oxygen species (ROS), but the effects of ROS from P450 and other enzymes in the endo-plasmic reticulum have been poorly studied from the perspective of effects on cell biology. In this study, we expressed low levels of CYP3A4 in HepG2 cells, a human hepatocarcinoma cell line, and examined effects on intracellular levels of ROS and on the secretion of a varietymore » of growth factors that are important in extracellular communication. Using the redox-sensitive dye RedoxSensor red, we demonstrate that CYP3A4 expression increases levels of ROS in viable cells. A customELISA microarray platform was employed to demonstrate that expression of CYP3A4 increased secretion of amphiregulin, intracellular adhesion molecule 1, matrix metalloprotease 2, platelet-derived growth factor (PDGF), and vascular endothelial growth factor, but suppressed secretion of CD14. The antioxidant N-acetylcysteine suppressed all P450-dependent changes in protein secretion except for CD14. Quantitative RT-PCR demonstrated that changes in protein secretion were consistently associated with corresponding changes in gene expression. Inhibition of the NF-{kappa}B pathway blocked P450 effects on PDGF secretion. CYP3A4 expression also altered protein secretion in human mammary epithelial cells and C10 mouse lung cells. Overall, these results suggest that increased ROS production in the endoplasmic reticulum alters the secretion of proteins that have key roles in paracrine and autocrine signaling.« less

Autocrine regulation of ecdysone synthesis by β3-octopamine receptor in the prothoracic gland is essential for Drosophila metamorphosis.

PubMed

Ohhara, Yuya; Shimada-Niwa, Yuko; Niwa, Ryusuke; Kayashima, Yasunari; Hayashi, Yoshiki; Akagi, Kazutaka; Ueda, Hitoshi; Yamakawa-Kobayashi, Kimiko; Kobayashi, Satoru

2015-02-03

In Drosophila, pulsed production of the steroid hormone ecdysone plays a pivotal role in developmental transitions such as metamorphosis. Ecdysone production is regulated in the prothoracic gland (PG) by prothoracicotropic hormone (PTTH) and insulin-like peptides (Ilps). Here, we show that monoaminergic autocrine regulation of ecdysone biosynthesis in the PG is essential for metamorphosis. PG-specific knockdown of a monoamine G protein-coupled receptor, β3-octopamine receptor (Octβ3R), resulted in arrested metamorphosis due to lack of ecdysone. Knockdown of tyramine biosynthesis genes expressed in the PG caused similar defects in ecdysone production and metamorphosis. Moreover, PTTH and Ilps signaling were impaired by Octβ3R knockdown in the PG, and activation of these signaling pathways rescued the defect in metamorphosis. Thus, monoaminergic autocrine signaling in the PG regulates ecdysone biogenesis in a coordinated fashion on activation by PTTH and Ilps. We propose that monoaminergic autocrine signaling acts downstream of a body size checkpoint that allows metamorphosis to occur when nutrients are sufficiently abundant.

Replication Fork Protection Factors Controlling R-Loop Bypass and Suppression.

PubMed

Chang, Emily Yun-Chia; Stirling, Peter C

2017-01-14

Replication-transcription conflicts have been a well-studied source of genome instability for many years and have frequently been linked to defects in RNA processing. However, recent characterization of replication fork-associated proteins has revealed that defects in fork protection can directly or indirectly stabilize R-loop structures in the genome and promote transcription-replication conflicts that lead to genome instability. Defects in essential DNA replication-associated activities like topoisomerase, or the minichromosome maintenance (MCM) helicase complex, as well as fork-associated protection factors like the Fanconi anemia pathway, both appear to mitigate transcription-replication conflicts. Here, we will highlight recent advances that support the concept that normal and robust replisome function itself is a key component of mitigating R-loop coupled genome instability.

PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact.

PubMed

Lee, Byung-Chul; Kim, Hyung-Sik; Shin, Tae-Hoon; Kang, Insung; Lee, Jin Young; Kim, Jae-Jun; Kang, Hyun Kyoung; Seo, Yoojin; Lee, Seunghee; Yu, Kyung-Rok; Choi, Soon Won; Kang, Kyung-Sun

2016-05-27

Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency.

Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways.

PubMed

Yu, Li; Liu, Qi; Canning, Brendan J

2018-03-05

Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways. By direct measures of histamine, cysteinyl-leukotriene and thromboxane release and with studies of allergen-evoked contractions of airway smooth muscle, we describe a complex interplay amongst these autacoids. Notably, we observed an autocrine effect of the cysteinyl-leukotrienes acting through cysLT 1 receptors on mast cell leukotriene release. We confirmed the results of previous studies demonstrating a marked enhancement of mast cell mediator release following cyclooxygenase inhibition, but we have extended these results by showing that COX-2 derived eicosanoids inhibit cysteinyl-leukotriene release and yet are without effect on histamine release. Given the prominent role of COX-1 inhibition in aspirin-sensitive asthma, these data implicate preformed mediators stored in granules as the initial drivers of these adverse reactions. Finally, we describe the paracrine signaling cascade leading to thromboxane synthesis in the guinea pig airways following allergen challenge, which occurs indirectly, secondary to cysLT 1 receptor activation on structural cells and/ or leukocytes within the airway wall, and a COX-2 dependent synthesis of the eicosanoid. The results highlight the importance of cell-cell and autocrine interactions in regulating allergic responses in the airways. Copyright © 2017. Published by Elsevier B.V.

Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival

PubMed Central

Pan, Yuan; Smithson, Laura J.; Ma, Yu; Hambardzumyan, Dolores; Gutmann, David H.

2017-01-01

Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a median survival of 15 months. These poor clinical outcomes have prompted the development of drugs that block neoplastic cancer cell growth; however, non-neoplastic cell-derived signals (chemokines and cytokines) in the tumor microenvironment may also represent viable treatment targets. One such chemokine, Ccl5, produced by low-grade tumor-associated microglia, is responsible for maintaining neurofibromatosis type 1 (NF1) mouse optic glioma growth in vivo. Since malignant gliomas may achieve partial independence from growth regulatory factors produced by non-neoplastic cells in the tumor microenvironment by producing the same cytokines secreted by the stromal cells in their low-grade counterparts, we tested the hypothesis that CCL5/CCL5-receptor signaling in glioblastoma creates an autocrine circuit important for high-grade glioma growth. Herein, we demonstrate that increased CCL5 expression was restricted to both human and mouse mesenchymal GBM (M-GBM), a molecular subtype characterized by NF1 loss. We further show that the NF1 protein, neurofibromin, negatively regulates Ccl5 expression through suppression of AKT/mTOR signaling. Consistent with its role as a glioblastoma growth regulator, Ccl5 knockdown in M-GBM cells reduces M-GBM cell survival in vitro, and increases mouse glioblastoma survival in vivo. Finally, we demonstrate that Ccl5 operates through an unconventional CCL5 receptor, CD44, to inhibit M-GBM apoptosis. Collectively, these findings reveal an NF1-dependent CCL5-mediated pathway that regulates M-GBM cell survival, and support the concept that paracrine factors important for low-grade glioma growth can be usurped by high-grade tumors to create autocrine regulatory circuits that maintain malignant glioma survival. PMID:28380429

WNT11 expression is induced by ERRα and β-catenin and acts in an autocrine manner to increase cancer cell migration

PubMed Central

Dwyer, Mary A.; Joseph, James; Wade, Hilary E.; Eaton, Matthew L.; Kunder, Rebecca S.; Kazmin, Dmitri; Chang, Ching-yi; McDonnell, Donald P.

2010-01-01

Elevated expression of the orphan nuclear receptor estrogen-related receptor alpha (ERRα) has been associated with a negative outcome in several cancers, although the mechanism(s) by which this receptor influences the pathophysiology of this disease and how its activity is regulated remains unknown. Using a chemical biology approach it was determined that compounds, previously shown to inhibit canonical Wnt signaling, also inhibited the transcriptional activity of ERRα. The significance of this association was revealed in a series of biochemical and genetic experiments that demonstrate that (a) ERRα, β-catenin (β-cat) and Lymphoid enhancer-binding factor-1 (LEF-1) form macromolecular complexes in cells, (b) ERRα transcriptional activity is enhanced by βcat expression and vice versa, and (c) there is a high level of overlap among genes previously shown to be regulated by ERRα or β-cat. Furthermore, silencing of ERRα and β-cat expression individually or together dramatically reduced the migratory capacity of both breast and prostate cancer cells in vitro. This increased migration could be attributed to the ERRα/β-cat dependent induction of WNT11. Specifically, using (a) conditioned media from cells overexpressing recombinant WNT11 or (b) WNT11 neutralizing antibodies, we were able to demonstrate that this protein was the key mediator of the promigratory activities of ERRα/β-cat. Together, these data provide evidence for an autocrine regulatory loop involving transcriptional upregulation of WNT11 by ERRα and β-cat that influences the migratory capacity of cancer cells. PMID:20870744

High-mobility group box-1 as an autocrine trophic factor in white matter stroke.

PubMed

Choi, Jun Young; Cui, Yuexian; Chowdhury, Samma Tasneem; Kim, Byung Gon

2017-06-20

Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions.

Stable Ectopic Expression of ST6GALNAC5 Induces Autocrine MET Activation and Anchorage-Independence in MDCK Cells.

PubMed

Chu, Chia; Bottaro, Donald P; Betenbaugh, Michael J; Shiloach, Joseph

2016-01-01

The epithelial-mesenchymal transition (EMT) is a complex cancer progression that can boost the metastatic potential of transformed cells by inducing migration, loss of cell adhesion, and promoting proliferation under anchorage-independent conditions. A DNA microarray analysis was performed comparing parental anchorage-dependent MDCK cells and anchorage-independent MDCK cells that were engineered to express human siat7e (ST6GALNAC5). The comparison identified several genes involved in the EMT process that were differentially expressed between the anchorage-dependent and the anchorage-independent MDCK cell lines. The hepatocyte growth factor gene (hgf) was found to be over-expressed in the engineered MDCK-siat7e cells at both transcription and protein expression levels. Phosphorylation analysis of the MET receptor tyrosine kinase confirmed the activation of an autocrine loop of the HGF/ MET signaling pathway in the MDCK-siat7e cells. When MET activities were suppressed by using the small-molecular inhibitor drug PF-02341066 (Crizotinib), the anchorage-independent MDCK-siat7e cells reverted to the cellular morphology of the parental anchorage-dependent MDCK cells. These observations indicate that the MET receptor plays a central role in the growth properties of the MDCK cells and its phosphorylation status is likely dependent on sialylation. Further investigation of the downstream signaling targets in the MET network showed that the degree of MDCK cell adhesion correlated with secretion levels of a matrix metalloproteinase, MMP1, suggesting a role of metalloproteinases in the EMT process. These results demonstrate that in addition to its application in biotechnology processes, MDCK-siat7e may serve as a model cell for metastasis studies to decipher the sequence of events leading up to the activation of EMT.

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation

PubMed Central

Luna-Gomes, Tatiana; Magalhães, Kelly G; Mesquita-Santos, Fabio P.; Bakker-Abreu, Ilka; Samico, Rafaela F.; Molinaro, Raphael; Calheiros, Andrea S.; Diaz, Bruno L.; Bozza, Patrícia T.

2011-01-01

Prostaglandin (PG)D2 is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD2 synthesis, the hematopoietic PGD synthase (H-PGDS). Here, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD2. PGD2 synthesis was evaluated within human blood eosinophils, in vitro-differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD2 was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within non-stimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1 – 5 μM) evoked PGD2 synthesis, which was located at the nuclear envelope and was inhibited by pre-treatment with HQL-79 (10 μM), a specific H-PGDS inhibitor. Pre-stimulation of human eosinophils with arachidonic acid (AA; 10 μM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD2 synthesis, which, by acting on membrane-expressed specific receptors (DP1 and DP2), displayed an autocrine/paracrine ability to trigger leukotriene (LT)C4 synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro-differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD2 in response to AA stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD2-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD2, hence representing during allergic inflammation an extra cell source of PGD2, which functions as an autocrine signal for eosinophil activation. PMID:22102725

Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization

PubMed Central

Tonkin, Joanne; Temmerman, Lieve; Sampson, Robert D; Gallego-Colon, Enrique; Barberi, Laura; Bilbao, Daniel; Schneider, Michael D; Musarò, Antonio; Rosenthal, Nadia

2015-01-01

Insulin-like growth factor 1 (IGF-1) is a potent enhancer of tissue regeneration, and its overexpression in muscle injury leads to hastened resolution of the inflammatory phase. Here, we show that monocytes/macrophages constitute an important initial source of IGF-1 in muscle injury, as conditional deletion of the IGF-1 gene specifically in mouse myeloid cells (ϕIGF-1 CKO) blocked the normal surge of local IGF-1 in damaged muscle and significantly compromised regeneration. In injured muscle, Ly6C+ monocytes/macrophages and CD206+ macrophages expressed equivalent IGF-1 levels, which were transiently upregulated during transition from the inflammation to repair. In injured ϕIGF-1 CKO mouse muscle, accumulation of CD206+ macrophages was impaired, while an increase in Ly6C+ monocytes/macrophages was favored. Transcriptional profiling uncovered inflammatory skewing in ϕIGF-1 CKO macrophages, which failed to fully induce a reparative gene program in vitro or in vivo, revealing a novel autocrine role for IGF-1 in modulating murine macrophage phenotypes. These data establish local macrophage-derived IGF-1 as a key factor in inflammation resolution and macrophage polarization during muscle regeneration. PMID:25896247

Regulation of Dense-Core Granule Replenishment by Autocrine BMP Signalling in Drosophila Secondary Cells.

PubMed

Redhai, Siamak; Hellberg, Josephine E E U; Wainwright, Mark; Perera, Sumeth W; Castellanos, Felix; Kroeger, Benjamin; Gandy, Carina; Leiblich, Aaron; Corrigan, Laura; Hilton, Thomas; Patel, Benjamin; Fan, Shih-Jung; Hamdy, Freddie; Goberdhan, Deborah C I; Wilson, Clive

2016-10-01

Regulated secretion by glands and neurons involves release of signalling molecules and enzymes selectively concentrated in dense-core granules (DCGs). Although we understand how many secretagogues stimulate DCG release, how DCG biogenesis is then accelerated to replenish the DCG pool remains poorly characterised. Here we demonstrate that each prostate-like secondary cell (SC) in the paired adult Drosophila melanogaster male accessory glands contains approximately ten large DCGs, which are loaded with the Bone Morphogenetic Protein (BMP) ligand Decapentaplegic (Dpp). These DCGs can be marked in living tissue by a glycophosphatidylinositol (GPI) lipid-anchored form of GFP. In virgin males, BMP signalling is sporadically activated by constitutive DCG secretion. Upon mating, approximately four DCGs are typically released immediately, increasing BMP signalling, primarily via an autocrine mechanism. Using inducible knockdown specifically in adult SCs, we show that secretion requires the Soluble NSF Attachment Protein, SNAP24. Furthermore, mating-dependent BMP signalling not only promotes cell growth, but is also necessary to accelerate biogenesis of new DCGs, restoring DCG number within 24 h. Our analysis therefore reveals an autocrine BMP-mediated feedback mechanism for matching DCG release to replenishment as secretion rates fluctuate, and might explain why in other disease-relevant systems, like pancreatic β-cells, BMP signalling is also implicated in the control of secretion.

Regulation of Dense-Core Granule Replenishment by Autocrine BMP Signalling in Drosophila Secondary Cells

PubMed Central

Redhai, Siamak; Hellberg, Josephine E. E. U.; Wainwright, Mark; Perera, Sumeth W.; Castellanos, Felix; Kroeger, Benjamin; Gandy, Carina; Leiblich, Aaron; Corrigan, Laura; Hilton, Thomas; Patel, Benjamin; Fan, Shih-Jung; Hamdy, Freddie; Goberdhan, Deborah C. I.

2016-01-01

Regulated secretion by glands and neurons involves release of signalling molecules and enzymes selectively concentrated in dense-core granules (DCGs). Although we understand how many secretagogues stimulate DCG release, how DCG biogenesis is then accelerated to replenish the DCG pool remains poorly characterised. Here we demonstrate that each prostate-like secondary cell (SC) in the paired adult Drosophila melanogaster male accessory glands contains approximately ten large DCGs, which are loaded with the Bone Morphogenetic Protein (BMP) ligand Decapentaplegic (Dpp). These DCGs can be marked in living tissue by a glycophosphatidylinositol (GPI) lipid-anchored form of GFP. In virgin males, BMP signalling is sporadically activated by constitutive DCG secretion. Upon mating, approximately four DCGs are typically released immediately, increasing BMP signalling, primarily via an autocrine mechanism. Using inducible knockdown specifically in adult SCs, we show that secretion requires the Soluble NSF Attachment Protein, SNAP24. Furthermore, mating-dependent BMP signalling not only promotes cell growth, but is also necessary to accelerate biogenesis of new DCGs, restoring DCG number within 24 h. Our analysis therefore reveals an autocrine BMP-mediated feedback mechanism for matching DCG release to replenishment as secretion rates fluctuate, and might explain why in other disease-relevant systems, like pancreatic β-cells, BMP signalling is also implicated in the control of secretion. PMID:27727275

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis.

PubMed

Charbonneau, Martine; Lavoie, Roxane R; Lauzier, Annie; Harper, Kelly; McDonald, Patrick P; Dubois, Claire M

2016-04-15

Fibroblast-like synoviocytes (FLS) play a major role in invasive joint destruction in rheumatoid arthritis (RA). This prodestructive phenotype has been shown to involve autocrine TGF-β that triggers formation of matrix-degrading invadosomes through molecular mechanisms that are not fully elucidated. The platelet-derived growth factor (PDGF) receptor (PDGFR) family of receptor tyrosine kinases (RTK) has been shown to cooperate with TGF-β in various pathological conditions. We therefore sought to determine whether RTK activity played a role in invadosome biogenesis. We demonstrated that, among the common RTKs, PDGFR-αβ was specifically phosphorylated in FLS from RA patients. Phosphorylation of PDGFR-αβ was also elevated in RA synovial tissues. Interference with PDGFR activation or PDGF neutralization inhibited invadosome formation in RA synoviocytes, indicating the presence of an autocrine PDGFR activation loop that involved endogenous PDGF. Among the PDGF-A-D isoforms, only PDGF-B was found both significantly elevated in FLS lines from RA patients, and related to high-invadosome forming cells. Addition of TGF-β upregulated invadosome formation, PDGF-B mRNA expression, and phosphorylation of PDGFR. All of these functions were efficiently suppressed by TGF-β neutralization or interference with the Smad/TβR1or PI3K/Akt pathway. Among the class 1 PI3K family proteins known to be expressed in RA synoviocytes, PI3Kα was selectively involved in PDGF-B expression, whereas both PI3Kα and PI3Kδ participated in invadosome formation. Our findings demonstrate that PDGFR is a critical RTK required for the prodestructive phenotype of RA synovial cells. They also provide evidence for an association between autocrine TGF-β and PDGFR-mediated invadosome formation in RA synoviocytes that involves the production of PDGF-B induced by TGF-β. Copyright © 2016 by The American Association of Immunologists, Inc.

Human Umbilical Cord Perivascular Cells Exhibited Enhanced Migration Capacity towards Hepatocellular Carcinoma in Comparison with Bone Marrow Mesenchymal Stromal Cells: A Role for Autocrine Motility Factor Receptor

PubMed Central

Aquino, Jorge B.; Malvicini, Mariana; Bolontrade, Marcela; Podhajcer, Osvaldo; Garcia, Mariana G.; Mazzolini, Guillermo

2014-01-01

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Unfortunately, the incidence and mortality associated with HCC are increasing. Therefore, new therapeutic strategies are urgently needed and the use of mesenchymal stromal cells (MSCs) as carrier of therapeutic genes is emerging as a promising option. Different sources of MSCs are being studied for cell therapy and bone marrow-derived cells are the most extensively explored; however, birth associated-tissues represent a very promising source. The aim of this work was to compare the in vitro and in vivo migration capacity between bone marrow MSCs (BM-MSCs) and human umbilical cord perivascular cells (HUCPVCs) towards HCC. We observed that HUCPVCs presented higher in vitro and in vivo migration towards factors released by HCC. The expression of autocrine motility factor (AMF) receptor, genes related with the availability of the receptor on the cell surface (caveolin-1 and -2) and metalloproteinase 3, induced by the receptor activation and important for cell migration, was increased in HUCPVCs. The chemotactic response towards recombinant AMF was increased in HUCPVCs compared to BM-MSCs, and its inhibition in the conditioned medium from HCC induced higher decrease in HUCPVC migration than in BM-MSC. Our results indicate that HUCPVCs could be a useful cellular source to deliver therapeutic genes to HCC. PMID:25147818

Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: a role for autocrine motility factor receptor.

PubMed

Bayo, Juan; Fiore, Esteban; Aquino, Jorge B; Malvicini, Mariana; Rizzo, Manglio; Peixoto, Estanislao; Alaniz, Laura; Piccioni, Flavia; Bolontrade, Marcela; Podhajcer, Osvaldo; Garcia, Mariana G; Mazzolini, Guillermo

2014-01-01

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Unfortunately, the incidence and mortality associated with HCC are increasing. Therefore, new therapeutic strategies are urgently needed and the use of mesenchymal stromal cells (MSCs) as carrier of therapeutic genes is emerging as a promising option. Different sources of MSCs are being studied for cell therapy and bone marrow-derived cells are the most extensively explored; however, birth associated-tissues represent a very promising source. The aim of this work was to compare the in vitro and in vivo migration capacity between bone marrow MSCs (BM-MSCs) and human umbilical cord perivascular cells (HUCPVCs) towards HCC. We observed that HUCPVCs presented higher in vitro and in vivo migration towards factors released by HCC. The expression of autocrine motility factor (AMF) receptor, genes related with the availability of the receptor on the cell surface (caveolin-1 and -2) and metalloproteinase 3, induced by the receptor activation and important for cell migration, was increased in HUCPVCs. The chemotactic response towards recombinant AMF was increased in HUCPVCs compared to BM-MSCs, and its inhibition in the conditioned medium from HCC induced higher decrease in HUCPVC migration than in BM-MSC. Our results indicate that HUCPVCs could be a useful cellular source to deliver therapeutic genes to HCC.

Autocrine stimulation of IL-10 is critical to the enrichment of IL-10-producing CD40(hi)CD5(+) regulatory B cells in vitro and in vivo.

PubMed

Kim, Hyuk Soon; Lee, Jun Ho; Han, Hee Dong; Kim, A-Ram; Nam, Seung Taek; Kim, Hyun Woo; Park, Young Hwan; Lee, Dajeong; Lee, Min Bum; Park, Yeong Min; Kim, Hyung Sik; Kim, Young Mi; You, Ji Chang; Choi, Wahn Soo

2015-01-01

IL-10-producing B (Breg) cells regulate various immune responses. However, their phenotype remains unclear. CD40 expression was significantly increased in B cells by LPS, and the Breg cells were also enriched in CD40(hi)CD5(+) B cells. Furthermore, CD40 expression on Breg cells was increased by IL-10, CD40 ligand, and B cell-activating factor, suggesting that CD40(hi) is a common phenotype of Breg cells. LPS-induced CD40 expression was largely suppressed by an anti-IL-10 receptor antibody and in IL-10(-/-)CD5(+)CD19(+) B cells. The autocrine effect of IL-10 on the CD40 expression was largely suppressed by an inhibitor of JAK/STAT3. In vivo, the LPS treatment increased the population of CD40(hi)CD5(+) Breg cells in mice. However, the population of CD40(hi)CD5(+) B cells was minimal in IL-10(-/-) mice by LPS. Altogether, our findings show that Breg cells are largely enriched in CD40(hi)CD5(+) B cells and the autocrine effect of IL-10 is critical to the formation of CD40(hi)CD5(+) Breg cells.

Regulative Loops, Step Loops and Task Loops

ERIC Educational Resources Information Center

VanLehn, Kurt

2016-01-01

This commentary suggests a generalization of the conception of the behavior of tutoring systems, which the target article characterized as having an outer loop that was executed once per task and an inner loop that was executed once per step of the task. A more general conception sees these two loops as instances of regulative loops, which…

Modulation of c-fms proto-oncogene in an ovarian carcinoma cell line by a hammerhead ribozyme.

PubMed Central

Yokoyama, Y.; Morishita, S.; Takahashi, Y.; Hashimoto, M.; Tamaya, T.

1997-01-01

Co-expression of macrophage colony-stimulating factor (M-CSF) and its receptor (c-fms) is often found in ovarian epithelial carcinoma, suggesting the existence of autocrine regulation of cell growth by M-CSF. To block this autocrine loop, we have developed hammerhead ribozymes against c-fms mRNA. As target sites of the ribozyme, we chose the GUC sequence in codon 18 and codon 27 of c-fms mRNA. Two kinds of ribozymes were able to cleave an artificial c-fms RNA substrate in a cell-free system, although the ribozyme against codon 18 was much more efficient than that against codon 27. We next constructed an expression vector carrying a ribozyme sequence that targeted the GUC sequence in codon 18 of c-fms mRNA. It was introduced into TYK-nu cells that expressed M-CSF and its receptor. Its transfectant showed a reduced growth potential. The expression levels of c-fms protein and mRNA in the transfectant were clearly decreased with the expression of ribozyme RNA compared with that of an untransfected control or a transfectant with the vector without the ribozyme sequence. These results suggest that the ribozyme against GUC in codon 18 of c-fms mRNA is a promising tool for blocking the autocrine loop of M-CSF in ovarian epithelial carcinoma. Images Figure 2 Figure 3 Figure 5 Figure 6 PMID:9376277

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

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

Briolay, A.; Lencel, P.; Bessueille, L.

2013-01-18

Highlights: ► Ankylosing spondylitis (AS) leads to bone fusions and ankylosis. ► TNF-α stimulates osteoblasts through growth factors in AS. ► We compare the involvement of canonical vs non-canonical Wnt signaling. ► Canonical Wnt signaling is not involved in TNF-α effects in differentiating hMSCs. ► TNF-α stimulates osteoblasts through Wnt5a autocrine secretion in hMSCs. -- Abstract: Although anti-tumor necrosis factor (TNF)-α treatments efficiently block inflammation in ankylosing spondylitis (AS), they are inefficient to prevent excessive bone formation. In AS, ossification seems more prone to develop in sites where inflammation has resolved following anti-TNF therapy, suggesting that TNF-α indirectly stimulates ossification.more » In this context, our objectives were to determine and compare the involvement of Wnt proteins, which are potent growth factors of bone formation, in the effects of TNF-α on osteoblast function. In human mesenchymal stem cells (MSCs), TNF-α significantly increased the levels of Wnt10b and Wnt5a. Associated with this effect, TNF-α stimulated tissue-non specific alkaline phosphatase (TNAP) and mineralization. This effect was mimicked by activation of the canonical β-catenin pathway with either anti-Dkk1 antibodies, lithium chloride (LiCl) or SB216763. TNF-α reduced, and activation of β-catenin had little effect on expression of osteocalcin, a late marker of osteoblast differentiation. Surprisingly, TNF-α failed to stabilize β-catenin and Dkk1 did not inhibit TNF-α effects. In fact, Dkk1 expression was also enhanced in response to TNF-α, perhaps explaining why canonical signaling by Wnt10b was not activated by TNF-α. However, we found that Wnt5a also stimulated TNAP in MSCs cultured in osteogenic conditions, and increased the levels of inflammatory markers such as COX-2. Interestingly, treatment with anti-Wnt5a antibodies reduced endogenous TNAP expression and activity. Collectively, these data suggest that

Transforming growth factor-alpha short-circuits downregulation of the epidermal growth factor receptor.

PubMed

Ouyang, X; Gulliford, T; Huang, G; Epstein, R J

1999-04-01

Transforming growth factor-alpha (TGFalpha) is an epidermal growth factor receptor (EGFR) ligand which is distinguished from EGF by its acid-labile structure and potent transforming function. We recently reported that TGFalpha induces less efficient EGFR heterodimerization and downregulation than does EGF (Gulliford et al., 1997, Oncogene, 15:2219-2223). Here we use isoform-specific EGFR and ErbB2 antibodies to show that the duration of EGFR signalling induced by a single TGFalpha exposure is less than that induced by equimolar EGF. The protein trafficking inhibitor brefeldin A (BFA) reduces the duration of EGF signalling to an extent similar to that seen with TGFalpha alone; the effects of TGFalpha and BFA on EGFR degradation are opposite, however, with TGFalpha sparing EGFR from downregulation but BFA accelerating EGF-dependent receptor loss. This suggests that BFA blocks EGFR recycling and thus shortens EGF-dependent receptor signalling, whereas TGFalpha shortens receptor signalling and thus blocks EGFR downregulation. Consistent with this, repeated application of TGFalpha is accompanied by prolonged EGFR expression and signalling, whereas similar application of EGF causes receptor downregulation and signal termination. These findings indicate that constitutive secretion of pH-labile TGFalpha may perpetuate EGFR signalling by permitting early oligomer dissociation and dephosphorylation within acidic endosomes, thereby extinguishing a phosphotyrosine-based downregulation signal and creating an irreversible autocrine growth loop.

Filter for third order phase locked loops

NASA Technical Reports Server (NTRS)

Crow, R. B.; Tausworthe, R. C. (Inventor)

1973-01-01

Filters for third-order phase-locked loops are used in receivers to acquire and track carrier signals, particularly signals subject to high doppler-rate changes in frequency. A loop filter with an open-loop transfer function and set of loop constants, setting the damping factor equal to unity are provided.

Extracellular Hsp70 Enhances Mesoangioblast Migration via an Autocrine Signaling Pathway.

PubMed

Barreca, Maria M; Spinello, Walter; Cavalieri, Vincenzo; Turturici, Giuseppina; Sconzo, Gabriella; Kaur, Punit; Tinnirello, Rosaria; Asea, Alexzander A A; Geraci, Fabiana

2017-07-01

Mouse mesoangioblasts are vessel-associated progenitor stem cells endowed with the ability of multipotent mesoderm differentiation. Therefore, they represent a promising tool in the regeneration of injured tissues. Several studies have demonstrated that homing of mesoangioblasts into blood and injured tissues are mainly controlled by cytokines/chemokines and other inflammatory factors. However, little is known about the molecular mechanisms regulating their ability to traverse the extracellular matrix (ECM). Here, we demonstrate that membrane vesicles released by mesoangioblasts contain Hsp70, and that the released Hsp70 is able to interact by an autocrine mechanism with Toll-like receptor 4 (TLR4) and CD91 to stimulate migration. We further demonstrate that Hsp70 has a positive role in regulating matrix metalloproteinase 2 (MMP2) and MMP9 expression and that MMP2 has a more pronounced effect on cell migration, as compared to MMP9. In addition, the analysis of the intracellular pathways implicated in Hsp70 regulated signal transduction showed the involvement of both PI3K/AKT and NF-κB. Taken together, our findings present a paradigm shift in our understanding of the molecular mechanisms that regulate mesoangioblast stem cells ability to traverse the extracellular matrix (ECM). J. Cell. Physiol. 232: 1845-1861, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease

PubMed Central

Blecharz, Kinga G; Frey, Dietmar; Schenkel, Tobias; Prinz, Vincent; Bedini, Gloria; Krug, Susanne M; Czabanka, Marcus; Wagner, Josephin; Fromm, Michael; Bersano, Anna

2016-01-01

Moyamoya disease is a rare steno-occlusive cerebrovascular disorder often resulting in hemorrhagic and ischemic strokes. Although sharing the same ischemic stimulus with atherosclerotic cerebrovascular disease, Moyamoya disease is characterized by a highly instable cerebrovascular system which is prone to rupture due to pathological neovascularization. To understand the molecular mechanisms underlying this instability, angiopoietin-2 gene expression was analyzed in middle cerebral artery lesions obtained from Moyamoya disease and atherosclerotic cerebrovascular disease patients. Angiopoietin-2 was significantly up-regulated in Moyamoya vessels, while serum concentrations of soluble angiopoietins were not changed. For further evaluations, cerebral endothelial cells incubated with serum from these patients in vitro were applied. In contrast to atherosclerotic cerebrovascular disease serum, Moyamoya disease serum induced an angiopoietin-2 overexpression and secretion, accompanied by loss of endothelial integrity. These effects were absent or inverse in endothelial cells of non-brain origin suggesting brain endothelium specificity. The destabilizing effects on brain endothelial cells to Moyamoya disease serum were partially suppressed by the inhibition of angiopoietin-2. Our findings define brain endothelial cells as the potential source of vessel-destabilizing factors inducing the high plasticity state and disintegration in Moyamoya disease in an autocrine manner. We also provide new insights into Moyamoya disease pathophysiology that may be helpful for preventive treatment strategies in future. PMID:27381827

Gibberellin-regulated gene in the basal region of rice leaf sheath encodes basic helix-loop-helix transcription factor.

PubMed

Komatsu, Setsuko; Takasaki, Hironori

2009-07-01

Genes regulated by gibberellin (GA) during leaf sheath elongation in rice seedlings were identified using the transcriptome approach. mRNA from the basal regions of leaf sheaths treated with GA3 was analyzed by high-coverage gene expression profiling. 33,004 peaks were detected, and 30 transcripts showed significant changes in the presence of GA3. Among these, basic helix-loop-helix transcription factor (AK073385) was significantly upregulated. Quantitative PCR analysis confirmed that expression of AK073385 was controlled by GA3 in a time- and dose-dependent manner. Basic helix-loop-helix transcription factor (AK073385) is therefore involved in the regulation of gene expression by GA3.

Aggressive melanoma cells escape from BMP7-mediated autocrine growth inhibition through coordinated Noggin upregulation

PubMed Central

Hsu, Mei-Yu; Rovinsky, Sherry; Lai, Chiou-Yan; Qasem, Shadi; Liu, Xiaoming; How, Joan; Engelhardt, John F.; Murphy, George F.

2009-01-01

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily responsible for mediating a diverse array of cellular functions both during embryogenesis and in adult life. Previously, we reported that upregulation of BMP7 in human melanoma correlates with tumor progression. However, melanoma cells are either inhibited by or become resistant to BMP7 as a function of tumor progression, with normal melanocytes being most susceptible. Herein, real-time quantitative reverse transcriptase-polymerase chain reactions and Western blotting revealed that the expression of BMP antagonist, Noggin, correlates with resistance to BMP7 in advanced melanoma cells. To test the hypothesis that coordinated upregulation of Noggin protects advanced melanoma cells from autocrine inhibition by BMP7, functional expression of Noggin in susceptible melanoma cells was achieved by adenoviral gene transfer. The Noggin-overexpressing cells exhibited a growth advantage in response to subsequent BMP7 transduction in vitro under anchorage-dependent and -independent conditions, in three-dimensional skin reconstructs, as well as in vivo in severe combined immune-deficiency mice. In concordance, Noggin knockdown by lentiviral shRNA confers sensitivity to BMP7-induced growth inhibition in advanced melanoma cells. Our findings suggest that, like TGF-β, BMP7 acts as an autocrine growth inhibitor in melanocytic cells, and that advanced melanoma cells may escape from BMP7-induced inhibition through concomitant aberrant expression of Noggin. PMID:18560367

Studying DNA Looping by Single-Molecule FRET

PubMed Central

Le, Tung T.; Kim, Harold D.

2014-01-01

Bending of double-stranded DNA (dsDNA) is associated with many important biological processes such as DNA-protein recognition and DNA packaging into nucleosomes. Thermodynamics of dsDNA bending has been studied by a method called cyclization which relies on DNA ligase to covalently join short sticky ends of a dsDNA. However, ligation efficiency can be affected by many factors that are not related to dsDNA looping such as the DNA structure surrounding the joined sticky ends, and ligase can also affect the apparent looping rate through mechanisms such as nonspecific binding. Here, we show how to measure dsDNA looping kinetics without ligase by detecting transient DNA loop formation by FRET (Fluorescence Resonance Energy Transfer). dsDNA molecules are constructed using a simple PCR-based protocol with a FRET pair and a biotin linker. The looping probability density known as the J factor is extracted from the looping rate and the annealing rate between two disconnected sticky ends. By testing two dsDNAs with different intrinsic curvatures, we show that the J factor is sensitive to the intrinsic shape of the dsDNA. PMID:24998459

Studying DNA looping by single-molecule FRET.

PubMed

Le, Tung T; Kim, Harold D

2014-06-28

Bending of double-stranded DNA (dsDNA) is associated with many important biological processes such as DNA-protein recognition and DNA packaging into nucleosomes. Thermodynamics of dsDNA bending has been studied by a method called cyclization which relies on DNA ligase to covalently join short sticky ends of a dsDNA. However, ligation efficiency can be affected by many factors that are not related to dsDNA looping such as the DNA structure surrounding the joined sticky ends, and ligase can also affect the apparent looping rate through mechanisms such as nonspecific binding. Here, we show how to measure dsDNA looping kinetics without ligase by detecting transient DNA loop formation by FRET (Fluorescence Resonance Energy Transfer). dsDNA molecules are constructed using a simple PCR-based protocol with a FRET pair and a biotin linker. The looping probability density known as the J factor is extracted from the looping rate and the annealing rate between two disconnected sticky ends. By testing two dsDNAs with different intrinsic curvatures, we show that the J factor is sensitive to the intrinsic shape of the dsDNA.

The growth and aggressive behavior of human osteosarcoma is regulated by a CaMKII-controlled autocrine VEGF signaling mechanism.

PubMed

Daft, Paul G; Yang, Yang; Napierala, Dobrawa; Zayzafoon, Majd

2015-01-01

Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50%) and protein secretion (55%), while α- CaMKII overexpression increases VEGF gene expression (250%) and protein secretion (1,200%). We show that aggressive OS cells (143B) express high levels of VEGF receptor 2 (VEGFR-2) and respond to exogenous VEGF (100nm) by increasing intracellular calcium (30%). This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor) and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease.

The Growth and Aggressive Behavior of Human Osteosarcoma Is Regulated by a CaMKII-Controlled Autocrine VEGF Signaling Mechanism

PubMed Central

Daft, Paul G.; Yang, Yang; Napierala, Dobrawa; Zayzafoon, Majd

2015-01-01

Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50%) and protein secretion (55%), while α- CaMKII overexpression increases VEGF gene expression (250%) and protein secretion (1,200%). We show that aggressive OS cells (143B) express high levels of VEGF receptor 2 (VEGFR-2) and respond to exogenous VEGF (100nm) by increasing intracellular calcium (30%). This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor) and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease. PMID:25860662

Loop Heat Pipe Startup Behaviors

NASA Technical Reports Server (NTRS)

Ku, Jentung

2016-01-01

A loop heat pipe must start successfully before it can commence its service. The startup transient represents one of the most complex phenomena in the loop heat pipe operation. This paper discusses various aspects of loop heat pipe startup behaviors. Topics include the four startup scenarios, the initial fluid distribution between the evaporator and reservoir that determines the startup scenario, factors that affect the fluid distribution between the evaporator and reservoir, difficulties encountered during the low power startup, and methods to enhance the startup success. Also addressed are the pressure spike and pressure surge during the startup transient, and repeated cycles of loop startup and shutdown under certain conditions.

Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation

PubMed Central

Cioce, M; Canino, C; Goparaju, C; Yang, H; Carbone, M; Pass, H I

2014-01-01

Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1Rpos cells exhibit a complex repertoire of pluripotency, epithelial–mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1Rpos cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention. PMID:24722292

Loop Heat Pipe Startup Behaviors

NASA Technical Reports Server (NTRS)

Ku, Jentung

2014-01-01

A loop heat pipe must start successfully before it can commence its service. The start-up transient represents one of the most complex phenomena in the loop heat pipe operation. This paper discusses various aspects of loop heat pipe start-up behaviors. Topics include the four start-up scenarios, the initial fluid distribution between the evaporator and reservoir that determines the start-up scenario, factors that affect the fluid distribution between the evaporator and reservoir, difficulties encountered during the low power start-up, and methods to enhance the start-up success. Also addressed are the thermodynamic constraint between the evaporator and reservoir in the loop heat pipe operation, the superheat requirement for nucleate boiling, pressure spike and pressure surge during the start-up transient, and repeated cycles of loop start-up andshutdown under certain conditions.

Stem cell autocrine CXCL12/CXCR4 stimulates invasion and metastasis of esophageal cancer.

PubMed

Wang, Xingwei; Cao, Yan; Zhang, Shirong; Chen, Zhihui; Fan, Ling; Shen, Xiaochun; Zhou, Shiwen; Chen, Dongfeng

2017-05-30

Esophageal cancer is one of the most common malignant tumors of the digestive tract. The greatest obstacle to the curing of esophageal cancer is its propensity to spread and metastasize. Esophageal cancer stem cells are considered the source for recurrence and metastasis of the tumors. While clinical evidence suggested that continuous up-regulation of CXCL12/CXCR4 was significantly associated with poor prognosis in patients with esophageal cancer, but the role and mechanism of CXCL12/CXCR4 in the invasion and metastasis of esophageal cancer has not been reported by far. This study found that esophageal cancer stem cells not only autocrine a great amount of CXCL12, but also high expression of its corresponding receptor CXCR4. Most importantly, the ability of esophageal cancer stem cells to spread and metastasize could be inhibited by blockage of CXCR4 with inhibitors or shRNA approaches both in vivo and in vitro studies. The important role of CXCL12 in the invasion and metastasis of esophageal cancer stem cells was also confirmed by loss-of-function and gain-of-function strategies. Mechanistically, we demonstrated that CXCL12/CXCR4 activated the ERK1/2 pathway and thereby ultimately maintained the characteristics of high-level invasion and metastasis of esophageal cancer stem cells. Taken together, our findings suggested that autocrine CXCL12/CXCR4 was one of the major mechanisms underlying the metastatic property of esophageal cancer stem cells through ERK1/2 signaling pathway, and might serve as a therapeutic target for esophageal cancer patients.

In vitro proliferation of axotomized rat facial nucleus-derived activated microglia in an autocrine fashion.

PubMed

Nakajima, Kazuyuki; Graeber, Manuel B; Sonoda, Maya; Tohyama, Yoko; Kohsaka, Shinichi; Kurihara, Tadashi

2006-08-01

Transection of rat adult facial nerve leads to an increase in the number of activated microglia in the facial nucleus (FN), with a peak in proliferation 3 days after transection. To investigate the characteristics of these activated microglia, we isolated the cells with high purity from axotomized FN (axFN) 3 days after transection according to the previously reported procedure for explant culture. The isolated microglia exhibited immunocytochemical properties similar to those in vivo, and their numbers increased approximately five- to sevenfold over a period of 10 days without the addition of any mitogens, suggesting that self-reproduction was occurring. Actually, the microglia actively incorporated bromodeoxyuridine (BrdU) and strongly expressed an S-phase-specific protein marker, proliferating cell nuclear antigen (PCNA). To examine the mechanism underlying this proliferation, the expression of the mitogens and specific receptors of the microglia were analyzed in conditioned medium (CM) and cells. Macrophage-colony stimulating factor (M-CSF) and granulocyte macrophage-CSF (GM-CSF) were detected in the CM as well as in the cells. Their specific receptor proteins, c-Fms and GMCSFRalpha, were also detected in the cell homogenate. These proliferating microglia were not found to produce deleterious factors for neurons. In summary, the microglia isolated from the axFN were found to be proliferative in an autocrine fashion and to have some cellular properties in common with those observed in vivo.

Theory on the mechanism of distal action of transcription factors: looping of DNA versus tracking along DNA

NASA Astrophysics Data System (ADS)

Murugan, R.

2010-10-01

In this paper, we develop a theory on the mechanism of distal action of the transcription factors, which are bound at their respective cis-regulatory enhancer modules on the promoter-RNA polymerase II (PR) complexes to initiate the transcription event in eukaryotes. We consider both the looping and tracking modes of their distal communication and calculate the mean first passage time that is required for the distal interactions of the complex of enhancer and transcription factor with the PR via both these modes. We further investigate how this mean first passage time is dependent on the length of the DNA segment (L, base-pairs) that connects the cis-regulatory binding site and the respective promoter. When the radius of curvature of this connecting segment of DNA is R that was induced upon binding of the transcription factor at the cis-acting element and RNAPII at the promoter in cis-positions, our calculations indicate that the looping mode of distal action will dominate when L is such that L > 2πR and the tracking mode of distal action will be favored when L < 2πR. The time required for the distal action will be minimum when L = 2πR where the typical value of R for the binding of histones will be R ~ 16 bps and L ~ 102 bps. It seems that the free energy associated with the binding of the transcription factor with its cis-acting element and the distance of this cis-acting element from the corresponding promoter of the gene of interest is negatively correlated. Our results suggest that the looping and tracking modes of distal action are concurrently operating on the transcription activation and the physics that determines the timescales associated with the looping/tracking in the mechanism of action of these transcription factors on the initiation of the transcription event must put a selection pressure on the distribution of the distances of cis-regulatory modules from their respective promoters of the genes. The computational analysis of the upstream sequences

Caveolin-1 regulates lipid droplet metabolism in endothelial cells via autocrine prostacyclin-stimulated, cAMP-mediated lipolysis.

PubMed

Kuo, Andrew; Lee, Monica Y; Yang, Kui; Gross, Richard W; Sessa, William C

2018-01-19

Lipid droplets (LD) are dynamic organelles involved in intracellular lipid metabolism in almost all eukaryotic cells, and LD-associated proteins tightly regulate their dynamics. One LD coat protein is caveolin-1 (Cav-1), an essential component for caveola assembly in highly differentiated cells, including adipocytes, smooth muscle cells, and endothelial cells (EC). However, the role of Cav-1 in LD dynamics is unclear. Here we report that EC lacking Cav-1 exhibit impaired LD formation. The decreased LD formation is due to enhanced lipolysis and not caused by reduced triglyceride synthesis or fatty acid uptake. Mechanistically, the absence of Cav-1 increased cAMP/PKA signaling in EC, as indicated by elevated phosphorylation of hormone-sensitive lipase and increased lipolysis. Unexpectedly, we also observed enhanced autocrine production of prostaglandin I 2 (PGI 2 , also called prostacyclin) in Cav-1 KO EC, and this PGI 2 increase appeared to stimulate cAMP/PKA pathways, contributing to the enhanced lipolysis in Cav-1 KO cells. Our results reveal an unanticipated role of Cav-1 in regulating lipolysis in non-adipose tissue, indicating that Cav-1 is required for LD metabolism in EC and that it regulates cAMP-dependent lipolysis in part via the autocrine production of PGI 2 .

TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion

PubMed Central

Kandhaya-Pillai, Renuka; Miro-Mur, Francesc; Alijotas-Reig, Jaume; Tchkonia, Tamara; Kirkland, James L.; Schwartz, Simo

2017-01-01

Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence. Furthermore, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from proliferative arrest, but rather suppressed cell cycle regulatory genes and altered TNFα-induced senescence. Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence. PMID:29176033

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

Dewitt, Ann E.; Dong, Jian Y.; Wiley, H S.

Autocrine signaling is important in normal tissue physiology as well as pathological conditions. It is difficult to analyze these systems, however, because they are both self-contained and recursive. To understand how parameters, such as ligand production and receptor expression influence autocrine activity, we investigated a human epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) loop engineered into mouse B82 fibroblasts. We varied the level of ligand production using the tet-off expression system and used metalloprotease inhibitors to modulate ligand release. Receptor expression was varied using antagonistic, blocking antibodies. We compared autocrine ligand release to receptor activation using a microphysiometer-based assay andmore » analyzed our data with a quantitative model of ligand release and receptor dynamics. We found that the activity of our autocrine system could be described in terms of a simple ratio between the rate of ligand production (VL) and the rate of receptor production (VR). At a VL/VR ratio of < 0.3, essentially no ligand was found in the extracellular medium, but a significant number cell receptors (30-40%) were occupied. As the VL/VR ratio increased from 0.3 towards unity, receptor occupancy increased, and significant amounts of ligand now appeared in the medium. Above a VL/VR ratio of 1.0, receptor occupancy approached saturation and most of the released ligand was lost into the medium. Analysis of human mammary epithelial cells showed that a VL/VR ratio of < 5 x 10 -4 was sufficient to evoke >20% of a maximal proliferative response. This suggests that natural autocrine systems are active even when no ligand appears in the extracellular medium; i.e., they operate 'invisibly' to general detection.« less

The Functional Effect of an Amphiregulin Autocrine Loop on Inflammatory Breast Cancer Progression

DTIC Science & Technology

2008-03-01

Darby canine kidney cells (15). Also, using targeted knockout mice, Luetteke et al. reported that specific loss of AR, but not EGF or TGF-a, severely...due to relocalization of E-cadherin in Madin-Darby canine kidney cells (15). Our laboratory has also discovered that AR signaling differs from EGF...growth factor induction of matrix metalloproteinases and their inhibitors in osteosarcoma cells is modulated by the metastasis associated protein CAPL

Autocrine CSF-1 and CSF-1 Receptor Co-expression Promotes Renal Cell Carcinoma Growth

PubMed Central

Menke, Julia; Kriegsmann, Jörg; Schimanski, Carl Christoph; Schwartz, Melvin M.; Schwarting, Andreas; Kelley, Vicki R.

2011-01-01

Renal cell carcinoma is increasing in incidence but the molecular mechanisms regulating its growth remain elusive. Co-expression of the monocytic growth factor CSF-1 and its receptor CSF-1R on renal tubular epithelial cells (TEC) will promote proliferation and anti-apoptosis during regeneration of renal tubules. Here we show that a CSF-1-dependent autocrine pathway is also responsible for the growth of renal cell carcinoma (RCC). CSF-1 and CSF-1R were co-expressed in RCC and TEC proximally adjacent to RCC. CSF-1 engagement of CSF-1R promoted RCC survival and proliferation and reduced apoptosis, in support of the likelihood that CSF-1R effector signals mediate RCC growth. In vivo CSF-1R blockade using a CSF-1R tyrosine kinase inhibitor decreased RCC proliferation and macrophage infiltration in a manner associated with a dramatic reduction in tumor mass. Further mechanistic investigations linked CSF-1 and EGF signaling in RCC. Taken together, our results suggest that budding RCC stimulates the proximal adjacent microenvironment in the kidney to release mediators of CSF-1, CSF-1R and EGF expression in RCC. Further, our findings imply that targeting CSF-1/CSF-1R signaling may be therapeutically effective in RCC. PMID:22052465

Corneal endothelial autocrine trophic factor VIP in a mechanism-based strategy to enhance human donor cornea preservation for transplantation.

PubMed

Koh, Shay-Whey Margaret

2012-02-01

Vasoactive intestinal peptide (VIP) and ciliary neurotrophic factor (CNTF) are identified as autocrines of human corneal endothelial (CE) cells working in concert to maintain the differentiated state and promote the survival of the corneal endothelium. From VIP gene knockdown study, endogenous VIP is shown to maintain the level of the differentiation marker, the adhesion molecule N-cadherin, CE cell size, shape, and retention, in situ in the human donor corneoscleral explants. Exogenous VIP protects the corneal endothelium against the killing effect of oxidative stress, in part by upholding ATP levels in CE cells dying of oxidative stress-induced injury, allowing them to die of an apoptotic death instead of an acute necrotic one. The switch from the acute necrosis to the programmed cell death (apoptosis) may have allowed the injured CE cell to be rescued by the VIP-upregulated pathways, including those of Bcl-2 and N-cadherin, and resulted in long-term CE cell survival. The endogenous VIP in CE cells is upregulated by CNTF, which is released by CE cells surviving the oxidative stress. The CNTF receptor (CNTFRα) is expressed in CE cells in human donor corneoscleral explant and gradually becomes lost during corneal storage. VIP treatment (10(-8) M, 37 °C, 30 min) prior to storage of freshly dissected human donor corneoscleral explants increases their CE cell CNTFRα level and responsiveness to CNTF in upregulating the gap junctional protein connexin-43 expression. VIP treatment of both fresh and preserved corneoscleral explants reduces CE damage in the corneoscleral explants and in the corneal buttons trephined from them. CE cell loss is a critical risk factor in corneal graft failure at any time in the life of the graft, which can be as late as 5-10 years after an initially successful transplant. A new procedure, Descemet's stripping automated endothelial keratoplasty (DSAEK), which is superior to the traditional full thickness transplantation in many aspects

Formation of PI 3-kinase products in platelets by thrombin, but not collagen, is dependent on synergistic autocrine stimulation, particularly through secreted ADP.

PubMed

Selheim, F; Idsøe, R; Fukami, M H; Holmsen, H; Vassbotn, F S

1999-10-05

Platelet activation by thrombin or collagen results in secretion and synthesis of several platelet agonists that enhance the responses to the primary agonists (autocrine stimulation). To disclose the effects of thrombin and collagen on the phosphorylation of 3-phosphoinositides per se we incubated platelets with five inhibitors of platelet autocrine stimulation (IAS) that act extracellularly. We found that IAS almost totally blocked thrombin-induced production of phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P(2)] and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)]. In contrast, collagen induced massive production of PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) in the presence of IAS. When testing the effect of each inhibitor individually we found the strongest inhibition of thrombin-induced PtdIns(3,4)P(2) production with the ADP scavenger system CP/CPK. Furthermore, we found a strong synergistic effect between exogenously added ADP and thrombin on production of PtdIns(3,4)P(2). In contrast to the results from 3-phosphorylated phosphoinositides, CP/CPK had little effect on thrombin-induced protein tyrosine phosphorylation. Our results show the importance of autocrine stimulation in thrombin-induced accumulation of 3-phosphorylated phosphoinositides and raise the question as to whether thrombin by itself is capable of inducing PI 3-K activation. In marked contrast to thrombin, collagen per se appears to be able to trigger increased production of PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). Copyright 1999 Academic Press.

Autocrine interleukin-23 promotes self-renewal of CD133+ ovarian cancer stem-like cells.

PubMed

Wang, Dan; Xiang, Tong; Zhao, Zhongquan; Lin, Kailong; Yin, Pin; Jiang, Lupin; Liang, Zhiqing; Zhu, Bo

2016-11-15

Cancer stem cells (CSCs) are a group of cells which possess the ability of self-renewing and unlimited proliferation. And these CSCs are thought to be the cause of metastasis, recurrence and resistance. Recent study has found that pro-inflammatory cytokine and chemotactic factor mediate the self-renewing and differentiation of most of CSCs. Thus we speculate that ovarian cancer stem cells (OCSCs) can also maintain the ability of self-renewing and differentiation by releasing inflammatory factor. This report we discuss the biological characteristics and the specific molecular mechanism mediated by interleukin-23 (IL-23) and its receptor on the self-renewing of OCSCs. We found that OCSCs had high expression of IL-23 and IL-23R. IL-23 could promote the self-renewal ability of OCSCs and played a very important role to maintain the stable expression of stem cell markers in vitro. Moreover, we verified that IL-23 could maintain the potential tumorigenic of OCSCs in vivo and mediate the self-renewal ability and the formation of tumor in OCSCs by activating the signal pathways of STAT3 and NF-κB. In addition, human low differentiation tissues showed overexpression of IL-23. And IL-23 positively correlated to the expression level of CD133, Nanog and Oct4. In conclusion, Our discoveries demonstrate that autocrine IL-23 contribute to ovarian cancer malignancy through promoting the self-renewal of CD133+ ovarian cancer stem-like cells, and this suggests that IL-23 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer.

Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival.

PubMed

Catrina, S-B; Lewitt, M; Massambu, C; Dricu, A; Grünler, J; Axelson, M; Biberfeld, P; Brismar, K

2005-04-25

Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130 +/- 27.6% (P < 0.05) similar to that induced by VEGF and with which it is additive (281 +/- 13%) (P < 0.05). Moreover, specific blockade of the receptor (either by alpha IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.

Design and verification of large-moment transmitter loops for geophysical applications

NASA Astrophysics Data System (ADS)

Sternberg, Ben K.; Dvorak, Steven L.; Feng, Wanjie

2017-01-01

In this paper we discuss the modeling, design and verification of large-moment transmitter (TX) loops for geophysical applications. We first develop two equivalent circuit models for TX loops. We show that the equivalent inductance can be predicted using one of two empirical formulas. The stray capacitance of the loop is then calculated using the measured self-resonant frequency and the loop inductance. We model the losses associated with both the skin effect and the dissipation factor in both of these equivalent circuits. We find that the two equivalent circuit models produce the same results provided that the dissipation factor is small. Next we compare the measured input impedances for three TX loops that were constructed with different wire configurations with the equivalent circuit model. We found excellent agreement between the measured and simulated results after adjusting the dissipation factor. Since the skin effect and dissipation factor yield good agreement with measurements, the proximity effect is negligible in the three TX loops that we tested. We found that the effects of the dissipation factor dominated those of the skin effect when the wires were relatively close together. When the wires were widely separated, then the skin effect was the dominant loss mechanism. We also found that loops with wider wire separations exhibited higher self-resonant frequencies and better high-frequency performance.

Curcumin inhibits autocrine growth hormone-mediated invasion and metastasis by targeting NF-κB signaling and polyamine metabolism in breast cancer cells.

PubMed

Coker-Gurkan, Ajda; Celik, Merve; Ugur, Merve; Arisan, Elif-Damla; Obakan-Yerlikaya, Pinar; Durdu, Zeynep Begum; Palavan-Unsal, Narcin

2018-05-16

Curcumin is assumed to be a plant-derived therapeutic drug that triggers apoptotic cell death in vitro and in vivo by affecting different molecular targets such as NF-κB. Phase I/II trial of curcumin alone or with chemotherapeutic drugs has been accomplished in pancreatic, colon, prostate and breast cancer cases. Recently, autocrine growth hormone (GH) signaling-induced cell growth, metastasis and drug resistance have been demonstrated in breast cancer. In this study, our aim was to investigate the potential therapeutic effect of curcumin by evaluating the molecular machinery of curcumin-triggered apoptotic cell death via focusing on NF-κB signaling and polyamine (PA) metabolism in autocrine GH-expressing MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells. For this purpose, a pcDNA3.1 (+) vector with a GH gene insert was transfected by a liposomal agent in all breast cancer cells and then selection was conducted in neomycin (G418) included media. Autocrine GH-induced curcumin resistance was overcome in a dose-dependent manner and curcumin inhibited cell proliferation, invasion-metastasis and phosphorylation of p65 (Ser536), and thereby partly prevented its DNA binding activity in breast cancer cells. Moreover, curcumin induced caspase-mediated apoptotic cell death by activating the PA catabolic enzyme expressions, which led to generation of toxic by-products such as H 2 O 2 in MCF-7, MDA-MB-453 and MDA-MB-231 GH+ breast cancer cells. In addition, transient silencing of SSAT prevented curcumin-induced cell viability loss and apoptotic cell death in each breast cancer cells. In conclusion, curcumin could overcome the GH-mediated resistant phenotype via modulating cell survival, death-related signaling routes and activating PA catabolic pathway.

Prognostic factors of craniopharyngioma with special reference to autocrine/paracrine signaling: underestimated implication of growth hormone receptor.

PubMed

Ogawa, Yoshikazu; Watanabe, Mika; Tominaga, Teiji

2015-10-01

Craniopharyngioma is a slow-growing tumor classified as benign, but tight adhesion and significant local infiltration to the vital structures are common. In spite of improvement of modern microsurgery techniques and precise anatomical understanding not few cases of this tumor recur, and long-term tumor control and maintenance of quality of life are sometimes difficult. However, very little is known about the effects of the molecular characters of craniopharyngioma on the prognosis. Ninety eight cases of craniopharyngioma surgically treated at the Department of Neurosurgery, Tohoku University Hospital and Kohnan Hospital from April 1996 to May 2014, 45 males and 53 females aged from 2 to 80 years (mean, 40.84 years) were retrospectively reviewed, and postoperative outcomes and the possible involvement of the autocrine/paracrine mechanism were investigated. The patients were followed up at intervals of 6 months to assess tumor recurrence, and clinical outcomes were correlated with the findings of immunohistochemical examinations used growth hormone receptor (GHR) and downstream hormones. The follow-up period ranged from 3 to 209 months. Hormone expression was examined in 88 patients, of which 46 specimens (52.3 %) showed high expression of GHR. The GHR high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.007). Simultaneous high expression of growth hormone (GH) and GHR was found in 33 specimens (37.5 %), and the high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.011). No other hormones showed statistically significant differences in outcomes. High expression of GHR is associated with shorter duration of postoperative stable disease in patients with craniopharyngioma. If the surgical specimens were craniopharyngiomas with high GHR expression, GH supplementation

Osmotic mechanism of the loop extrusion process

NASA Astrophysics Data System (ADS)

Yamamoto, Tetsuya; Schiessel, Helmut

2017-09-01

The loop extrusion theory assumes that protein factors, such as cohesin rings, act as molecular motors that extrude chromatin loops. However, recent single molecule experiments have shown that cohesin does not show motor activity. To predict the physical mechanism involved in loop extrusion, we here theoretically analyze the dynamics of cohesin rings on a loop, where a cohesin loader is in the middle and unloaders at the ends. Cohesin monomers bind to the loader rather frequently and cohesin dimers bind to this site only occasionally. Our theory predicts that a cohesin dimer extrudes loops by the osmotic pressure of cohesin monomers on the chromatin fiber between the two connected rings. With this mechanism, the frequency of the interactions between chromatin segments depends on the loading and unloading rates of dimers at the corresponding sites.

Positive Feedback Loops for Factor V and Factor VII Activation Supply Sensitivity to Local Surface Tissue Factor Density During Blood Coagulation

PubMed Central

Balandina, A.N.; Shibeko, A.M.; Kireev, D.A.; Novikova, A.A.; Shmirev, I.I.; Panteleev, M.A.; Ataullakhanov, F.I.

2011-01-01

Blood coagulation is triggered not only by surface tissue factor (TF) density but also by surface TF distribution. We investigated recognition of surface TF distribution patterns during blood coagulation and identified the underlying molecular mechanisms. For these investigations, we employed 1), an in vitro reaction-diffusion experimental model of coagulation; and 2), numerical simulations using a mathematical model of coagulation in a three-dimensional space. When TF was uniformly immobilized over the activating surface, the clotting initiation time in normal plasma increased from 4 min to >120 min, with a decrease in TF density from 100 to 0.7 pmol/m2. In contrast, surface-immobilized fibroblasts initiated clotting within 3–7 min, independently of fibroblast quantity and despite a change in average surface TF density from 0.5 to 130 pmol/m2. Experiments using factor V-, VII-, and VIII-deficient plasma and computer simulations demonstrated that different responses to these two TF distributions are caused by two positive feedback loops in the blood coagulation network: activation of the TF–VII complex by factor Xa, and activation of factor V by thrombin. This finding suggests a new role for these reactions: to supply sensitivity to local TF density during blood coagulation. PMID:22004734

Formation of chromosomal domains in interphase by loop extrusion

NASA Astrophysics Data System (ADS)

Fudenberg, Geoffrey

While genomes are often considered as one-dimensional sequences, interphase chromosomes are organized in three dimensions with an essential role for regulating gene expression. Recent studies have shown that Topologically Associating Domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes. Despite observations that architectural proteins, including CTCF, demarcate and maintain the borders of TADs, the mechanisms underlying TAD formation remain unknown. Here we propose that loop extrusion underlies the formation TADs. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops, but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. This process dynamically forms loops of various sizes within but not between TADs. Using polymer simulations, we find that loop extrusion can produce TADs as determined by our analyses of the highest-resolution experimental data. Moreover, we find that loop extrusion can explain many diverse experimental observations, including: the preferential orientation of CTCF motifs and enrichments of architectural proteins at TAD boundaries; TAD boundary deletion experiments; and experiments with knockdown or depletion of CTCF, cohesin, and cohesin-loading factors. Together, the emerging picture from our work is that TADs are formed by rapidly associating, growing, and dissociating loops, presenting a clear framework for understanding interphase chromosomal organization.

A local autocrine axis in the testes that regulates spermatogenesis

PubMed Central

Cheng, C. Yan; Mruk, Dolores D.

2014-01-01

Spermiation—the release of mature spermatozoa from Sertoli cells into the seminiferous tubule lumen—occurs by the disruption of an anchoring device known as the apical ectoplasmic specialization (apical ES). At the same time, the blood–testis barrier (BTB) undergoes extensive restructuring to facilitate the transit of preleptotene spermatocytes. While these two cellular events take place at opposite ends of the Sertoli cell epithelium, the events are in fact tightly coordinated, as any disruption in either process will lead to infertility. A local regulatory axis exists between the apical ES and the BTB in which biologically active laminin fragments produced at the apical ES by the action of matrix metalloproteinase 2 can regulate BTB restructuring directly or indirectly via the hemidesmosome. Equally important, polarity proteins play a crucial part in coordinating cellular events within this apical ES–BTB–hemidesmosome axis. Additionally, testosterone and cytokines work in concert to facilitate BTB restructuring, which enables the transit of spermatocytes while maintaining immunological barrier function. Herein, we will discuss this important autocrine-based cellular axis that parallels the hormonal-based hypothalamic–pituitary–testicular axis that regulates spermatogenesis. This local regulatory axis is the emerging target for male contraception. PMID:20571538

Kinin-B2 receptor expression and activity during differentiation of embryonic rat neurospheres.

PubMed

Martins, Antonio H; Alves, Janaína M; Trujillo, Cleber A; Schwindt, Telma T; Barnabé, Gabriela F; Motta, Fabiana L T; Guimaraes, Alessander O; Casarini, Dulce E; Mello, Luiz E; Pesquero, João B; Ulrich, Henning

2008-04-01

Neural progenitor cells were isolated from rat fetal telencephalon and proliferate as neurospheres in the presence of EGF, FGF-2, and heparin. In the absence of these growth factors, neurospheres differentiate into neurons, astrocytes, and oligodendrocytes. Using an embryonal carcinoma cell line as in vitro differentiation model, we have already demonstrated the presence of an autocrine loop system between kinin-B2 receptor activity and secretion of its ligand bradykinin (BK) as prerequisites for final neuronal differentiation (Martins et al., J Biol Chem 2005; 280: 19576-19586). The aim of this study was to verify the activity of the kallikrein-kinin system (KKS) during neural progenitor cell differentiation. Immunofluorescence studies and flow cytometry analysis revealed increases in glial fibrillary acidic protein and beta-3 tubulin expression and decrease in the number of nestin-positive cells along neurospheres differentiation, indicating the transition of neural progenitor cells to astrocytes and neurons. Kinin-B2 receptor expression and activity, secretion of BK into the medium, and presence of high-molecular weight kininogen suggest the participation of the KKS in neurosphere differentiation. Functional kinin-B2 receptors and BK secretion indicate an autocrine loop during neurosphere differentiation to neurons, astrocytes, and oligodendrocytes, reflecting events occurring during early brain development. (c) 2008 International Society for Analytical Cytology.

Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer.

PubMed

Ronca, Roberto; Alessi, Patrizia; Coltrini, Daniela; Di Salle, Emanuela; Giacomini, Arianna; Leali, Daria; Corsini, Michela; Belleri, Mirella; Tobia, Chiara; Garlanda, Cecilia; Bonomi, Elisa; Tardanico, Regina; Vermi, William; Presta, Marco

2013-06-01

Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up-regulates FGF2 and FGF8b production in murine TRAMP-C2 prostate cancer cells, activating a FGF-dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin-3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N-terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3-derived pentapeptide Ac-ARPCA-NH2 abolish the mitogenic response of murine TRAMP-C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT-activated TRAMP-C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP-C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP-C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP-C2 cells overexpress only the FGF-binding N-terminal PTX3 domain. In keeping with the anti-tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high-grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti-angiogenic and anti-neoplastic activity in prostate cancer. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Minimally doubled fermions at one loop

NASA Astrophysics Data System (ADS)

Capitani, Stefano; Weber, Johannes; Wittig, Hartmut

2009-10-01

Minimally doubled fermions have been proposed as a cost-effective realization of chiral symmetry at non-zero lattice spacing. Using lattice perturbation theory at one loop, we study their renormalization properties. Specifically, we investigate the consequences of the breaking of hyper-cubic symmetry, which is a typical feature of this class of fermionic discretizations. Our results for the quark self-energy indicate that the four-momentum undergoes a renormalization which is linearly divergent. We also compute renormalization factors for quark bilinears, construct the conserved vector and axial-vector currents and verify that at one loop the renormalization factors of the latter are equal to one.

Water Stream "Loop-the-Loop"

ERIC Educational Resources Information Center

Jefimenko, Oleg

1974-01-01

Discusses the design of a modified loop-the-loop apparatus in which a water stream is used to illustrate centripetal forces and phenomena of high-velocity hydrodynamics. Included are some procedures of carrying out lecture demonstrations. (CC)

Parallel tiled Nussinov RNA folding loop nest generated using both dependence graph transitive closure and loop skewing.

PubMed

Palkowski, Marek; Bielecki, Wlodzimierz

2017-06-02

RNA secondary structure prediction is a compute intensive task that lies at the core of several search algorithms in bioinformatics. Fortunately, the RNA folding approaches, such as the Nussinov base pair maximization, involve mathematical operations over affine control loops whose iteration space can be represented by the polyhedral model. Polyhedral compilation techniques have proven to be a powerful tool for optimization of dense array codes. However, classical affine loop nest transformations used with these techniques do not optimize effectively codes of dynamic programming of RNA structure predictions. The purpose of this paper is to present a novel approach allowing for generation of a parallel tiled Nussinov RNA loop nest exposing significantly higher performance than that of known related code. This effect is achieved due to improving code locality and calculation parallelization. In order to improve code locality, we apply our previously published technique of automatic loop nest tiling to all the three loops of the Nussinov loop nest. This approach first forms original rectangular 3D tiles and then corrects them to establish their validity by means of applying the transitive closure of a dependence graph. To produce parallel code, we apply the loop skewing technique to a tiled Nussinov loop nest. The technique is implemented as a part of the publicly available polyhedral source-to-source TRACO compiler. Generated code was run on modern Intel multi-core processors and coprocessors. We present the speed-up factor of generated Nussinov RNA parallel code and demonstrate that it is considerably faster than related codes in which only the two outer loops of the Nussinov loop nest are tiled.

Risk factors for early cytologic abnormalities after loop electrosurgical excision procedure.

PubMed

Dietrich, Charles S; Yancey, Michael K; Miyazawa, Kunio; Williams, David L; Farley, John

2002-02-01

To evaluate risk factors for early cytologic abnormalities and recurrent cervical dysplasia after loop electrosurgical excision procedure (LEEP). A retrospective analysis was performed of all pathology records for LEEPs performed at our institution from January 1996 through July 1998. Follow-up cytology from 2 through 12 months after LEEP was reviewed. Patients with abnormal cytology were referred for further colposcopic evaluation. Statistical analysis using chi2 test for trend, proportional hazards model test, Fisher exact tests, and life table analysis were performed to identify risk factors for early cytologic abnormalities after LEEP and to determine relative risk of recurrent dysplasia. A total of 298 women underwent LEEP during the study period, and 29% of these had cytologic abnormalities after LEEP. Grade of dysplasia, ectocervical marginal status, endocervical marginal status, and glandular involvement with dysplasia were not found to be independent risk factors for early cytologic abnormalities. However, when risk factors were analyzed cumulatively, the abnormal cytology rate increased from 24% with no risk factors to 67% with three risk factors present (P =.037). Of patients with abnormal cytology after LEEP, 40% developed subsequent dysplasia, and the mean time to diagnosis was approximately 6 months. The relative risk of subsequent dysplasia ranged from a 20% increase to twice the risk if post-LEEP cytology was low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion, respectively. Based on these results, consideration should be given for early colposcopic examination of patients who have evidence of marginal involvement or endocervical glandular involvement with dysplasia. These patients are at increased risk for abnormal cytology and recurrent dysplasia. This initial visit should occur at 6 months, as the mean time to recurrence of dysplasia was 6.5 months.

Loop technique.

PubMed

Seeburger, Joerg; Noack, Thilo; Winkfein, Michael; Ender, Joerg; Mohr, Friedrich Wilhelm

2010-01-01

The loop technique facilitates mitral valve repair for leaflet prolapse by implantation of Gore-Tex neo-chordae. The key feature of the technique is a premade bundle of four loops made out of one suture. The loops are available in different lengths ranging from 10 to 26 mm. After assessment of the ideal length of neo-chordae with a caliper the loops are then secured to the body of the papillary muscle over an additional felt pledget. In the following step, the free ends of the loops are distributed along the free margin of the prolapsing segment using one additional suture for each loop.

Control of adipogenesis by the autocrine interplays between angiotensin 1-7/Mas receptor and angiotensin II/AT1 receptor signaling pathways.

PubMed

Than, Aung; Leow, Melvin Khee-Shing; Chen, Peng

2013-05-31

Angiotensin II (AngII), a peptide hormone released by adipocytes, can be catabolized by adipose angiotensin-converting enzyme 2 (ACE2) to form Ang(1-7). Co-expression of AngII receptors (AT1 and AT2) and Ang(1-7) receptors (Mas) in adipocytes implies the autocrine regulation of the local angiotensin system upon adipocyte functions, through yet unknown interactive mechanisms. In the present study, we reveal the adipogenic effects of Ang(1-7) through activation of Mas receptor and its subtle interplays with the antiadipogenic AngII-AT1 signaling pathways. Specifically, in human and 3T3-L1 preadipocytes, Ang(1-7)-Mas signaling promotes adipogenesis via activation of PI3K/Akt and inhibition of MAPK kinase/ERK pathways, and Ang(1-7)-Mas antagonizes the antiadipogenic effect of AngII-AT1 by inhibiting the AngII-AT1-triggered MAPK kinase/ERK pathway. The autocrine regulation of the AngII/AT1-ACE2-Ang(1-7)/Mas axis upon adipogenesis has also been revealed. This study suggests the importance of the local regulation of the delicately balanced angiotensin system upon adipogenesis and its potential as a novel therapeutic target for obesity and related metabolic disorders.

Noncanonical transforming growth factor β signaling in scleroderma fibrosis

PubMed Central

Trojanowska, Maria

2014-01-01

Purpose of review Persistent transforming growth factor β (TGF-β) signaling is the major factor contributing to scleroderma (SSc) fibrosis. This review will summarize recent progress on the noncanonical TGF-β signaling pathways and their role in SSc fibrosis. Recent findings Canonical TGF-β signaling involves activation of the TGF-β receptors and downstream signal transducers Smad2/3. The term noncanonical TGF-β signaling includes a variety of intracellular signaling pathways activated by TGF-β independently of Smad2/3 activation. There is evidence that these pathways play important role in SSc fibrosis. In a subset of SSc fibroblasts, a multiligand receptor complex consisting of TGF-β and CCN2 receptors drives constitutive activation of the Smad1 pathway. CCN2 is also a primary effector of this pathway, thus establishing an autocrine loop that amplifies TGF-β signaling. SSc fibroblasts also demonstrate reduced expression of endogenous antagonists of TGF-β signaling including transcriptional repressors, Friend leukemia integration-1 and perixosome proliferator-activated receptor-γ, as well as inhibitor of Smad3 phosphorylation, PTEN. PTEN is a key mediator of the cross-talk between the sphingosine kinase and the TGF-β pathways. Summary Discovery of the role of noncanonical TGF-β signaling in fibrosis offers new molecular targets for the antifibrotic therapies. Due to the heterogeneous nature of SSc, knowledge of these pathways could help to tailor the therapy to the individual patient depending on the activation status of a specific profibrotic pathway. PMID:19713852

Rapid and Simple Detection of Hot Spot Point Mutations of Epidermal Growth Factor Receptor, BRAF, and NRAS in Cancers Using the Loop-Hybrid Mobility Shift Assay

PubMed Central

Matsukuma, Shoichi; Yoshihara, Mitsuyo; Kasai, Fumio; Kato, Akinori; Yoshida, Akira; Akaike, Makoto; Kobayashi, Osamu; Nakayama, Haruhiko; Sakuma, Yuji; Yoshida, Tsutomu; Kameda, Yoichi; Tsuchiya, Eiju; Miyagi, Yohei

2006-01-01

A simple and rapid method to detect the epidermal growth factor receptor hot spot mutation L858R in lung adenocarcinoma was developed based on principles similar to the universal heteroduplex generator technology. A single-stranded oligonucleotide with an internal deletion was used to generate heteroduplexes (loop-hybrids) bearing a loop in the complementary strand derived from the polymerase chain reaction product of the normal or mutant allele. By placing deletion in the oligonucleotide adjacent to the mutational site, difference in electrophoretic mobility between loop-hybrids with normal and mutated DNA was distinguishable in a native polyacrylamide gel. The method was also modified to detect in-frame deletion mutations of epidermal growth factor receptor in lung adenocarcinomas. In addition, the method was adapted to detect hot spot mutations in the B-type Raf kinase (BRAF) at V600 and in a Ras-oncogene (NRAS) at Q61, the mutations commonly found in thyroid carcinomas. Our mutation detection system, designated the loop-hybrid mobility shift assay was sensitive enough to detect mutant DNA comprising 7.5% of the total DNA. As a simple and straightforward mutation detection technique, loop-hybrid mobility shift assay may be useful for the molecular diagnosis of certain types of clinical cancers. Other applications are also discussed. PMID:16931592

Loop series for discrete statistical models on graphs

NASA Astrophysics Data System (ADS)

Chertkov, Michael; Chernyak, Vladimir Y.

2006-06-01

In this paper we present the derivation details, logic, and motivation for the three loop calculus introduced in Chertkov and Chernyak (2006 Phys. Rev. E 73 065102(R)). Generating functions for each of the three interrelated discrete statistical models are expressed in terms of a finite series. The first term in the series corresponds to the Bethe-Peierls belief-propagation (BP) contribution; the other terms are labelled by loops on the factor graph. All loop contributions are simple rational functions of spin correlation functions calculated within the BP approach. We discuss two alternative derivations of the loop series. One approach implements a set of local auxiliary integrations over continuous fields with the BP contribution corresponding to an integrand saddle-point value. The integrals are replaced by sums in the complementary approach, briefly explained in Chertkov and Chernyak (2006 Phys. Rev. E 73 065102(R)). Local gauge symmetry transformations that clarify an important invariant feature of the BP solution are revealed in both approaches. The individual terms change under the gauge transformation while the partition function remains invariant. The requirement for all individual terms to be nonzero only for closed loops in the factor graph (as opposed to paths with loose ends) is equivalent to fixing the first term in the series to be exactly equal to the BP contribution. Further applications of the loop calculus to problems in statistical physics, computer and information sciences are discussed.

Genome-wide identification and analysis of the chicken basic helix-loop-helix factors.

PubMed

Liu, Wu-Yi; Zhao, Chun-Jiang

2010-01-01

Members of the basic helix-loop-helix (bHLH) family of transcription factors play important roles in a wide range of developmental processes. In this study, we conducted a genome-wide survey using the chicken (Gallus gallus) genomic database, and identified 104 bHLH sequences belonging to 42 gene families in an effort to characterize the chicken bHLH transcription factor family. Phylogenetic analyses revealed that chicken has 50, 21, 15, 4, 8, and 3 bHLH members in groups A, B, C, D, E, and F, respectively, while three members belonging to none of these groups were classified as ''orphans". A comparison between chicken and human bHLH repertoires suggested that both organisms have a number of lineage-specific bHLH members in the proteomes. Chromosome distribution patterns and phylogenetic analyses strongly suggest that the bHLH members should have arisen through gene duplication at an early date. Gene Ontology (GO) enrichment statistics showed 51 top GO annotations of biological processes counted in the frequency. The present study deepens our understanding of the chicken bHLH transcription factor family and provides much useful information for further studies using chicken as a model system.

Autocrine hemokinin-1 functions as endogenous adjuvant for IgE-mediated mast cell inflammatory responses

PubMed Central

Sumpter, Tina L.; Ho, Chin H.; Pleet, Anna R.; Tkacheva, Olga A.; Shufesky, William J.; Rojas-Canales, Darling M.; Morelli, Adrian E.; Larregina, Adriana T.

2014-01-01

Background Efficient development of atopic diseases requires interaction between allergen and adjuvant to initiate and amplify underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal via the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 following FcεRI crosslinking by Ag-IgE complexes, (FcεRI-MCs). Additionally, MCs express the NK1R suggesting an adjuvant role of NK1R agonists for FcεRI-MC mediated pathologies, however in depth research addressing this relevant aspect of MC biology is lacking. Objective To investigate the effect of NK1R-signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC mediated allergic disorders. Methods Bone marrow (BM) MCs derived from C57BL/6-wild type (WT) or NK1R−/− mice were used to investigate the effects of NK1R signaling of FcεRI-activated MCs. BMMCs generated from Tac1−/− mice or following culture with Tac4 siRNA were used to address the adjuvancy of SP and HK-1. WT, NK1R−/− and c-KitW-sh/W-sh mice reconstituted with WT or NK1R−/− BMMCs were utilized to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and airway inflammation. Results FcεRI-activated MCs up-regulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP. In a positive signaling loop, HK-1 promoted TNF and IL6 secretion by MC degranulation and protein synthesis the later via the PI3K/Akt/NFκB pathways. In vivo, NK1R signaling was necessary for development of passive local and systemic anaphylaxis and chronic airway inflammation. Conclusions FcεRI-stimulation of MCs promotes autocrine secretion of HK-1 which signals via NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders. PMID:25201259

Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway.

PubMed

Yang, Jing; Zhang, Dan; Yu, Ying; Zhang, Run-Ju; Hu, Xiao-Ling; Huang, He-Feng; Lu, Yong-Chao

2015-01-01

Fibroblast growth factors (FGF1, FGF2 and FGF4) and fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) have been reported to be expressed in preimplantation embryos and be required for their development. However, the functions of these molecules in trophectoderm cells (TEs) that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts. This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Besides, the present results suggest that FGF2/FGFR2 may act in an autocrine fashion and activate the downstream PKC/p38 pathway in TEs during expanded blastocyst formation.

Novel Growth Factor as Prognostic Marker for Estrogen-Independence in Breast Cancer

DTIC Science & Technology

2002-08-01

factor (PCDGF, also known as progranulin ) is a novel autocrine growth factor shown to be overexpressed and to be mitogenic in human breast cancer cell...kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC (1, 2). PCDGF (also known as progranulin ) is the...requirement for the insulin-like growth factor 1 receptor for growth in vitro. J Biol Chem, 273: 20078-20083, 1998. 6. He, Z. and Bateman, A. Progranulin gene

A LabVIEW model incorporating an open-loop arterial impedance and a closed-loop circulatory system.

PubMed

Cole, R T; Lucas, C L; Cascio, W E; Johnson, T A

2005-11-01

While numerous computer models exist for the circulatory system, many are limited in scope, contain unwanted features or incorporate complex components specific to unique experimental situations. Our purpose was to develop a basic, yet multifaceted, computer model of the left heart and systemic circulation in LabVIEW having universal appeal without sacrificing crucial physiologic features. The program we developed employs Windkessel-type impedance models in several open-loop configurations and a closed-loop model coupling a lumped impedance and ventricular pressure source. The open-loop impedance models demonstrate afterload effects on arbitrary aortic pressure/flow inputs. The closed-loop model catalogs the major circulatory waveforms with changes in afterload, preload, and left heart properties. Our model provides an avenue for expanding the use of the ventricular equations through closed-loop coupling that includes a basic coronary circuit. Tested values used for the afterload components and the effects of afterload parameter changes on various waveforms are consistent with published data. We conclude that this model offers the ability to alter several circulatory factors and digitally catalog the most salient features of the pressure/flow waveforms employing a user-friendly platform. These features make the model a useful instructional tool for students as well as a simple experimental tool for cardiovascular research.

Wilson loops and QCD/string scattering amplitudes

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

Makeenko, Yuri; Olesen, Poul; Niels Bohr International Academy, Niels Bohr Institute, Blegdamsvej 17, 2100 Copenhagen O

2009-07-15

We generalize modern ideas about the duality between Wilson loops and scattering amplitudes in N=4 super Yang-Mills theory to large N QCD by deriving a general relation between QCD meson scattering amplitudes and Wilson loops. We then investigate properties of the open-string disk amplitude integrated over reparametrizations. When the Wilson-loop is approximated by the area behavior, we find that the QCD scattering amplitude is a convolution of the standard Koba-Nielsen integrand and a kernel. As usual poles originate from the first factor, whereas no (momentum-dependent) poles can arise from the kernel. We show that the kernel becomes a constant whenmore » the number of external particles becomes large. The usual Veneziano amplitude then emerges in the kinematical regime, where the Wilson loop can be reliably approximated by the area behavior. In this case, we obtain a direct duality between Wilson loops and scattering amplitudes when spatial variables and momenta are interchanged, in analogy with the N=4 super Yang-Mills theory case.« less

Histone Methyltransferase NSD2/MMSET Mediates Constitutive NF-κB Signaling for Cancer Cell Proliferation, Survival, and Tumor Growth via a Feed-Forward Loop

PubMed Central

Yang, Ping; Guo, Linlang; Duan, Zhijian J.; Tepper, Clifford G.; Xue, Ling; Chen, Xinbin; Kung, Hsing-Jien; Gao, Allen C.

2012-01-01

Constitutive NF-κB activation by proinflammatory cytokines plays a major role in cancer progression. However, the underlying mechanism is still unclear. We report here that histone methyltransferase NSD2 (also known as MMSET or WHSC1), a target of bromodomain protein ANCCA/ATAD2, acts as a strong coactivator of NF-κB by directly interacting with NF-κB for activation of target genes, including those for interleukin-6 (IL-6), IL-8, vascular endothelial growth factor A (VEGFA), cyclin D, Bcl-2, and survivin, in castration-resistant prostate cancer (CRPC) cells. NSD2 is recruited to the target gene promoters upon induction and mediates NF-κB activation-associated elevation of histone H3K36me2 and H3K36me3 marks at the promoter, which involves its methylase activity. Interestingly, we found that NSD2 is also critical for cytokine-induced recruitment of NF-κB and acetyltransferase p300 and histone hyperacetylation. Importantly, NSD2 is overexpressed in prostate cancer tumors, and its overexpression correlates with NF-κB activation. Furthermore, NSD2 expression is strongly induced by tumor necrosis factor alpha (TNF-α) and IL-6 via NF-κB and plays a crucial role in tumor growth. These results identify NSD2 to be a key chromatin regulator of NF-κB and mediator of the cytokine autocrine loop for constitutive NF-κB activation and emphasize the important roles played by NSD2 in cancer cell proliferation and survival and tumor growth. PMID:22645312

A basic helix-loop-helix transcription factor, PhFBH4, regulates flower senescence by modulating ethylene biosynthesis pathway in petunia

USDA-ARS?s Scientific Manuscript database

The basic helix-loop-helix (bHLH) transcription factors (TFs) play important roles in regulating multiple biological processes in plants. However, there are few reports about the function of bHLHs in flower senescence. In this study, a bHLH TF, PhFBH4, was found to be dramatically upregulated during...

Research on phase locked loop in optical memory servo system

NASA Astrophysics Data System (ADS)

Qin, Liqin; Ma, Jianshe; Zhang, Jianyong; Pan, Longfa; Deng, Ming

2005-09-01

Phase locked loop (PLL) is a closed loop automatic control system, which can track the phase of input signal. It widely applies in each area of electronic technology. This paper research the phase locked loop in optical memory servo area. This paper introduces the configuration of digital phase locked loop (PLL) and phase locked servo system, the control theory, and analyses system's stability. It constructs the phase locked loop experiment system of optical disk spindle servo, which based on special chip. DC motor is main object, this system adopted phase locked servo technique and digital signal processor (DSP) to achieve constant linear velocity (CLV) in controlling optical spindle motor. This paper analyses the factors that affect the stability of phase locked loop in spindle servo system, and discusses the affection to the optical disk readout signal and jitter due to the stability of phase locked loop.

Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells by controlling bFGF and PDGF autocrine/paracrine loops

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

Ma, Yang; Han, Chen-chen; Li, Yifan

Basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) produced by hepatocellular carcinoma (HCC) cells are responsible for the growth of HCC cells. Accumulating evidence shows that insulin-like growth factor-binding protein-3 (IGFBP-3) suppresses HCC cell proliferation in both IGF-dependent and independent manners. It's unknown, however, whether treatment with exogenous IGFBP-3 inhibits bFGF and PDGF production in HCC cells. The present study demonstrates that IGFBP-3 suppressed IGF-1-induced bFGF and PDGF expression while it does not affect their expression in the absence of IGF-1. To delineate the underlying mechanism, western-blot and RT-PCR assays confirmed that the transcription factor early growth responsemore » protein 1 (EGR1) is involved in IGFBP-3 regulation of bFGF and PDGF. IGFBP-3 inhibition of type 1 insulin-like growth factor receptor (IGF1R), ERK and AKT activation is IGF-1-dependent. Furthermore, transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1, bFGF and PDGF expression. In conclusion, these findings suggest that IGFBP-3 suppresses transcription of EGR1 and its target genes bFGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation. It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation, suggesting that IGFBP-3 could be a target for the treatment of HCC. - Highlights: • IGFBP-3 plays an inhibition role in IGF1-induced HCC cell growth. • IGFBP-3 inhibits bFGF and PDGF production in the IGF-dependent manner. • EGR1 is involved in IGFBP-3 regulation of bFGF and PDGF in HCC cells. • IGFBP-3 suppresses EGR1 and its target genes bFGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.« less

An autocrine γ-aminobutyric acid signaling system exists in pancreatic β-cell progenitors of fetal and postnatal mice.

PubMed

Feng, Mary M; Xiang, Yun-Yan; Wang, Shuanglian; Lu, Wei-Yang

2013-01-01

Gamma-aminobutyric acid (GABA) is produced and secreted by adult pancreatic β-cells, which also express GABA receptors mediating autocrine signaling and regulating β-cell proliferation. However, whether the autocrine GABA signaling involves in β-cell progenitor development or maturation remains uncertain. By means of immunohistochemistry we analyzed the expression profiles of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the α1-subunit of type-A GABA receptor (GABAARα1) in the pancreas of mice at embryonic day 15.5 (E15.5), E18.5, postnatal day 1 (P1) and P7. Our data showed that at E15.5 the pancreatic and duodenum homeobox-1 (Pdx1) was expressed in the majority of cells in the developing pancreata. Notably, insulin immunoreactivity was identified in a subpopulation of pancreatic cells with a high level of Pdx1 expression. About 80% of the high-level Pdx-1 expressing cells in the pancreas expressed GAD and GABAARα1 at all pancreatic developmental stages. In contrast, only about 30% of the high-level Pdx-1 expressing cells in the E15.5 pancreas expressed insulin; i.e., a large number of GAD/GABAARα1-expressing cells did not express insulin at this early developmental stage. The expression level of GAD and GABAARα1 increased steadily, and progressively more GAD/GABAARα1-expressing cells expressed insulin in the course of pancreatic development. These results suggest that 1) GABA signaling proteins appear in β-cell progenitors prior to insulin expression; and 2) the increased expression of GABA signaling proteins may be involved in β-cell progenitor maturation.

Two-loop hard-thermal-loop thermodynamics with quarks

NASA Astrophysics Data System (ADS)

Andersen, Jens O.; Petitgirard, Emmanuel; Strickland, Michael

2004-08-01

We calculate the quark contribution to the free energy of a hot quark-gluon plasma to two-loop order using hard-thermal-loop (HTL) perturbation theory. All ultraviolet divergences can be absorbed into renormalizations of the vacuum energy and the HTL quark and gluon mass parameters. The quark and gluon HTL mass parameters are determined self-consistently by a variational prescription. Combining the quark contribution with the two-loop HTL perturbation theory free energy for pure glue we obtain the total two-loop QCD free energy. Comparisons are made with lattice estimates of the free energy for Nf=2 and with exact numerical results obtained in the large-Nf limit.

Paracrine and autocrine signals promoting full chondrogenic differentiation of a mesoblastic cell line.

PubMed

Locker, Morgane; Kellermann, Odile; Boucquey, Marie; Khun, Huot; Huerre, Michel; Poliard, Anne

2004-01-01

The pluripotent mesoblastic C1 cell line was used under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to drive chondrogenesis. Sequential addition of two systemic hormones, dexamethasone and triiodothyronine, permits full chondrogenic differentiation. The cell intrinsic activation of the BMP signaling pathway and Sox9 expression occurring on mesoblastic condensation is insufficient for recruitment of the progenitors. Dexamethasone-dependent Sox9 upregulation is essential for chondrogenesis. Differentiation of lineage stem cells relies on cell autonomous regulations modulated by external signals. We used the pluripotent mesoblastic C1 cell line under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to induce differentiation of a precursor clone along the chondrogenic lineage. C1 cells, cultured as aggregates, were induced toward chondrogenesis by addition of 10(-7) M dexamethasone in serum-free medium. After 30 days, dexamethasone was replaced by 10 nM triiodothyronine to promote final hypertrophic conversion. Mature and hypertrophic phenotypes were characterized by immunocytochemistry using specific antibodies against types II and X collagens, respectively. Type II collagen, bone morphogenetic proteins (BMPs), BMP receptors, Smads, and Sox9 expression were monitored by reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot, and/or Western blot analysis. Once C1 cells have formed nodules, sequential addition of two systemic hormones is sufficient to promote full chondrogenic differentiation. In response to dexamethasone, nearly 100% of the C1 precursors engage in chondrogenesis and convert within 30 days into mature chondrocytes, which triggers a typical cartilage matrix. On day 25, a switch in type II procollagen mRNA splicing acted as a limiting step in the acquisition of the mature chondrocyte phenotype. On day 30, substitution of dexamethasone with

Positive and negative feedback loops in nutrient phytoplankton interactions related to climate dynamics factors in a shallow temperate estuary (Vistula Lagoon, southern Baltic)

NASA Astrophysics Data System (ADS)

Kruk, Marek; Kobos, Justyna; Nawrocka, Lidia; Parszuto, Katarzyna

2018-04-01

This study aims to demonstrate that factors associated with climate dynamics, such as temperature and wind, affect the ecosystem of the shallow Vistula Lagoon in the southern Baltic and cause nutrient forms phytoplankton interactions: the growth of biomass and constraints of it. This occurs through a network of direct and indirect relationships between environmental and phytoplankton factors, including interactions of positive and negative feedback loops. Path analysis supported by structural equation modeling (SEM) was used to test hypotheses regarding the impact of climate factors on algal assemblages. Increased phytoplankton biomass was affected directly by water temperature and salinity, while the wind speed effect was indirect as it resulted in increased concentrations of suspended solids (SS) in the water column. Simultaneously, the concentration of SS in the water was positively correlated with particulate organic carbon (POC), particulate nitrogen (PN), and particulate phosphorus (PP), and was negatively correlated with the total nitrogen to phosphorus (N:P) ratio. Particulate forms of C, N, and phosphorus (P), concentrations of soluble reactive phosphorus (SRP) and nitrate and nitrite nitrogen (NO3-N + NO2-N), and ratios of the total N:P and DIN:SRP, all indirectly effected Cyanobacteria C concentrations. These processes influence other phytoplankton groups (Chlorophyta, Bacillariophyceae and the picophytoplankton fraction). Increased levels of SRP associated with organic matter (POC), which stemmed from reduced DIN:SRP ratios, contributed to increased Cyanoprokaryota and picophytoplankton C concentrations, which created a positive feedback loop. However, a simultaneous reduction in the total N:P ratio could have inhibited increases in the biomass of these assemblages by limiting N, which likely formed a negative feedback loop. The study indicates that the nutrients-phytoplankton feedback loop phenomenon can intensify eutrophication in a temperate lagoon

Getting in (and out of) the loop: regulating higher order telomere structures.

PubMed

Luke-Glaser, Sarah; Poschke, Heiko; Luke, Brian

2012-01-01

The DNA at the ends of linear chromosomes (the telomere) folds back onto itself and forms an intramolecular lariat-like structure. Although the telomere loop has been implicated in the protection of chromosome ends from nuclease-mediated resection and unscheduled DNA repair activities, it potentially poses an obstacle to the DNA replication machinery during S-phase. Therefore, the coordinated regulation of telomere loop formation, maintenance, and resolution is required in order to establish a balance between protecting the chromosome ends and promoting their duplication prior to cell division. Until recently, the only factor known to influence telomere looping in human cells was TRF2, a component of the shelterin complex. Recent work in yeast and mouse cells has uncovered additional regulatory factors that affect the loop structure at telomeres. In the following "perspective" we outline what is known about telomere looping and highlight the latest results regarding the regulation of this chromosome end structure. We speculate about how the manipulation of the telomere loop may have therapeutic implications in terms of diseases associated with telomere dysfunction and uncontrolled proliferation.

A Looping-Based Model for Quenching Repression

PubMed Central

Pollak, Yaroslav; Goldberg, Sarah; Amit, Roee

2017-01-01

We model the regulatory role of proteins bound to looped DNA using a simulation in which dsDNA is represented as a self-avoiding chain, and proteins as spherical protrusions. We simulate long self-avoiding chains using a sequential importance sampling Monte-Carlo algorithm, and compute the probabilities for chain looping with and without a protrusion. We find that a protrusion near one of the chain’s termini reduces the probability of looping, even for chains much longer than the protrusion–chain-terminus distance. This effect increases with protrusion size, and decreases with protrusion-terminus distance. The reduced probability of looping can be explained via an eclipse-like model, which provides a novel inhibitory mechanism. We test the eclipse model on two possible transcription-factor occupancy states of the D. melanogaster eve 3/7 enhancer, and show that it provides a possible explanation for the experimentally-observed eve stripe 3 and 7 expression patterns. PMID:28085884

Effect of supercoiling on formation of protein-mediated DNA loops

NASA Astrophysics Data System (ADS)

Purohit, P. K.; Nelson, P. C.

2006-12-01

DNA loop formation is one of several mechanisms used by organisms to regulate genes. The free energy of forming a loop is an important factor in determining whether the associated gene is switched on or off. In this paper we use an elastic rod model of DNA to determine the free energy of forming short (50-100 basepair), protein mediated DNA loops. Superhelical stress in the DNA of living cells is a critical factor determining the energetics of loop formation, and we explicitly account for it in our calculations. The repressor protein itself is regarded as a rigid coupler; its geometry enters the problem through the boundary conditions it applies on the DNA. We show that a theory with these ingredients is sufficient to explain certain features observed in modulation of in vivo gene activity as a function of the distance between operator sites for the lac repressor. We also use our theory to make quantitative predictions for the dependence of looping on superhelical stress, which may be testable both in vivo and in single-molecule experiments such as the tethered particle assay and the magnetic bead assay.

Pluripotency Gene Expression and Growth Control in Cultures of Peripheral Blood Monocytes during Their Conversion into Programmable Cells of Monocytic Origin (PCMO): Evidence for a Regulatory Role of Autocrine Activin and TGF-β

PubMed Central

Ungefroren, Hendrik; Hyder, Ayman; Hinz, Hebke; Groth, Stephanie; Lange, Hans; El-Sayed, Karim M. Fawzy; Ehnert, Sabrina; Nüssler, Andreas K.; Fändrich, Fred; Gieseler, Frank

2015-01-01

Previous studies have shown that peripheral blood monocytes can be converted in vitro to a stem cell-like cell termed PCMO as evidenced by the re-expression of pluripotency-associated genes, transient proliferation, and the ability to adopt the phenotype of hepatocytes and insulin-producing cells upon tissue-specific differentiation. However, the regulatory interactions between cultured cells governing pluripotency and mitotic activity have remained elusive. Here we asked whether activin(s) and TGF-β(s), are involved in PCMO generation. De novo proliferation of PCMO was higher under adherent vs. suspended culture conditions as revealed by the appearance of a subset of Ki67-positive monocytes and correlated with down-regulation of p21WAF1 beyond day 2 of culture. Realtime-PCR analysis showed that PCMO express ActRIIA, ALK4, TβRII, ALK5 as well as TGF-β1 and the βA subunit of activin. Interestingly, expression of ActRIIA and ALK4, and activin A levels in the culture supernatants increased until day 4 of culture, while levels of total and active TGF-β1 strongly declined. PCMO responded to both growth factors in an autocrine fashion with intracellular signaling as evidenced by a rise in the levels of phospho-Smad2 and a drop in those of phospho-Smad3. Stimulation of PCMO with recombinant activins (A, B, AB) and TGF-β1 induced phosphorylation of Smad2 but not Smad3. Inhibition of autocrine activin signaling by either SB431542 or follistatin reduced both Smad2 activation and Oct4A/Nanog upregulation. Inhibition of autocrine TGF-β signaling by either SB431542 or anti-TGF-β antibody reduced Smad3 activation and strongly increased the number of Ki67-positive cells. Furthermore, anti-TGF-β antibody moderately enhanced Oct4A/Nanog expression. Our data show that during PCMO generation pluripotency marker expression is controlled positively by activin/Smad2 and negatively by TGF-β/Smad3 signaling, while relief from growth inhibition is primarily the result of reduced

Inhibition of connective tissue growth factor (CTGF/CCN2) expression decreases the survival and myogenic differentiation of human rhabdomyosarcoma cells.

PubMed

Croci, Stefania; Landuzzi, Lorena; Astolfi, Annalisa; Nicoletti, Giordano; Rosolen, Angelo; Sartori, Francesca; Follo, Matilde Y; Oliver, Noelynn; De Giovanni, Carla; Nanni, Patrizia; Lollini, Pier-Luigi

2004-03-01

Connective tissue growth factor (CTGF/CCN2), a cysteine-rich protein of the CCN (Cyr61, CTGF, Nov) family of genes, emerged from a microarray screen of genes expressed by human rhabdomyosarcoma cells. Rhabdomyosarcoma is a soft tissue sarcoma of childhood deriving from skeletal muscle cells. In this study, we investigated the role of CTGF in rhabdomyosarcoma. Human rhabdomyosarcoma cells of the embryonal (RD/12, RD/18, CCA) and the alveolar histotype (RMZ-RC2, SJ-RH4, SJ-RH30), rhabdomyosarcoma tumor specimens, and normal skeletal muscle cells expressed CTGF. To determine the function of CTGF, we treated rhabdomyosarcoma cells with a CTGF antisense oligonucleotide or with a CTGF small interfering RNA (siRNA). Both treatments inhibited rhabdomyosarcoma cell growth, suggesting the existence of a new autocrine loop based on CTGF. CTGF antisense oligonucleotide-mediated growth inhibition was specifically due to a significant increase in apoptosis, whereas cell proliferation was unchanged. CTGF antisense oligonucleotide induced a strong decrease in the level of myogenic differentiation of rhabdomyosarcoma cells, whereas the addition of recombinant CTGF significantly increased the proportion of myosin-positive cells. CTGF emerges as a survival and differentiation factor and could be a new therapeutic target in human rhabdomyosarcoma.

Behaviour of fractional loop delay zero crossing digital phase locked loop (FR-ZCDPLL)

NASA Astrophysics Data System (ADS)

Nasir, Qassim

2018-01-01

This article analyses the performance of the first-order zero crossing digital phase locked loops (FR-ZCDPLL) when fractional loop delay is added to loop. The non-linear dynamics of the loop is presented, analysed and examined through bifurcation behaviour. Numerical simulation of the loop is conducted to proof the mathematical analysis of the loop operation. The results of the loop simulation show that the proposed FR-ZCDPLL has enhanced the performance compared to the conventional zero crossing DPLL in terms of wider lock range, captured range and stable operation region. In addition, extensive experimental simulation was conducted to find the optimum loop parameters for different loop environmental conditions. The addition of the fractional loop delay network in the conventional loop also reduces the phase jitter and its variance especially when the signal-to-noise ratio is low.

IL-1beta suppresses the formation of osteoclasts by increasing OPG production via an autocrine mechanism involving celecoxib-related prostaglandins in chondrocytes.

PubMed

Watanabe, Yusuke; Namba, Aki; Aida, Yukiko; Honda, Kazuhiro; Tanaka, Hideki; Suzuki, Naoto; Matsumura, Hideo; Maeno, Masao

2009-01-01

Elevated interleukin (IL)-1 concentrations in synovial fluid have been implicated in joint bone and cartilage destruction. Previously, we showed that IL-1beta stimulated the expression of prostaglandin (PG) receptor EP4 via increased PGE(2) production. However, the effect of IL-1beta on osteoclast formation via chondrocytes is unclear. Therefore, we examined the effect of IL-1beta and/or celecoxib on the expression of macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) in human chondrocytes, and the indirect effect of IL-1beta on osteoclast-like cell formation using RAW264.7 cells. OPG and RANKL expression increased with IL-1beta; whereas M-CSF expression decreased. Celecoxib blocked the stimulatory effect of IL-1beta. Conditioned medium from IL-1beta-treated chondrocytes decreased TRAP staining in RAW264.7 cells. These results suggest that IL-1beta suppresses the formation of osteoclast-like cells via increased OPG production and decreased M-CSF production in chondrocytes, and OPG production may increase through an autocrine mechanism involving celecoxib-related PGs.

R-loops: targets for nuclease cleavage and repeat instability.

PubMed

Freudenreich, Catherine H

2018-01-11

R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias. Recently, it was found that R-loops at an expanded CAG/CTG repeat tract cause DNA breaks as well as repeat instability (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Two factors were identified as causing R-loop-dependent breaks at CAG/CTG tracts: deamination of cytosines and the MutLγ (Mlh1-Mlh3) endonuclease, defining two new mechanisms for how R-loops can generate DNA breaks (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Following R-loop-dependent nicking, base excision repair resulted in repeat instability. These results have implications for human repeat expansion diseases and provide a paradigm for how RNA:DNA hybrids can cause genome instability at structure-forming DNA sequences. This perspective summarizes mechanisms of R-loop-induced fragility at G-rich repeats and new links between DNA breaks and repeat instability.

Investigation of Low Power Operation in a Loop Heat Pipe

NASA Technical Reports Server (NTRS)

Ku, Jentung; Ottenstein, Laura; Rogers, Paul; Cheung, Kwok; Powers, Edward I. (Technical Monitor)

2001-01-01

This paper presents test results of an experimental study of low power operation in a loop heat pipe. The main objective was to demonstrate how changes in the vapor void fraction inside the evaporator core would affect the loop behavior, The fluid inventory and the relative tilt between the evaporator and the compensation chamber were varied so as to create different vapor void fractions in the evaporator core. The effect on the loop start-up, operating temperature, and capillary limit was investigated. Test results indicate that the vapor void fraction inside the evaporator core is the single most important factor in determining the loop operation at low powers.

Leukocytosis due to markedly elevated granulocyte-colony stimulating factor levels in a patient with endometrial cancer: Case report and literature review.

PubMed

Clark, Leslie H; Moll, Stephan; Houghton, Damon; O'Connor, Siohban; Soper, John T

2017-05-01

•Granulocyte-colony stimulating factor (GCSF) secretion by gynecologic tumors is rare.•Elevations in serum GCSF can be seen in the absence of tumor GSCF secretion.•Extreme leukocytosis is associated with autocrine tumor growth and poor prognosis.

Role of B61, the Ligand for the Eck Receptor Tyrosine Kinase, in TNF- α-Induced Angiogenesis

NASA Astrophysics Data System (ADS)

Pandey, Akhilesh; Shao, Haining; Marks, Rory M.; Polverini, Peter J.; Dixit, Vishva M.

1995-04-01

B61, a cytokine-inducible endothelial gene product, is the ligand for the Eck receptor protein tyrosine kinase (RPTK). Expression of a B61-immunoglobulin chimera showed that B61 could act as an angiogenic factor in vivo and a chemoattractant for endothelial cells in vitro. The Eck RPTK was activated by tumor necrosis factor-α (TNF-α) through induction of B61, and an antibody to B61 attenuated angiogenesis induced by TNF-α but not by basic fibroblast growth factor. This finding suggests the existence of an autocrine or paracrine loop involving activation of the Eck RPTK by its inducible ligand B61 after an inflammatory stimulus, the net effect of which would be to promote angiogenesis, a hallmark of chronic inflammation.

Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis.

PubMed

Pandey, A; Shao, H; Marks, R M; Polverini, P J; Dixit, V M

1995-04-28

B61, a cytokine-inducible endothelial gene product, is the ligand for the Eck receptor protein tyrosine kinase (RPTK). Expression of a B61-immunoglobulin chimera showed that B61 could act as an angiogenic factor in vivo and a chemoattractant for endothelial cells in vitro. The Eck RPTK was activated by tumor necrosis factor-alpha (TNF-alpha) through induction of B61, and an antibody to B61 attenuated angiogenesis induced by TNF-alpha but not by basic fibroblast growth factor. This finding suggests the existence of an autocrine or paracrine loop involving activation of the Eck RPTK by its inducible ligand B61 after an inflammatory stimulus, the net effect of which would be to promote angiogenesis, a hallmark of chronic inflammation.

Varietal Loops

NASA Image and Video Library

2016-09-15

A series of active regions stretched along the right side of the sun exhibited a wide variety of loops cascading above them (Sept. 12-14, 2016). The active region near the center has tightly coiled loops, while the region rotating over the right edge has some elongated and some very stretched loops above it. The loops are actually charged particles spiraling along magnetic field lines, observed here in a wavelength of extreme ultraviolet light. Near the middle of the video the Earth quickly passes in front of a portion of the sun as viewed by SDO. http://photojournal.jpl.nasa.gov/catalog/PIA16997

Basic helix-loop-helix transcription factors in evolution: Roles in development of mesoderm and neural tissues.

PubMed

Gyoja, Fuki

2017-09-01

Basic helix-loop-helix (bHLH) transcription factors have attracted the attention of developmental and evolutionary biologists for decades because of their conserved functions in mesodermal and neural tissue formation in both vertebrates and fruit flies. Their evolutionary history is of special interest because it will likely provide insights into developmental processes and refinement of metazoan-specific traits. This review briefly considers advances in developmental biological studies on bHLHs/HLHs. I also discuss recent genome-wide surveys and molecular phylogenetic analyses of these factors in a wide range of metazoans. I hypothesize that interactions between metazoan-specific Group A, D, and E bHLH/HLH factors enabled a sophisticated transition system from cell proliferation to differentiation in multicellular development. This control mechanism probably emerged initially to organize a multicellular animal body and was subsequently recruited to form evolutionarily novel tissues, which differentiated during a later ontogenetic phase. © 2017 Wiley Periodicals, Inc.

Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming

PubMed Central

Dumitru, Claudia A.; Hemeda, Hatim; Jakob, Mark; Lang, Stephan; Brandau, Sven

2014-01-01

Mesenchymal stem/stromal cells (MSCs) are emerging as important regulators of innate and adaptive immunity. In this context, both proinflammatory and anti-inflammatory effects have been described for MSCs. The mechanisms mediating this functional plasticity are poorly characterized at present. Here, we investigated the inflammatory responses of MSCs isolated from human nasal mucosa (nmMSCs) upon challenge with different Toll-like receptor (TLR) ligands. We found that TLR3 ligands induced the strongest release of both proinflammatory cytokines [interleukin (IL)-6 and IL-8] and type I interferon by nmMSCs compared with other TLR ligands. Notably, TLR3 ligands triggered a biphasic cytokine response, with an early peak of type I interferon at 4 h poststimulation and a late release of proinflammatory cytokines at 24 h poststimulation. While the early interferon response was subject to direct stimulation, the proinflammatory response was regulated by factors released during the early cytokine response, which subsequently enhanced sensitivity to TLR3 ligation and amplified the production of IL-6 and IL-8 but not that of interferon. Taken together, our findings indicate that TLR3 ligands polarize the inflammatory phenotype of MSCs in a time-dependent manner. Thus, our study proposes a novel model that helps to explain the strikingly dichotomous functionality of MSCs in inflammation and immunoregulation.—Dumitru, C. A., Hemeda, H., Jakob, M., Lang, S., Brandau, S. Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming. PMID:24830384

Expression of the transforming growth factor alpha protooncogene in differentiating human promyelocytic leukemia (HL-60) cells.

PubMed

Walz, T M; Malm, C; Wasteson, A

1993-01-01

The process of myeloid differentiation in human promyelocytic leukemia cells (HL-60) is accompanied by the coordinate expression of numerous protooncogenes. To investigate the expression of transforming growth factor alpha (TGF-alpha) in myeloid differentiation, HL-60 cells were induced to differentiate into granulocytes with 1.25% dimethyl sulfoxide, 0.2 microM all-trans retinoic acid, or 500 microM N6,O2-dibutyryladenosine-3'5'-cyclic monophosphate or differentiated along the monocyte/macrophage pathway with 0.1 microM phorbol-12-myristate-13-acetate. Using Northern blot analyses, TGF-alpha transcripts were detected within 24 h of treatment in cells differentiating toward granulocytes; maximal levels of gene expression were reached after 3 days or later and remained essentially constant throughout the observation period. These cells released TGF-alpha protein, as demonstrated by analysis of the incubation medium. In contrast, no TGF-alpha RNA or protein was detectable in HL-60 cell cultures when induced with phorbol-12-myristate-13-acetate. Epidermal growth factor receptor transcripts could not be detected either in undifferentiated or in differentiated HL-60 cells; therefore it appears as if an autocrine loop involving TGF-alpha in HL-60 cells is unlikely. In conclusion, the results demonstrate, for the first time, the expression of TGF-alpha in human granulocyte precursor cells. Our findings may indicate novel regulatory pathways in hematopoiesis.

Nongenomic Glucocorticoid Suppression of a Postsynaptic Potassium Current via Emergent Autocrine Endocannabinoid Signaling in Hypothalamic Neuroendocrine Cells following Chronic Dehydration

PubMed Central

Wu, Ning

2017-01-01

Glucocorticoids rapidly stimulate endocannabinoid synthesis and modulation of synaptic transmission in hypothalamic neuroendocrine cells via a nongenomic signaling mechanism. The endocannabinoid actions are synapse-constrained by astrocyte restriction of extracellular spatial domains. Exogenous cannabinoids have been shown to modulate postsynaptic potassium currents, including the A-type potassium current (IA), in different cell types. The activity of magnocellular neuroendocrine cells is shaped by a prominent IA. We tested for a rapid glucocorticoid modulation of the postsynaptic IK and IA in magnocellular neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) using whole-cell recordings in rat brain slices. Application of the synthetic glucocorticoid dexamethasone (Dex) had no rapid effect on the IK or IA amplitude, voltage dependence, or kinetics in magnocellular neurons in slices from untreated rats. In magnocellular neurons from salt-loaded rats, however, Dex application caused a rapid suppression of the IA and a depolarizing shift in IA voltage dependence. Exogenously applied endocannabinoids mimicked the rapid Dex modulation of the IA, and CB1 receptor antagonists and agonists blocked and occluded the Dex-induced changes in the IA, respectively, suggesting an endocannabinoid dependence of the rapid glucocorticoid effect. Preincubation of control slices in a gliotoxin resulted in the partial recapitulation of the glucocorticoid-induced rapid suppression of the IA. These findings demonstrate a glucocorticoid suppression of the postsynaptic IA in PVN magnocellular neurons via an autocrine endocannabinoid-dependent mechanism following chronic dehydration, and suggest a possible role for astrocytes in the control of the autocrine endocannabinoid actions. PMID:28966975

Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging.

PubMed

Jeffery, Justin J; Lux, Katie; Vogel, John S; Herrera, Wynetta D; Greco, Stephen; Woo, Ho-Hyung; AbuShahin, Nisreen; Pagel, Mark D; Chambers, Setsuko K

2014-04-01

Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.

Ponderomotive Acceleration in Coronal Loops

NASA Astrophysics Data System (ADS)

Dahlburg, Russell B.; Laming, J. Martin; Taylor, Brian; Obenschain, Keith

2017-08-01

Ponderomotive acceleration has been asserted to be a cause of the First Ionization Potential (FIP) effect, the by now well known enhancement in abundance by a factor of 3-4 over photospheric values of elements in the solar corona with FIP less than about 10 eV. It is shown here by means of numerical simulations that ponderomotive acceleration occurs in solar coronal loops, with the appropriate magnitude and direction, as a ``byproduct'' of coronal heating. The numerical simulations are performed with the HYPERION code, which solves the fully compressible three-dimensional magnetohydrodynamic equations including nonlinear thermal conduction and optically thin radiation. Numerical simulations of a coronal loops with an axial magnetic field from 0.005 Teslas to 0.02 Teslas and lengths from 25000 km to 75000 km are presented. In the simulations the footpoints of the axial loop magnetic field are convected by random, large-scale motions. There is a continuous formation and dissipation of field-aligned current sheets which act to heat the loop. As a consequence of coronal magnetic reconnection, small scale, high speed jets form. The familiar vortex quadrupoles form at reconnection sites. Between the magnetic footpoints and the corona the reconnection flow merges with the boundary flow. It is in this region that the ponderomotive acceleration occurs. Mirroring the character of the coronal reconnection, the ponderomotive acceleration is also found to be intermittent.

Evidence for Nonuniform Heating of Coronal Loops Inferred from Multithread Modeling of TRACE Data

NASA Astrophysics Data System (ADS)

Aschwanden, Markus J.; Nightingale, Richard W.; Alexander, David

2000-10-01

The temperature Te(s) and density structure ne(s) of active region loops in EUV observed with TRACE is modeled with a multithread model, synthesized from the summed emission of many loop threads that have a distribution of maximum temperatures and that satisfy the steady state Rosner-Tucker-Vaiana (RTV) scaling law, modified by Serio et al. for gravitational stratification (called RTVSp in the following). In a recent Letter, Reale & Peres demonstrated that this method can explain the almost isothermal appearance of TRACE loops (observed by Lenz et al.) as derived from the filter-ratio method. From model-fitting of the 171 and 195 Å fluxes of 41 loops, which have loop half-lengths in the range of L=4-320 Mm, we find that (1) the EUV loops consist of near-isothermal loop threads with substantially smaller temperature gradients than are predicted by the RTVSp model; (2) the loop base pressure, p0~0.3+/-0.1 dynes cm-2, is independent of the loop length L, and it agrees with the RTVSp model for the shortest loops but exceeds the RTVSp model up to a factor of 35 for the largest loops; and (3) the pressure scale height is consistent with hydrostatic equilibrium for the shortest loops but exceeds the temperature scale height up to a factor of ~3 for the largest loops. The data indicate that cool EUV loops in the temperature range of Te~0.8-1.6 MK cannot be explained with the static steady state RTVSp model in terms of uniform heating but are fully consistent with Serio's model in the case of nonuniform heating (RTVSph), with heating scale heights in the range of sH=17+/-6 Mm. This heating function provides almost uniform heating for small loops (L<~20 Mm), but restricts heating to the footpoints of large loops (L~50-300 Mm).

Loop-the-Loop: An Easy Experiment, A Challenging Explanation

NASA Astrophysics Data System (ADS)

Asavapibhop, B.; Suwonjandee, N.

2010-07-01

A loop-the-loop built by the Institute for the Promotion of Teaching Science and Technology (IPST) was used in Thai high school teachers training program to demonstrate a circular motion and investigate the concept of the conservation of mechanical energy. We took videos using high speed camera to record the motions of a spherical steel ball moving down the aluminum inclined track at different released positions. The ball then moved into the circular loop and underwent a projectile motion upon leaving the track. We then asked the teachers to predict the landing position of the ball if we changed the height of the whole loop-the-loop system. We also analyzed the videos using Tracker, a video analysis software. It turned out that most teachers did not realize the effect of the friction between the ball and the track and could not obtain the correct relationship hence their predictions were inconsistent with the actual landing positions of the ball.

Loop-the-Loop: Bringing Theory into Practice

ERIC Educational Resources Information Center

Suwonjandee, N.; Asavapibhop, B.

2012-01-01

During the Thai high-school physics teacher training programme, we used an aluminum loop-the-loop system built by the Institute for the Promotion of Teaching Science and Technology (IPST) to demonstrate a circular motion and investigate the concept of the conservation of mechanical energy. There were 27 high-school teachers from three provinces,…

Comprehensive modulation of tumor progression and regression with periodic fasting and refeeding circles via boosting IGFBP-3 loops and NK responses.

PubMed

Chen, Xiancheng; Lin, Xiaojuan; Li, Meng

2012-10-01

Progressive tumor-bearing patients deserve to benefit from more realistic approaches. Here, a study revealed the impact of modified periodic fasting and refeeding regimen on tumor progression or regression with little or no loss of food intake and body weight. Human A549 lung, HepG-2 liver, and SKOV-3 ovary progressive tumor-bearing mice were established and subjected to 4 wk of periodic fasting/refeeding cycles (PFRC), including periodic 1-d fasting/6-d refeeding weekly (protocol 1) and periodic 2-d fasting/5-d refeeding weekly (P2DF/5DR, protocol 2), with ad libitum (AL)-fed hosts as controls. Afterwards, PFRC groups exhibited tumor growth arrest with some tendency towards regression; especially, complete regression of progressive tumors and metastases comprised between 43.75 and 56.25% of tumor-challenged hosts in P2DF/5DR group (P < 0.05). AL controls, in contrast, showed continuous tumor progression and metastasis. Finally, 100% hosts in P2DF/5DR and 62.5-68.75% in periodic 1-d fasting/6-d refeeding weekly groups survived a 4-month study period vs. only 31.25-37.5% in AL control group. Immunological assays and Luminex microarray revealed that tumor growth remission is mainly via natural killer cell (NK) reactivity and cross-regulation of IGF-binding protein-3, IGF/IGF-receptor, and megakaryocyte growth and development factor autocrine and paracrine loops. In vivo cellular and humoral assays indicated that tumor-regressive induction by PFRC protocols could be partly terminated by NK cell and IGF-binding protein-3 blockade or replenishment of IGF-I/-II and megakaryocyte growth and development factor. These findings offer a better understanding of comprehensive modulation of periodic fasting/refeeding strategy on the balance between tumor progression and regression.

Development of Antidepressants as Novel Agents To Treat Small Cell Lung Cancer

DTIC Science & Technology

2014-08-01

least in part by the capacity of these drugs to disrupt autocrine survival loops between neuro - transmitters and their receptors at the surface of SCLC...Ser10 (p-H3; Millipore), cleaved caspase-3 (CC3; Cell Signal- ing Technology), insulin (DAKO), and synaptophysin (SYN; Neuro - mics). Alexa Fluor

Sequence-structure relationships in RNA loops: establishing the basis for loop homology modeling.

PubMed

Schudoma, Christian; May, Patrick; Nikiforova, Viktoria; Walther, Dirk

2010-01-01

The specific function of RNA molecules frequently resides in their seemingly unstructured loop regions. We performed a systematic analysis of RNA loops extracted from experimentally determined three-dimensional structures of RNA molecules. A comprehensive loop-structure data set was created and organized into distinct clusters based on structural and sequence similarity. We detected clear evidence of the hallmark of homology present in the sequence-structure relationships in loops. Loops differing by <25% in sequence identity fold into very similar structures. Thus, our results support the application of homology modeling for RNA loop model building. We established a threshold that may guide the sequence divergence-based selection of template structures for RNA loop homology modeling. Of all possible sequences that are, under the assumption of isosteric relationships, theoretically compatible with actual sequences observed in RNA structures, only a small fraction is contained in the Rfam database of RNA sequences and classes implying that the actual RNA loop space may consist of a limited number of unique loop structures and conserved sequences. The loop-structure data sets are made available via an online database, RLooM. RLooM also offers functionalities for the modeling of RNA loop structures in support of RNA engineering and design efforts.

Two-Stage Design Method for Enhanced Inductive Energy Transmission with Q-Constrained Planar Square Loops.

PubMed

Eteng, Akaa Agbaeze; Abdul Rahim, Sharul Kamal; Leow, Chee Yen; Chew, Beng Wah; Vandenbosch, Guy A E

2016-01-01

Q-factor constraints are usually imposed on conductor loops employed as proximity range High Frequency Radio Frequency Identification (HF-RFID) reader antennas to ensure adequate data bandwidth. However, pairing such low Q-factor loops in inductive energy transmission links restricts the link transmission performance. The contribution of this paper is to assess the improvement that is reached with a two-stage design method, concerning the transmission performance of a planar square loop relative to an initial design, without compromise to a Q-factor constraint. The first stage of the synthesis flow is analytical in approach, and determines the number and spacing of turns by which coupling between similar paired square loops can be enhanced with low deviation from the Q-factor limit presented by an initial design. The second stage applies full-wave electromagnetic simulations to determine more appropriate turn spacing and widths to match the Q-factor constraint, and achieve improved coupling relative to the initial design. Evaluating the design method in a test scenario yielded a more than 5% increase in link transmission efficiency, as well as an improvement in the link fractional bandwidth by more than 3%, without violating the loop Q-factor limit. These transmission performance enhancements are indicative of a potential for modifying proximity HF-RFID reader antennas for efficient inductive energy transfer and data telemetry links.

LOOP CALCULUS AND BELIEF PROPAGATION FOR Q-ARY ALPHABET: LOOP TOWER

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

CHERTKOV, MICHAEL; CHERNYAK, VLADIMIR

Loop calculus introduced in [1], [2] constitutes a new theoretical tool that explicitly expresses symbol Maximum-A-Posteriori (MAP) solution of a general statistical inference problem via a solution of the Belief Propagation (BP) equations. This finding brought a new significance to the BP concept, which in the past was thought of as just a loop-free approximation. In this paper they continue a discussion of the Loop Calculus, partitioning the results into three Sections. In Section 1 they introduce a new formulation of the Loop Calculus in terms of a set of transformations (gauges) that keeping the partition function of the problemmore » invariant. The full expression contains two terms referred to as the 'ground state' and 'excited states' contributions. The BP equations are interpreted as a special (BP) gauge fixing condition that emerges as a special orthogonality constraint between the ground state and excited states, which also selects loop contributions as the only surviving ones among the excited states. In Section 2 they demonstrate how the invariant interpretation of the Loop Calculus, introduced in Section 1, allows a natural extension to the case of a general q-ary alphabet, this is achieved via a loop tower sequential construction. The ground level in the tower is exactly equivalent to assigning one color (out of q available) to the 'ground state' and considering all 'excited' states colored in the remaining (q-1) colors, according to the loop calculus rule. Sequentially, the second level in the tower corresponds to selecting a loop from the previous step, colored in (q-1) colors, and repeating the same ground vs excited states splitting procedure into one and (q-2) colors respectively. The construction proceeds till the full (q-1)-levels deep loop tower (and the corresponding contributions to the partition function) are established. In Section 3 they discuss an ultimate relation between the loop calculus and the Bethe-Free energy variational

Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor

PubMed Central

Armant, D. Randall; Kilburn, Brian A.; Petkova, Anelia; Edwin, Samuel S.; Duniec-Dmuchowski, Zophia M.; Edwards, Holly J.; Romero, Roberto; Leach, Richard E.

2006-01-01

Heparin-binding EGF-like growth factor (HBEGF), which is expressed in the placenta during normal pregnancy, is downregulated in pre-eclampsia, a human pregnancy disorder associated with poor trophoblast differentiation and survival. This growth factor protects against apoptosis during stress, suggesting a role in trophoblast survival in the relatively low O2 (∼2%) environment of the first trimester conceptus. Using a well-characterized human first trimester cytotrophoblast cell line, we found that a 4-hour exposure to 2% O2 upregulates HBEGF synthesis and secretion independently of an increase in its mRNA. Five other expressed members of the EGF family are largely unaffected. At 2% O2, signaling via HER1 or HER4, known HBEGF receptors, is required for both HBEGF upregulation and protection against apoptosis. This positive-feedback loop is dependent on metalloproteinase-mediated cleavage and shedding of the HBEGF ectodomain. The restoration of trophoblast survival by the addition of soluble HBEGF in cultures exposed to low O2 and metalloproteinase inhibitor suggests that the effects of HBEGF are mediated by autocrine/paracrine, rather than juxtacrine, signaling. Our results provide evidence that a post-transcriptional mechanism induced in trophoblasts by low O2 rapidly amplifies HBEGF signaling to inhibit apoptosis. These findings have a high clinical significance, as the downregulation of HBEGF in pre-eclampsia is likely to be a contributing factor leading to the demise of trophoblasts. PMID:16407398

Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor.

PubMed

Armant, D Randall; Kilburn, Brian A; Petkova, Anelia; Edwin, Samuel S; Duniec-Dmuchowski, Zophia M; Edwards, Holly J; Romero, Roberto; Leach, Richard E

2006-02-01

Heparin-binding EGF-like growth factor (HBEGF), which is expressed in the placenta during normal pregnancy, is down regulated in pre-eclampsia, a human pregnancy disorder associated with poor trophoblast differentiation and survival. This growth factor protects against apoptosis during stress, suggesting a role in trophoblast survival in the relatively low O(2) ( approximately 2%) environment of the first trimester conceptus. Using a well-characterized human first trimester cytotrophoblast cell line, we found that a 4-hour exposure to 2% O(2) upregulates HBEGF synthesis and secretion independently of an increase in its mRNA. Five other expressed members of the EGF family are largely unaffected. At 2% O(2), signaling via HER1 or HER4, known HBEGF receptors, is required for both HBEGF upregulation and protection against apoptosis. This positive-feedback loop is dependent on metalloproteinase-mediated cleavage and shedding of the HBEGF ectodomain. The restoration of trophoblast survival by the addition of soluble HBEGF in cultures exposed to low O(2) and metalloproteinase inhibitor suggests that the effects of HBEGF are mediated by autocrine/paracrine, rather than juxtacrine, signaling. Our results provide evidence that a post-transcriptional mechanism induced in trophoblasts by low O(2) rapidly amplifies HBEGF signaling to inhibit apoptosis. These findings have a high clinical significance, as the downregulation of HBEGF in pre-eclampsia is likely to be a contributing factor leading to the demise of trophoblasts.

Livermore Compiler Analysis Loop Suite

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

Hornung, R. D.

2013-03-01

LCALS is designed to evaluate compiler optimizations and performance of a variety of loop kernels and loop traversal software constructs. Some of the loop kernels are pulled directly from "Livermore Loops Coded in C", developed at LLNL (see item 11 below for details of earlier code versions). The older suites were used to evaluate floating-point performances of hardware platforms prior to porting larger application codes. The LCALS suite is geared toward assissing C++ compiler optimizations and platform performance related to SIMD vectorization, OpenMP threading, and advanced C++ language features. LCALS contains 20 of 24 loop kernels from the older Livermoremore » Loop suites, plus various others representative of loops found in current production appkication codes at LLNL. The latter loops emphasize more diverse loop constructs and data access patterns than the others, such as multi-dimensional difference stencils. The loops are included in a configurable framework, which allows control of compilation, loop sampling for execution timing, which loops are run and their lengths. It generates timing statistics for analysis and comparing variants of individual loops. Also, it is easy to add loops to the suite as desired.« less

Fast flux locked loop

DOEpatents

Ganther, Jr., Kenneth R.; Snapp, Lowell D.

2002-09-10

A flux locked loop for providing an electrical feedback signal, the flux locked loop employing radio-frequency components and technology to extend the flux modulation frequency and tracking loop bandwidth. The flux locked loop of the present invention has particularly useful application in read-out electronics for DC SQUID magnetic measurement systems, in which case the electrical signal output by the flux locked loop represents an unknown magnetic flux applied to the DC SQUID.

RNA polymerase gate loop guides the nontemplate DNA strand in transcription complexes.

PubMed

NandyMazumdar, Monali; Nedialkov, Yuri; Svetlov, Dmitri; Sevostyanova, Anastasia; Belogurov, Georgiy A; Artsimovitch, Irina

2016-12-27

Upon RNA polymerase (RNAP) binding to a promoter, the σ factor initiates DNA strand separation and captures the melted nontemplate DNA, whereas the core enzyme establishes interactions with the duplex DNA in front of the active site that stabilize initiation complexes and persist throughout elongation. Among many core RNAP elements that participate in these interactions, the β' clamp domain plays the most prominent role. In this work, we investigate the role of the β gate loop, a conserved and essential structural element that lies across the DNA channel from the clamp, in transcription regulation. The gate loop was proposed to control DNA loading during initiation and to interact with NusG-like proteins to lock RNAP in a closed, processive state during elongation. We show that the removal of the gate loop has large effects on promoter complexes, trapping an unstable intermediate in which the RNAP contacts with the nontemplate strand discriminator region and the downstream duplex DNA are not yet fully established. We find that although RNAP lacking the gate loop displays moderate defects in pausing, transcript cleavage, and termination, it is fully responsive to the transcription elongation factor NusG. Together with the structural data, our results support a model in which the gate loop, acting in concert with initiation or elongation factors, guides the nontemplate DNA in transcription complexes, thereby modulating their regulatory properties.

Introduction to Loop Heat Pipes

NASA Technical Reports Server (NTRS)

Ku, Jentung

2015-01-01

This is the presentation file for the short course Introduction to Loop Heat Pipes, to be conducted at the 2015 Thermal Fluids and Analysis Workshop, August 3-7, 2015, Silver Spring, Maryland. This course will discuss operating principles and performance characteristics of a loop heat pipe. Topics include: 1) pressure profiles in the loop; 2) loop operating temperature; 3) operating temperature control; 4) loop startup; 4) loop shutdown; 5) loop transient behaviors; 6) sizing of loop components and determination of fluid inventory; 7) analytical modeling; 8) examples of flight applications; and 9) recent LHP developments.

OPE for super loops

NASA Astrophysics Data System (ADS)

Sever, Amit; Vieira, Pedro; Wang, Tianheng

2011-11-01

We extend the Operator Product Expansion for Null Polygon Wilson loops to the Mason-Skinner-Caron-Huot super loop dual to non MHV gluon amplitudes. We explain how the known tree level amplitudes can be promoted into an infinite amount of data at any loop order in the OPE picture. As an application, we re-derive all one loop NMHV six gluon amplitudes by promoting their tree level expressions. We also present some new all loops predictions for these amplitudes.

Provider risk factors for medication administration error alerts: analyses of a large-scale closed-loop medication administration system using RFID and barcode.

PubMed

Hwang, Yeonsoo; Yoon, Dukyong; Ahn, Eun Kyoung; Hwang, Hee; Park, Rae Woong

2016-12-01

To determine the risk factors and rate of medication administration error (MAE) alerts by analyzing large-scale medication administration data and related error logs automatically recorded in a closed-loop medication administration system using radio-frequency identification and barcodes. The subject hospital adopted a closed-loop medication administration system. All medication administrations in the general wards were automatically recorded in real-time using radio-frequency identification, barcodes, and hand-held point-of-care devices. MAE alert logs recorded during a full 1 year of 2012. We evaluated risk factors for MAE alerts including administration time, order type, medication route, the number of medication doses administered, and factors associated with nurse practices by logistic regression analysis. A total of 2 874 539 medication dose records from 30 232 patients (882.6 patient-years) were included in 2012. We identified 35 082 MAE alerts (1.22% of total medication doses). The MAE alerts were significantly related to administration at non-standard time [odds ratio (OR) 1.559, 95% confidence interval (CI) 1.515-1.604], emergency order (OR 1.527, 95%CI 1.464-1.594), and the number of medication doses administered (OR 0.993, 95%CI 0.992-0.993). Medication route, nurse's employment duration, and working schedule were also significantly related. The MAE alert rate was 1.22% over the 1-year observation period in the hospital examined in this study. The MAE alerts were significantly related to administration time, order type, medication route, the number of medication doses administered, nurse's employment duration, and working schedule. The real-time closed-loop medication administration system contributed to improving patient safety by preventing potential MAEs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Energetics analysis of interstitial loops in single-phase concentrated solid-solution alloys

NASA Astrophysics Data System (ADS)

Wang, Xin-Xin; Niu, Liang-Liang; Wang, Shaoqing

2018-04-01

Systematic energetics analysis on the shape preference, relative stability and radiation-induced segregation of interstitial loops in nickel-containing single-phase concentrated solid-solution alloys have been conducted using atomistic simulations. It is shown that the perfect loops prefer rhombus shape for its low potential energy, while the Frank faulted loops favor ellipse for its low potential energy and the possible large configurational entropy. The decrease of stacking fault energy with increasing compositional complexity provides the energetic driving force for the formation of faulted loops, which, in conjunction with the kinetic factors, explains the experimental observation that the fraction of faulted loops rises with increasing compositional complexity. Notably, the kinetics is primarily responsible for the absence of faulted loops in nickel-cobalt with a very low stacking fault energy. We further demonstrate that the simultaneous nickel enrichment and iron/chromium depletion on interstitial loops can be fully accounted for by their energetics.

A loop resonator for slice-selective in vivo EPR imaging in rats

PubMed Central

Hirata, Hiroshi; He, Guanglong; Deng, Yuanmu; Salikhov, Ildar; Petryakov, Sergey; Zweier, Jay L.

2008-01-01

A loop resonator was developed for 300-MHz continuous-wave electron paramagnetic resonance (CW-EPR) spectroscopy and imaging in live rats. A single-turn loop (55 mm in diameter) was used to provide sufficient space for the rat body. Efficiency for generating a radiofrequency magnetic field of 38 µT/W1/2 was achieved at the center of the loop. For the resonator itself, an unloaded quality factor of 430 was obtained. When a 350 g rat was placed in the resonator at the level of the lower abdomen, the quality factor decreased to 18. The sensitive volume in the loop was visualized with a bottle filled with an aqueous solution of the nitroxide spin probe 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxy (3-CP). The resonator was shown to enable EPR imaging in live rats. Imaging was performed for 3-CP that had been infused intravenously into the rat and its distribution was visualized within the lower abdomen. PMID:18006343

Hard matching for boosted tops at two loops

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

Hoang, Andre H.; Pathak, Aditya; Pietrulewicz, Piotr

2015-12-10

Here, cross sections for top quarks provide very interesting physics opportunities, being both sensitive to new physics and also perturbatively tractable due to the large top quark mass. Rigorous factorization theorems for top cross sections can be derived in several kinematic scenarios, including the boosted regime in the peak region that we consider here. In the context of the corresponding factorization theorem for e +e – collisions we extract the last missing ingredient that is needed to evaluate the cross section differential in the jet-mass at two-loop order, namely the matching coefficient at the scale μ≃m t. Our extraction alsomore » yields the final ingredients needed to carry out logarithmic re-summation at next-to-next-to-leading logarithmic order (or N 3LL if we ignore the missing 4-loop cusp anomalous dimension). This coefficient exhibits an amplitude level rapidity logarithm starting at O(α 2 s) due to virtual top quark loops, which we treat using rapidity renormalization group (RG) evolution. Interestingly, this rapidity RG evolution appears in the matching coefficient between two effective theories around the heavy quark mass scale μ ≃ m t.« less

Regulation of TCF ETS-domain transcription factors by helix-loop-helix motifs.

PubMed

Stinson, Julie; Inoue, Toshiaki; Yates, Paula; Clancy, Anne; Norton, John D; Sharrocks, Andrew D

2003-08-15

DNA binding by the ternary complex factor (TCF) subfamily of ETS-domain transcription factors is tightly regulated by intramolecular and intermolecular interactions. The helix-loop-helix (HLH)-containing Id proteins are trans-acting negative regulators of DNA binding by the TCFs. In the TCF, SAP-2/Net/ERP, intramolecular inhibition of DNA binding is promoted by the cis-acting NID region that also contains an HLH-like motif. The NID also acts as a transcriptional repression domain. Here, we have studied the role of HLH motifs in regulating DNA binding and transcription by the TCF protein SAP-1 and how Cdk-mediated phosphorylation affects the inhibitory activity of the Id proteins towards the TCFs. We demonstrate that the NID region of SAP-1 is an autoinhibitory motif that acts to inhibit DNA binding and also functions as a transcription repression domain. This region can be functionally replaced by fusion of Id proteins to SAP-1, whereby the Id moiety then acts to repress DNA binding in cis. Phosphorylation of the Ids by cyclin-Cdk complexes results in reduction in protein-protein interactions between the Ids and TCFs and relief of their DNA-binding inhibitory activity. In revealing distinct mechanisms through which HLH motifs modulate the activity of TCFs, our results therefore provide further insight into the role of HLH motifs in regulating TCF function and how the inhibitory properties of the trans-acting Id HLH proteins are themselves regulated by phosphorylation.

Risk factors of stoma re-creation after closure of diverting ileostomy in patients with rectal cancer who underwent low anterior resection or intersphincteric resection with loop ileostomy.

PubMed

Song, Ook; Kim, Kyung Hwan; Lee, Soo Young; Kim, Chang Hyun; Kim, Young Jin; Kim, Hyeong Rok

2018-04-01

The aim of this study was to identify the risk factors of stoma re-creation after closure of diverting ileostomy in patients with rectal cancer who underwent low anterior resection (LAR) or intersphincteric resection (ISR) with loop ileostomy. We retrospectively reviewed 520 consecutive patients with rectal cancer who underwent LAR or ISR with loop ileostomy from January 2005 to December 2014 at Chonnam National University Hwasun Hospital. Risk factors for stoma re-creation after ileostomy closure were evaluated. Among 520 patients with rectal cancer who underwent LAR or ISR with loop ileostomy, 458 patients underwent stoma closure. Among these patients, 45 (9.8%) underwent stoma re-creation. The median period between primary surgery and stoma closure was 5.5 months (range, 0.5-78.3 months), and the median period between closure and re-creation was 6.8 months (range, 0-71.5 months). Stoma re-creation was performed because of anastomosis-related complications (26, 57.8%), local recurrence (15, 33.3%), and anal sphincter dysfunction (3, 6.7%). Multivariate analysis showed that independent risk factors for stoma re-creation were anastomotic leakage (odds ratio [OR], 4.258; 95% confidence interval [CI], 1.814-9.993), postoperative radiotherapy (OR, 3.947; 95% CI, 1.624-9.594), and ISR (OR, 3.293; 95% CI, 1.462-7.417). Anastomotic leakage, postoperative radiotherapy, and ISR were independent risk factors for stoma re-creation after closure of ileostomy in patients with rectal cancer.

Effect of Loop Geometry on TEM Response Over Layered Earth

NASA Astrophysics Data System (ADS)

Qi, Youzheng; Huang, Ling; Wu, Xin; Fang, Guangyou; Yu, Gang

2014-09-01

A large horizontal loop located on the ground or carried by an aircraft are the most common sources of the transient electromagnetic method. Although topographical factors or airplane outlines make the loop of arbitrary shape, magnetic sources are generally represented as a magnetic dipole or a circular loop, which may bring about significant errors in the calculated response. In this paper, we present a method for calculating the response of a loop of arbitrary shape (for which the description can be obtained by different methods, including GPS localization) in air or on the surface of a stratified earth. The principle of reciprocity is firstly used to exchange the functions of the transmitting loop and the dipole receiver, then the response of a vertical or a horizontal magnetic dipole is calculated beforehand, and finally the line integral of the second kind is employed to get the transient response. Analytical analysis and comparisons depict that our work got very good results in many situations. Synthetic and field examples are given in the end to show the effect of loop geometry and how our method improves the precision of the EM response.

High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression.

PubMed

Hyndman, Kelly Anne; Dugas, Courtney; Arguello, Alexandra M; Goodchild, Traci T; Buckley, Kathleen M; Burch, Mariah; Yanagisawa, Masashi; Pollock, Jennifer S

2016-08-01

The collecting duct endothelin-1 (ET-1), endothelin B (ETB) receptor, and nitric oxide synthase-1 (NOS1) pathways are critical for regulation of fluid-electrolyte balance and blood pressure control during high-salt feeding. ET-1, ETB receptor, and NOS1 are highly expressed in the inner medullary collecting duct (IMCD) and vasa recta, suggesting that there may be cross talk or paracrine signaling between the vasa recta and IMCD. The purpose of this study was to test the hypothesis that endothelial cell-derived ET-1 (paracrine) and collecting duct-derived ET-1 (autocrine) promote IMCD nitric oxide (NO) production through activation of the ETB receptor during high-salt feeding. We determined that after 7 days of a high-salt diet (HS7), there was a shift to 100% ETB expression in IMCDs, as well as a twofold increase in nitrite production (a metabolite of NO), and this increase could be prevented by acute inhibition of the ETB receptor. ETB receptor blockade or NOS1 inhibition also prevented the ET-1-dependent decrease in ion transport from primary IMCDs, as determined by transepithelial resistance. IMCD were also isolated from vascular endothelial ET-1 knockout mice (VEETKO), collecting duct ET-1 KO (CDET-1KO), and flox controls. Nitrite production by IMCD from VEETKO and flox mice was similarly increased twofold with HS7. However, IMCD NO production from CDET-1KO mice was significantly blunted with HS7 compared with flox control. Taken together, these data indicate that during high-salt feeding, the autocrine actions of ET-1 via upregulation of the ETB receptor are critical for IMCD NO production, facilitating inhibition of ion reabsorption. Copyright © 2016 the American Physiological Society.

Multiple Flow Loop SCADA System Implemented on the Production Prototype Loop

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

Baily, Scott A.; Dalmas, Dale Allen; Wheat, Robert Mitchell

2015-11-16

The following report covers FY 15 activities to develop supervisory control and data acquisition (SCADA) system for the Northstar Moly99 production prototype gas flow loop. The goal of this effort is to expand the existing system to include a second flow loop with a larger production-sized blower. Besides testing the larger blower, this system will demonstrate the scalability of our solution to multiple flow loops.

Engineering the thermostability of β-glucuronidase from Penicillium purpurogenum Li-3 by loop transplant.

PubMed

Feng, Xudong; Tang, Heng; Han, Beijia; Zhang, Liang; Lv, Bo; Li, Chun

2016-12-01

In this study, we proposed a loop transplant strategy to improve the thermostability of Penicillium purpurogenum Li-3 β-glucuronidase expressed in Escherichia coli (abbreviated to PGUS-E). Firstly, three unstable surface loops of PGUS-E to be replaced were identified with regards to B-factor values and in-depth structure analysis: loops 205-211, 258-263, and 25-31. Then, based on B-factor analysis, eight stable loops for substitution were selected from two typical thermophilic glycosidases which had low homology with PGUS-E (less than 25 %). By analyzing the common features of these stable loops, it was found that they shared a common residue skeleton DXXTX(X)R, based on this, three chimera loops were also manually designed: RSQTSND, RSSTQRD, and DDQTSR. All these loops were introduced to replace the unstable loops of PGUS-E by homology structure modeling, and only mutants with increased hydrogen bonds number and good compatibility with the local mutated region were further subjected to experimental verification. By using this strategy, 10 mutants were experimentally generated, among which three mutants, M1, M3, and M8, were obtained which showed 11.8, 3.3, and 9.4 times higher half-life at 70 °C than that of wild-type (8.5 min). Finally, the MD simulation indicated that the increased hydrogen bonds, decreased flexibility of N-terminal, and increased π-π stacking interaction were responsible for the improved thermostability.

N -loop running should be combined with N -loop matching

NASA Astrophysics Data System (ADS)

Braathen, Johannes; Goodsell, Mark D.; Krauss, Manuel E.; Opferkuch, Toby; Staub, Florian

2018-01-01

We investigate the high-scale behavior of Higgs sectors beyond the Standard Model, pointing out that the proper matching of the quartic couplings before applying the renormalization group equations (RGEs) is of crucial importance for reliable predictions at larger energy scales. In particular, the common practice of leading-order parameters in the RGE evolution is insufficient to make precise statements on a given model's UV behavior, typically resulting in uncertainties of many orders of magnitude. We argue that, before applying N -loop RGEs, a matching should even be performed at N -loop order in contrast to common lore. We show both analytical and numerical results where the impact is sizable for three minimal extensions of the Standard Model: a singlet extension, a second Higgs doublet and finally vector-like quarks. We highlight that the known two-loop RGEs tend to moderate the running of their one-loop counterparts, typically delaying the appearance of Landau poles. For the addition of vector-like quarks we show that the complete two-loop matching and RGE evolution hints at a stabilization of the electroweak vacuum at high energies, in contrast to results in the literature.

Unmixing Magnetic Hysteresis Loops

NASA Astrophysics Data System (ADS)

Heslop, D.; Roberts, A. P.

2012-04-01

Magnetic hysteresis loops provide important information in rock and environmental magnetic studies. Natural samples often contain an assemblage of magnetic particles composed of components with different origins. Each component potentially carries important environmental information. Hysteresis loops, however, provide information concerning the bulk magnetic assemblage, which makes it difficult to isolate the specific contributions from different sources. For complex mineral assemblages an unmixing strategy with which to separate hysteresis loops into their component parts is therefore essential. Previous methods to unmix hysteresis data have aimed at separating individual loops into their constituent parts using libraries of type-curves thought to correspond to specific mineral types. We demonstrate an alternative approach, which rather than decomposing a single loop into monomineralic contributions, examines a collection of loops to determine their constituent source materials. These source materials may themselves be mineral mixtures, but they provide a genetically meaningful decomposition of a magnetic assemblage in terms of the processes that controlled its formation. We show how an empirically derived hysteresis mixing space can be created, without resorting to type-curves, based on the co-variation within a collection of measured loops. Physically realistic end-members, which respect the expected behaviour and symmetries of hysteresis loops, can then be extracted from the mixing space. These end-members allow the measured loops to be described as a combination of invariant parts that are assumed to represent the different sources in the mixing model. Particular attention is paid to model selection and estimating the complexity of the mixing model, specifically, how many end-members should be included. We demonstrate application of this approach using lake sediments from Butte Valley, northern California. Our method successfully separates the hysteresis loops

Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

PubMed Central

Hamerlik, Petra; Lathia, Justin D.; Rasmussen, Rikke; Wu, Qiulian; Bartkova, Jirina; Lee, MyungHee; Moudry, Pavel; Bartek, Jiri; Fischer, Walter; Lukas, Jiri

2012-01-01

Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133+ human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2–Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF–VEGFR2–NRP1, which is associated with VEGFR2–NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF–VEGFR2–NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach. PMID:22393126

All-loop Mondrian diagrammatics and 4-particle amplituhedron

NASA Astrophysics Data System (ADS)

An, Yang; Li, Yi; Li, Zhinan; Rao, Junjie

2018-06-01

Based on 1712.09990 which handles the 4-particle amplituhedron at 3-loop, we have found an extremely simple pattern, yet far more non-trivial than one might naturally expect: the all-loop Mondrian diagrammatics. By further simplifying and rephrasing the key relation of positivity in the amplituhedron setting, remarkably, we find a completeness relation unifying all diagrams of the Mondrian types for the 4-particle integrand of planar N = 4 SYM to all loop orders, each of which can be mapped to a simple product following a few plain rules designed for this relation. The explicit examples we investigate span from 3-loop to 7-loop order, and based on them, we classify the basic patterns of Mondrian diagrams into four types: the ladder, cross, brick-wall and spiral patterns. Interestingly, for some special combinations of ordered subspaces (a concept defined in the previous work), we find failed exceptions of the completeness relation which are called "anomalies", nevertheless, they substantially give hints on the all-loop recursive proof of this relation. These investigations are closely related to the combinatoric knowledge of separable permutations and Schröder numbers, and go even further from a diagrammatic perspective. For physical relevance, we need to further consider dual conformal invariance for two basic diagrammatic patterns to correct the numerator for a local integrand involving one or both of such patterns, while the denominator encoding its pole structure and also the sign factor, are already fixed by rules of the completeness relation. With this extra treatment to ensure the integrals are dual conformally invariant, each Mondrian diagram can be exactly translated to its corresponding physical loop integrand after being summed over all ordered subspaces that admit it.

Hematopoietic growth factors and human acute leukemia.

PubMed

Löwenberg, B; Touw, I

1988-10-22

The study of myelopoietic maturation arrest in acute myeloblastic leukemia (AML) has been eased by availability of the human recombinant hemopoietic growth factors, macrophage colony stimulating factor (M-CSF), granulocyte-(G-CSF), granulocyte-macrophage-(GM-CSF) and multilineage stimulating factor (IL-3). Nonphysiological expansion of the leukemic population is not due to escape from control by these factors. Proliferation in vitro of AML cells is dependent on the presence of one or several factors in most cases. The pattern of factor-dependency does not correlate with morphological criteria in individual cases, and may thus offer a new tool for classification of AML. Overproduction of undifferentiated cells is not due to abnormal expression of receptors for the stimulating factors acting at an immature level. Rather, autocrine secretion of early acting lymphokines maintains proliferation of the leukemic clone. When looking at causes of leukemic dysregulation, yet undefined inhibitors of differentiation probably are of equal importance as dysequilibrated stimulation by lymphokines.

Power Impact of Loop Buffer Schemes for Biomedical Wireless Sensor Nodes

PubMed Central

Artes, Antonio; Ayala, Jose L.; Catthoor, Francky

2012-01-01

Instruction memory organisations are pointed out as one of the major sources of energy consumption in embedded systems. As these systems are characterised by restrictive resources and a low-energy budget, any enhancement in this component allows not only to decrease the energy consumption but also to have a better distribution of the energy budget throughout the system. Loop buffering is an effective scheme to reduce energy consumption in instruction memory organisations. In this paper, the loop buffer concept is applied in real-life embedded applications that are widely used in biomedical Wireless Sensor Nodes, to show which scheme of loop buffer is more suitable for applications with certain behaviour. Post-layout simulations demonstrate that a trade-off exists between the complexity of the loop buffer architecture and the energy savings of utilising it. Therefore, the use of loop buffer architectures in order to optimise the instruction memory organisation from the energy efficiency point of view should be evaluated carefully, taking into account two factors: (1) the percentage of the execution time of the application that is related to the execution of the loops, and (2) the distribution of the execution time percentage over each one of the loops that form the application. PMID:23202202

Power impact of loop buffer schemes for biomedical wireless sensor nodes.

PubMed

Artes, Antonio; Ayala, Jose L; Catthoor, Francky

2012-11-06

Instruction memory organisations are pointed out as one of the major sources of energy consumption in embedded systems. As these systems are characterised by restrictive resources and a low-energy budget, any enhancement in this component allows not only to decrease the energy consumption but also to have a better distribution of the energy budget throughout the system. Loop buffering is an effective scheme to reduce energy consumption in instruction memory organisations. In this paper, the loop buffer concept is applied in real-life embedded applications that are widely used in biomedical Wireless Sensor Nodes, to show which scheme of loop buffer is more suitable for applications with certain behaviour. Post-layout simulations demonstrate that a trade-off exists between the complexity of the loop buffer architecture and the energy savings of utilising it. Therefore, the use of loop buffer architectures in order to optimise the instruction memory organisation from the energy efficiency point of view should be evaluated carefully, taking into account two factors: (1) the percentage of the execution time of the application that is related to the execution of the loops, and (2) the distribution of the execution time percentage over each one of the loops that form the application.

Closing loop base pairs in RNA loop-loop complexes: structural behavior, interaction energy and solvation analysis through molecular dynamics simulations.

PubMed

Golebiowski, Jérôme; Antonczak, Serge; Fernandez-Carmona, Juan; Condom, Roger; Cabrol-Bass, Daniel

2004-12-01

Nanosecond molecular dynamics using the Ewald summation method have been performed to elucidate the structural and energetic role of the closing base pair in loop-loop RNA duplexes neutralized by Mg2+ counterions in aqueous phases. Mismatches GA, CU and Watson-Crick GC base pairs have been considered for closing the loop of an RNA in complementary interaction with HIV-1 TAR. The simulations reveal that the mismatch GA base, mediated by a water molecule, leads to a complex that presents the best compromise between flexibility and energetic contributions. The mismatch CU base pair, in spite of the presence of an inserted water molecule, is too short to achieve a tight interaction at the closing-loop junction and seems to force TAR to reorganize upon binding. An energetic analysis has allowed us to quantify the strength of the interactions of the closing and the loop-loop pairs throughout the simulations. Although the water-mediated GA closing base pair presents an interaction energy similar to that found on fully geometry-optimized structure, the water-mediated CU closing base pair energy interaction reaches less than half the optimal value.

Thermal Vacuum Testing of a Helium Loop Heat Pipe for Large Area Cryocooling

NASA Technical Reports Server (NTRS)

Ku, Jentung; Robinson, Franklin

2016-01-01

A loop heat pipe must start successfully before it can commence its service. The startup transient represents one of the most complex phenomena in the loop heat pipe operation. This paper discusses various aspects of loop heat pipe startup behaviors. Topics include the four startup scenarios, the initial fluid distribution between the evaporator and reservoir that determines the startup scenario, factors that affect the fluid distribution between the evaporator and reservoir, difficulties encountered during the low power startup, and methods to enhance the startup success. Also addressed are the pressure spike and pressure surge during the startup transient, and repeated cycles of loop startup and shutdown under certain conditions.

Coupled dual loop absorption heat pump

DOEpatents

Sarkisian, Paul H.; Reimann, Robert C.; Biermann, Wendell J.

1985-01-01

A coupled dual loop absorption system which utilizes two separate complete loops. Each individual loop operates at three temperatures and two pressures. This low temperature loop absorber and condenser are thermally coupled to the high temperature loop evaporator, and the high temperature loop condenser and absorber are thermally coupled to the low temperature generator.

Functional sub-division of the Drosophila genome via chromatin looping

PubMed Central

Ahanger, Sajad H.; Shouche, Yogesh S.; Mishra, Rakesh K.

2013-01-01

Insulators help in organizing the eukaryotic genomes into physically and functionally autonomous regions through the formation of chromatin loops. Recent findings in Drosophila and vertebrates suggest that insulators anchor multiple loci through long-distance interactions which may be mechanistically linked to insulator function. Important to such processes in Drosophila is CP190, a common co-factor of insulator complexes. CP190 is also known to associate with the nuclear matrix, components of the RNAi machinery, active promoters and borders of the repressive chromatin domains. Although CP190 plays a pivotal role in insulator function in Drosophila, vertebrates lack a probable functional equivalent of CP190 and employ CTCF as the major factor to carry out insulator function/chromatin looping. In this review, we discuss the emerging role of CP190 in tethering genome, specifically in the perspective of insulator function in Drosophila. Future studies aiming genome-wide role of CP190 in chromatin looping is likely to give important insights into the mechanism of genome organization. PMID:23333867

The Inverse Optimal Control Problem for a Three-Loop Missile Autopilot

NASA Astrophysics Data System (ADS)

Hwang, Donghyeok; Tahk, Min-Jea

2018-04-01

The performance characteristics of the autopilot must have a fast response to intercept a maneuvering target and reasonable robustness for system stability under the effect of un-modeled dynamics and noise. By the conventional approach, the three-loop autopilot design is handled by time constant, damping factor and open-loop crossover frequency to achieve the desired performance requirements. Note that the general optimal theory can be also used to obtain the same gain as obtained from the conventional approach. The key idea of using optimal control technique for feedback gain design revolves around appropriate selection and interpretation of the performance index for which the control is optimal. This paper derives an explicit expression, which relates the weight parameters appearing in the quadratic performance index to the design parameters such as open-loop crossover frequency, phase margin, damping factor, or time constant, etc. Since all set of selection of design parameters do not guarantee existence of optimal control law, explicit inequalities, which are named the optimality criteria for the three-loop autopilot (OC3L), are derived to find out all set of design parameters for which the control law is optimal. Finally, based on OC3L, an efficient gain selection procedure is developed, where time constant is set to design objective and open-loop crossover frequency and phase margin as design constraints. The effectiveness of the proposed technique is illustrated through numerical simulations.

Observable Signatures of Energy Release in Braided Coronal Loops

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

Pontin, D. I.; Janvier, M.; Tiwari, S. K.

We examine the turbulent relaxation of solar coronal loops containing non-trivial field line braiding. Such field line tangling in the corona has long been postulated in the context of coronal heating models. We focus on the observational signatures of energy release in such braided magnetic structures using MHD simulations and forward modeling tools. The aim is to answer the following question: if energy release occurs in a coronal loop containing braided magnetic flux, should we expect a clearly observable signature in emissions? We demonstrate that the presence of braided magnetic field lines does not guarantee a braided appearance to themore » observed intensities. Observed intensities may—but need not necessarily—reveal the underlying braided nature of the magnetic field, depending on the degree and pattern of the field line tangling within the loop. However, in all cases considered, the evolution of the braided loop is accompanied by localized heating regions as the loop relaxes. Factors that may influence the observational signatures are discussed. Recent high-resolution observations from Hi-C have claimed the first direct evidence of braided magnetic fields in the corona. Here we show that both the Hi-C data and some of our simulations give the appearance of braiding at a range of scales.« less

The diversity of H3 loops determines the antigen-binding tendencies of antibody CDR loops.

PubMed

Tsuchiya, Yuko; Mizuguchi, Kenji

2016-04-01

Of the complementarity-determining regions (CDRs) of antibodies, H3 loops, with varying amino acid sequences and loop lengths, adopt particularly diverse loop conformations. The diversity of H3 conformations produces an array of antigen recognition patterns involving all the CDRs, in which the residue positions actually in contact with the antigen vary considerably. Therefore, for a deeper understanding of antigen recognition, it is necessary to relate the sequence and structural properties of each residue position in each CDR loop to its ability to bind antigens. In this study, we proposed a new method for characterizing the structural features of the CDR loops and obtained the antigen-binding ability of each residue position in each CDR loop. This analysis led to a simple set of rules for identifying probable antigen-binding residues. We also found that the diversity of H3 loop lengths and conformations affects the antigen-binding tendencies of all the CDR loops. © 2016 The Protein Society.

DNA Looping Facilitates Targeting of a Chromatin Remodeling Enzyme

PubMed Central

Yadon, Adam N; Singh, Badri Nath; Hampsey, Michael; Tsukiyama, Toshio

2013-01-01

Summary ATP-dependent chromatin remodeling enzymes are highly abundant and play pivotal roles regulating DNA-dependent processes. The mechanisms by which they are targeted to specific loci have not been well understood on a genome-wide scale. Here we present evidence that a major targeting mechanism for the Isw2 chromatin remodeling enzyme to specific genomic loci is through sequence-specific transcription factor (TF)-dependent recruitment. Unexpectedly, Isw2 is recruited in a TF-dependent fashion to a large number of loci without TF binding sites. Using the 3C assay, we show that Isw2 can be targeted by Ume6- and TFIIB-dependent DNA looping. These results identify DNA looping as a previously unknown mechanism for the recruitment of a chromatin remodeling enzyme and defines a novel function for DNA looping. We also present evidence suggesting that Ume6-dependent DNA looping is involved in chromatin remodeling and transcriptional repression, revealing a mechanism by which the three-dimensional folding of chromatin affects DNA-dependent processes. PMID:23478442

N =4 supergravity next-to-maximally-helicity-violating six-point one-loop amplitude

NASA Astrophysics Data System (ADS)

Dunbar, David C.; Perkins, Warren B.

2016-12-01

We construct the six-point, next-to-maximally-helicity-violating one-loop amplitude in N =4 supergravity using unitarity and recursion. The use of recursion requires the introduction of rational descendants of the cut-constructible pieces of the amplitude and the computation of the nonstandard factorization terms arising from the loop integrals.

The grape berry-specific basic helix-loop-helix transcription factor VvCEB1 affects cell size.

PubMed

Nicolas, Philippe; Lecourieux, David; Gomès, Eric; Delrot, Serge; Lecourieux, Fatma

2013-02-01

The development of fleshy fruits involves complex physiological and biochemical changes. After fertilization, fruit growth usually begins with cell division, continues with both cell division and expansion, allowing fruit set to occur, and ends with cell expansion only. In spite of the economical importance of grapevine, the molecular mechanisms controlling berry growth are not fully understood. The present work identified and characterized Vitis vinifera cell elongation bHLH protein (VvCEB1), a basic helix-loop-helix (bHLH) transcription factor controlling cell expansion in grape. VvCEB1 was expressed specifically in berry-expanding tissues with a maximum around veraison. The study of VvCEB1 promoter activity in tomato confirmed its specific fruit expression during the expansion phase. Overexpression of VvCEB1 in grape embryos showed that this protein stimulates cell expansion and affects the expression of genes involved in cell expansion, including genes of auxin metabolism and signalling. Taken together, these data show that VvCEB1 is a fruit-specific bHLH transcription factor involved in grape berry development.

Hard-thermal-loop perturbation theory to two loops

NASA Astrophysics Data System (ADS)

Andersen, Jens O.; Braaten, Eric; Petitgirard, Emmanuel; Strickland, Michael

2002-10-01

We calculate the pressure for pure-glue QCD at high temperature to two-loop order using hard-thermal-loop (HTL) perturbation theory. At this order, all the ultraviolet divergences can be absorbed into renormalizations of the vacuum energy density and the HTL mass parameter. We determine the HTL mass parameter by a variational prescription. The resulting predictions for the pressure fail to agree with results from lattice gauge theory at temperatures for which they are available.

Multiprotein DNA Looping

NASA Astrophysics Data System (ADS)

Vilar, Jose M. G.; Saiz, Leonor

2006-06-01

DNA looping plays a fundamental role in a wide variety of biological processes, providing the backbone for long range interactions on DNA. Here we develop the first model for DNA looping by an arbitrarily large number of proteins and solve it analytically in the case of identical binding. We uncover a switchlike transition between looped and unlooped phases and identify the key parameters that control this transition. Our results establish the basis for the quantitative understanding of fundamental cellular processes like DNA recombination, gene silencing, and telomere maintenance.

Closed-Loop Control Better than Open-Loop Control of Profofol TCI Guided by BIS: A Randomized, Controlled, Multicenter Clinical Trial to Evaluate the CONCERT-CL Closed-Loop System

PubMed Central

Zhang, Xuena; Wu, Anshi; Yao, Shanglong; Xue, Zhanggang; Yue, Yun

2015-01-01

Background The CONCERT-CL closed-loop infusion system designed by VERYARK Technology Co., Ltd. (Guangxi, China) is an innovation using TCI combined with closed-loop controlled intravenous anesthesia under the guide of BIS. In this study we performed a randomized, controlled, multicenter study to compare closed-loop control and open-loop control of propofol by using the CONCERT-CL closed-loop infusion system. Methods 180 surgical patients from three medical centers undergone TCI intravenous anesthesia with propofol and remifentanil were randomly assigned to propofol closed-loop group and propofol opened-loop groups. Primary outcome was global score (GS, GS = (MDAPE+Wobble)/% of time of bispectral index (BIS) 40-60). Secondary outcomes were doses of the anesthetics and emergence time from anesthesia, such as, time to tracheal extubation. Results There were 89 and 86 patients in the closed-loop and opened-loop groups, respectively. GS in the closed-loop groups (22.21±8.50) were lower than that in the opened-loop group (27.19±15.26) (p=0.009). The higher proportion of time of BIS between 40 and 60 was also observed in the closed-loop group (84.11±9.50%), while that was 79.92±13.17% in the opened-loop group, (p=0.016). No significant differences in propofol dose and time of tracheal extubation were observed. The frequency of propofol regulation in the closed-loop group (31.55±9.46 times/hr) was obverse higher than that in the opened-loop group (6.84±6.21 times/hr) (p=0.000). Conclusion The CONCERT-CL closed-loop infusion system can automatically regulate the TCI of propofol, maintain the BIS value in an adequate range and reduce the workload of anesthesiologists better than open-loop system. Trial Registration ChiCTR ChiCTR-OOR-14005551 PMID:25886041

Loop-loop interactions govern multiple steps in indole-3-glycerol phosphate synthase catalysis

PubMed Central

Zaccardi, Margot J; O'Rourke, Kathleen F; Yezdimer, Eric M; Loggia, Laura J; Woldt, Svenja; Boehr, David D

2014-01-01

Substrate binding, product release, and likely chemical catalysis in the tryptophan biosynthetic enzyme indole-3-glycerol phosphate synthase (IGPS) are dependent on the structural dynamics of the β1α1 active-site loop. Statistical coupling analysis and molecular dynamic simulations had previously indicated that covarying residues in the β1α1 and β2α2 loops, corresponding to Arg54 and Asn90, respectively, in the Sulfolobus sulfataricus enzyme (ssIGPS), are likely important for coordinating functional motions of these loops. To test this hypothesis, we characterized site mutants at these positions for changes in catalytic function, protein stability and structural dynamics for the thermophilic ssIGPS enzyme. Although there were only modest changes in the overall steady-state kinetic parameters, solvent viscosity and solvent deuterium kinetic isotope effects indicated that these amino acid substitutions change the identity of the rate-determining step across multiple temperatures. Surprisingly, the N90A substitution had a dramatic effect on the general acid/base catalysis of the dehydration step, as indicated by the loss of the descending limb in the pH rate profile, which we had previously assigned to Lys53 on the β1α1 loop. These changes in enzyme function are accompanied with a quenching of ps-ns and µs-ms timescale motions in the β1α1 loop as measured by nuclear magnetic resonance studies. Altogether, our studies provide structural, dynamic and functional rationales for the coevolution of residues on the β1α1 and β2α2 loops, and highlight the multiple roles that the β1α1 loop plays in IGPS catalysis. Thus, substitution of covarying residues in the active-site β1α1 and β2α2 loops of indole-3-glycerol phosphate synthase results in functional, structural, and dynamic changes, highlighting the multiple roles that the β1α1 loop plays in enzyme catalysis and the importance of regulating the structural dynamics of this loop through noncovalent

In vitro treatment with 17,20b-dihydroxy-4-pregnen-3-one regulates mRNA levels of transforming growth factor beta superfamily members in rainbow trout (Oncorhynchus mykiss) ovarian tissue

USDA-ARS?s Scientific Manuscript database

Transforming growth factor beta (TGFB) superfamily members are important paracrine/autocrine regulators of ovarian development and steroidogenesis in mammals, but their reproductive role in fishes is not well understood. Our objectives were 3-fold: to determine if key TGFB superfamily transcripts a...

High-resolution retinal imaging through open-loop adaptive optics

NASA Astrophysics Data System (ADS)

Li, Chao; Xia, Mingliang; Li, Dayu; Mu, Quanquan; Xuan, Li

2010-07-01

Using the liquid crystal spatial light modulator (LC-SLM) as the wavefront corrector, an open-loop adaptive optics (AO) system for fundus imaging in vivo is constructed. Compared with the LC-SLM closed-loop AO system, the light energy efficiency is increased by a factor of 2, which is helpful for the safety of fundus illumination in vivo. In our experiment, the subjective accommodation method is used to precorrect the defocus aberration, and three subjects with different myopia 0, -3, and -5 D are tested. Although the residual wavefront error after correction cannot to detected, the fundus images adequately demonstrate that the imaging system reaches the resolution of a single photoreceptor cell through the open-loop correction. Without dilating and cyclopleging the eye, the continuous imaging for 8 s is recorded for one of the subjects.

Identification and expression analysis of the apple (Malus × domestica) basic helix-loop-helix transcription factor family.

PubMed

Yang, Jinhua; Gao, Min; Huang, Li; Wang, Yaqiong; van Nocker, Steve; Wan, Ran; Guo, Chunlei; Wang, Xiping; Gao, Hua

2017-02-09

Basic helix-loop-helix (bHLH) proteins, which are characterized by a conserved bHLH domain, comprise one of the largest families of transcription factors in both plants and animals, and have been shown to have a wide range of biological functions. However, there have been very few studies of bHLH proteins from perennial tree species. We describe here the identification and characterization of 175 bHLH transcription factors from apple (Malus × domestica). Phylogenetic analysis of apple bHLH (MdbHLH) genes and their Arabidopsis thaliana (Arabidopsis) orthologs indicated that they can be classified into 23 subgroups. Moreover, integrated synteny analysis suggested that the large-scale expansion of the bHLH transcription factor family occurred before the divergence of apple and Arabidopsis. An analysis of the exon/intron structure and protein domains was conducted to suggest their functional roles. Finally, we observed that MdbHLH subgroup III and IV genes displayed diverse expression profiles in various organs, as well as in response to abiotic stresses and various hormone treatments. Taken together, these data provide new information regarding the composition and diversity of the apple bHLH transcription factor family that will provide a platform for future targeted functional characterization.

A Negative-Feedback Loop between the Detoxification/Antioxidant Response Factor SKN-1 and Its Repressor WDR-23 Matches Organism Needs with Environmental Conditions

PubMed Central

Leung, Chi K.; Wang, Ying; Deonarine, Andrew; Tang, Lanlan; Prasse, Stephanie

2013-01-01

Negative-feedback loops between transcription factors and repressors in responses to xenobiotics, oxidants, heat, hypoxia, DNA damage, and infection have been described. Although common, the function of feedback is largely unstudied. Here, we define a negative-feedback loop between the Caenorhabditis elegans detoxification/antioxidant response factor SKN-1/Nrf and its repressor wdr-23 and investigate its function in vivo. Although SKN-1 promotes stress resistance and longevity, we find that tight regulation by WDR-23 is essential for growth and reproduction. By disabling SKN-1 transactivation of wdr-23, we reveal that feedback is required to set the balance between growth/reproduction and stress resistance/longevity. We also find that feedback is required to set the sensitivity of a core SKN-1 target gene to an electrophile. Interestingly, the effect of feedback on target gene induction is greatly reduced when the stress response is strongly activated, presumably to ensure maximum activation of cytoprotective genes during potentially fatal conditions. Our work provides a framework for understanding the function of negative feedback in inducible stress responses and demonstrates that manipulation of feedback alone can shift the balance of competing animal processes toward cell protection, health, and longevity. PMID:23836880

EGFR ligands drive multipotential stromal cells to produce multiple growth factors and cytokines via early growth response-1.

PubMed

Kerpedjieva, Svetoslava S; Kim, Duk Soo; Barbeau, Dominique J; Tamama, Kenichi

2012-09-01

Cell therapy with adult bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) presents a promising approach to promote wound healing and tissue regeneration. The strong paracrine capability of various growth factors and cytokines is a key mechanism of MSC-mediated wound healing and tissue regeneration, and the goal of this study is to understand the underlying mechanism that supports the strong paracrine machineries in MSCs. Microarray database analyses revealed that early growth response-1 (EGR1) is highly expressed in MSCs. Our previous studies showed that epidermal growth factor (EGF) treatment induces growth factor production in MSCs in vitro. Since EGF strongly upregulates EGR1, we hypothesized that EGF receptor (EGFR)-EGR1 signaling plays a pivotal role in MSC paracrine activity. EGF treatment upregulated the gene expression of growth factors and cytokines, including EGFR ligands in a protein kinase C (PKC)- and/or mitogen-activated protein kinase-extracellular-signal-regulated kinase-dependent manner, and it was reversed by shRNA against EGR1. PKC activator phorbol 12-myristate 13-acetate enhanced EGFR tyrosyl phosphorylation and upregulated the gene expression of growth factors and cytokines in a heparin-binding EGF-like growth factor (HBEGF) inhibitor CRM197 sensitive manner, indicating an involvement of autocrined HBEGF in the downstream of PKC signaling. Moreover, stimulation with growth factors and cytokines induced the expression of EGFR ligands, presumably via EGR1 upregulation. These data indicate EGR1 as a convergence point of multiple signaling pathways, which in turn augments the production of multiple growth factors and cytokines by enhancing the autocrine signaling with EGFR ligands.

Fiber lasers with loop reflectors.

PubMed

Urquhart, P

1989-09-01

The theory of homogeneously broadened four level fiber lasers, which use fiber loops as distributed reflective elements, is examined. Such cavities can be made entirely from rare earth doped fiber. The amplifying characteristics of doped fiber loops are examined. The threshold pump power and the loop reflectivity necessary to optimize the lasing output power from an oscillator formed from two loops in series are predicted.

Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis*

PubMed Central

Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

2015-01-01

The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1−/−) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4−/− mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. PMID:26475855

Loop-bed combustion apparatus

DOEpatents

Shang, Jer-Yu; Mei, Joseph S.; Slagle, Frank D.; Notestein, John E.

1984-01-01

The present invention is directed to a combustion apparatus in the configuration of a oblong annulus defining a closed loop. Particulate coal together with a sulfur sorbent such as sulfur or dolomite is introduced into the closed loop, ignited, and propelled at a high rate of speed around the loop. Flue gas is withdrawn from a location in the closed loop in close proximity to an area in the loop where centrifugal force imposed upon the larger particulate material maintains these particulates at a location spaced from the flue gas outlet. Only flue gas and smaller particulates resulting from the combustion and innerparticle grinding are discharged from the combustor. This structural arrangement provides increased combustion efficiency due to the essentially complete combustion of the coal particulates as well as increased sulfur absorption due to the innerparticle grinding of the sorbent which provides greater particle surface area.

Iron-Binding E3 Ligase Mediates Iron Response in Plants by Targeting Basic Helix-Loop-Helix Transcription Factors1[OPEN

PubMed Central

Selote, Devarshi; Samira, Rozalynne; Matthiadis, Anna; Gillikin, Jeffrey W.; Long, Terri A.

2015-01-01

Iron uptake and metabolism are tightly regulated in both plants and animals. In Arabidopsis (Arabidopsis thaliana), BRUTUS (BTS), which contains three hemerythrin (HHE) domains and a Really Interesting New Gene (RING) domain, interacts with basic helix-loop-helix transcription factors that are capable of forming heterodimers with POPEYE (PYE), a positive regulator of the iron deficiency response. BTS has been shown to have E3 ligase capacity and to play a role in root growth, rhizosphere acidification, and iron reductase activity in response to iron deprivation. To further characterize the function of this protein, we examined the expression pattern of recombinant ProBTS::β-GLUCURONIDASE and found that it is expressed in developing embryos and other reproductive tissues, corresponding with its apparent role in reproductive growth and development. Our findings also indicate that the interactions between BTS and PYE-like (PYEL) basic helix-loop-helix transcription factors occur within the nucleus and are dependent on the presence of the RING domain. We provide evidence that BTS facilitates 26S proteasome-mediated degradation of PYEL proteins in the absence of iron. We also determined that, upon binding iron at the HHE domains, BTS is destabilized and that this destabilization relies on specific residues within the HHE domains. This study reveals an important and unique mechanism for plant iron homeostasis whereby an E3 ubiquitin ligase may posttranslationally control components of the transcriptional regulatory network involved in the iron deficiency response. PMID:25452667

Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

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

Luo, Fei; Xu, Yuan; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University

2013-11-15

Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3 days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3more » signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis. - Highlights: • Arsenite evokes IL-6 secretion. • IL-6 autocrine mediates STAT3 signaling and up-regulates miR-21expression. • Inflammation is involved in arsenite-induced EMT.« less

Full parabolic trough qualification from prototype to demonstration loop

NASA Astrophysics Data System (ADS)

Janotte, Nicole; Lüpfert, Eckhard; Pottler, Klaus; Schmitz, Mark

2017-06-01

On the example of the HelioTrough® collector development the full accompanying and supporting qualification program for large-scale parabolic trough collectors for solar thermal power plants is described from prototype to demonstration loop scale. In the evaluation process the actual state and the optimization potential are assessed. This includes the optical and geometrical performance determined by concentrator shape, deformation, assembly quality and local intercept factor values. Furthermore, its mechanical performance in terms of tracking accuracy and torsional stiffness and its thermal system performance on the basis of the overall thermal output and heat loss are evaluated. Demonstration loop tests deliver results of collector modules statistical slope deviation of 1.9 to 2.6 mrad, intercept factor above 98%, peak optical performance of 81.6% and heat loss coefficients from field tests. The benefit of such a closely monitored development lies in prompt feedback on strengths, weaknesses and potential improvements on the new product at any development stage from first module tests until demonstration loop evaluation. The product developer takes advantage of the achieved technical maturity, already before the implementation in a commercial power plant. The well-understood performance characteristics allow the reduction of safety margins making the new HelioTrough collector competitive from the start.

Pro-tumorigenic effects of transforming growth factor beta 1 in canine osteosarcoma.

PubMed

Portela, R F; Fadl-Alla, B A; Pondenis, H C; Byrum, M L; Garrett, L D; Wycislo, K L; Borst, L B; Fan, T M

2014-01-01

Transforming growth factor beta 1 (TGFβ1) is a pleiotropic cytokine that contributes to reparative skeletal remodeling by inducing osteoblast proliferation, migration, and angiogenesis. Organic bone matrix is the largest bodily reservoir for latent TGFβ1, and active osteoblasts express cognate receptors for TGFβ1 (TGFβRI and TGFβRII). During malignant osteolysis, TGFβ1 is liberated from eroded bone matrix and promotes local progression of osteotropic solid tumors by its mitogenic and prosurvival activities. Canine osteosarcoma (OS) cells will possess TGFβ1 signaling machinery. Blockade of TGFβ1 signaling will attenuate pro-tumorigenic activities in OS cells. Naturally occurring primary OS samples will express cognate TGFβ1 receptors; and in dogs with OS, focal malignant osteolysis will contribute to circulating TGFβ1 concentrations. Thirty-three dogs with appendicular OS. Expression of TGFβ1 and its cognate receptors, as well as the biologic effects of TGFβ1 blockade, was characterized in OS cells. Ten spontaneous OS samples were characterized for TGFβRI/II expressions by immunohistochemistry. In 33 dogs with OS, plasma TGFβ1 concentrations were quantified and correlated with bone resorption. Canine OS cells secrete TGFβ1, express cognate receptors, and TGFβ1 signaling blockade decreases proliferation, migration, and vascular endothelial growth factor secretion. Naturally occurring OS samples abundantly and uniformly express TGFβRI/II, and in OS-bearing dogs, circulating TGFβ1 concentrations correlate with urine N-telopeptide excretion. Canine OS cells possess TGFβ1 signaling machinery, potentially allowing for the establishment of an autocrine and paracrine pro-tumorigenic signaling loop. As such, TGFβ1 inhibitors might impede localized OS progression in dogs. Copyright © 2014 by the American College of Veterinary Internal Medicine.

A complex approach to the blue-loop problem

NASA Astrophysics Data System (ADS)

Ostrowski, Jakub; Daszynska-Daszkiewicz, Jadwiga

2015-08-01

The problem of the blue loops during the core helium burning, outstanding for almost fifty years, is one of the most difficult and poorly understood problems in stellar astrophysics. Most of the work focused on the blue loops done so far has been performed with old stellar evolution codes and with limited computational resources. In the end the obtained conclusions were based on a small sample of models and could not have taken into account more advanced effects and interactions between them.The emergence of the blue loops depends on many details of the evolution calculations, in particular on chemical composition, opacity, mixing processes etc. The non-linear interactions between these factors contribute to the statement that in most cases it is hard to predict without a precise stellar modeling whether a loop will emerge or not. The high sensitivity of the blue loops to even small changes of the internal structure of a star yields one more issue: a sensitivity to numerical problems, which are common in calculations of stellar models on advanced stages of the evolution.To tackle this problem we used a modern stellar evolution code MESA. We calculated a large grid of evolutionary tracks (about 8000 models) with masses in the range of 3.0 - 25.0 solar masses from the zero age main sequence to the depletion of helium in the core. In order to make a comparative analysis, we varied metallicity, helium abundance and different mixing parameters resulting from convective overshooting, rotation etc.The better understanding of the properties of the blue loops is crucial for our knowledge of the population of blue supergiants or pulsating variables such as Cepheids, α-Cygni or Slowly Pulsating B-type supergiants. In case of more massive models it is also of great importance for studies of the progenitors of supernovae.

SpalLoop

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

Sabau, Adrian; Wright, Ian

Boiler tubes in steam power plants experience tube blockages due to exfoliation of oxide grown on the inner side of the tubes. In extreme cases, significant tube blockages can lead to forced power plant outages. It is thus desired to predict through modeling the amount of tube blockage in order to inform power plant operators of possible forced outages. SpalLoop solves for the stress-strain equations in an axisymmetric geometry, tracking the stress/strain evolution during boiler operation including outages for the entire boiler tube length. At each operational outage, i.e., temperature excursions down to room temperature, the amount of exfoliated areamore » for the entire tube loop is estimated the amount of tube blockage is predicted based assumed blockage geometry and site. The SpaLLoop code contains modules developed for oxide growth, stress analysis, tube loop geometry, blockage area by taking into account the following phenomena and features, (a) Plant operation schedule with periodic alternate full-load and partial-load regimes and shut-downs, i.e., temperature excursions from high-load to room temperature, (b) axisymmetric formulation for cylindrical tubes, (c) oxide growth in a temperature gradient with multiple oxide layers, (d) geometry of a boiler tube with a single tube loop or two tube loops, (e) temperature variation along the tube length based on hot gas temperature distribution outside the tube and inlet steam temperature, (f) non-uniform oxide growth along the tube length according to the local steam tube temperature, (g) exfoliated area module: at each operational outage considered, the amount of exfoliated area and exfoliated volume along the tube is estimated, (h) blockage module: at each operational outage considered, the exfoliated volume/mass for each tube loop is estimated from which the amount of tube blockage is predicted based on given blockage geometry (length, location, and geometry). The computer program is written in FORTRAN90. Its

Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

PubMed Central

Sampathkumar, Charanya; Wu, Yuan-Ju; Vadhvani, Mayur; Trimbuch, Thorsten; Eickholt, Britta; Rosenmund, Christian

2016-01-01

Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. DOI: http://dx.doi.org/10.7554/eLife.19374.001 PMID:27782879

Bandwidth controller for phase-locked-loop

NASA Technical Reports Server (NTRS)

Brockman, Milton H. (Inventor)

1992-01-01

A phase locked loop utilizing digital techniques to control the closed loop bandwidth of the RF carrier phase locked loop in a receiver provides high sensitivity and a wide dynamic range for signal reception. After analog to digital conversion, a digital phase locked loop bandwidth controller provides phase error detection with automatic RF carrier closed loop tracking bandwidth control to accommodate several modes of transmission.

Explaining Warm Coronal Loops

NASA Technical Reports Server (NTRS)

Klimchuk, James A.; Karpen, Judy T.; Patsourakos, Spiros

2008-01-01

One of the great mysteries of coronal physics that has come to light in the last few years is the discovery that warn (- 1 INK) coronal loops are much denser than expected for quasi-static equilibrium. Both the excess densities and relatively long lifetimes of the loops can be explained with bundles of unresolved strands that are heated impulsively to very high temperatures. Since neighboring strands are at different stages of cooling, the composite loop bundle is multi-thermal, with the distribution of temperatures depending on the details of the "nanoflare storm." Emission hotter than 2 MK is predicted, but it is not clear that such emission is always observed. We consider two possible explanations for the existence of over-dense warm loops without corresponding hot emission: (1) loops are bundles of nanoflare heated strands, but a significant fraction of the nanoflare energy takes the form of a nonthermal electron beam rather then direct plasma heating; (2) loops are bundles of strands that undergo thermal nonequilibrium that results when steady heating is sufficiently concentrated near the footpoints. We present numerical hydro simulations of both of these possibilities and explore the observational consequences, including the production of hard X-ray emission and absorption by cool material in the corona.

Displacement Fields and Self-Energies of Circular and Polygonal Dislocation Loops in Homogeneous and Layered Anisotropic Solids

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

Gao, Yanfei; Larson, Ben C.

There are large classes of materials problems that involve the solutions of stress, displacement, and strain energy of dislocation loops in elastically anisotropic solids, including increasingly detailed investigations of the generation and evolution of irradiation induced defect clusters ranging in sizes from the micro- to meso-scopic length scales. Based on a two-dimensional Fourier transform and Stroh formalism that are ideal for homogeneous and layered anisotropic solids, we have developed robust and computationally efficient methods to calculate the displacement fields for circular and polygonal dislocation loops. Using the homogeneous nature of the Green tensor of order -1, we have shown thatmore » the displacement and stress fields of dislocation loops can be obtained by numerical quadrature of a line integral. In addition, it is shown that the sextuple integrals associated with the strain energy of loops can be represented by the product of a pre-factor containing elastic anisotropy effects and a universal term that is singular and equal to that for elastic isotropic case. Furthermore, we have found that the self-energy pre-factor of prismatic loops is identical to the effective modulus of normal contact, and the pre-factor of shear loops differs from the effective indentation modulus in shear by only a few percent. These results provide a convenient method for examining dislocation reaction energetic and efficient procedures for numerical computation of local displacements and stresses of dislocation loops, both of which play integral roles in quantitative defect analyses within combined experimental–theoretical investigations.« less

Displacement Fields and Self-Energies of Circular and Polygonal Dislocation Loops in Homogeneous and Layered Anisotropic Solids

DOE PAGES

Gao, Yanfei; Larson, Ben C.

2015-06-19

There are large classes of materials problems that involve the solutions of stress, displacement, and strain energy of dislocation loops in elastically anisotropic solids, including increasingly detailed investigations of the generation and evolution of irradiation induced defect clusters ranging in sizes from the micro- to meso-scopic length scales. Based on a two-dimensional Fourier transform and Stroh formalism that are ideal for homogeneous and layered anisotropic solids, we have developed robust and computationally efficient methods to calculate the displacement fields for circular and polygonal dislocation loops. Using the homogeneous nature of the Green tensor of order -1, we have shown thatmore » the displacement and stress fields of dislocation loops can be obtained by numerical quadrature of a line integral. In addition, it is shown that the sextuple integrals associated with the strain energy of loops can be represented by the product of a pre-factor containing elastic anisotropy effects and a universal term that is singular and equal to that for elastic isotropic case. Furthermore, we have found that the self-energy pre-factor of prismatic loops is identical to the effective modulus of normal contact, and the pre-factor of shear loops differs from the effective indentation modulus in shear by only a few percent. These results provide a convenient method for examining dislocation reaction energetic and efficient procedures for numerical computation of local displacements and stresses of dislocation loops, both of which play integral roles in quantitative defect analyses within combined experimental–theoretical investigations.« less

Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects.

PubMed

Zhang, Hongkai; Sturchler, Emmanuel; Zhu, Jiang; Nieto, Ainhoa; Cistrone, Philip A; Xie, Jia; He, LinLing; Yea, Kyungmoo; Jones, Teresa; Turn, Rachel; Di Stefano, Peter S; Griffin, Patrick R; Dawson, Philip E; McDonald, Patricia H; Lerner, Richard A

2015-12-01

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein β-arrestin; preferential signalling of ligands through one or the other of these branches is known as 'ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced β-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM.

Autocrine Complement Inhibits IL10-Dependent T-Cell Mediated Antitumor Immunity to Promote Tumor Progression

PubMed Central

Wang, Yu; Sun, Sheng-Nan; Liu, Qing; Yu, Yang-Yang; Guo, Jian; Wang, Kun; Xing, Bao-Cai; Zheng, Qing-Feng; Campa, Michael J.; Patz, Edward F.; Li, Shi-You; He, You-Wen

2016-01-01

In contrast to its inhibitory effects on many cells, IL-10 activates CD8+ tumor infiltrating lymphocytes (TILs) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL-10 as autocrine complement C3 inhibits IL-10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL-10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T cell- and IL-10-dependent manner; human TILs expanded with IL-2 plus IL-10 increase the killing of primary tumors in vitro compared to IL-2 treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL-10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. PMID:27297552

RCD+: Fast loop modeling server.

PubMed

López-Blanco, José Ramón; Canosa-Valls, Alejandro Jesús; Li, Yaohang; Chacón, Pablo

2016-07-08

Modeling loops is a critical and challenging step in protein modeling and prediction. We have developed a quick online service (http://rcd.chaconlab.org) for ab initio loop modeling combining a coarse-grained conformational search with a full-atom refinement. Our original Random Coordinate Descent (RCD) loop closure algorithm has been greatly improved to enrich the sampling distribution towards near-native conformations. These improvements include a new workflow optimization, MPI-parallelization and fast backbone angle sampling based on neighbor-dependent Ramachandran probability distributions. The server starts by efficiently searching the vast conformational space from only the loop sequence information and the environment atomic coordinates. The generated closed loop models are subsequently ranked using a fast distance-orientation dependent energy filter. Top ranked loops are refined with the Rosetta energy function to obtain accurate all-atom predictions that can be interactively inspected in an user-friendly web interface. Using standard benchmarks, the average root mean squared deviation (RMSD) is 0.8 and 1.4 Å for 8 and 12 residues loops, respectively, in the challenging modeling scenario in where the side chains of the loop environment are fully remodeled. These results are not only very competitive compared to those obtained with public state of the art methods, but also they are obtained ∼10-fold faster. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Evaluation of selected strapdown inertial instruments and pulse torque loops, volume 1

NASA Technical Reports Server (NTRS)

Sinkiewicz, J. S.; Feldman, J.; Lory, C. B.

1974-01-01

Design, operational and performance variations between ternary, binary and forced-binary pulse torque loops are presented. A fill-in binary loop which combines the constant power advantage of binary with the low sampling error of ternary is also discussed. The effects of different output-axis supports on the performance of a single-degree-of-freedom, floated gyroscope under a strapdown environment are illustrated. Three types of output-axis supports are discussed: pivot-dithered jewel, ball bearing and electromagnetic. A test evaluation on a Kearfott 2544 single-degree-of-freedom, strapdown gyroscope operating with a pulse torque loop, under constant rates and angular oscillatory inputs is described and the results presented. Contributions of the gyroscope's torque generator and the torque-to-balance electronics on scale factor variation with rate are illustrated for a SDF 18 IRIG Mod-B strapdown gyroscope operating with various pulse rebalance loops. Also discussed are methods of reducing this scale factor variation with rate by adjusting the tuning network which shunts the torque coil. A simplified analysis illustrating the principles of operation of the Teledyne two-degree-of-freedom, elastically-supported, tuned gyroscope and the results of a static and constant rate test evaluation of that instrument are presented.

Fragmentation of cosmic-string loops

NASA Technical Reports Server (NTRS)

York, Thomas

1989-01-01

The fragmentation of cosmic string loops is discussed, and the results of a simulation of this process are presented. The simulation can evolve any of a large class of loops essentially exactly, including allowing fragments that collide to join together. Such reconnection enhances the production of small fragments, but not drastically. With or without reconnections, the fragmentation process produces a collection of nonself-intersecting loops whose typical length is on the order of the persistence length of the initial loop.

Central safety factor and βN control on NSTX-U via beam power and plasma boundary shape modification, using TRANSP for closed loop simulations

NASA Astrophysics Data System (ADS)

Boyer, M. D.; Andre, R.; Gates, D. A.; Gerhardt, S.; Goumiri, I. R.; Menard, J.

2015-05-01

The high-performance operational goals of NSTX-U will require development of advanced feedback control algorithms, including control of βN and the safety factor profile. In this work, a novel approach to simultaneously controlling βN and the value of the safety factor on the magnetic axis, q0, through manipulation of the plasma boundary shape and total beam power, is proposed. Simulations of the proposed scheme show promising results and motivate future experimental implementation and eventual integration into a more complex current profile control scheme planned to include actuation of individual beam powers, density, and loop voltage. As part of this work, a flexible framework for closed loop simulations within the high-fidelity code TRANSP was developed. The framework, used here to identify control-design-oriented models and to tune and test the proposed controller, exploits many of the predictive capabilities of TRANSP and provides a means for performing control calculations based on user-supplied data (controller matrices, target waveforms, etc). The flexible framework should enable high-fidelity testing of a variety of control algorithms, thereby reducing the amount of expensive experimental time needed to implement new control algorithms on NSTX-U and other devices.

Suppressing Transients In Digital Phase-Locked Loops

NASA Technical Reports Server (NTRS)

Thomas, J. B.

1993-01-01

Loop of arbitrary order starts in steady-state lock. Method for initializing variables of digital phase-locked loop reduces or eliminates transients in phase and frequency typically occurring during acquisition of lock on signal or when changes made in values of loop-filter parameters called "loop constants". Enables direct acquisition by third-order loop without prior acquisition by second-order loop of greater bandwidth, and eliminates those perturbations in phase and frequency lock occurring when loop constants changed by arbitrarily large amounts.

Navigating around the algebraic jungle of QCD: efficient evaluation of loop helicity amplitudes

NASA Astrophysics Data System (ADS)

Lam, C. S.

1993-05-01

A method is developed whereby spinor helicity techniques can be used to simlify the calculation of loop amplitudes. This is achieved by using the Feynman-parameter representation where the offending off-shell loop momenta do not appear. Other shortcuts motivated by the Bern-Kosower one-loop string calculations can be incorporated into the formalism. This includes color reorganization into Chan-Paton factors and the use of background Feynman gauge. This method is applicable to any Feynman diagram with any number of loops as long as the external masses can be ignored. In order to minimize the very considerable algebra encountered in non-abelian gauge theories, graphical methods are developed for most of the calculations. This enables the large number of terms encountered to be organized implicitly in the Feynman diagram without the necessity of writing down any of them algebraically. A one-loop four-gluon amplitude in a particular helicity configuration is computed explicitly to illustrate the method.

Study of the Open Loop and Closed Loop Oscillator Techniques

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

Imel, George R.; Baker, Benjamin; Riley, Tony

This report presents the progress and completion of a five-year study undertaken at Idaho State University of the measurement of very small worth reactivity samples comparing open and closed loop oscillator techniques.The study conclusively demonstrated the equivalency of the two techniques with regard to uncertainties in reactivity values, i.e., limited by reactor noise. As those results are thoroughly documented in recent publications, in this report we will concentrate on the support work that was necessary. For example, we describe in some detail the construction and calibration of a pilot rod for the closed loop system. We discuss the campaign tomore » measure the required reactor parameters necessary for inverse-kinetics. Finally, we briefly discuss the transfer of the open loop technique to other reactor systems.« less

Study of the open loop and closed loop oscillator techniques

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

Baker, Benjamin; Riley, Tony; Langbehn, Adam

This paper presents some aspects of a five year study undertaken at Idaho State University of the measurement of very small worth reactivity samples comparing open and closed loop oscillator techniques. The study conclusively demonstrated the equivalency of the two techniques with regard to uncertainties in reactivity values, i.e., limited by reactor noise. As those results are thoroughly documented in recent publications, in this paper we will concentrate on the support work that was necessary. For example, we describe in some detail the construction and calibration of a pilot rod for the closed loop system. We discuss the campaign tomore » measure the required reactor parameters necessary for inverse-kinetics. Finally, we briefly discuss the transfer of the open loop technique to other reactor systems. (authors)« less

Modulation of Enhancer Looping and Differential Gene Targeting by Epstein-Barr Virus Transcription Factors Directs Cellular Reprogramming

PubMed Central

McClellan, Michael J.; Wood, C. David; Ojeniyi, Opeoluwa; Cooper, Tim J.; Kanhere, Aditi; Arvey, Aaron; Webb, Helen M.; Palermo, Richard D.; Harth-Hertle, Marie L.; Kempkes, Bettina; Jenner, Richard G.; West, Michelle J.

2013-01-01

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of

TGF-β1 stimulates movement of renal proximal tubular epithelial cells in a three-dimensional cell culture via an autocrine TGF-β2 production.

PubMed

Luo, Deyi; Guan, Qiunong; Wang, Kunjie; Nguan, Christopher Y C; Du, Caigan

2017-01-01

TGF-βs are multifunctional cytokines, but their roles in human renal homeostasis are not fully understood. This study investigated the role of TGF-β1 in the movement of human renal proximal tubular epithelial cells (PTECs) in a three-dimensional (3D) model. HKC-8 cells, a human PTEC line, were grown in a 3D collagen culture system. Cell movement was observed under a microscope. The gene expression was examined using PCR Arrays or qRT-PCR, and protein levels by Western blot. Here, we showed that the tight junction structure formed between adjacent cells of a HKC-8 cell colony in 3D cultures, and TGF-β1 stimulated their movement, evidenced by the appearance of fingerlike pseudopodia in the leader cells at the edge of the colonies. The cell movement of these human PTECs was correlated with up-regulation of both MMP2 and MMP9 and down-regulation or inactivation of PLAUR and PTK2B. Analysis of TGF-β signaling targets confirmed autocrine production of TGF-β2 and its cleaving enzyme furin as well as SNAI1 by TGF-β1stimulation. Knockdown of TGF-β2 expression disrupted TGF-β1-stimulated PTEC invasiveness, which was correlated with the down-regulation of MMP2 and MMP9. In conclusion, the activation of TGF-β receptor autocrine signaling by up-regulated TGF-β2 may play a pivotal role in TGF-β1-induced human PTEC movement, which could be mediated at least by both MMP2 and MMP9. Copyright © 2016 Elsevier Inc. All rights reserved.

Probing the closed-loop model of mRNA translation in living cells

PubMed Central

Archer, Stuart K; Shirokikh, Nikolay E; Hallwirth, Claus V; Beilharz, Traude H; Preiss, Thomas

2015-01-01

The mRNA closed-loop, formed through interactions between the cap structure, poly(A) tail, eIF4E, eIF4G and PAB, features centrally in models of eukaryotic translation initiation, although direct support for its existence in vivo is not well established. Here, we investigated the closed-loop using a combination of mRNP isolation from rapidly cross-linked cells and high-throughput qPCR. Using the interaction between these factors and the opposing ends of mRNAs as a proxy for the closed-loop, we provide evidence that it is prevalent for eIF4E/4G-bound but unexpectedly sparse for PAB1-bound mRNAs, suggesting it primarily occurs during a distinct phase of polysome assembly. We observed mRNA-specific variation in the extent of closed-loop formation, consistent with a role for polysome topology in the control of gene expression. PMID:25826658

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

PubMed Central

Audette, Dylan S.; Anand, Deepti; So, Tammy; Rubenstein, Troy B.; Lachke, Salil A.; Lovicu, Frank J.; Duncan, Melinda K.

2016-01-01

Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF. PMID:26657765

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression.

PubMed

Audette, Dylan S; Anand, Deepti; So, Tammy; Rubenstein, Troy B; Lachke, Salil A; Lovicu, Frank J; Duncan, Melinda K

2016-01-15

Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF. © 2016. Published by The Company of Biologists Ltd.

RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage.

PubMed

Cristini, Agnese; Groh, Matthias; Kristiansen, Maiken S; Gromak, Natalia

2018-05-08

R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA. They play important biological roles and are implicated in pathology. Even so, proteins recognizing these structures are largely undefined. Using affinity purification with the S9.6 antibody coupled to mass spectrometry, we defined the RNA/DNA hybrid interactome in HeLa cells. This consists of known R-loop-associated factors SRSF1, FACT, and Top1, and yet uncharacterized interactors, including helicases, RNA processing, DNA repair, and chromatin factors. We validate specific examples of these interactors and characterize their involvement in R-loop biology. A top candidate DHX9 helicase promotes R-loop suppression and transcriptional termination. DHX9 interacts with PARP1, and both proteins prevent R-loop-associated DNA damage. DHX9 and other interactome helicases are overexpressed in cancer, linking R-loop-mediated DNA damage and disease. Our RNA/DNA hybrid interactome provides a powerful resource to study R-loop biology in health and disease. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Simulated binding of transcription factors to active and inactive regions folds human chromosomes into loops, rosettes and topological domains

PubMed Central

Brackley, Chris A.; Johnson, James; Kelly, Steven; Cook, Peter R.; Marenduzzo, Davide

2016-01-01

Biophysicists are modeling conformations of interphase chromosomes, often basing the strengths of interactions between segments distant on the genetic map on contact frequencies determined experimentally. Here, instead, we develop a fitting-free, minimal model: bivalent or multivalent red and green ‘transcription factors’ bind to cognate sites in strings of beads (‘chromatin’) to form molecular bridges stabilizing loops. In the absence of additional explicit forces, molecular dynamic simulations reveal that bound factors spontaneously cluster—red with red, green with green, but rarely red with green—to give structures reminiscent of transcription factories. Binding of just two transcription factors (or proteins) to active and inactive regions of human chromosomes yields rosettes, topological domains and contact maps much like those seen experimentally. This emergent ‘bridging-induced attraction’ proves to be a robust, simple and generic force able to organize interphase chromosomes at all scales. PMID:27060145

ANALYSIS AND MODELING OF TWO FLARE LOOPS OBSERVED BY AIA AND EIS

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

Li, Y.; Ding, M. D.; Qiu, J.

2012-10-10

We analyze and model an M1.0 flare observed by SDO/AIA and Hinode/EIS to investigate how flare loops are heated and evolve subsequently. The flare is composed of two distinctive loop systems observed in extreme ultraviolet (EUV) images. The UV 1600 A emission at the feet of these loops exhibits a rapid rise, followed by enhanced emission in different EUV channels observed by the Atmospheric Imaging Assembly (AIA) and the EUV Imaging Spectrometer (EIS). Such behavior is indicative of impulsive energy deposit and the subsequent response in overlying coronal loops that evolve through different temperatures. Using the method we recently developed,more » we infer empirical heating functions from the rapid rise of the UV light curves for the two loop systems, respectively, treating them as two big loops with cross-sectional area of 5'' by 5'', and compute the plasma evolution in the loops using the EBTEL model. We compute the synthetic EUV light curves, which, with the limitation of the model, reasonably agree with observed light curves obtained in multiple AIA channels and EIS lines: they show the same evolution trend and their magnitudes are comparable by within a factor of two. Furthermore, we also compare the computed mean enthalpy flow velocity with the Doppler shift measurements by EIS during the decay phase of the two loops. Our results suggest that the two different loops with different heating functions as inferred from their footpoint UV emission, combined with their different lengths as measured from imaging observations, give rise to different coronal plasma evolution patterns captured both in the model and in observations.« less

EGFR Ligands Drive Multipotential Stromal Cells to Produce Multiple Growth Factors and Cytokines via Early Growth Response-1

PubMed Central

Kerpedjieva, Svetoslava S.; Kim, Duk Soo; Barbeau, Dominique J.

2012-01-01

Cell therapy with adult bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) presents a promising approach to promote wound healing and tissue regeneration. The strong paracrine capability of various growth factors and cytokines is a key mechanism of MSC-mediated wound healing and tissue regeneration, and the goal of this study is to understand the underlying mechanism that supports the strong paracrine machineries in MSCs. Microarray database analyses revealed that early growth response-1 (EGR1) is highly expressed in MSCs. Our previous studies showed that epidermal growth factor (EGF) treatment induces growth factor production in MSCs in vitro. Since EGF strongly upregulates EGR1, we hypothesized that EGF receptor (EGFR)–EGR1 signaling plays a pivotal role in MSC paracrine activity. EGF treatment upregulated the gene expression of growth factors and cytokines, including EGFR ligands in a protein kinase C (PKC)- and/or mitogen-activated protein kinase–extracellular-signal-regulated kinase-dependent manner, and it was reversed by shRNA against EGR1. PKC activator phorbol 12-myristate 13-acetate enhanced EGFR tyrosyl phosphorylation and upregulated the gene expression of growth factors and cytokines in a heparin-binding EGF-like growth factor (HBEGF) inhibitor CRM197 sensitive manner, indicating an involvement of autocrined HBEGF in the downstream of PKC signaling. Moreover, stimulation with growth factors and cytokines induced the expression of EGFR ligands, presumably via EGR1 upregulation. These data indicate EGR1 as a convergence point of multiple signaling pathways, which in turn augments the production of multiple growth factors and cytokines by enhancing the autocrine signaling with EGFR ligands. PMID:22316125

Chemical Looping Technology: Oxygen Carrier Characteristics.

PubMed

Luo, Siwei; Zeng, Liang; Fan, Liang-Shih

2015-01-01

Chemical looping processes are characterized as promising carbonaceous fuel conversion technologies with the advantages of manageable CO2 capture and high energy conversion efficiency. Depending on the chemical looping reaction products generated, chemical looping technologies generally can be grouped into two types: chemical looping full oxidation (CLFO) and chemical looping partial oxidation (CLPO). In CLFO, carbonaceous fuels are fully oxidized to CO2 and H2O, as typically represented by chemical looping combustion with electricity as the primary product. In CLPO, however, carbonaceous fuels are partially oxidized, as typically represented by chemical looping gasification with syngas or hydrogen as the primary product. Both CLFO and CLPO share similar operational features; however, the optimum process configurations and the specific oxygen carriers used between them can vary significantly. Progress in both CLFO and CLPO is reviewed and analyzed with specific focus on oxygen carrier developments that characterize these technologies.

Transverse Oscillations of Coronal Loops

NASA Astrophysics Data System (ADS)

Ruderman, Michael S.; Erdélyi, Robert

2009-12-01

On 14 July 1998 TRACE observed transverse oscillations of a coronal loop generated by an external disturbance most probably caused by a solar flare. These oscillations were interpreted as standing fast kink waves in a magnetic flux tube. Firstly, in this review we embark on the discussion of the theory of waves and oscillations in a homogeneous straight magnetic cylinder with the particular emphasis on fast kink waves. Next, we consider the effects of stratification, loop expansion, loop curvature, non-circular cross-section, loop shape and magnetic twist. An important property of observed transverse coronal loop oscillations is their fast damping. We briefly review the different mechanisms suggested for explaining the rapid damping phenomenon. After that we concentrate on damping due to resonant absorption. We describe the latest analytical results obtained with the use of thin transition layer approximation, and then compare these results with numerical findings obtained for arbitrary density variation inside the flux tube. Very often collective oscillations of an array of coronal magnetic loops are observed. It is natural to start studying this phenomenon from the system of two coronal loops. We describe very recent analytical and numerical results of studying collective oscillations of two parallel homogeneous coronal loops. The implication of the theoretical results for coronal seismology is briefly discussed. We describe the estimates of magnetic field magnitude obtained from the observed fundamental frequency of oscillations, and the estimates of the coronal scale height obtained using the simultaneous observations of the fundamental frequency and the frequency of the first overtone of kink oscillations. In the last part of the review we summarise the most outstanding and acute problems in the theory of the coronal loop transverse oscillations.

The Structure of Coronal Loops

NASA Technical Reports Server (NTRS)

Antiochos, Spiro K.

2009-01-01

It is widely believed that the simple coronal loops observed by XUV imagers, such as EIT, TRACE, or XRT, actually have a complex internal structure consisting of many (perhaps hundreds) of unresolved, interwoven "strands". According to the nanoflare model, photospheric motions tangle the strands, causing them to reconnect and release the energy required to produce the observed loop plasma. Although the strands, themselves, are unresolved by present-generation imagers, there is compelling evidence for their existence and for the nanoflare model from analysis of loop intensities and temporal evolution. A problem with this scenario is that, although reconnection can eliminate some of the strand tangles, it cannot destroy helicity, which should eventually build up to observable scales. we consider, therefore, the injection and evolution of helicity by the nanoflare process and its implications for the observed structure of loops and the large-scale corona. we argue that helicity does survive and build up to observable levels, but on spatial and temporal scales larger than those of coronal loops. we discuss the implications of these results for coronal loops and the corona, in general .

Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis.

PubMed

Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

2015-12-11

The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Senataxin Mutation Reveals How R-Loops Promote Transcription by Blocking DNA Methylation at Gene Promoters.

PubMed

Grunseich, Christopher; Wang, Isabel X; Watts, Jason A; Burdick, Joshua T; Guber, Robert D; Zhu, Zhengwei; Bruzel, Alan; Lanman, Tyler; Chen, Kelian; Schindler, Alice B; Edwards, Nancy; Ray-Chaudhury, Abhik; Yao, Jianhua; Lehky, Tanya; Piszczek, Grzegorz; Crain, Barbara; Fischbeck, Kenneth H; Cheung, Vivian G

2018-02-01

R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor β (TGF-β), is reduced; that then leads to the activation of the TGF-β pathway. We uncovered that genome-wide R-loops influence promoter methylation of over 1,200 human genes. DNA methyl-transferase 1 favors binding to double-stranded DNA over R-loops. Thus, in forming R-loops, nascent RNA blocks DNA methylation and promotes further transcription. Hence, our results show that nucleic acid structures, in addition to sequences, influence the binding and activity of regulatory proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

Fabrication techniques for superconducting readout loops

NASA Technical Reports Server (NTRS)

Payne, J. E.

1982-01-01

Procedures for the fabrication of superconducting readout loops out of niobium on glass substrates were developed. A computer program for an existing fabrication system was developed. Both positive and negative resist procedures for the production of the readout loops were investigated. Methods used to produce satisfactory loops are described and the various parameters affecting the performance of the loops are analyzed.

LoopX: A Graphical User Interface-Based Database for Comprehensive Analysis and Comparative Evaluation of Loops from Protein Structures.

PubMed

Kadumuri, Rajashekar Varma; Vadrevu, Ramakrishna

2017-10-01

Due to their crucial role in function, folding, and stability, protein loops are being targeted for grafting/designing to create novel or alter existing functionality and improve stability and foldability. With a view to facilitate a thorough analysis and effectual search options for extracting and comparing loops for sequence and structural compatibility, we developed, LoopX a comprehensively compiled library of sequence and conformational features of ∼700,000 loops from protein structures. The database equipped with a graphical user interface is empowered with diverse query tools and search algorithms, with various rendering options to visualize the sequence- and structural-level information along with hydrogen bonding patterns, backbone φ, ψ dihedral angles of both the target and candidate loops. Two new features (i) conservation of the polar/nonpolar environment and (ii) conservation of sequence and conformation of specific residues within the loops have also been incorporated in the search and retrieval of compatible loops for a chosen target loop. Thus, the LoopX server not only serves as a database and visualization tool for sequence and structural analysis of protein loops but also aids in extracting and comparing candidate loops for a given target loop based on user-defined search options.

Coronal loops and active region structure

NASA Technical Reports Server (NTRS)

Webb, D. F.; Zirin, H.

1981-01-01

Synoptic H-alpha Ca K, magnetograph and Skylab soft X-ray and EUV data were compared for the purpose of identifying the basic coronal magnetic structure of loops in a 'typical' active region and studying its evolution. A complex of activity in July 1973, especially McMath 12417, was emphasized. The principal results are: (1) most of the brightest loops connected the bright f plage to either the sunspot penumbra or to p satellite spots; no non-flaring X-ray loops end in umbrae; (2) short, bright loops had one or both ends in regions of emergent flux, strong field or high field gradients; (3) stable, strongly sheared loop arcades formed over filaments; (4) EFRs were always associated with compact X-ray arcades; and (5) loops connecting to other active regions had their bases in outlying plage of weak field strength in McM 417 where H-alpha fibrils marked the direction of the loops

Run-time parallelization and scheduling of loops

NASA Technical Reports Server (NTRS)

Saltz, Joel H.; Mirchandaney, Ravi; Crowley, Kay

1990-01-01

Run time methods are studied to automatically parallelize and schedule iterations of a do loop in certain cases, where compile-time information is inadequate. The methods presented involve execution time preprocessing of the loop. At compile-time, these methods set up the framework for performing a loop dependency analysis. At run time, wave fronts of concurrently executable loop iterations are identified. Using this wavefront information, loop iterations are reordered for increased parallelism. Symbolic transformation rules are used to produce: inspector procedures that perform execution time preprocessing and executors or transformed versions of source code loop structures. These transformed loop structures carry out the calculations planned in the inspector procedures. Performance results are presented from experiments conducted on the Encore Multimax. These results illustrate that run time reordering of loop indices can have a significant impact on performance. Furthermore, the overheads associated with this type of reordering are amortized when the loop is executed several times with the same dependency structure.

Proliferation of NS0 cells in protein-free medium: the role of cell-derived proteins, known growth factors and cellular receptors.

PubMed

Spens, Erika; Häggström, Lena

2009-05-20

NS0 cells proliferate without external supply of growth factors in protein-free media. We hypothesize that the cells produce their own factors to support proliferation. Understanding the mechanisms behind this autocrine regulation of proliferation may open for the novel approaches to improve animal cell processes. The following proteins were identified in NS0 conditioned medium (CM): cyclophilin A, cyclophilin B (CypB), cystatin C, D-dopachrome tautomerase, IL-25, isopentenyl-diphosphate delta-isomerase, macrophage migration inhibitory factor (MIF), beta(2)-microglobulin, Niemann pick type C2, secretory leukocyte protease inhibitor, thioredoxin-1, TNF-alpha, tumour protein translationally controlled 1 and ubiquitin. Further, cDNA microarray analysis indicated that the genes for IL-11, TNF receptor 6, TGF-beta receptor 1 and the IFN-gamma receptor were transcribed. CypB, IFN-alpha/beta/gamma, IL-11, IL-25, MIF, TGF-beta and TNF-alpha as well as the known growth factors EGF, IGF-I/II, IL-6, leukaemia inhibitory factor and oncostatin M (OSM) were excluded as involved in autocrine regulation of NS0 cell proliferation. The receptors for TGF-beta, IGF and OSM are however present in NS0 cell membranes since TGF-beta(1) caused cell death, and IGF-I/II and OSM improved cell growth. Even though no ligand was found, the receptor subunit gp130, active in signal transduction of the IL-6 like proteins, was shown to be essential for NS0 cells as demonstrated by siRNA gene silencing.

Coronal Loops: Observations and Modeling of Confined Plasma.

PubMed

Reale, Fabio

Coronal loops are the building blocks of the X-ray bright solar corona. They owe their brightness to the dense confined plasma, and this review focuses on loops mostly as structures confining plasma. After a brief historical overview, the review is divided into two separate but not independent parts: the first illustrates the observational framework, the second reviews the theoretical knowledge. Quiescent loops and their confined plasma are considered and, therefore, topics such as loop oscillations and flaring loops (except for non-solar ones, which provide information on stellar loops) are not specifically addressed here. The observational section discusses the classification, populations, and the morphology of coronal loops, its relationship with the magnetic field, and the loop stranded structure. The section continues with the thermal properties and diagnostics of the loop plasma, according to the classification into hot, warm, and cool loops. Then, temporal analyses of loops and the observations of plasma dynamics, hot and cool flows, and waves are illustrated. In the modeling section, some basics of loop physics are provided, supplying fundamental scaling laws and timescales, a useful tool for consultation. The concept of loop modeling is introduced and models are divided into those treating loops as monolithic and static, and those resolving loops into thin and dynamic strands. More specific discussions address modeling the loop fine structure and the plasma flowing along the loops. Special attention is devoted to the question of loop heating, with separate discussion of wave (AC) and impulsive (DC) heating. Large-scale models including atmosphere boxes and the magnetic field are also discussed. Finally, a brief discussion about stellar coronal loops is followed by highlights and open questions.

Plasticity of 150-loop in influenza neuraminidase explored by Hamiltonian replica exchange molecular dynamics simulations.

PubMed

Han, Nanyu; Mu, Yuguang

2013-01-01

Neuraminidase (NA) of influenza is a key target for antiviral inhibitors, and the 150-cavity in group-1 NA provides new insight in treating this disease. However, NA of 2009 pandemic influenza (09N1) was found lacking this cavity in a crystal structure. To address the issue of flexibility of the 150-loop, Hamiltonian replica exchange molecular dynamics simulations were performed on different groups of NAs. Free energy landscape calculated based on the volume of 150-cavity indicates that 09N1 prefers open forms of 150-loop. The turn A (residues 147-150) of the 150-loop is discovered as the most dynamical motif which induces the inter-conversion of this loop among different conformations. In the turn A, the backbone dynamic of residue 149 is highly related with the shape of 150-loop, thus can function as a marker for the conformation of 150-loop. As a contrast, the closed conformation of 150-loop is more energetically favorable in N2, one of group-2 NAs. The D147-H150 salt bridge is found having no correlation with the conformation of 150-loop. Instead the intimate salt bridge interaction between the 150 and 430 loops in N2 variant contributes the stabilizing factor for the closed form of 150-loop. The clustering analysis elaborates the structural plasticity of the loop. This enhanced sampling simulation provides more information in further structural-based drug discovery on influenza virus.

Plasticity of 150-Loop in Influenza Neuraminidase Explored by Hamiltonian Replica Exchange Molecular Dynamics Simulations

PubMed Central

Han, Nanyu; Mu, Yuguang

2013-01-01

Neuraminidase (NA) of influenza is a key target for antiviral inhibitors, and the 150-cavity in group-1 NA provides new insight in treating this disease. However, NA of 2009 pandemic influenza (09N1) was found lacking this cavity in a crystal structure. To address the issue of flexibility of the 150-loop, Hamiltonian replica exchange molecular dynamics simulations were performed on different groups of NAs. Free energy landscape calculated based on the volume of 150-cavity indicates that 09N1 prefers open forms of 150-loop. The turn A (residues 147–150) of the 150-loop is discovered as the most dynamical motif which induces the inter-conversion of this loop among different conformations. In the turn A, the backbone dynamic of residue 149 is highly related with the shape of 150-loop, thus can function as a marker for the conformation of 150-loop. As a contrast, the closed conformation of 150-loop is more energetically favorable in N2, one of group-2 NAs. The D147-H150 salt bridge is found having no correlation with the conformation of 150-loop. Instead the intimate salt bridge interaction between the 150 and 430 loops in N2 variant contributes the stabilizing factor for the closed form of 150-loop. The clustering analysis elaborates the structural plasticity of the loop. This enhanced sampling simulation provides more information in further structural-based drug discovery on influenza virus. PMID:23593372

On higher order discrete phase-locked loops.

NASA Technical Reports Server (NTRS)

Gill, G. S.; Gupta, S. C.

1972-01-01

An exact mathematical model is developed for a discrete loop of a general order particularly suitable for digital computation. The deterministic response of the loop to the phase step and the frequency step is investigated. The design of the digital filter for the second-order loop is considered. Use is made of the incremental phase plane to study the phase error behavior of the loop. The model of the noisy loop is derived and the optimization of the loop filter for minimum mean-square error is considered.

A positive feedback loop between progesterone and microsomal prostaglandin E synthase-1-mediated PGE2 promotes production of both in mouse granulosa cells.

PubMed

Tamura, Kazuhiro; Naraba, Hiroaki; Hara, Takahiko; Nakamura, Kota; Yoshie, Mikihiro; Kogo, Hiroshi; Tachikawa, Eiichi

2016-03-01

Microsomal prostaglandin E synthase-1 (mPGES-1) is primarily expressed in granulosa cells (GCs) in the preovulatory follicle. Both prostaglandin E2 (PGE2) and progesterone (P4) are implicated in various reproductive functions. Here, we demonstrate that mPges-1 may be a direct downstream target gene of the P4 receptor and P4-stimulated PGE2 secretion can stimulate P4 production in a newly generated mouse GC line (GtsT). Treatment of GtsT cells with a P4 receptor agonist, norgestrel, markedly increased mPGES-1 expression detected by RT-PCR analysis. PGE2 secretion measured by an enzyme-linked immunosorbent assay was enhanced by P4 treatment. Luciferase assays revealed that the proximal promoter region of the mPges-1 gene was responsible for the effects of P4 treatment. Conversely, PGE2 treatment stimulated P4 secretion, which coordinated with mRNA expression of steroidogenic acute regulatory protein. Taken together, P4 may regulate mPGES-1 expression to increase PGE2 secretion and in turn P4 production. An autocrine loop between P4 and PGE2 might function to maintain the increased levels of both in GCs. Copyright © 2016 Elsevier Inc. All rights reserved.

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

PubMed Central

Louizos, Christopher; Yáñez, Jaime A.; Forrest, Laird; Davies, Neal M.

2015-01-01

Hysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed. PMID:24735761

Stretched Loops

NASA Image and Video Library

2017-03-16

When an active region rotated over to the edge of the sun, it presented us with a nice profile view of its elongated loops stretching and swaying above it (Mar. 8-9, 2017). These loops are actually charged particles (made visible in extreme ultraviolet light) swirling along the magnetic field lines of the active region. The video covers about 30 hours of activity. Also of note is a darker twisting mass of plasma to the left of the active region being pulled and spun about by magnetic forces. Video is available at http://photojournal.jpl.nasa.gov/catalog/PIA21562

Run-time parallelization and scheduling of loops

NASA Technical Reports Server (NTRS)

Saltz, Joel H.; Mirchandaney, Ravi; Crowley, Kay

1991-01-01

Run-time methods are studied to automatically parallelize and schedule iterations of a do loop in certain cases where compile-time information is inadequate. The methods presented involve execution time preprocessing of the loop. At compile-time, these methods set up the framework for performing a loop dependency analysis. At run-time, wavefronts of concurrently executable loop iterations are identified. Using this wavefront information, loop iterations are reordered for increased parallelism. Symbolic transformation rules are used to produce: inspector procedures that perform execution time preprocessing, and executors or transformed versions of source code loop structures. These transformed loop structures carry out the calculations planned in the inspector procedures. Performance results are presented from experiments conducted on the Encore Multimax. These results illustrate that run-time reordering of loop indexes can have a significant impact on performance.

Hyperstaticity and loops in frictional granular packings

NASA Astrophysics Data System (ADS)

Tordesillas, Antoinette; Lam, Edward; Metzger, Philip T.

2009-06-01

The hyperstatic nature of granular packings of perfectly rigid disks is analyzed algebraically and through numerical simulation. The elementary loops of grains emerge as a fundamental element in addressing hyperstaticity. Loops consisting of an odd number of grains behave differently than those with an even number. For odd loops, the latent stresses are exterior and are characterized by the sum of frictional forces around each loop. For even loops, the latent stresses are interior and are characterized by the alternating sum of frictional forces around each loop. The statistics of these two types of loop sums are found to be Gibbsian with a "temperature" that is linear with the friction coefficient μ when μ<1.

HRD Motif as the Central Hub of the Signaling Network for Activation Loop Autophosphorylation in Abl Kinase.

PubMed

La Sala, Giuseppina; Riccardi, Laura; Gaspari, Roberto; Cavalli, Andrea; Hantschel, Oliver; De Vivo, Marco

2016-11-08

A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. First, only the open conformation of the Abl kinase domain's activation loop (A-loop) favors ATP binding to the catalytic cleft. In this regard, the trans-autophosphorylation of the Y412 residue, which is located along the A-loop, favors the stability of the open conformation, in turn enhancing Abl activity. Another key factor for full Abl activity is the formation of active conformations of the catalytic DFG motif in the Abl kinase domain. Furthermore, binding of the SH2 domain to the N-lobe of the Abl kinase was recently demonstrated to have a long-range allosteric effect on the stabilization of the A-loop open state. Intriguingly, these distinct structural factors imply a complex signal transmission network for controlling the A-loop's flexibility and conformational preference for optimal Abl function. However, the exact dynamical features of this signal transmission network structure remain unclear. Here, we report on microsecond-long molecular dynamics coupled with enhanced sampling simulations of multiple Abl model systems, in the presence or absence of the SH2 domain and with the DFG motif flipped in two ways (in or out conformation). Through comparative analysis, our simulations augment the interpretation of the existing Abl experimental data, revealing a dynamical network of interactions that interconnect SH2 domain binding with A-loop plasticity and Y412 autophosphorylation in Abl. This signaling network engages the DFG motif and, importantly, other conserved structural elements of the kinase domain, namely, the EPK-ELK H-bond network and the HRD motif. Our results show that the signal propagation for modulating the A-loop spatial localization is highly dependent on the HRD motif conformation, which thus acts as the central hub of this (allosteric) signaling network controlling Abl activation and function.

Islet amyloid polypeptide exerts a novel autocrine action in β-cell signaling and proliferation.

PubMed

Visa, Montse; Alcarraz-Vizán, Gema; Montane, Joel; Cadavez, Lisa; Castaño, Carlos; Villanueva-Peñacarrillo, María Luisa; Servitja, Joan-Marc; Novials, Anna

2015-07-01

The toxic effects of human islet amyloid polypeptide (IAPP) on pancreatic islets have been widely studied. However, much less attention has been paid to the physiologic actions of IAPP on pancreatic β cells, which secrete this peptide together with insulin upon glucose stimulation. Here, we aimed to explore the signaling pathways and mitogenic actions of IAPP on β cells. We show that IAPP activated Erk1/2 and v-akt murine thymoma viral oncogene homolog 1 (Akt) at the picomolar range (10-100 pM) in mouse pancreatic islets and MIN6 β cells cultured at low glucose concentrations. In contrast, IAPP decreased the induction of these pathways by high glucose levels. Consistently, IAPP induced a 1.7-fold increase of β-cell proliferation at low-glucose conditions, whereas it reduced β-cell proliferation at high glucose levels. Strikingly, the specific antagonist of the IAPP receptor AC187 (100 nM) decreased the activation of Erk1/2 and Akt and reduced β-cell proliferation by 24% in glucose-stimulated β cells, uncovering a key role of endogenously released IAPP in β-cell responses to glucose. We conclude that exogenously added IAPP exerts a dual effect on β-cell mitogenic signaling and proliferation, depending on the glucose concentration. Importantly, secreted IAPP contributes to the signaling and mitogenic response of β cells to glucose through an autocrine mechanism. © FASEB.

Vascular endothelial growth factor and the kidney: something of the marvellous.

PubMed

Advani, Andrew

2014-01-01

The vascular endothelial growth factor (VEGF) system is a multifarious network and an exemplar of an intraglomerular signalling pathway. Here, we review recent advances that highlight the subtle nature of the renal VEGF system and its influencers. The VEGF system is no longer considered as a simple paracrine, ligand-receptor interaction under the regulatory control of a soluble 'decoy', soluble fms-like tyrosine kinase-1 (sFLT1). Rather, the abundantly expressed, podocyte-derived VEGF isoform, VEGF-A, is now recognized to mediate both paracrine effects across the filtration barrier and autocrine actions, functioning to preserve the integrity of the cells from which it arises. Autocrine actions of the podocyte VEGF system extend beyond those of the VEGF-A isoform, however, with sFLT1 itself now appreciated as regulating podocyte morphology by binding to lipid microdomains. These and other functions of the VEGF system are profoundly affected by the presence, nature and abundance of influencers both intrinsic and extrinsic to the pathway, the latter most readily exemplified by the role of the cytokine in the diabetic kidney. The glomerular VEGF system plays a delicate, yet critical, role in preserving renal homeostasis. It may be intricate, but 'in all things of nature there is something of the marvellous'.

Central safety factor and β N control on NSTX-U via beam power and plasma boundary shape modification, using TRANSP for closed loop simulations

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

Boyer, M. D.; Andre, R.; Gates, D. A.

The high-performance operational goals of NSTX-U will require development of advanced feedback control algorithms, including control of ßN and the safety factor profile. In this work, a novel approach to simultaneously controlling ßN and the value of the safety factor on the magnetic axis, q0, through manipulation of the plasma boundary shape and total beam power, is proposed. Simulations of the proposed scheme show promising results and motivate future experimental implementation and eventual integration into a more complex current profile control scheme planned to include actuation of individual beam powers, density, and loop voltage. As part of this work, amore » flexible framework for closed loop simulations within the high-fidelity code TRANSP was developed. The framework, used here to identify control-design-oriented models and to tune and test the proposed controller, exploits many of the predictive capabilities of TRANSP and provides a means for performing control calculations based on user-supplied data (controller matrices, target waveforms, etc.). The flexible framework should enable high-fidelity testing of a variety of control algorithms, thereby reducing the amount of expensive experimental time needed to implement new control algorithms on NSTX-U and other devices.« less

Corrosion of type 316L stainless steel in a mercury thermal convection loop

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

DiStefano, J.R.; Manneschmidt, E.T.; Pawel, S.J.

1999-04-01

Two thermal convection loops fabricated from 316L stainless steel containing mercury (Hg) and Hg with 1000 wppm gallium (Ga), respectively, were operated continuously for about 5000 h. In each case, the maximum loop temperature was constant at about 305 degrees C and the minimum temperature was constant at about 242 degrees C. Coupons in the hot leg of the Hg-loop developed a posous surface layer substantially depleted of nickel and chromium, which resulted in a transformation to ferrite. The coupon exposed at the top of the hot leg in the Hg-loop experienced the maximum degradation, exhibiting a surface layer extendingmore » an average of 9-10 mu m after almost 5000 h. Analysis of the corrosion rate data as a function of temperature (position) in the Hg-loop suggests wetting by the mer cury occurred only above about 255 degrees C and that the rate limiting step in the corrosion process above 255 degrees C is solute diffusion through the saturated liquid boundary layer adjacent to the corroding surface. The latter factor suggests that the corrosion of 316L stainless steel in a mercury loop may be velocity dependent. No wetting and no corrosion were observed on the coupons and wall specimens removed from the Hg/Ga loop after 5000 h of operation.« less

Digital phase-locked loop

NASA Technical Reports Server (NTRS)

Cliff, R. A. (Inventor)

1975-01-01

An digital phase-locked loop is provided for deriving a loop output signal from an accumulator output terminal. A phase detecting exclusive OR gate is fed by the loop digital input and output signals. The output of the phase detector is a bi-level digital signal having a duty cycle indicative of the relative phase of the input and output signals. The accumulator is incremented at a first rate in response to a first output level of the phase detector and at a second rate in response to a second output level of the phase detector.

Tracheophytes Contain Conserved Orthologs of a Basic Helix-Loop-Helix Transcription Factor That Modulate ROOT HAIR SPECIFIC Genes[OPEN

PubMed Central

Cho, Hyun-Min

2017-01-01

ROOT HAIR SPECIFIC (RHS) genes, which contain the root hair-specific cis-element (RHE) in their regulatory regions, function in root hair morphogenesis. Here, we demonstrate that an Arabidopsis thaliana basic helix-loop-helix transcription factor, ROOT HAIR DEFECTVE SIX-LIKE4 (RSL4), directly binds to the RHE in vitro and in vivo, upregulates RHS genes, and stimulates root hair formation in Arabidopsis. Orthologs of RSL4 from a eudicot (poplar [Populus trichocarpa]), a monocot (rice [Oryza sativa]), and a lycophyte (Selaginella moellendorffii) each restored root hair growth in the Arabidopsis rsl4 mutant. In addition, the rice and S. moellendorffii RSL4 orthologs bound to the RHE in in vitro and in vivo assays. The RSL4 orthologous genes contain RHEs in their promoter regions, and RSL4 was able to bind to its own RHEs in vivo and amplify its own expression. This process likely provides a positive feedback loop for sustainable root hair growth. When RSL4 and its orthologs were expressed in cells in non-root-hair positions, they induced ectopic root hair growth, indicating that these genes are sufficient to specify root hair formation. Our results suggest that RSL4 mediates root hair formation by regulating RHS genes and that this mechanism is conserved throughout the tracheophyte (vascular plant) lineage. PMID:28087829

Method of implementing digital phase-locked loops

NASA Technical Reports Server (NTRS)

Stephens, Scott A. (Inventor); Thomas, Jess Brooks, Jr. (Inventor)

1993-01-01

In a new formulation for digital phase-locked loops, loop-filter constants are determined from loop roots that can each be selectively placed in the s-plane on the basis of a new set of parameters, each with simple and direct physical meaning in terms of loop noise bandwidth, root-specific decay rate, or root-specific damping. Loops of first to fourth order are treated in the continuous-update approximation (BLT yields 0) and in a discrete-update formulation with arbitrary BLT. Deficiencies of the continuous-update approximation in large-BLT applications are avoided in the new discrete-update formulation. A new method for direct, transient-free acquisition with third- and fourth-order loops can improve the versatility and reliability of acquisition with such loops.

Some finite terms from ladder diagrams in three and four loop maximal supergravity

NASA Astrophysics Data System (ADS)

Basu, Anirban

2015-10-01

We consider the finite part of the leading local interactions in the low energy expansion of the four graviton amplitude from the ladder skeleton diagrams in maximal supergravity on T 2, at three and four loops. At three loops, we express the {D}8{{R}}4 and {D}10{{R}}4 amplitudes as integrals over the moduli space of an underlying auxiliary geometry. These amplitudes are evaluated exactly for special values of the the moduli of the auxiliary geometry, where the integrand simplifies. We also perform a similar analysis for the {D}8{{R}}4 amplitude at four loops that arise from the ladder skeleton diagrams for a special value of a parameter in the moduli space of the auxiliary geometry. While the dependence of the amplitudes on the volume of the T 2 is very simple, the dependence on the complex structure of the T 2 is quite intricate. In some of the cases, the amplitude consists of terms each of which factorizes into a product of two {SL}(2,{{Z}}) invariant modular forms. While one of the factors is a non-holomorphic Eisenstein series, the other factor splits into a sum of modular forms each of which satisfies a Poisson equation on moduli space with source terms that are bilinear in the Eisenstein series. This leads to several possible perturbative contributions unto genus 5 in type II string theory on S1. Unlike the one and two loop supergravity analysis, these amplitudes also receive non-perturbative contributions from bound states of three D-(anti)instantons in the IIB theory.

Observations of loops and prominences

NASA Technical Reports Server (NTRS)

Strong, Keith T.

1994-01-01

We review recent observations by the Yohkoh-SXT (Soft X-ray Telescope) in collaboration with other spacecraft and ground-based observatories of coronal loops and prominences. These new results point to problems that SoHO will be able to address. With a unique combination of rapid-cadence digital imaging (greater than or equal to 32 s full-disk and greater than or equal to 2 s partial-frame images), high spatial resolution (greater than or equal to 2.5 arcsec pixels), high sensitivity (EM less than or equal to 10(exp 42) cm(exp -3)), a low-scatter mirror, and large dynamic range, SXT can observe a vast range of targets on the Sun. Over the first 21 months of Yohkoh operations SXT has taken over one million images of the corona and so is building up an invaluable long-term database on the large-scale corona and loop geometry. The most striking thing about the SXT images is the range of loop sizes and shapes. The active regions are a bright tangle of magnetic field lines, surrounded by a network of large-scale quiet-Sun loops stretching over distances in excess of 105 km. The cross-section of most loops seems to be constant. Loops displaying significant Gamma's are the exception, not the rule, implying the presence of widespread currents in the corona. All magnetic structures show changes. Time scales range from seconds to months. The question of how these structures are formed, become filled with hot plasma, and are maintained is still open. While we see the propagation of brightenings along the length of active-region loops and in X-ray jets with velocities of several hundred km/s, much higher velocities are seen in the quiet Sun. In XBP flares, for example, velocities of over 1000 km/s are common. Active-region loops seem to be in constant motion, moving slowly outward, carrying plasma with them. During flares, loops often produce localized brightenings at the base and later at the apex of the loop. Quiescent filaments and prominences have been observed regularly

Extrusion without a motor: a new take on the loop extrusion model of genome organization

PubMed Central

Johnson, J.; Michieletto, D.; Morozov, A. N.; Nicodemi, M.; Cook, P. R.; Marenduzzo, D.

2018-01-01

ABSTRACT Chromatin loop extrusion is a popular model for the formation of CTCF loops and topological domains. Recent HiC data have revealed a strong bias in favour of a particular arrangement of the CTCF binding motifs that stabilize loops, and extrusion is the only model to date which can explain this. However, the model requires a motor to generate the loops, and although cohesin is a strong candidate for the extruding factor, a suitable motor protein (or a motor activity in cohesin itself) has yet to be found. Here we explore a new hypothesis: that there is no motor, and thermal motion within the nucleus drives extrusion. Using theoretical modelling and computer simulations we ask whether such diffusive extrusion could feasibly generate loops. Our simulations uncover an interesting ratchet effect (where an osmotic pressure promotes loop growth), and suggest, by comparison to recent in vitro and in vivo measurements, that diffusive extrusion can in principle generate loops of the size observed in the data. Extra View on : C. A. Brackley, J. Johnson, D. Michieletto, A. N. Morozov, M. Nicodemi, P. R. Cook, and D. Marenduzzo “Non-equilibrium chromosome looping via molecular slip-links”, Physical Review Letters 119 138101 (2017) PMID:29300120

Decay-less kink oscillations in coronal loops

NASA Astrophysics Data System (ADS)

Anfinogentov, S.; Nisticò, G.; Nakariakov, V. M.

2013-12-01

Context. Kink oscillations of coronal loops in an off-limb active region are detected with the Imaging Assembly Array (AIA) instruments of the Solar Dynamics Observatory (SDO) at 171 Å. Aims: We aim to measure periods and amplitudes of kink oscillations of different loops and to determinate the evolution of the oscillation phase along the oscillating loop. Methods: Oscillating coronal loops were visually identified in the field of view of SDO/AIA and STEREO/EUVI-A: the loop length was derived by three-dimensional analysis. Several slits were taken along the loops to assemble time-distance maps. We identified oscillatory patterns and retrieved periods and amplitudes of the oscillations. We applied the cross-correlation technique to estimate the phase shift between oscillations at different segments of oscillating loops. Results: We found that all analysed loops show low-amplitude undamped transverse oscillations. Oscillation periods of loops in the same active region range from 2.5 to 11 min, and are different for different loops. The displacement amplitude is lower than 1 Mm. The oscillation phase is constant along each analysed loop. The spatial structure of the phase of the oscillations corresponds to the fundamental standing kink mode. We conclude that the observed behaviour is consistent with the empirical model in terms of a damped harmonic resonator affected by a non-resonant continuously operating external force. A movie is available in electronic form at http://www.aanda.org

Near optimum digital phase locked loops.

NASA Technical Reports Server (NTRS)

Polk, D. R.; Gupta, S. C.

1972-01-01

Near optimum digital phase locked loops are derived utilizing nonlinear estimation theory. Nonlinear approximations are employed to yield realizable loop structures. Baseband equivalent loop gains are derived which under high signal to noise ratio conditions may be calculated off-line. Additional simplifications are made which permit the application of the Kalman filter algorithms to determine the optimum loop filter. Performance is evaluated by a theoretical analysis and by simulation. Theoretical and simulated results are discussed and a comparison to analog results is made.

Wilson loop from a Dyson equation

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

Pak, M.; Reinhardt, H.

2009-12-15

The Dyson equation proposed for planar temporal Wilson loops in the context of supersymmetric gauge theories is critically analyzed thereby exhibiting its ingredients and approximations involved. We reveal its limitations and identify its range of applicability in nonsupersymmetric gauge theories. In particular, we show that this equation is applicable only to strongly asymmetric planar Wilson loops (consisting of a long and a short pair of loop segments) and as a consequence the Wilsonian potential can be extracted only up to intermediate distances. By this equation the Wilson loop is exclusively determined by the gluon propagator. We solve the Dyson equationmore » in Coulomb gauge for the temporal Wilson loop with the instantaneous part of the gluon propagator and for the spatial Wilson loop with the static gluon propagator obtained in the Hamiltonian approach to continuum Yang-Mills theory and on the lattice. In both cases we find a linearly rising color potential.« less

Single-molecule manipulation reveals supercoiling-dependent modulation of lac repressor-mediated DNA looping

PubMed Central

Normanno, Davide; Vanzi, Francesco; Pavone, Francesco Saverio

2008-01-01

Gene expression regulation is a fundamental biological process which deploys specific sets of genomic information depending on physiological or environmental conditions. Several transcription factors (including lac repressor, LacI) are present in the cell at very low copy number and increase their local concentration by binding to multiple sites on DNA and looping the intervening sequence. In this work, we employ single-molecule manipulation to experimentally address the role of DNA supercoiling in the dynamics and stability of LacI-mediated DNA looping. We performed measurements over a range of degrees of supercoiling between −0.026 and +0.026, in the absence of axial stretching forces. A supercoiling-dependent modulation of the lifetimes of both the looped and unlooped states was observed. Our experiments also provide evidence for multiple structural conformations of the LacI–DNA complex, depending on torsional constraints. The supercoiling-dependent modulation demonstrated here adds an important element to the model of the lac operon. In fact, the complex network of proteins acting on the DNA in a living cell constantly modifies its topological and mechanical properties: our observations demonstrate the possibility of establishing a signaling pathway from factors affecting DNA supercoiling to transcription factors responsible for the regulation of specific sets of genes. PMID:18310101

An approach toward the numerical evaluation of multi-loop Feynman diagrams

NASA Astrophysics Data System (ADS)

Passarino, Giampiero

2001-12-01

A scheme for systematically achieving accurate numerical evaluation of multi-loop Feynman diagrams is developed. This shows the feasibility of a project aimed to produce a complete calculation for two-loop predictions in the Standard Model. As a first step an algorithm, proposed by F.V. Tkachov and based on the so-called generalized Bernstein functional relation, is applied to one-loop multi-leg diagrams with particular emphasis to the presence of infrared singularities, to the problem of tensorial reduction and to the classification of all singularities of a given diagram. Successively, the extension of the algorithm to two-loop diagrams is examined. The proposed solution consists in applying the functional relation to the one-loop sub-diagram which has the largest number of internal lines. In this way the integrand can be made smooth, a part from a factor which is a polynomial in xS, the vector of Feynman parameters needed for the complementary sub-diagram with the smallest number of internal lines. Since the procedure does not introduce new singularities one can distort the xS-integration hyper-contour into the complex hyper-plane, thus achieving numerical stability. The algorithm is then modified to deal with numerical evaluation around normal thresholds. Concise and practical formulas are assembled and presented, numerical results and comparisons with the available literature are shown and discussed for the so-called sunset topology.

DNA looping by FokI: the impact of twisting and bending rigidity on protein-induced looping dynamics

PubMed Central

Laurens, Niels; Rusling, David A.; Pernstich, Christian; Brouwer, Ineke; Halford, Stephen E.; Wuite, Gijs J. L.

2012-01-01

Protein-induced DNA looping is crucial for many genetic processes such as transcription, gene regulation and DNA replication. Here, we use tethered-particle motion to examine the impact of DNA bending and twisting rigidity on loop capture and release, using the restriction endonuclease FokI as a test system. To cleave DNA efficiently, FokI bridges two copies of an asymmetric sequence, invariably aligning the sites in parallel. On account of the fixed alignment, the topology of the DNA loop is set by the orientation of the sites along the DNA. We show that both the separation of the FokI sites and their orientation, altering, respectively, the twisting and the bending of the DNA needed to juxtapose the sites, have profound effects on the dynamics of the looping interaction. Surprisingly, the presence of a nick within the loop does not affect the observed rigidity of the DNA. In contrast, the introduction of a 4-nt gap fully relaxes all of the torque present in the system but does not necessarily enhance loop stability. FokI therefore employs torque to stabilise its DNA-looping interaction by acting as a ‘torsional’ catch bond. PMID:22373924

Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue.

PubMed

Mydlo, J H; Michaeli, J; Cordon-Cardo, C; Goldenberg, A S; Heston, W D; Fair, W R

1989-06-15

Using Northern blot analysis, we have demonstrated that mRNA for transforming growth factor alpha (TGF-alpha) was expressed in five malignant kidney tissue specimens but was not detected in their autologous nonneoplastic homologues. In addition, the expression of epidermal growth factor (EGF) receptor mRNA in these malignant tissues was 2- to 3-fold greater than in nontransformed tissues. In two cases examined using immunohistochemistry, we were able to correlate the increased expression of the mRNA with an increase in protein expression. Since TGF-alpha is known to bind to the EGF receptor, the finding of an increased expression of both TGF-alpha and EGF receptor mRNA in kidney tumor tissue suggests that interaction between TGF-alpha and the EGF receptor may play a role in promoting transformation and/or proliferation of kidney neoplasms, perhaps by an autocrine mechanism.

Optical fiber loops and helices: tools for integrated photonic device characterization and microfluidic trapping

NASA Astrophysics Data System (ADS)

Ren, Yundong; Zhang, Rui; Ti, Chaoyang; Liu, Yuxiang

2016-09-01

Tapered optical fibers can deliver guided light into and carry light out of micro/nanoscale systems with low loss and high spatial resolution, which makes them ideal tools in integrated photonics and microfluidics. Special geometries of tapered fibers are desired for probing monolithic devices in plane as well as optical manipulation of micro particles in fluids. However, for many specially shaped tapered fibers, it remains a challenge to fabricate them in a straightforward, controllable, and repeatable way. In this work, we fabricated and characterized two special geometries of tapered optical fibers, namely fiber loops and helices, that could be switched between one and the other. The fiber loops in this work are distinct from previous ones in terms of their superior mechanical stability and high optical quality factors in air, thanks to a post-annealing process. We experimentally measured an intrinsic optical quality factor of 32,500 and a finesse of 137 from a fiber loop. A fiber helix was used to characterize a monolithic cavity optomechanical device. Moreover, a microfluidic "roller coaster" was demonstrated, where microscale particles in water were optically trapped and transported by a fiber helix. Tapered fiber loops and helices can find various applications ranging from on-the-fly characterization of integrated photonic devices to particle manipulation and sorting in microfluidics.

Tritium Management Loop Design Status

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

Rader, Jordan D.; Felde, David K.; McFarlane, Joanna

This report summarizes physical, chemical, and engineering analyses that have been done to support the development of a test loop to study tritium migration in 2LiF-BeF2 salts. The loop will operate under turbulent flow and a schematic of the apparatus has been used to develop a model in Mathcad to suggest flow parameters that should be targeted in loop operation. The introduction of tritium into the loop has been discussed as well as various means to capture or divert the tritium from egress through a test assembly. Permeation was calculated starting with a Modelica model for a transport through amore » nickel window into a vacuum, and modifying it for a FLiBe system with an argon sweep gas on the downstream side of the permeation interface. Results suggest that tritium removal with a simple tubular permeation device will occur readily. Although this system is idealized, it suggests that rapid measurement capability in the loop may be necessary to study and understand tritium removal from the system.« less

The SUMO Pathway Promotes Basic Helix-Loop-Helix Proneural Factor Activity via a Direct Effect on the Zn Finger Protein Senseless

PubMed Central

Chen, Angela; Huang, Yan Chang; Wang, Pin Yao; Kemp, Sadie E.

2012-01-01

During development, proneural transcription factors of the basic helix-loop-helix (bHLH) family are required to commit cells to a neural fate. In Drosophila neurogenesis, a key mechanism promoting sense organ precursor (SOP) fate is the synergy between proneural factors and their coactivator Senseless in transcriptional activation of target genes. Here we present evidence that posttranslational modification by SUMO enhances this synergy via an effect on Senseless protein. We show that Senseless is a direct target for SUMO modification and that mutagenesis of a predicted SUMOylation motif in Senseless reduces Senseless/proneural synergy both in vivo and in cell culture. We propose that SUMOylation of Senseless via lysine 509 promotes its synergy with proneural proteins during transcriptional activation and hence regulates an important step in neurogenesis leading to the formation and maturation of the SOPs. PMID:22586269

Expression and localization of insulin-like growth factor system in corpus luteum during different stages of estrous cycle in water buffaloes (Bubalus bubalis) and the effect of insulin-like growth factor I on production of vascular endothelial growth factor and progesterone in luteal cells cultured in vitro.

PubMed

Uniyal, S; Panda, R P; Chouhan, V S; Yadav, V P; Hyder, I; Dangi, S S; Gupta, M; Khan, F A; Sharma, G T; Bag, S; Sarkar, M

2015-01-01

This study investigated the expression and localization of insulin-like growth factor (IGF) system at different stages of buffalo CL and the role of IGF-I in stimulating vascular endothelial growth factor (VEGF) and progesterone (P4) production in cultured luteal cells. The mRNA expression of IGF system, VEGF, steroidogenic acute regulatory protein, P450scc, and hydroxysteroid dehydrogenase (HSD) was investigated by quantitative real-time polymerase chain reaction (PCR). Protein expression of IGF was demonstrated by Western blot and localization by immunohistochemistry. Progesterone and VEGF production was assayed using RIA and ELISA. A relatively high mRNA expression of IGF-I and IGF-II in early, mid- and late luteal phases with immunoreactivity mostly restricted to cytoplasm of large luteal cells indicates their autocrine role, whereas very weak immunoreactivity in endothelial cells during the mid-luteal phase indicates their paracrine role. Insulin-like growth factor receptors, IGF-IR and IGF-IIR, were restricted to large luteal cells with high mRNA and protein expressions in the mid-luteal phase. The significantly higher expression of insulin-like growth factor binding protein (IGFBP)-1, -3, -5, and -6 in the early or mid-luteal phase suggested their stimulatory role, whereas that of IGFBP-2 and -4 in mid-, late, and regressive luteal stages implied their inhibitory role. The mRNA expressions of key steroidogenic factors and VEGF were significantly higher (P < 0.05) when the culture medium was supplemented with 100 ng/mL of IGF-I for 72 hours. Moreover, IGF-I at a dose of 100 ng/mL increased P4 and VEGF production (P < 0.05). It can be concluded that IGF family members via their autocrine and paracrine effect play significant roles in promoting angiogenesis through the production of VEGF in luteal cells and steroid synthesis through the production of key steroidogenic factors. Copyright © 2015 Elsevier Inc. All rights reserved.

Polyakov loop modeling for hot QCD

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

Fukushima, Kenji; Skokov, Vladimir

Here, we review theoretical aspects of quantum chromodynamics (QCD) at finite temperature. The most important physical variable to characterize hot QCD is the Polyakov loop, which is an approximate order parameter for quark deconfinement in a hot gluonic medium. Additionally to its role as an order parameter, the Polyakov loop has rich physical contents in both perturbative and non-perturbative sectors. This review covers a wide range of subjects associated with the Polyakov loop from topological defects in hot QCD to model building with coupling to the Polyakov loop.

Capillary-Condenser-Pumped Heat-Transfer Loop

NASA Technical Reports Server (NTRS)

Silverstein, Calvin C.

1989-01-01

Heat being transferred supplies operating power. Capillary-condenser-pumped heat-transfer loop similar to heat pipe and to capillary-evaporator-pumped heat-transfer loop in that heat-transfer fluid pumped by evaporation and condensation of fluid at heat source and sink, respectively. Capillary condenser pump combined with capillary evaporator pump to form heat exchanger circulating heat-transfer fluids in both loops. Transport of heat more nearly isothermal. Thermal stress in loop reduced, and less external surface area needed in condenser section for rejection of heat to heat sink.

Polyakov loop modeling for hot QCD

DOE PAGES

Fukushima, Kenji; Skokov, Vladimir

2017-06-19

Here, we review theoretical aspects of quantum chromodynamics (QCD) at finite temperature. The most important physical variable to characterize hot QCD is the Polyakov loop, which is an approximate order parameter for quark deconfinement in a hot gluonic medium. Additionally to its role as an order parameter, the Polyakov loop has rich physical contents in both perturbative and non-perturbative sectors. This review covers a wide range of subjects associated with the Polyakov loop from topological defects in hot QCD to model building with coupling to the Polyakov loop.

Kalman Orbit Optimized Loop Tracking

NASA Technical Reports Server (NTRS)

Young, Lawrence E.; Meehan, Thomas K.

2011-01-01

Under certain conditions of low signal power and/or high noise, there is insufficient signal to noise ratio (SNR) to close tracking loops with individual signals on orbiting Global Navigation Satellite System (GNSS) receivers. In addition, the processing power available from flight computers is not great enough to implement a conventional ultra-tight coupling tracking loop. This work provides a method to track GNSS signals at very low SNR without the penalty of requiring very high processor throughput to calculate the loop parameters. The Kalman Orbit-Optimized Loop (KOOL) tracking approach constitutes a filter with a dynamic model and using the aggregate of information from all tracked GNSS signals to close the tracking loop for each signal. For applications where there is not a good dynamic model, such as very low orbits where atmospheric drag models may not be adequate to achieve the required accuracy, aiding from an IMU (inertial measurement unit) or other sensor will be added. The KOOL approach is based on research JPL has done to allow signal recovery from weak and scintillating signals observed during the use of GPS signals for limb sounding of the Earth s atmosphere. That approach uses the onboard PVT (position, velocity, time) solution to generate predictions for the range, range rate, and acceleration of the low-SNR signal. The low- SNR signal data are captured by a directed open loop. KOOL builds on the previous open loop tracking by including feedback and observable generation from the weak-signal channels so that the MSR receiver will continue to track and provide PVT, range, and Doppler data, even when all channels have low SNR.

Parallel Digital Phase-Locked Loops

NASA Technical Reports Server (NTRS)

Sadr, Ramin; Shah, Biren N.; Hinedi, Sami M.

1995-01-01

Wide-band microwave receivers of proposed type include digital phase-locked loops in which band-pass filtering and down-conversion of input signals implemented by banks of multirate digital filters operating in parallel. Called "parallel digital phase-locked loops" to distinguish them from other digital phase-locked loops. Systems conceived as cost-effective solution to problem of filtering signals at high sampling rates needed to accommodate wide input frequency bands. Each of M filters process 1/M of spectrum of signal.

Rapid Damping of the Oscillations of Coronal Loops with an Azimuthal Magnetic Field

NASA Astrophysics Data System (ADS)

Mikhalyaev, B. B.

2005-06-01

We consider the MHD oscillations of an inhomogeneous coronal loop that consists of a dense cord surrounded by a shell. The magnetic field is longitudinal in the cord and has only an azimuthal component in the shell. The parameters of the loop are chosen to be such that there are no resonances; i.e., the resonance points are cut off. This choice is dictated by the formulated problem of considering the influence of the radiation of MHD waves into the surrounding space on the loop oscillations, thereby ruling out the possibility of resonant energy absorption. The wave radiation efficiency is high and allows low oscillation Q-factors, which are equal in order of magnitude to their observed values, to be obtained.

Severe coagulation factor VII deficiency caused by a novel homozygous mutation (p. Trp284Gly) in loop 140s.

PubMed

Hao, Xiuping; Cheng, XiaoLi; Ye, Jiajia; Wang, Yingyu; Yang, LiHong; Wang, Mingshan; Jin, Yanhui

2016-06-01

Congenital coagulation factor VII (FVII) deficiency is a rare disorder caused by mutation in F7 gene. Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%). The thrombin generation tests verified that the proband has obstacles in producing thrombin. Direct sequencing analysis revealed a novel homozygous missense mutation p.Trp284Gly. Also noteworthy is the fact that the mutational residue belongs to structurally conserved loop 140s, which majorly undergo rearrangement after FVII activation. Model analysis indicated that the substitution disrupts these native hydrophobic interactions, which are of great importance to the conformation in the activation domain of FVIIa.

The Prevalence and Use of Walking Loops in Neighborhood Parks: A National Study.

PubMed

Cohen, Deborah A; Han, Bing; Evenson, Kelly R; Nagel, Catherine; McKenzie, Thomas L; Marsh, Terry; Williamson, Stephanie; Harnik, Peter

2017-02-01

Previous studies indicate that the design of streets and sidewalks can influence physical activity among residents. Park features also influence park use and park-based physical activity. Although individuals can walk on streets and sidewalks, walking loops in parks offer a setting to walk in nature and to avoid interruptions from traffic. Here we describe the use of walking loops in parks and compare the number of park users and their physical activity in urban neighborhood parks with and without walking loops. We analyzed data from the National Study of Neighborhood Parks in which a representative sample of neighborhood parks (n = 174) from 25 U.S. cities with > 100,000 population were observed systematically to document facilities and park users by age group and sex. We compared the number of people and their physical activity in parks with and without walking loops, controlling for multiple factors, including park size, facilities, and population density. Overall, compared with parks without walking loops, on average during an hourly observation, parks with walking loops had 80% more users (95% CI: 42, 139%), and levels of moderate-to-vigorous physical activity were 90% higher (95% CI: 49, 145%). The additional park use and park-based physical activity occurred not only on the walking loops but throughout the park. Walking loops may be a promising means of increasing population level physical activity. Further studies are needed to confirm a causal relationship. Citation: Cohen DA, Han B, Evenson KR, Nagel C, McKenzie TL, Marsh T, Williamson S, Harnik P. 2017. The prevalence and use of walking loops in neighborhood parks: a national study. Environ Health Perspect 125:170-174; http://dx.doi.org/10.1289/EHP293.

The Prevalence and Use of Walking Loops in Neighborhood Parks: A National Study

PubMed Central

Cohen, Deborah A.; Han, Bing; Evenson, Kelly R.; Nagel, Catherine; McKenzie, Thomas L.; Marsh, Terry; Williamson, Stephanie; Harnik, Peter

2016-01-01

Background: Previous studies indicate that the design of streets and sidewalks can influence physical activity among residents. Park features also influence park use and park-based physical activity. Although individuals can walk on streets and sidewalks, walking loops in parks offer a setting to walk in nature and to avoid interruptions from traffic. Objectives: Here we describe the use of walking loops in parks and compare the number of park users and their physical activity in urban neighborhood parks with and without walking loops. Methods: We analyzed data from the National Study of Neighborhood Parks in which a representative sample of neighborhood parks (n = 174) from 25 U.S. cities with > 100,000 population were observed systematically to document facilities and park users by age group and sex. We compared the number of people and their physical activity in parks with and without walking loops, controlling for multiple factors, including park size, facilities, and population density. Results: Overall, compared with parks without walking loops, on average during an hourly observation, parks with walking loops had 80% more users (95% CI: 42, 139%), and levels of moderate-to-vigorous physical activity were 90% higher (95% CI: 49, 145%). The additional park use and park-based physical activity occurred not only on the walking loops but throughout the park. Conclusions: Walking loops may be a promising means of increasing population level physical activity. Further studies are needed to confirm a causal relationship. Citation: Cohen DA, Han B, Evenson KR, Nagel C, McKenzie TL, Marsh T, Williamson S, Harnik P. 2017. The prevalence and use of walking loops in neighborhood parks: a national study. Environ Health Perspect 125:170–174; http://dx.doi.org/10.1289/EHP293 PMID:27517530

Assessing catchment connectivity using hysteretic loops

NASA Astrophysics Data System (ADS)

Keesstra, Saskia; Masselink, Rens; Goni, Mikel; Campo, Miguel Angel; Gimenez, Rafael; Casali, Javier; Seeger, Manuel

2015-04-01

Sediment connectivity is a concept which can explain the origin, pathways and sinks of sediments within landscapes. This information is valuable for land managers to be able to take appropriate action at the correct place. Hysteresis between sediment and water discharge can give important information about the sources , pathways and conditions of sediment that arrives at the outlet of a catchment. "Hysteresis" happens when the sediment concentration associated with a certain flow rate is different depending on the direction in which the analysis is performed -towards the increase or towards the diminution of the flow. This phenomenon to some extent reflects the way in which the runoff generation processes are conjugated with those of the production and transport of sediments, hence the usefulness of hysteresis as a diagnostic hydrological parameter. However, the complexity of the phenomena and factors which determine hysteresis make its interpretation uncertain or, at the very least, problematic. Many types of hysteretic loops have been described as well as the cause for the shape of the loop, mainly describing the origin of the sediments. In this study, several measures to objectively classify hysteretic loops in an automated way were developed. These were consecutively used to classify several hundreds of loops from several agricultural catchments in Northern Spain. The data set for this study comes from four experimental watersheds in Navarre (Spain), owned and maintained by the Government of Navarre. These experimental watersheds have been monitored and studied since 1996 (La Tejería and Latxaga) and 2001 (Oskotz "principal", Op, and Oskotz "woodland", Ow). La Tejería and Latxaga watersheds, located in the Central Western part of Navarre, are roughly similar to each other regarding size (approximately 200 ha), geology (marls and sandstones), soils (fine texture topsoil), climate (humid sub Mediterranean) and land use (80-90% cultivated with winter grain crops

Autocrine pathways involving S100A8 and/or S100A9 that are postulated to regulate the immunological functions of macrophages in rats.

PubMed

Okada, Kohki; Arai, Satoshi; Nakase, Hiroshi; Kohno, Hisashi; Nakamura, Fumihiko; Takeda, Mayu; Toda, Yoshinobu; Itoh, Hiroshi; Adachi, Souichi; Ikemoto, Masaki

2015-01-02

The development of ulcerative colitis (UC) is closely associated with abnormally functioning macrophages. Rat S100A8 (r-S100A8) and r-S100A9 (S100 proteins) is abundantly expressed in immune cells of myeloid origin, macrophages; however, it remains unclear why r-S100A9 is dominantly expressed in the macrophages of UC rats (UCR). The purpose of this study was to verify the immunological roles of S100 proteins in UCR. We observed the distribution of S100 protein-positive macrophages in the large colons of UCR using a fluorescent immunological staining method, so that S100 protein-positive macrophages were restricted to the rectal tissues of the UCR, and that the mRNA levels of r-S100A8 and r-S100A9 were up-regulated by stimulation with recombinant rat S100A8 (rr-S100A8) alone and rr-S100A9 alone, respectively. When the changes in the mRNA levels of r-S100A8 and r-S100A9 in macrophages were examined in in vitro study by PCR and real-time PCR, the mRNA levels of anti-inflammatory and inflammatory cytokines increased selectively after stimulation with rr-S100A8 alone and rr-S100A9 alone, respectively. These results suggest that autocrine signal transduction pathways involving S100 proteins regulate the immunological functions of macrophages to maintain homeostasis in the gastrointestinal tract. This may be depended on expression balance of S100 proteins in macrophages. It is strongly suggested that in UCR the immune functions of macrophages are regulated in a complex manner by r-S100A8 and/or r-S100A9 through undefined autocrine pathways on the cells. Copyright © 2014 Elsevier Inc. All rights reserved.

State demonstration project : loop detectors.

DOT National Transportation Integrated Search

1985-01-01

The Virginia Department of Highways and Transportation frequently utilizes induction loops in its vehicle detector systems. Although not documented, there have been many instances of loop failure; therefore, the practices and materials used by the De...

An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism.

PubMed

Hodroj, Dana; Recolin, Bénédicte; Serhal, Kamar; Martinez, Susan; Tsanov, Nikolay; Abou Merhi, Raghida; Maiorano, Domenico

2017-05-02

Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear R-loops. Ddx19 depletion induces R-loop accumulation, proliferation-dependent DNA damage and defects in replication fork progression. Further, we show that Ddx19 resolves R-loops in vitro via its helicase activity. Furthermore, mutation of a residue phosphorylated by Chk1 in Ddx19 disrupts its interaction with Nup214 and allows its nuclear relocalization. Finally, we show that Ddx19 operates in resolving R-loops independently of the RNA helicase senataxin. Altogether these observations put forward a novel, ATR-dependent function for Ddx19 in R-loop metabolism to preserve genome integrity in mammalian cells. © 2017 The Authors.

Effect of proline and glycine residues on dynamics and barriers of loop formation in polypeptide chains.

PubMed

Krieger, Florian; Möglich, Andreas; Kiefhaber, Thomas

2005-03-16

Glycine and proline residues are frequently found in turn and loop structures of proteins and are believed to play an important role during chain compaction early in folding. We investigated their effect on the dynamics of intrachain loop formation in various unstructured polypeptide chains. Loop formation is significantly slower around trans prolyl peptide bonds and faster around glycine residues compared to any other amino acid. However, short loops are formed fastest around cis prolyl bonds with a time constant of 6 ns for end-to-end contact formation in a four-residue loop. Formation of short loops encounters activation energies in the range of 15 to 30 kJ/mol. The altered dynamics around glycine and trans prolyl bonds can be mainly ascribed to their effects on the activation energy. The fast dynamics around cis prolyl bonds, in contrast, originate in a higher Arrhenius pre-exponential factor, which compensates for an increased activation energy for loop formation compared to trans isomers. All-atom simulations of proline-containing peptides indicate that the conformational space for cis prolyl isomers is largely restricted compared to trans isomers. This leads to decreased average end-to-end distances and to a smaller loss in conformational entropy upon loop formation in cis isomers. The results further show that glycine and proline residues only influence formation of short loops containing between 2 and 10 residues, which is the typical loop size in native proteins. Formation of larger loops is not affected by the presence of a single glycine or proline residue.

Role for Heat Shock Protein 90α in the Proliferation and Migration of HaCaT Cells and in the Deep Second-Degree Burn Wound Healing in Mice

PubMed Central

Li, Na; Li, Xiaoqiang; Han, Fei; Su, Linlin; Hu, Dahai

2014-01-01

Inflammation, proliferation, and tissue remodeling are essential steps for wound healing. The hypoxic wound microenvironment promotes cell migration through a hypoxia—heat shock protein 90 alpha (Hsp90α)—low density lipoprotein receptor-related protein-1 (LRP-1) autocrine loop. To elucidate the role of this autocrine loop on burn wound healing, we investigated the expression profile of Hsp90α at the edge of burn wounds and found a transient increase in both mRNA and protein levels. Experiments performed with a human keratinocyte cell line—HaCaT also confirmed above results. 17-dimethylaminoethylamino-17demethoxygeldanamycin hydrochloride (17-DMAG), an Hsp90α inhibitor, was used to further evaluate the function of Hsp90α in wound healing. Consistently, topical application of Hsp90α in the early stage of deep second-degree burn wounds led to reduced inflammation and increased tissue granulation, with a concomitant reduction in the size of the wound at each time point tested (p<0.05). Consequently, epidermal cells at the wound margin progressed more rapidly causing an expedited healing process. In conclusion, these results provided a rationale for the therapeutic effect of Hsp90α on the burn wound management. PMID:25111496

Steady State Model for Solar Coronal Loops

NASA Astrophysics Data System (ADS)

Sugiyama, L.; Asgari-Targhi, M.

2017-12-01

Solar coronal loops on the surface of the sun provide background magnetic and plasma structures for the release of a significant amount of the sun's energy, through energetic solar flares and coronal mass ejections and more gradual processes. Understanding their steady states is the first step in understanding loop dynamics. A consistent MHD steady state model, for a curved magnetic flux rope that contains plasma, has been developed[1] for simple coronal loops with both ends anchored in the photosphere. Plasma pressure or current makes the loop unstable to expansion in major radius and must be balanced by external forces, such as the solar gravity. The MHD momentum equation has a well defined small parameter ordering in the loop inverse aspect ratio ɛ=a/Ro (minor/major radius). Different types of common coronal loops fall in different parameter regimes, determined by the relative values of the plasma beta β=po/(Bo2/2μo), the MHD gravity parameter Ĝ≡ga/vA2 (the gravitational acceleration g normalized to the minor radius a and shear Alfvén velocity vA), and ɛ. The largest possible gravity, Ĝ ɛ1β, corresponds to the largest loops because it reduces the plasma density at the top of the loop exponentially compared to its lower ends, reducing the downward gravitational force -ρĜ there. The thin loops that are ubiquitous in solar active regions have ``high'' beta, β ɛ1, for ɛ≃0.02, and fit the predicted model scalings. The thicker loops that can give rise to flares and CMEs have ``low'' beta, β ɛ2. Cool loops, such as solar filaments outside active regions, that have a central pressure lower than that of the surrounding corona would have the strongest stability against radial expansion. The model raises a number of questions about the connection of loops to the photosphere and the force-free nature of the magnetic field there. [1] L. Sugiyama, M. Asgari-Targhi, Phys. Plasmas 24, 022904 (2017).

A dynamic flare with anomalously dense flare loops

NASA Technical Reports Server (NTRS)

Svestka, Z.; Fontenla, J. M.; Machado, M. E.; Martin, S. F.; Neidig, D. F.

1986-01-01

The dynamic flare of November 6, 1980 developed a rich system of growing loops which could be followed in H-alpha for 1.5 hours. Throughout the flare, these loops, near the limb, were seen in emission against the disk. Theoretical computations of b-values for a hydrogen atom reveal that this requires electron densities in the loops to be close to 10 to the 12th per cu cm. From measured widths of higher Balmer lines the density at the tops of the loops was found to be 4 x 10 to the 12th per cu cm if no nonthermal motions were present. It is now general knowledge that flare loops are initially observed in X-rays and become visible in H-alpha only after cooling. For such a high density a loop would cool through radiation from 10 to the 7th K to 10 to the 4th K within a few minutes so that the dense H-alpha loops should have heights very close to the heights of the X-ray loops. This, however, contradicts the observations obtained by the HXIS and FCS instruments on board SMM which show the X-ray loops at much higher altitudes than the loops in H-alpha. Therefore, the density must have been significantly smaller when the loops were formed and the flare loops were apparently both shrinking and becoming denser while cooling.

Combining Charge Couple Devices and Rate Sensors for the Feedforward Control System of a Charge Coupled Device Tracking Loop.

PubMed

Tang, Tao; Tian, Jing; Zhong, Daijun; Fu, Chengyu

2016-06-25

A rate feed forward control-based sensor fusion is proposed to improve the closed-loop performance for a charge couple device (CCD) tracking loop. The target trajectory is recovered by combining line of sight (LOS) errors from the CCD and the angular rate from a fiber-optic gyroscope (FOG). A Kalman filter based on the Singer acceleration model utilizes the reconstructive target trajectory to estimate the target velocity. Different from classical feed forward control, additive feedback loops are inevitably added to the original control loops due to the fact some closed-loop information is used. The transfer function of the Kalman filter in the frequency domain is built for analyzing the closed loop stability. The bandwidth of the Kalman filter is the major factor affecting the control stability and close-loop performance. Both simulations and experiments are provided to demonstrate the benefits of the proposed algorithm.

Automatic blocking of nested loops

NASA Technical Reports Server (NTRS)

Schreiber, Robert; Dongarra, Jack J.

1990-01-01

Blocked algorithms have much better properties of data locality and therefore can be much more efficient than ordinary algorithms when a memory hierarchy is involved. On the other hand, they are very difficult to write and to tune for particular machines. The reorganization is considered of nested loops through the use of known program transformations in order to create blocked algorithms automatically. The program transformations used are strip mining, loop interchange, and a variant of loop skewing in which invertible linear transformations (with integer coordinates) of the loop indices are allowed. Some problems are solved concerning the optimal application of these transformations. It is shown, in a very general setting, how to choose a nearly optimal set of transformed indices. It is then shown, in one particular but rather frequently occurring situation, how to choose an optimal set of block sizes.

Lipocalin 2 functions as a negative regulator of red blood cell production in an autocrine fashion.

PubMed

Miharada, Ken-ichi; Hiroyama, Takashi; Sudo, Kazuhiro; Nagasawa, Toshiro; Nakamura, Yukio

2005-11-01

Members of the lipocalin protein family are typically small, secreted proteins that possess a variety of functions. Although the physiological role of lipocalin 2 remains to be fully elucidated, a few pivotal functions have recently been reported, e.g., regulation of the apoptosis of leukocytes. Unexpectedly, lipocalin 2 is abundantly expressed in erythroid progenitor cells. An in vitro culture experiment demonstrated that lipocalin 2 induces apoptosis and inhibits differentiation of erythroid progenitor cells. During acute anemia the expression of lipocalin 2 was reduced in erythroid cells by a feedback system. Furthermore, injection of recombinant lipocalin 2 into mice suffering from acute anemia retarded the recovery of red blood cell (RBC) numbers, suggesting the importance of reduced expression of lipocalin 2 for the efficient recovery of RBC numbers. These results indicate that lipocalin 2 suppresses RBC production in an autocrine fashion. Hence, anemia arising from pathological conditions, such as chronic inflammation, might be partly due to increased levels of lipocalin 2 secreted from expanded leukocytes and/or macrophages. Also, anemia arising from malignancies might be partly due to the abundant secretion of lipocalin 2 from tumor cells. Thus, lipocalin 2 may represent an attractive therapeutic target for anemia under certain pathological conditions.

Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways

PubMed Central

Hayashi, Yujiro; Asuzu, David T.; Gibbons, Simon J.; Aarsvold, Kirsten H.; Bardsley, Michael R.; Lomberk, Gwen A.; Mathison, Angela J.; Kendrick, Michael L.; Shen, K. Robert; Taguchi, Takahiro; Gupta, Anu; Rubin, Brian P.; Fletcher, Jonathan A.; Farrugia, Gianrico; Urrutia, Raul A.; Ordog, Tamas

2013-01-01

Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes. PMID:24116170

Autocrine class 3 semaphorin system regulates slit diaphragm proteins and podocyte survival.

PubMed

Guan, F; Villegas, G; Teichman, J; Mundel, P; Tufro, A

2006-05-01

Class 3 semaphorins are guidance proteins that play crucial roles during development. Semaphorins 3A (sema 3A) and 3F are expressed by podocytes in vivo throughout ontogeny and their function is unknown. Here we examined the expression of class 3 semaphorins (3A, 3B, 3C, 3D, 3E, and 3F) and their receptors (neuropilins 1 and 2, plexins A1, A2, A3, B2, and D1) in undifferentiated and differentiated mouse podocytes using reverse transcriptase-polymerase chain reaction (RT-PCR). All class 3 semaphorins, neuropilins 1 and 2 are expressed by undifferentiated and differentiated podocytes at similar levels. Differentiated podocytes expressed 2-4-fold higher plexin A1, A2, and A3 mRNA levels than undifferentiated podocytes. To examine semaphorin regulation, we exposed podocytes to recombinant sema 3A. Sema 3A decreased semaphorin 3B, plexin A1, A3, and D1 >/=50% and reduced plexin A2 mRNA to undetectable levels. To identify sema 3A function in podocytes, we examined whether sema 3A regulates slit diaphragm proteins and podocyte survival. Sema 3A induced a dose-response podocin downregulation and decreased its interaction with CD2-associated protein and nephrin, as determined by Western analysis and co-immunoprecipitation. To evaluate sema 3A role in podocyte survival, we quantified podocyte apoptosis using a caspase 3 activity marker. Sema 3A induced a 10-fold increase in podocyte apoptosis and significantly decreased the activity of the Akt survival pathway. Our data indicate that (1) immortalized podocytes in culture have a functional autocrine semaphorin system that is regulated by differentiation and ligand availability; (2) sema 3A signaling regulates the expression and interactions of slit-diaphragm proteins and decreases podocyte survival.

Autocrine A2 in the T-System of Ventricular Myocytes Creates Transmural Gradients in Ion Transport: A Mechanism to Match Contraction with Load?

PubMed Central

Gao, Junyuan; Sun, Xiurong; Potapova, Irina A.; Cohen, Ira S.; Mathias, Richard T.; Kim, Jeremy H.

2014-01-01

Transmural heterogeneities in Na/K pump current (IP), transient outward K+-current (Ito), and Ca2+-current (ICaL) play an important role in regulating electrical and contractile activities in the ventricular myocardium. Prior studies indicated angiotensin II (A2) may determine the transmural gradient in Ito, but the effects of A2 on IP and ICaL were unknown. In this study, myocytes were isolated from five muscle layers between epicardium and endocardium. We found a monotonic gradient in both Ip and Ito, with the lowest currents in ENDO. When AT1Rs were inhibited, EPI currents were unaffected, but ENDO currents increased, suggesting endogenous extracellular A2 inhibits both currents in ENDO. IP- and Ito-inhibition by A2 yielded essentially the same K0.5 values, so they may both be regulated by the same mechanism. A2/AT1R-mediated inhibition of IP or Ito or stimulation of ICaL persisted for hours in isolated myocytes, suggesting continuous autocrine secretion of A2 into a restricted diffusion compartment, like the T-system. Detubulation brought EPI IP to its low ENDO value and eliminated A2 sensitivity, so the T-system lumen may indeed be the restricted diffusion compartment. These studies showed that 33–50% of IP, 57–65% of Ito, and a significant fraction of ICaL reside in T-tubule membranes where they are transmurally regulated by autocrine secretion of A2 into the T-system lumen and activation of AT1Rs. Increased AT1R activation regulates each of these currents in a direction expected to increase contractility. Endogenous A2 activation of AT1Rs increases monotonically from EPI to ENDO in a manner similar to reported increases in passive tension when the ventricular chamber fills with blood. We therefore hypothesize load is the signal that regulates A2-activation of AT1Rs, which create a contractile gradient that matches the gradient in load. PMID:24896115

Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused by Theileria parva infection

PubMed Central

Palmer, Guy H.; Machado, Joel; Fernandez, Paula; Heussler, Volker; Perinat, Therese; Dobbelaere, Dirk A. E.

1997-01-01

Infection of cattle with the protozoan Theileria parva results in uncontrolled T lymphocyte proliferation resulting in lesions resembling multicentric lymphoma. Parasitized cells exhibit autocrine growth characterized by persistent translocation of the transcriptional regulatory factor nuclear factor κB (NFκB) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How T. parva induces persistent NFκB activation, required for T cell activation and proliferation, is unknown. We hypothesized that the parasite induces degradation of the IκB molecules which normally sequester NFκB in the cytoplasm and that continuous degradation requires viable parasites. Using T. parva-infected T cells, we showed that the parasite mediates continuous phosphorylation and proteolysis of IκBα. However, IκBα reaccumulated to high levels in parasitized cells, which indicated that T. parva did not alter the normal NFκB-mediated positive feedback loop which restores cytoplasmic IκBα. In contrast, T. parva mediated continuous degradation of IκBβ resulting in persistently low cytoplasmic IκBβ levels. Normal IκBβ levels were only restored following T. parva killing, indicating that viable parasites are required for IκBβ degradation. Treatment of T. parva-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both IκB degradation and consequent enhanced expression of NFκB dependent genes. However treatment using the antioxidant N-acetylcysteine had no effect on either IκB levels or NFκB activation, indicating that the parasite subverts the normal IκB regulatory pathway downstream of the requirement for reactive oxygen intermediates. Identification of the critical points regulated by T. parva may provide new approaches for disease control as well as increase our understanding of normal T cell function. PMID:9356483

Ballet of Loops

NASA Image and Video Library

2018-06-11

Giant, bright coronal loops trace out the magnetic field lines above an active region from June 4-6, 2018. The wavelength of extreme ultraviolet light shown here is emitted by ionized iron travelling along the field lines, super-heated to approximately 1 million degrees K. Coronal loops were not seen in this level of detail until the Solar Dynamics Observatory was launched in 2010 and came online, giving solar scientists new data with which to study the Sun and its processes. https://photojournal.jpl.nasa.gov/catalog/PIA22508

Basic helix-loop-helix transcription factors JASMONATE-ASSOCIATED MYC2-LIKE1 (JAM1), JAM2, and JAM3 are negative regulators of jasmonate responses in Arabidopsis.

PubMed

Sasaki-Sekimoto, Yuko; Jikumaru, Yusuke; Obayashi, Takeshi; Saito, Hikaru; Masuda, Shinji; Kamiya, Yuji; Ohta, Hiroyuki; Shirasu, Ken

2013-09-01

Jasmonates regulate transcriptional reprogramming during growth, development, and defense responses. Jasmonoyl-isoleucine, an amino acid conjugate of jasmonic acid (JA), is perceived by the protein complex composed of the F-box protein CORONATINE INSENSITIVE1 (COI1) and JASMONATE ZIM DOMAIN (JAZ) proteins, leading to the ubiquitin-dependent degradation of JAZ proteins. This activates basic helix-loop-helix-type MYC transcription factors to regulate JA-responsive genes. Here, we show that the expression of genes encoding other basic helix-loop-helix transcription factors, JASMONATE ASSOCIATED MYC2-LIKE1 (JAM1), JAM2, and JAM3, is positively regulated in a COI1- and MYC2-dependent manner in Arabidopsis (Arabidopsis thaliana). However, contrary to myc2, the jam1jam2jam3 triple mutant exhibited shorter roots when treated with methyl jasmonate (MJ), indicating enhanced responsiveness to JA. Our genome-wide expression analyses revealed that key jasmonate metabolic genes as well as a set of genes encoding transcription factors that regulate the JA-responsive metabolic genes are negatively regulated by JAMs after MJ treatment. Consistently, loss of JAM genes resulted in higher accumulation of anthocyanin in MJ-treated plants as well as higher accumulation of JA and 12-hydroxyjasmonic acid in wounded plants. These results show that JAMs negatively regulate the JA responses in a manner that is mostly antagonistic to MYC2.

The Projectile Inside the Loop

ERIC Educational Resources Information Center

Varieschi, Gabriele U.

2006-01-01

The loop-the-loop demonstration can be easily adapted to study the kinematics of projectile motion, when the moving body falls inside the apparatus. Video capturing software can be used to reveal peculiar geometrical effects of this simple but educational experiment.

Students' Understanding of Loops and Nested Loops in Computer Programming: An APOS Theory Perspective

ERIC Educational Resources Information Center

Cetin, Ibrahim

2015-01-01

The purpose of this study is to explore students' understanding of loops and nested loops concepts. Sixty-three mechanical engineering students attending an introductory programming course participated in the study. APOS (Action, Process, Object, Schema) is a constructivist theory developed originally for mathematics education. This study is the…

Improvement of mechanical performance for vibratory microgyroscope based on sense mode closed-loop control

NASA Astrophysics Data System (ADS)

Xiao, Dingbang; Su, Jianbin; Chen, Zhihua; Hou, Zhanqiang; Wang, Xinghua; Wu, Xuezhong

2013-04-01

In order to improve its structural sensitivity, a vibratory microgyroscope is commonly sealed in high vacuum to increase the drive mode quality factor. The sense mode quality factor of the microgyroscope will also increase simultaneously after vacuum sealing, which will lead to a long decay time of free response and even self-oscillation of the sense mode. As a result, the mechanical performance of the microgyroscope will be seriously degraded. In order to solve this problem, a closed-loop control technique is presented to adjust and optimize the sense mode quality factor. A velocity feedback loop was designed to increase the electric damping of the sense mode vibration. A circuit was fabricated based on this technique, and experimental results indicate that the sense mode quality factor of the microgyroscope was adjusted from 8052 to 428. The decay time of the sense mode free response was shortened from 3 to 0.5 s, and the vibration-rejecting ability of the microgyroscope was improved obviously without sensitivity degradation.

Method of Implementing Digital Phase-Locked Loops

NASA Technical Reports Server (NTRS)

Stephens, Scott A. (Inventor); Thomas, J. Brooks (Inventor)

1997-01-01

In a new formulation for digital phase-locked loops, loop-filter constants are determined from loop roots that can each be selectively placed in the s-plane on the basis of a new set of parameters, each with simple and direct physical meaning in terms of loop noise bandwidth, root-specific decay rate, and root-specific damping. Loops of first to fourth order are treated in the continuous-update approximation (B(sub L)T approaches 0) and in a discrete-update formulation with arbitrary B(sub L)T. Deficiencies of the continuous-update approximation in large-B(sub L)T applications are avoided in the new discrete-update formulation.

Premeasured Chordal Loops for Mitral Valve Repair.

PubMed

Gillinov, Marc; Quinn, Reed; Kerendi, Faraz; Gaudiani, Vince; Shemin, Richard; Barnhart, Glenn; Raines, Edward; Gerdisch, Marc W; Banbury, Michael

2016-09-01

Premeasured expanded polytetrafluoroethylene chordal loops with integrated sutures for attachment to the papillary muscle and leaflet edges facilitate correction of mitral valve prolapse. Configured as a group of 3 loops (length range 12 to 24 mm), the loops are attached to a pledget that is passed through the papillary muscle and tied. Each of the loops has 2 sutures with attached needles; these needles are passed through the free edge of the leaflet and then the sutures are tied to each other, securing the chordal loop to the leaflet. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Attrition Rate of Oxygen Carriers in Chemical Looping Combustion Systems

NASA Astrophysics Data System (ADS)

Feilen, Harry Martin

This project developed an evaluation methodology for determining, accurately and rapidly, the attrition resistance of oxygen carrier materials used in chemical looping technologies. Existing test protocols, to evaluate attrition resistance of granular materials, are conducted under non-reactive and ambient temperature conditions. They do not accurately reflect the actual behavior under the unique process conditions of chemical looping, including high temperatures and cyclic operation between oxidizing and reducing atmospheres. This project developed a test method and equipment that represented a significant improvement over existing protocols. Experimental results obtained from this project have shown that hematite exhibits different modes of attrition, including both due to mechanical stresses and due to structural changes in the particles due to chemical reaction at high temperature. The test methodology has also proven effective in providing reactivity changes of the material with continued use, a property, which in addition to attrition, determines material life. Consumption/replacement cost due to attrition or loss of reactivity is a critical factor in the economic application of the chemical looping technology. This test method will allow rapid evaluation of a wide range of materials that are best suited for this technology. The most important anticipated public benefit of this project is the acceleration of the development of chemical looping technology for lowering greenhouse gas emissions from fossil fuel combustion.

The QCD form factor of heavy quarks at NNLO

NASA Astrophysics Data System (ADS)

Gluza, J.; Mitov, A.; Moch, S.; Riemann, T.

2009-07-01

We present an analytical calculation of the two-loop QCD corrections to the electromagnetic form factor of heavy quarks. The two-loop contributions to the form factor are reduced to linear combinations of master integrals, which are computed through higher orders in the parameter of dimensional regularization epsilon = (4-D)/2. Our result includes all terms of order epsilon at two loops and extends the previous literature. We apply the exponentiation of the heavy-quark form factor to derive new improved three-loop expansions in the high-energy limit. We also discuss the implications for predictions of massive n-parton amplitudes based on massless results in the limit, where the quark mass is small compared to all kinematical invariants.

Interleukin-8 (IL-8) over-production and autocrine cell activation are key factors in monomethylarsonous acid [MMA(III)]-induced malignant transformation of urothelial cells.

PubMed

Escudero-Lourdes, C; Wu, T; Camarillo, J M; Gandolfi, A J

2012-01-01

The association between chronic human exposure to arsenicals and bladder cancer development is well recognized; however, the underlying molecular mechanisms have not been fully determined. We propose that inflammatory responses can play a pathogenic role in arsenic-related bladder carcinogenesis. In previous studies, it was demonstrated that chronic exposure to 50 nM monomethylarsenous acid [MMA(III)] leads to malignant transformation of an immortalized model of urothelial cells (UROtsa), with only 3 mo of exposure necessary to trigger the transformation-related changes. In the three-month window of exposure, the cells over-expressed pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), consistent with the sustained activation of NFKβ and AP1/c-jun, ERK2, and STAT3. IL-8 was over-expressed within hours after exposure to MMA(III), and sustained over-expression was observed during chronic exposure. In this study, we profiled IL-8 expression in UROtsa cells exposed to 50 nM MMA(III) for 1 to 5 mo. IL-8 expression was increased mainly in cells after 3 mo MMA(III) exposure, and its production was also found increased in tumors derived from these cells after heterotransplantation in SCID mice. UROtsa cells do express both receptors, CXCR1 and CXCR2, suggesting that autocrine cell activation could be important in cell transformation. Supporting this observation and consistent with IL-8 over-expression, CXCR1 internalization was significantly increased after three months of exposure to MMA(III). The expression of MMP-9, cyclin D1, bcl-2, and VGEF was significantly increased in cells exposed to MMA(III) for 3 mo, but these mitogen-activated kinases were significantly decreased after IL-8 gene silencing, together with a decrease in cell proliferation rate and in anchorage-independent colony formation. These results suggest a relevant role of IL-8 in MMA(III)-induced UROtsa cell transformation. Copyright © 2011 Elsevier Inc. All rights reserved.

The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction.

PubMed

Mavrommatis, Evangelos; Shioura, Krystyna M; Los, Tamara; Goldspink, Paul H

2013-09-01

Insulin-like growth factor-1 (IGF-1) isoforms are expressed via alternative splicing. Expression of the minor isoform IGF-1Eb [also known as mechano-growth factor (MGF)] is responsive to cell stress. Since IGF-1 isoforms differ in their E-domain regions, we are interested in determining the biological function of the MGF E-domain. To do so, a synthetic peptide analog was used to gain mechanistic insight into the actions of the E-domain. Treatment of H9c2 cells indicated a rapid cellular uptake mechanism that did not involve IGF-1 receptor activation but resulted in a nuclear localization. Peptide treatment inhibited the intrinsic apoptotic pathway in H9c2 cells subjected to cell stress with sorbitol by preventing the collapse of the mitochondrial membrane potential and inhibition of caspase-3 activation. Therefore, we administered the peptide at the time of myocardial infarction (MI) in mice. At 2 weeks post-MI cardiac function, gene expression and cell death were assayed. A significant decline in both systolic and diastolic function was evident in untreated mice based on PV loop analysis. Delivery of the E-peptide ameliorated the decline in function and resulted in significant preservation of cardiac contractility. Associated with these changes were an inhibition of pathologic hypertrophy and significantly fewer apoptotic nuclei in the viable myocardium of E-peptide-treated mice post-MI. We conclude that administration of the MGF E-domain peptide may provide a means of modulating local tissue IGF-1 autocrine/paracrine actions to preserve cardiac function, prevent cell death, and pathologic remodeling in the heart.

Loop Evolution Observed with AIA and Hi-C

NASA Technical Reports Server (NTRS)

Mulu-Moore, Fana; Winebarger, Amy R.; Cirtain, Jonathan W.; Kobayashi, Ken; Korreck, Kelly E.; Golub, Leon; Kuzin, Sergei; Walsh, Robert William; DeForest, Craig E.; De Pontieu, Bart;

On the feasibility of closed-loop control of intra-aortic balloon pumping

NASA Technical Reports Server (NTRS)

Clark, J. W., Jr.; Bourland, H. M.; Kane, G. R.

1973-01-01

A closed-loop control scheme for the control of intra-aortic balloon pumping has been developed and tested in dog experiments. A performance index reflecting the general objectives of balloon-assist pumping is developed and a modified steepest ascent control algorithm is utilized for the selection of a proper operating point for the balloon during its pumping cycle. This paper attempts to indicate the feasibility of closed-loop control of balloon pumping, and particularly its flexibility in achieving both diastolic augmentation of mean aortic pressure and control of the level of end-diastolic pressure (EDP) an important factor in reducing heart work.

The effects of magnetic structure on the conduction cooling of flare loops

NASA Technical Reports Server (NTRS)

Van Hoven, G.

1979-01-01

A model of the sheared magnetic field in a coronal loop is used to evaluate the average cross-field suppression of axial thermal conduction. If the energy source is uniform in radius, this can lead to heat-flux reduction by a factor greater than three. When the source is annular, in a region of radius where the current density and shear are peaked, the effect can be significantly larger. In one extreme case, however, in which magnetic tearing provides the heating in a very narrow layer, the spatial resonance of the source excitation in a long loop leads to approximately axial conduction.

Development of a Small Molecule P2X7R Antagonist as a Treatment for Acute SCI

DTIC Science & Technology

2013-10-01

microglia in response to SCI, and of the role of P2X7 receptor activation in that process . Indeed, in parallel work using uninjured human brain tissue...distinct glial fates are instructed, and how that process may be manipulated for therapeutic purposes. Thus, on the basis of the injury-associated...autocrine loop for the self -maintenance of glial progenitors, the perturbation of which might dictate progenitor recruitment as either reactive glia or

FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro

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

Ishino, Ruri; Minami, Kaori; Tanaka, Satowa

2013-10-11

Highlights: •FGF7 is downregulated in MED1-deficient mesenchymal cells. •FGF7 produced by mesenchymal stromal cells is a novel hematopoietic niche molecule. •FGF7 supports hematopoietic progenitor cells and niche-dependent leukemia cells. •FGF7 activates FGFR2IIIb of bone marrow stromal cells in an autocrine manner. •FGF7 indirectly acts on hematopoietic cells lacking FGFR2IIIb via stromal cells. -- Abstract: FGF1 and FGF2 support hematopoietic stem and progenitor cells (HSPCs) under stress conditions. In this study, we show that fibroblast growth factor (FGF7) may be a novel niche factor for HSPC support and leukemic growth. FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient formore » the MED1 subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with Med1{sup +/+} MEFs or BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long-time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1{sup −/−} MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in Med1{sup +/+} and Med1{sup −/−} MEFs and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells.« less

First cytoplasmic loop of glucagon-like peptide-1 receptor can function at the third cytoplasmic loop position of rhodopsin.

PubMed

Yamashita, Takahiro; Tose, Koji; Shichida, Yoshinori

2008-01-01

G protein-coupled receptors (GPCRs) are classified into several families based on their amino acid sequences. In family 1, GPCRs such as rhodopsin and adrenergic receptor, the structure-function relationship has been extensively investigated to demonstrate that exposure of the third cytoplasmic loop is essential for selective G protein activation. In contrast, much less is known about other families. Here we prepared chimeric mutants between Gt-coupled rhodopsin and Gi/Go- and Gs-coupled glucagon-like peptide-1 (GLP-1) receptor of family 2 and tried to identify the loop region that functions at the third cytoplasmic loop position of rhodopsin. We succeeded in expressing a mutant having the first cytoplasmic loop of GLP-1 receptor and found that this mutant activated Gi and Go efficiently but did not activate Gt. Moreover, the rhodopsin mutant having the first loop of Gs-coupled secretin receptor of family 2 decreased the Gi and Go activation efficiencies. Therefore, the first loop of GLP-1 receptor would share a similar role to the third loop of rhodopsin in G protein activation. This result strongly suggested that different families of GPCRs have maintained molecular architectures of their ancestral types to generate a common mechanism, namely exposure of the cytoplasmic loop, to activate peripheral G protein.

Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

PubMed

Bernardo, Ana R; Cosgaya, José M; Aranda, Ana; Jiménez-Lara, Ana M

2017-07-01

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

The effect of proximity on open-loop accommodation responses measured with pinholes.

PubMed

Morrison, K A; Seidel, D; Strang, N C; Gray, L S

2010-07-01

Open-loop accommodation levels were measured in 41 healthy, young subjects using a Shin-Nippon SRW-5000 autorefractor in the three viewing conditions: a small physical pinhole pupil (SP), an optically projected pinhole in Maxwellian view (MV) and in the dark (DF). The target viewed through the pinholes was a high-contrast letter presented at 0 D vergence in a +5 D Badal lens system. Overall, results showed that SP open-loop accommodation levels were significantly higher than MV and DF levels. Subjects could be divided into two distinct subgroups according to their response behaviour: responders to the proximal effect of the small physical pinhole (SP accommodation > MV accommodation) and non-responders to the proximal effect of the small physical pinhole (SP accommodation approximately MV accommodation). Correlation analysis demonstrated that open-loop accommodation for both pinhole conditions was correlated with DF for the responders, while for the non-responders SP and MV accommodation were correlated, but were not related to DF accommodation. This suggests that under open-loop conditions some individuals' accommodation levels are mainly affected by proximal and cognitive factors (responders) while others are guided primarily by the presence of the more distal target (non-responders). In conclusion, MV reduces the proximal effect of the physical pinhole and produces open-loop accommodation responses which are more consistent than SP and DF responses.

Sensory feedback in prosthetics: a standardized test bench for closed-loop control.

PubMed

Dosen, Strahinja; Markovic, Marko; Hartmann, Cornelia; Farina, Dario

2015-03-01

Closing the control loop by providing sensory feedback to the user of a prosthesis is an important challenge, with major impact on the future of prosthetics. Developing and comparing closed-loop systems is a difficult task, since there are many different methods and technologies that can be used to implement each component of the system. Here, we present a test bench developed in Matlab Simulink for configuring and testing the closed-loop human control system in standardized settings. The framework comprises a set of connected generic blocks with normalized inputs and outputs, which can be customized by selecting specific implementations from a library of predefined components. The framework is modular and extensible and it can be used to configure, compare and test different closed-loop system prototypes, thereby guiding the development towards an optimal system configuration. The use of the test bench was demonstrated by investigating two important aspects of closed-loop control: performance of different electrotactile feedback interfaces (spatial versus intensity coding) during a pendulum stabilization task and feedforward methods (joystick versus myocontrol) for force control. The first experiment demonstrated that in the case of trained subjects the intensity coding might be superior to spatial coding. In the second experiment, the control of force was rather poor even with a stable and precise control interface (joystick), demonstrating that inherent characteristics of the prosthesis can be an important limiting factor when considering the overall effectiveness of the closed-loop control. The presented test bench is an important instrument for investigating different aspects of human manual control with sensory feedback.

Loops of Jupiter

NASA Astrophysics Data System (ADS)

Opolski, Antoni

2014-12-01

Professor Antoni Opolski was actively interested in astronomy after his retirement in 1983. He especially liked to study the works of the famous astronomer Copernicus getting inspiration for his own work. Opolski started his work on planetary loops in 2011 continuing it to the end of 2012 . During this period calculations, drawings, tables, and basic descriptions of all the planets of the Solar System were created with the use of a piece of paper and a pencil only. In 2011 Antoni Opolski asked us to help him in editing the manuscript and preparing it for publication. We have been honored having the opportunity to work on articles on planetary loops with Antoni Opolski in his house for several months. In the middle of 2012 the detailed material on Jupiter was ready. However, professor Opolski improved the article by smoothing the text and preparing new, better drawings. Finally the article ''Loops of Jupiter'', written by the 99- year old astronomer, was published in the year of his 100th birthday.

Digital phase-lock loop

NASA Technical Reports Server (NTRS)

Thomas, Jr., Jess B. (Inventor)

1991-01-01

An improved digital phase lock loop incorporates several distinctive features that attain better performance at high loop gain and better phase accuracy. These features include: phase feedback to a number-controlled oscillator in addition to phase rate; analytical tracking of phase (both integer and fractional cycles); an amplitude-insensitive phase extractor; a more accurate method for extracting measured phase; a method for changing loop gain during a track without loss of lock; and a method for avoiding loss of sampled data during computation delay, while maintaining excellent tracking performance. The advantages of using phase and phase-rate feedback are demonstrated by comparing performance with that of rate-only feedback. Extraction of phase by the method of modeling provides accurate phase measurements even when the number-controlled oscillator phase is discontinuously updated.

Optimum design of hybrid phase locked loops

NASA Technical Reports Server (NTRS)

Lee, P.; Yan, T.

1981-01-01

The design procedure of phase locked loops is described in which the analog loop filter is replaced by a digital computer. Specific design curves are given for the step and ramp input changes in phase. It is shown that the designed digital filter depends explicitly on the product of the sampling time and the noise bandwidth of the phase locked loop. This technique of optimization can be applied to the design of digital analog loops for other applications.

Loop-quantum-gravity vertex amplitude.

PubMed

Engle, Jonathan; Pereira, Roberto; Rovelli, Carlo

2007-10-19

Spin foam models are hoped to provide the dynamics of loop-quantum gravity. However, the most popular of these, the Barrett-Crane model, does not have the good boundary state space and there are indications that it fails to yield good low-energy n-point functions. We present an alternative dynamics that can be derived as a quantization of a Regge discretization of Euclidean general relativity, where second class constraints are imposed weakly. Its state space matches the SO(3) loop gravity one and it yields an SO(4)-covariant vertex amplitude for Euclidean loop gravity.

THE CORONAL LOOP INVENTORY PROJECT: EXPANDED ANALYSIS AND RESULTS

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

Schmelz, J. T.; Christian, G. M.; Chastain, R. A., E-mail: jschmelz@usra.edu

We have expanded upon earlier work that investigates the relative importance of coronal loops with isothermal versus multithermal cross-field temperature distributions. These results are important for determining if loops have substructure in the form of unresolved magnetic strands. We have increased the number of loops targeted for temperature analysis from 19 to 207 with the addition of 188 new loops from multiple regions. We selected all loop segments visible in the 171 Å images of the Atmospheric Imaging Assembly (AIA) that had a clean background. Eighty-six of the new loops were rejected because they could not be reliably separated frommore » the background in other AIA filters. Sixty-one loops required multithermal models to reproduce the observations. Twenty-eight loops were effectively isothermal, that is, the plasma emission to which AIA is sensitive could not be distinguished from isothermal emission, within uncertainties. Ten loops were isothermal. Also, part of our inventory was one small flaring loop, one very cool loop whose temperature distribution could not be constrained by the AIA data, and one loop with inconclusive results. Our survey can confirm an unexpected result from the pilot study: we found no isothermal loop segments where we could properly use the 171-to-193 ratio method, which would be similar to the analysis done for many loops observed with TRACE and EIT. We recommend caution to observers who assume the loop plasma is isothermal, and hope that these results will influence the direction of coronal heating models and the effort modelers spend on various heating scenarios.« less

Study of the post-flare loops on 29 July 1973. I - Dynamics of the X-ray loops

NASA Technical Reports Server (NTRS)

Nolte, J. T.; Gerassimenko, M.; Krieger, A. S.; Petrasso, R. D.; Svestka, Z.

1979-01-01

We derive an empirical model of the X-ray emitting post-flare loops observed during the decay phase of the 29 July 1973 flare. We find that the loops are elliptical, with the brightest emitting region at the tops. We determine the height, velocity of growth, and ratio of height to width of the loops at times from 3 to 12 hr after the flare onset.

Electron Densities in Solar Flare Loops, Chromospheric Evaporation Upflows, and Acceleration Sites

NASA Technical Reports Server (NTRS)

Aschwanden, Markus J.; Benz, Arnold O.

1996-01-01

We compare electron densities measured at three different locations in solar flares: (1) in Soft X-Ray (SXR) loops, determined from SXR emission measures and loop diameters from Yohkoh Soft X-Ray Telescope maps (n(sub e, sup SXR) = (0.2-2.5) x 10(exp 11)/ cu cm); (2) in chromospheric evaporation upflows, inferred from plasma frequency cutoffs of decimetric radio bursts detected with the 0.1-3 GHz spectrometer Phoenix of ETH Zuerich (n(sub e, sup upflow) = (0.3-11) x 10(exp 10)/cu cm; and (3) in acceleration sites, inferred from the plasma frequency at the separatrix between upward-accelerated (type III bursts) and downward-accelerated (reverse-drift bursts) electron beams [n(sub e, sup acc) = (0.6-10) x 10(exp 9)/cu cm]. The comparison of these density measurements, obtained from 44 flare episodes (during 14 different flares), demonstrates the compatibility of flare plasma density diagnostics with SXR and radio methods. The density in the upflowing plasma is found to be somewhat lower than in the filled loops, having ratios in a range n(sub e, sup upflow)/n(sub e, sup SXR) = 0.02-1.3, and a factor of 3.6 higher behind the upflow front. The acceleration sites are found to have a much lower density than the SXR-bright flare loops, i.e., n(sub e, sup acc)/n(sub e, sup SXR) = 0.005- 0.13, and thus must be physically displaced from the SXR-bright flare loops. The scaling law between electron time-of-flight distances l' and loop half-lengths s, l'/s = 1.4 +/- 0.3, recently established by Aschwanden et al. suggests that the centroid of the acceleration region is located above the SXR-bright flare loop, as envisioned in cusp geometries (e.g., in magnetic reconnection models).

Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway.

PubMed

Momeny, Majid; Ghasemi, Reza; Valenti, Giovanni; Miranda, Mariska; Zekri, Ali; Zarrinrad, Ghazaleh; Javadikooshesh, Sepehr; Yaghmaie, Marjan; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

2016-03-01

Epithelial ovarian cancer (EOC) is the most fatal gynecological malignancy due to its high proliferative and invasive capacities. A heregulin (HRG)/HER3 autocrine loop increases proliferative and metastatic properties of EOC cells, suggesting that modulators of this signaling pathway may prove effective to trammel growth and motility of these cells. This study aimed to evaluate the effects of multi-tyrosine kinase inhibitor silibinin on proliferative and invasive characteristics of EOC cell lines OVCAR8 and SKOV3 through suppression of the HRG/HER3 pathway. To achieve this, the effects of silibinin on proliferation, DNA synthesis, clonogenicity, cell cycle progression, cathepsin B enzymatic activity, and migration and invasion were explored in vitro. Silibinin suppressed proliferation, DNA synthesis, and clonogenic abilities of OVCAR8 and SKOV3 cells through inhibition of the autocrine HRG/HER3 circuit. Silibinin-mediated attenuation of the HER3 signaling disabled the HER3/AKT/survivin axis and thereby, induced G1/S cell cycle arrest. Furthermore, silibinin reduced invasive potentials of the EOC cells through quelling the HRG/HER3 pathway and suppression of cathepsin B activity. Altogether, these results suggest that silibinin is a potential anti-cancer drug to inhibit proliferative and invasive characteristics of the EOC cells that exhibit an autocrine HRG/HER3 pathway.

A simple second-order digital phase-locked loop.

NASA Technical Reports Server (NTRS)

Tegnelia, C. R.

1972-01-01

A simple second-order digital phase-locked loop has been designed for the Viking Orbiter 1975 command system. Excluding analog-to-digital conversion, implementation of the loop requires only an adder/subtractor, two registers, and a correctable counter with control logic. The loop considers only the polarity of phase error and corrects system clocks according to a filtered sequence of this polarity. The loop is insensitive to input gain variation, and therefore offers the advantage of stable performance over long life. Predictable performance is guaranteed by extreme reliability of acquisition, yet in the steady state the loop produces only a slight degradation with respect to analog loop performance.

Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption.

PubMed

Lockwood, C J; Paidas, M; Murk, W K; Kayisli, U A; Gopinath, A; Huang, S J; Krikun, G; Schatz, F

2009-11-01

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression.

Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption

PubMed Central

Lockwood, C.J.; Paidas, M.; Murk, W.K.; Kayisli, U.A.; Gopinath, A.; Krikun, G.; Huang, S.J.; Schatz, F.

2009-01-01

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Our recent observations that: 1) among the cell types at the maternal fetal interface at term TF expression is highest in decidual cells indicates that this TF meets the hemostatic demands of labor and delivery; 2) TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggest that maintenance of elevated circulating progesterone at term provides hemostatic protection, whereas abruption-generated thrombin can act in autocrine/paracrine fashion on DCs to promote hemostasis via enhanced TF expression. PMID:19720393

Study of the post-flare loops on 29 July 1973. II - Physical parameters in the X-ray loops

NASA Technical Reports Server (NTRS)

Petrasso, R. D.; Nolte, J. T.; Gerassimenko, M.; Krieger, A. S.; Krogstad, R.; Seguin, F. H.; Svestka, Z.

1979-01-01

We use the filter ratio method of analysis to determine spatially resolved values of plasma parameters in the X-ray emitting post-flare loop system which developed on 29 and 30 July 1973. We find that the loops were hotter and had higher plasma pressure at their tops than near their footpoints. The loop tops were at nearly the same temperature at different places 3 hr after the flare maximum and were also at nearly this same temperature 3 and 8 hr later. Variations in brightness transverse to the loops were due to variations in emission measure. We show by consideration of radiative losses alone that energy must have been added to the hottest part of the flare, at the tops of the loops, late in the decay phase of the flare.

A second-order all-digital phase-locked loop

NASA Technical Reports Server (NTRS)

Holmes, J. K.; Tegnelia, C. R.

1974-01-01

A simple second-order digital phase-locked loop has been designed to synchronize itself to a square-wave subcarrier. Analysis and experimental performance are given for both acquisition behavior and steady-state phase error performance. In addition, the damping factor and the noise bandwidth are derived analytically. Although all the data are given for the square-wave subcarrier case, the results are applicable to arbitrary subcarriers that are odd symmetric about their transition region.

Autocrine effect of Zn²⁺ on the glucose-stimulated insulin secretion.

PubMed

Slepchenko, Kira G; Daniels, Nigel A; Guo, Aili; Li, Yang V

2015-09-01

It is well known that zinc (Zn(2+)) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (β)-cells, and that changes in Zn(2+) levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn(2+) and insulin with similar kinetics. However, we do not know whether Zn(2+) regulates insulin availability and secretion. Here we investigated the effect of Zn(2+) on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn(2+) alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn(2+) from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn(2+) on GSIS. The inhibitory action of Zn(2+) was mostly mediated through the activities of KATP/Ca(2+) channels. Furthermore, during brief paired-pulse glucose-stimulated Zn(2+) secretion (GSZS), Zn(2+) secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn(2+) after the first pulse. Such an inhibition on Zn(2+) secretion following the second pulse was completely reversed by Zn(2+) chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn(2+) release inhibits subsequent Zn(2+) secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn(2+) secreted from β-cells, and the co-secreted Zn(2+) may act as an autocrine inhibitory modulator.

Mapping the Structural and Dynamical Features of Multiple p53 DNA Binding Domains: Insights into Loop 1 Intrinsic Dynamics

PubMed Central

Lukman, Suryani; Lane, David P.; Verma, Chandra S.

2013-01-01

The transcription factor p53 regulates cellular integrity in response to stress. p53 is mutated in more than half of cancerous cells, with a majority of the mutations localized to the DNA binding domain (DBD). In order to map the structural and dynamical features of the DBD, we carried out multiple copy molecular dynamics simulations (totaling 0.8 μs). Simulations show the loop 1 to be the most dynamic element among the DNA-contacting loops (loops 1-3). Loop 1 occupies two major conformational states: extended and recessed; the former but not the latter displays correlations in atomic fluctuations with those of loop 2 (~24 Å apart). Since loop 1 binds to the major groove whereas loop 2 binds to the minor groove of DNA, our results begin to provide some insight into the possible mechanism underpinning the cooperative nature of DBD binding to DNA. We propose (1) a novel mechanism underlying the dynamics of loop 1 and the possible tread-milling of p53 on DNA and (2) possible mutations on loop 1 residues to restore the transcriptional activity of an oncogenic mutation at a distant site. PMID:24324553

Binary phase locked loops for Omega receivers

NASA Technical Reports Server (NTRS)

Chamberlin, K.

1974-01-01

An all-digital phase lock loop (PLL) is considered because of a number of problems inherent in an employment of analog PLL. The digital PLL design presented solves these problems. A single loop measures all eight Omega time slots. Memory-aiding leads to the name of this design, the memory-aided phase lock loop (MAPLL). Basic operating principles are discussed and the superiority of MAPLL over the conventional digital phase lock loop with regard to the operational efficiency for Omega applications is demonstrated.

Wilson-loop instantons

NASA Technical Reports Server (NTRS)

Lee, Kimyeong; Holman, Richard; Kolb, Edward W.

1987-01-01

Wilson-loop symmetry breaking is considered on a space-time of the form M4 x K, where M4 is a four-dimensional space-time and K is an internal space with nontrivial and finite fundamental group. It is shown in a simple model that the different vacua obtained by breaking a non-Abelian gauge group by Wilson loops are separated in the space of gauge potentials by a finite energy barrier. An interpolating gauge configuration is then constructed between these vacua and shown to have minimum energy. Finally some implications of this construction are discussed.

Loop quantum cosmology and singularities.

PubMed

Struyve, Ward

2017-08-15

Loop quantum gravity is believed to eliminate singularities such as the big bang and big crunch singularity. This belief is based on studies of so-called loop quantum cosmology which concerns symmetry-reduced models of quantum gravity. In this paper, the problem of singularities is analysed in the context of the Bohmian formulation of loop quantum cosmology. In this formulation there is an actual metric in addition to the wave function, which evolves stochastically (rather than deterministically as the case of the particle evolution in non-relativistic Bohmian mechanics). Thus a singularity occurs whenever this actual metric is singular. It is shown that in the loop quantum cosmology for a homogeneous and isotropic Friedmann-Lemaître-Robertson-Walker space-time with arbitrary constant spatial curvature and cosmological constant, coupled to a massless homogeneous scalar field, a big bang or big crunch singularity is never obtained. This should be contrasted with the fact that in the Bohmian formulation of the Wheeler-DeWitt theory singularities may exist.

Optical injection phase-lock loops

NASA Astrophysics Data System (ADS)

Bordonalli, Aldario Chrestani

Locking techniques have been widely applied for frequency synchronisation of semiconductor lasers used in coherent communication and microwave signal generation systems. Two main locking techniques, the optical phase-lock loop (OPLL) and optical injection locking (OIL) are analysed in this thesis. The principal limitations on OPLL performance result from the loop propagation delay, which makes difficult the implementation of high gain and wide bandwidth loops, leading to poor phase noise suppression performance and requiring the linewidths of the semiconductor laser sources to be less than a few megahertz for practical values of loop delay. The OIL phase noise suppression is controlled by the injected power. The principal limitations of the OIL implementation are the finite phase error under locked conditions and the narrow stable locking range the system provides at injected power levels required to reduce the phase noise output of semiconductor lasers significantly. This thesis demonstrates theoretically and experimentally that it is possible to overcome the limitations of OPLL and OIL systems by combining them, to form an optical injection phase-lock loop (OIPLL). The modelling of an OIPLL system is presented and compared with the equivalent OPLL and OIL results. Optical and electrical design of an homodyne OIPLL is detailed. Experimental results are given which verify the theoretical prediction that the OIPLL would keep the phase noise suppression as high as that of the OIL system over a much wider stable locking range, even with wide linewidth lasers and long loop delays. The experimental results for lasers with summed linewidth of 36 MHz and a loop delay of 15 ns showed measured phase error variances as low as 0.006 rad2 (500 MHz bandwidth) for locking bandwidths greater than 26 GHz, compared with the equivalent OPLL phase error variance of around 1 rad2 (500 MHz bandwidth) and the equivalent OIL locking bandwidth of less than 1.2 GHz.

Statistical Characteristic of Global Tropical Cyclone Looping Motion

NASA Astrophysics Data System (ADS)

Shen, W.; Song, J.; Wang, Y.

2016-12-01

Statistical characteristic of looping motion of tropical cyclones (TCs) in the Western North Pacific (WPAC), North Atlantic (NATL), Eastern North Pacific (EPAC), Northern Indian Ocean (NIO), Southern Indian Ocean (SIO) and South Pacific (SPAC) basins are investigated by using IBTrACS archive maintained by NOAA. From global perspective, about ten percent TCs experience a looping motion in the above six basins. The southern hemisphere (SH) including SIO and SPAC basins have higher looping percentage than the northern hemisphere (NH), while the EPAC basin has the least looping percentage. The interannual variation of the number of looping TCs are significantly correlated with that of total TCs in the NATL, SIO and SPAC basins, while there are no correlations between the EPAC and NIO basins. The numbers of looping TCs have a higher percentage in the early and late cyclone season in the NH rather than the peak period of cyclone season, while the SIO and SPAC basins have the higher looping percentage in the early and late cyclone season, respectively. The looping motion of TCs mainly concentrates on the scale of tropical depression to category 2 and has its peak value on the scale of tropical storm. The looping motion appears more frequently and has a higher percentage at the pre-mature stage than the post-mature stage of TCs in most basins except EPAC. Comparing the intensity and intensity variation caused by the looping motion, the weaker TCs tend to intensify after looping, while the more intense ones weaken.

Space Station evolution study oxygen loop closure

NASA Technical Reports Server (NTRS)

Wood, M. G.; Delong, D.

1993-01-01

In the current Space Station Freedom (SSF) Permanently Manned Configuration (PMC), physical scars for closing the oxygen loop by the addition of oxygen generation and carbon dioxide reduction hardware are not included. During station restructuring, the capability for oxygen loop closure was deferred to the B-modules. As such, the ability to close the oxygen loop in the U.S. Laboratory module (LAB A) and the Habitation A module (HAB A) is contingent on the presence of the B modules. To base oxygen loop closure of SSF on the funding of the B-modules may not be desirable. Therefore, this study was requested to evaluate the necessary hooks and scars in the A-modules to facilitate closure of the oxygen loop at or subsequent to PMC. The study defines the scars for oxygen loop closure with impacts to cost, weight and volume and assesses the effects of byproduct venting. In addition, the recommended scenarios for closure with regard to topology and packaging are presented.

Closed-Loop Neuromorphic Benchmarks

PubMed Central

Stewart, Terrence C.; DeWolf, Travis; Kleinhans, Ashley; Eliasmith, Chris

2015-01-01

Evaluating the effectiveness and performance of neuromorphic hardware is difficult. It is even more difficult when the task of interest is a closed-loop task; that is, a task where the output from the neuromorphic hardware affects some environment, which then in turn affects the hardware's future input. However, closed-loop situations are one of the primary potential uses of neuromorphic hardware. To address this, we present a methodology for generating closed-loop benchmarks that makes use of a hybrid of real physical embodiment and a type of “minimal” simulation. Minimal simulation has been shown to lead to robust real-world performance, while still maintaining the practical advantages of simulation, such as making it easy for the same benchmark to be used by many researchers. This method is flexible enough to allow researchers to explicitly modify the benchmarks to identify specific task domains where particular hardware excels. To demonstrate the method, we present a set of novel benchmarks that focus on motor control for an arbitrary system with unknown external forces. Using these benchmarks, we show that an error-driven learning rule can consistently improve motor control performance across a randomly generated family of closed-loop simulations, even when there are up to 15 interacting joints to be controlled. PMID:26696820

Analysis of laser energy characteristics of laser guided weapons based on the hardware-in-the-loop simulation system

NASA Astrophysics Data System (ADS)

Zhu, Yawen; Cui, Xiaohong; Wang, Qianqian; Tong, Qiujie; Cui, Xutai; Li, Chenyu; Zhang, Le; Peng, Zhong

2016-11-01

The hardware-in-the-loop simulation system, which provides a precise, controllable and repeatable test conditions, is an important part of the development of the semi-active laser (SAL) guided weapons. In this paper, laser energy chain characteristics were studied, which provides a theoretical foundation for the SAL guidance technology and the hardware-in-the-loop simulation system. Firstly, a simplified equation was proposed to adjust the radar equation according to the principles of the hardware-in-the-loop simulation system. Secondly, a theoretical model and calculation method were given about the energy chain characteristics based on the hardware-in-the-loop simulation system. We then studied the reflection characteristics of target and the distance between the missile and target with major factors such as the weather factors. Finally, the accuracy of modeling was verified by experiment as the values measured experimentally generally follow the theoretical results from the model. And experimental results revealed that ratio of attenuation of the laser energy exhibited a non-linear change vs. pulse number, which were in accord with the actual condition.

Acute cholangitis due to afferent loop syndrome after a Whipple procedure: a case report.

PubMed

Spiliotis, John; Karnabatidis, Demetrios; Vaxevanidou, Archodoula; Datsis, Anastasios C; Rogdakis, Athanasios; Zacharis, Georgios; Siamblis, Demetrios

2009-08-25

Patients with resection of stomach and especially with Billroth II reconstruction (gastro jejunal anastomosis), are more likely to develop afferent loop syndrome which is a rare complication. When the afferent part is obstructed, biliary and pancreatic secretions accumulate and cause the distention of this part. In the case of a complete obstruction (rare), there is a high risk developing necrosis and perforation. This complication has been reported once in the literature. A 54-year-old Greek male had undergone a pancreato-duodenectomy (Whipple procedure) one year earlier due to a pancreatic adenocarcinoma. Approximately 10 months after the initial operation, the patient started having episodes of cholangitis (fever, jaundice) and abdominal pain. This condition progressively worsened and the suspicion of local recurrence or stenosis of the biliary-jejunal anastomosis was discussed. A few days before his admission the patient developed signs of septic cholangitis. Our case demonstrates a rare complication with serious clinical manifestation of the afferent loop syndrome. This advanced form of afferent loop syndrome led to the development of huge enterobiliary reflux, which had a serious clinical manifestation as cholangitis and systemic sepsis, due to bacterial overgrowth, which usually present in the afferent loop. The diagnosis is difficult and the interventional radiology gives all the details to support the therapeutic decision making. A variety of factors can contribute to its development including adhesions, kinking and angulation of the loop, stenosis of gastro-jejunal anastomosis and internal herniation. In order to decompress the afferent loop dilatation due to adhesions, a lateral-lateral jejunal anastomosis was performed between the afferent loop and a small bowel loop.

Two-phase Heating in Flaring Loops

NASA Astrophysics Data System (ADS)

Zhu, Chunming; Qiu, Jiong; Longcope, Dana W.

2018-03-01

We analyze and model a C5.7 two-ribbon solar flare observed by the Solar Dynamics Observatory, Hinode, and GOES on 2011 December 26. The flare is made of many loops formed and heated successively over one and half hours, and their footpoints are brightened in the UV 1600 Å before enhanced soft X-ray and EUV missions are observed in flare loops. Assuming that anchored at each brightened UV pixel is a half flaring loop, we identify more than 6700 half flaring loops, and infer the heating rate of each loop from the UV light curve at the footpoint. In each half loop, the heating rate consists of two phases: intense impulsive heating followed by a low-rate heating that is persistent for more than 20 minutes. Using these heating rates, we simulate the evolution of their coronal temperatures and densities with the model of the “enthalpy-based thermal evolution of loops.” In the model, suppression of thermal conduction is also considered. This model successfully reproduces total soft X-ray and EUV light curves observed in 15 passbands by four instruments GOES, AIA, XRT, and EVE. In this flare, a total energy of 4.9 × 1030 erg is required to heat the corona, around 40% of this energy is in the slow-heating phase. About two-fifths of the total energy used to heat the corona is radiated by the coronal plasmas, and the other three fifth transported to the lower atmosphere by thermal conduction.

Control-structure interaction in precision pointing servo loops

NASA Technical Reports Server (NTRS)

Spanos, John T.

1989-01-01

The control-structure interaction problem is addressed via stability analysis of a generic linear servo loop model. With the plant described by the rigid body mode and a single elastic mode, structural flexibility is categorized into one of three types: (1) appendage, (2) in-the-loop minimum phase, and (3) in-the-loop nonminimum phase. Closing the loop with proportional-derivative (PD) control action and introducing sensor roll-off dynamics in the feedback path, stability conditions are obtained. Trade studies are conducted with modal frequency, modal participation, modal damping, loop bandwidth, and sensor bandwidth treated as free parameters. Results indicate that appendage modes are most likely to produce instability if they are near the sensor rolloff, whereas in-the-loop modes are most dangerous near the loop bandwidth. The main goal of this paper is to provide a fundamental understanding of the control-structure interaction problem so that it may benefit the design of complex spacecraft and pointing system servo loops. In this framework, the JPL Pathfinder gimbal pointer is considered as an example.

Comparative assessment of the efficacy of closed helical loop and T-loop for space closure in lingual orthodontics-a finite element study.

PubMed

Chacko, Ajay; Tikku, Tripti; Khanna, Rohit; Maurya, Rana Pratap; Srivastava, Kamna

2018-05-28

Retraction in lingual orthodontics has biomechanical differences when compared to labial orthodontics, which is not yet established. Thus, we have intended to compare the biomechanical characteristics of closed helical loop and T-loop on 1 mm activation with 30° of compensatory curvatures during retraction in lingual orthodontics. STb lingual brackets were indirectly bonded to maxillary typhodont model that was scanned to obtain FEM model. Closed helical loop (2 × 7 mm) and T-loop (6 × 2 × 7 mm) of 0.016″ × 0.016″ TMA wire were modeled without preactivation bends. Preactivation bends at 30° were given in the software. Boundary conditions were set. The force (F) and moment (M) of both the loops were determined on 1 mm activation, using ANSYS software. M/F ratio was also calculated for both the loops. T-loop exerted less force, thus increased M/F ratio as compared to closed helical loop on 1 mm activation. When torque has to be preserved in the anterior segment during retraction in lingual orthodontics, T-loop can be preferred over closed helical loop.

Functional sub-division of the Drosophila genome via chromatin looping: the emerging importance of CP190.

PubMed

Ahanger, Sajad H; Shouche, Yogesh S; Mishra, Rakesh K

2013-01-01

Insulators help in organizing the eukaryotic genomes into physically and functionally autonomous regions through the formation of chromatin loops. Recent findings in Drosophila and vertebrates suggest that insulators anchor multiple loci through long-distance interactions which may be mechanistically linked to insulator function. Important to such processes in Drosophila is CP190, a common co-factor of insulator complexes. CP190 is also known to associate with the nuclear matrix, components of the RNAi machinery, active promoters and borders of the repressive chromatin domains. Although CP190 plays a pivotal role in insulator function in Drosophila, vertebrates lack a probable functional equivalent of CP190 and employ CTCF as the major factor to carry out insulator function/chromatin looping. In this review, we discuss the emerging role of CP190 in tethering genome, specifically in the perspective of insulator function in Drosophila. Future studies aiming genome-wide role of CP190 in chromatin looping is likely to give important insights into the mechanism of genome organization.

Acquisition and Tracking Behavior of Phase-Locked Loops

NASA Technical Reports Server (NTRS)

Viterbi, A. J.

1958-01-01

Phase-locked or APC loops have found increasing applications in recent years as tracking filters, synchronizing devices, and narrowband FM discriminators. Considerable work has been performed to determine the noise-squelching properties of the loop when it is operating in or near phase lock and is functioning as a linear coherent detector. However, insufficient consideration has been devoted to the non-linear behavior of the loop when it is out of lock and in the process of pulling in. Experimental evidence has indicated that there is a strong tendency for phase-locked loops to achieve lock under most circumstances. However, the analysis which has appeared in the literature iis limited to the acquisition of a constant frequency reference signal with only one phase-locked loop filter configuration. This work represents an investigation of frequency acquisition properties of phase-locked loops for a variety of reference-signal behavior and loop configurations

A totally diverting loop colostomy.

PubMed Central

Merrett, N. D.; Gartell, P. C.

1993-01-01

A technique is described where the distal limb of a loop colostomy is tied with nylon or polydioxanone. This ensures total faecal diversion and dispenses with the supporting rod, enabling early application of stoma appliances. The technique does not interfere with the traditional transverse closure of a loop colostomy. PMID:8379632

[Enhancement of wound healing by taspine and its effect on fibroblast].

PubMed

Dong, Yalin; He, Langchong; Chen, Fang

2005-07-01

To study the effect of taspine on enhancement of skin wound healing and its effect on fibroblast proliferation and autocrine. The plerosis effect of taspine on experimental skin wound was observed in vivo. Different concentrations of taspine were added in vitro and MTT technique was applied to observe its effect on fibroblast proliferation, the levels of transforming growth factor-beta1 (TGF-13P) and epidermal growth factor (EGF) were determined by ELISA. In vivo, exo-applied taspine 300 microg and 150 microg accelerated the recovery of skin wound. In vitro, 0.50-0.4 microg/ml taspine could increase autocrine of TGF-beta1and EGF by fibroblast, but it showed no effect on L929 fibroblast proliferation. Taspine enhances wound healing by increasing the autocrine of TGF-beta1 and EGF by fibroblast.

Wilson loops in supersymmetric gauge theories

NASA Astrophysics Data System (ADS)

Pestun, Vasily

This thesis is devoted to several exact computations in four-dimensional supersymmetric gauge field theories. In the first part of the thesis we prove conjecture due to Erickson-Semenoff-Zarembo and Drukker-Gross which relates supersymmetric circular Wilson loop operators in the N = 4 supersymmetric Yang-Mills theory with a Gaussian matrix model. We also compute the partition function and give a new matrix model formula for the expectation value of a supersymmetric circular Wilson loop operator for the pure N = 2 and the N* = 2 supersymmetric Yang-Mills theory on a four-sphere. Circular supersymmetric Wilson loops in four-dimensional N = 2 superconformal gauge theory are treated similarly. In the second part we consider supersymmetric Wilson loops of arbitrary shape restricted to a two-dimensional sphere in the four-dimensional N = 4 supersymmetric Yang-Mills theory. We show that expectation value for these Wilson loops can be exactly computed using a two-dimensional theory closely related to the topological two-dimensional Higgs-Yang-Mills theory, or two-dimensional Yang-Mills theory for the complexified gauge group.

On-the-fly reduction of open loops

NASA Astrophysics Data System (ADS)

Buccioni, Federico; Pozzorini, Stefano; Zoller, Max

2018-01-01

Building on the open-loop algorithm we introduce a new method for the automated construction of one-loop amplitudes and their reduction to scalar integrals. The key idea is that the factorisation of one-loop integrands in a product of loop segments makes it possible to perform various operations on-the-fly while constructing the integrand. Reducing the integrand on-the-fly, after each segment multiplication, the construction of loop diagrams and their reduction are unified in a single numerical recursion. In this way we entirely avoid objects with high tensor rank, thereby reducing the complexity of the calculations in a drastic way. Thanks to the on-the-fly approach, which is applied also to helicity summation and for the merging of different diagrams, the speed of the original open-loop algorithm can be further augmented in a very significant way. Moreover, addressing spurious singularities of the employed reduction identities by means of simple expansions in rank-two Gram determinants, we achieve a remarkably high level of numerical stability. These features of the new algorithm, which will be made publicly available in a forthcoming release of the OpenLoops program, are particularly attractive for NLO multi-leg and NNLO real-virtual calculations.

Mitotic chromosome compaction via active loop extrusion

NASA Astrophysics Data System (ADS)

Goloborodko, Anton; Imakaev, Maxim; Marko, John; Mirny, Leonid; MIT-Northwestern Team

During cell division, two copies of each chromosome are segregated from each other and compacted more than hundred-fold into the canonical X-shaped structures. According to earlier microscopic observations and the recent Hi-C study, chromosomes are compacted into arrays of consecutive loops of ~100 kilobases. Mechanisms that lead to formation of such loop arrays are largely unknown. Here we propose that, during cell division, chromosomes can be compacted by enzymes that extrude loops on chromatin fibers. First, we use computer simulations and analytical modeling to show that a system of loop-extruding enzymes on a chromatin fiber self-organizes into an array of consecutive dynamic loops. Second, we model the process of loop extrusion in 3D and show that, coupled with the topo II strand-passing activity, it leads to robust compaction and segregation of sister chromatids. This mechanism of chromosomal condensation and segregation does not require additional proteins or specific DNA markup and is robust against variations in the number and properties of such loop extruding enzymes. Work at NU was supported by the NSF through Grants DMR-1206868 and MCB-1022117, and by the NIH through Grants GM105847 and CA193419. Work at MIT was supported by the NIH through Grants GM114190 R01HG003143.

Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status.

PubMed

Wang, Naitao; Dong, Bai-Jun; Quan, Yizhou; Chen, Qianqian; Chu, Mingliang; Xu, Jin; Xue, Wei; Huang, Yi-Ran; Yang, Ru; Gao, Wei-Qiang

2016-05-10

Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS) in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3) was upregulated in a large subset of benign prostatic hyperplasia (BPH) tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Loop Quantum Cosmology.

PubMed

Bojowald, Martin

2008-01-01

Quantum gravity is expected to be necessary in order to understand situations in which classical general relativity breaks down. In particular in cosmology one has to deal with initial singularities, i.e., the fact that the backward evolution of a classical spacetime inevitably comes to an end after a finite amount of proper time. This presents a breakdown of the classical picture and requires an extended theory for a meaningful description. Since small length scales and high curvatures are involved, quantum effects must play a role. Not only the singularity itself but also the surrounding spacetime is then modified. One particular theory is loop quantum cosmology, an application of loop quantum gravity to homogeneous systems, which removes classical singularities. Its implications can be studied at different levels. The main effects are introduced into effective classical equations, which allow one to avoid the interpretational problems of quantum theory. They give rise to new kinds of early-universe phenomenology with applications to inflation and cyclic models. To resolve classical singularities and to understand the structure of geometry around them, the quantum description is necessary. Classical evolution is then replaced by a difference equation for a wave function, which allows an extension of quantum spacetime beyond classical singularities. One main question is how these homogeneous scenarios are related to full loop quantum gravity, which can be dealt with at the level of distributional symmetric states. Finally, the new structure of spacetime arising in loop quantum gravity and its application to cosmology sheds light on more general issues, such as the nature of time. Supplementary material is available for this article at 10.12942/lrr-2008-4.

The performance of a sampled data delay lock loop implemented with a Kalman loop filter

NASA Astrophysics Data System (ADS)

Eilts, H. S.

1980-01-01

The purpose of this study is to evaluate the steady-state and transient (lock-up) performance of a tracking loop implemented with a Kalman filter. Steady-state performance criteria are errors due to measurement noise (jitter) and Doppler errors due to motion of the tracking loop. Trade-offs exist between the two criteria such that increasing performance with respect to either one will cause performance decrease with respect to the other. It is shown that by carefully selecting filter parameters reasonable performance can be obtained for both criteria simultaneously. It is also shown that lock-up performance for the loop is acceptable when these parameters are used.

The morbidity of a divided stoma compared to a loop colostomy in patients with anorectal malformation.

PubMed

Liechty, Shawn T; Barnhart, Douglas C; Huber, Jordan T; Zobell, Sarah; Rollins, Michael D

2016-01-01

Loop colostomies may contaminate the genitourinary (GU) tract in patients with anorectal malformations (ARM) owing to incomplete diversion of stool. Stoma complications are also thought to be higher with a loop versus divided colostomy. We sought to compare the morbidity, including urinary tract infections (UTI), in these two types of colostomies in children with ARM. A review was performed at a children's hospital (1989-2014). Children with ARM who had a colostomy performed were identified. Demographic data and outcome variables were collected. Analyses included Student's t-test, Fischer's exact and logistic regression as appropriate. 171 patients were identified (loop=78; divided=93). Thirty percent of patients with a divided colostomy and 24% with a loop experienced a stoma complication (p=0.5). A subgroup analysis of children with a rectourinary fistula (54 divided, 26 loop) was performed to assess for effect of colostomy type on UTI. After controlling for other UTI risk factors (major GU anomalies, vesicostomy, and prophylactic antibiotics), loop ostomies were not associated with risk of UTI (OR 0.83, 95% CI 0.27-2.63). No patient with a loop colostomy developed megarectum. Children with ARM who undergo a loop colostomy are not at a detectable increased risk of experiencing a UTI compared to a divided stoma. The rate of stoma complication is high regardless of the type of stoma created. Copyright © 2016 Elsevier Inc. All rights reserved.

Direct-contact closed-loop heat exchanger

DOEpatents

Berry, Gregory F.; Minkov, Vladimir; Petrick, Michael

1984-01-01

A high temperature heat exchanger with a closed loop and a heat transfer liquid within the loop, the closed loop having a first horizontal channel with inlet and outlet means for providing direct contact of a first fluid at a first temperature with the heat transfer liquid, a second horizontal channel with inlet and outlet means for providing direct contact of a second fluid at a second temperature with the heat transfer liquid, and means for circulating the heat transfer liquid.

Chromosomal Organization by an Interplay of Loop Extrusion and Compartment Interaction

NASA Astrophysics Data System (ADS)

Nuebler, Johannes; Fudenberg, Geoffrey; Imakaev, Maxim; Lu, Carolyn; Goloborodko, Anton; Abdennur, Nezar; Mirny, Leonid

The chromatin fiber in eukaryotic nuclei is far from being simply a confined but otherwise randomly arranged polymer. Rather, it shows a high degree of spatial organization on all length scales, from individual nucleosomes up to well-segregated chromosome territories. On intermediate scales, chromosome conformation capture techniques have revealed two ubiquitous modes of organization: an alternating structure of A/B compartments, where each type preferentially associates with other base pairs of its type, and, typically on a smaller scale, the formation of topologically associating domains (TADs) with increased association within each domain but not across boundaries. The mechanisms behind this organization are only beginning to emerge. We review how the model of active loop extrusion can explain in a unified way such diverse phenomena as TAD formation and mitotic compaction and segregation, and we address in particular to what extent the interplay of active loop extrusion and compartment structure is compatible with recent experiments that interfere with the loading of the proposed loop extrusion factor cohesin. 4D Nucleome.

Autocrine prostaglandin E2 signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway

PubMed Central

Lee, Jaetae; Lee, Young Sup

2015-01-01

The COX-2/PGE2 pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, PGE2, in cancer survival remain unknown. Herein, we investigated PGE2-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with PGE2 activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. PGE2 not only induced COX-2 expression, but also prevented casapse-3, PARP, and lamin B cleavage. Silencing and inhibition of COX-2 with siRNA transfection or treatment with indomethacin led to a pronounced reduction of the extracellular levels of PGE2, and restored the menadione-induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the PGE2-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that PGE2 signaling acts in an autocrine manner, and specific inhibition of PGE2 will provide a novel approach for the treatment of leukemia. [BMB Reports 2015; 48(2): 109-114] PMID:24965577

Loop equations and bootstrap methods in the lattice

DOE PAGES

Anderson, Peter D.; Kruczenski, Martin

2017-06-17

Pure gauge theories can be formulated in terms of Wilson Loops by means of the loop equation. In the large-N limit this equation closes in the expectation value of single loops. In particular, using the lattice as a regulator, it becomes a well defined equation for a discrete set of loops. In this paper we study different numerical approaches to solving this equation.

Mathematical Modeling of Loop Heat Pipes

NASA Technical Reports Server (NTRS)

Kaya, Tarik; Ku, Jentung; Hoang, Triem T.; Cheung, Mark L.

1998-01-01

The primary focus of this study is to model steady-state performance of a Loop Heat Pipe (LHP). The mathematical model is based on the steady-state energy balance equations at each component of the LHP. The heat exchange between each LHP component and the surrounding is taken into account. Both convection and radiation environments are modeled. The loop operating temperature is calculated as a function of the applied power at a given loop condition. Experimental validation of the model is attempted by using two different LHP designs. The mathematical model is tested at different sink temperatures and at different elevations of the loop. Tbc comparison of the calculations and experimental results showed very good agreement (within 3%). This method proved to be a useful tool in studying steady-state LHP performance characteristics.

Actin Hydrophobic Loop (262-274) and Filament Nucleation and Elongation

PubMed Central

Shvetsov, Alexander; Galkin, Vitold E.; Orlova, Albina; Phillips, Martin; Bergeron, Sarah E.; Rubenstein, Peter A.; Egelman, Edward H.; Reisler, Emil

2014-01-01

Summary The importance of actin hydrophobic loop 262-274 dynamics to actin polymerization and filament stability has been shown recently using a yeast actin mutant, L180C/L269C/C374A, in which the hydrophobic loop could be locked in a “parked” conformation by a disulfide bond between C180 and C269. Such a cross-linked G-actin does not form filaments, suggesting nucleation and/or elongation inhibition. To determine the role of loop dynamics in filament nucleation and/or elongation, we studied the polymerization of the cross-linked actin in the presence of cofilin - to assist with actin nucleation - and with phalloidin, to stabilize the elongating filament segments. We demonstrate here that together, but not alone, phalloidin and cofilin co-rescue the polymerization of cross-linked actin. The polymerization was also rescued by filament seeds added together with phalloidin but not with cofilin. Thus, loop immobilization via cross-linking inhibits both filament nucleation and elongation. Nevertheless, the conformational changes needed to catalyze ATP hydrolysis by actin occur in the cross-linked actin. When actin filaments are fully decorated by cofilin the helical twist of F-actin changes by ~ 5° per subunit. Electron microscopic analysis of filaments rescued by cofilin and phalloidin revealed a dense contact between opposite strands in F-actin, and a change of twist by ~ 1° per subunit, indicating either partial or disordered attachment of cofilin to F-actin and/or a competition between cofilin and phalloidin to alter F-actin symmetry. Our findings show an importance of the hydrophobic loop conformational dynamics to both actin nucleation and elongation and reveal that the inhibition of these two steps in the cross-linked actin can be relieved by appropriate factors. PMID:18037437

DNA Topoisomerase 1 Prevents R-loop Accumulation to Modulate Auxin-Regulated Root Development in Rice.

PubMed

Shafiq, Sarfraz; Chen, Chunli; Yang, Jing; Cheng, Lingling; Ma, Fei; Widemann, Emilie; Sun, Qianwen

2017-06-05

R-loop structures (RNA:DNA hybrids) have important functions in many biological processes, including transcriptional regulation and genome instability among diverse organisms. DNA topoisomerase 1 (TOP1), an essential manipulator of DNA topology during RNA transcription and DNA replication processes, can prevent R-loop accumulation by removing the positive and negative DNA supercoiling that is made by RNA polymerases during transcription. TOP1 is required for plant development, but little is known about its function in preventing co-transcriptional R-loop accumulation in various biological processes in plants. Here we show that knockdown of OsTOP1 strongly affects rice development, causing defects in root architecture and gravitropism, which are the consequences of misregulation of auxin signaling and transporter genes. We found that R-loops are naturally formed at rice auxin-related gene loci, and overaccumulate when OsTOP1 is knocked down or OsTOP1 protein activity is inhibited. OsTOP1 therefore sets the accurate expression levels of auxin-related genes by preventing the overaccumulation of inherent R-loops. Our data reveal R-loops as important factors in polar auxin transport and plant root development, and highlight that OsTOP1 functions as a key to link transcriptional R-loops with plant hormone signaling, provide new insights into transcriptional regulation of hormone signaling in plants. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

A predictive model of asymmetric morphogenesis from 3D reconstructions of mouse heart looping dynamics

PubMed Central

Le Garrec, Jean-François; Ivanovitch, Kenzo D; Raphaël, Etienne; Bangham, J Andrew; Torres, Miguel; Coen, Enrico; Mohun, Timothy J

2017-01-01

How left-right patterning drives asymmetric morphogenesis is unclear. Here, we have quantified shape changes during mouse heart looping, from 3D reconstructions by HREM. In combination with cell labelling and computer simulations, we propose a novel model of heart looping. Buckling, when the cardiac tube grows between fixed poles, is modulated by the progressive breakdown of the dorsal mesocardium. We have identified sequential left-right asymmetries at the poles, which bias the buckling in opposite directions, thus leading to a helical shape. Our predictive model is useful to explore the parameter space generating shape variations. The role of the dorsal mesocardium was validated in Shh-/- mutants, which recapitulate heart shape changes expected from a persistent dorsal mesocardium. Our computer and quantitative tools provide novel insight into the mechanism of heart looping and the contribution of different factors, beyond the simple description of looping direction. This is relevant to congenital heart defects. PMID:29179813

Te homogeneous precipitation in Ge dislocation loop vicinity

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

Perrin Toinin, J.; Portavoce, A., E-mail: alain.portavoce@im2np.fr; Texier, M.

2016-06-06

High resolution microscopies were used to study the interactions of Te atoms with Ge dislocation loops, after a standard n-type doping process in Ge. Te atoms neither segregate nor precipitate on dislocation loops, but form Te-Ge clusters at the same depth as dislocation loops, in contradiction with usual dopant behavior and thermodynamic expectations. Atomistic kinetic Monte Carlo simulations show that Te atoms are repulsed from dislocation loops due to elastic interactions, promoting homogeneous Te-Ge nucleation between dislocation loops. This phenomenon is enhanced by coulombic interactions between activated Te{sup 2+} or Te{sup 1+} ions.

The effects of spaceflight on open-loop and closed-loop postural control mechanisms: human neurovestibular studies on SLS-2

NASA Technical Reports Server (NTRS)

Collins, J. J.; De Luca, C. J.; Pavlik, A. E.; Roy, S. H.; Emley, M. S.; Young, L. R. (Principal Investigator)

1995-01-01

Stabilogram-diffusion analysis was used to examine how prolonged periods in microgravity affect the open-loop and closed-loop postural control mechanisms. It was hypothesized that following spaceflight: (1) the effective stochastic activity of the open-loop postural control schemes in astronauts is increased; (2) the effective stochastic activity and uncorrelated behavior, respectively, of the closed-loop postural control mechanisms in astronauts are increased; and (3) astronauts utilized open-loop postural controls schemes for shorter time intervals and smaller displacements. Four crew members and two alternates from the 14-day Spacelab Life Sciences 2 Mission were included in the study. Each subject was tested under eyes-open, quiet-standing conditions on multiple preflight and postflight days. The subjects' center-of-pressure trajectories were measured with a force platform and analyzed according to stabilogram-diffusion analysis. It was found that the effective stochastic activity of the open-loop postural control schemes in three of the four crew members was increased following spaceflight. This result is interpreted as an indication that there may be in-flight adaptations to higher-level descending postural control pathways, e.g., a postflight increase in the tonic activation of postural muscles. This change may also be the consequence of a compensatory (e.g., "stiffening") postural control strategy that is adopted by astronauts to account for general feeling of postflight unsteadiness. The crew members, as a group, did not exhibit any consistent preflight/postflight differences in the steady-state behavior of their closed-loop postural control mechanisms or in the functional interaction of their open-loop and closed-loop postural control mechanisms. These results are interpreted as indications that although there may be in-flight adaptations to the vestibular system and/or proprioceptive system, input from the visual system can compensate for such changes

A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

PubMed

Nordqvist, A C; Peyrard, M; Pettersson, H; Mathiesen, T; Collins, V P; Dumanski, J P; Schalling, M

1997-07-01

Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas. A strong correlation was also found between clinical outcome and IGF-II/IGFBP-2 ratio, whereas previously used histochemical markers were less correlated to outcome. We suggest that a high IGF-II/IGFBP-2 mRNA ratio may be a sign of biologically aggressive behavior in meningiomas that can influence treatment strategies. We propose that low IGFBP-2 levels in combination with increased levels of IGF-II would result in more free IGF-II and consequently greater stimulation of proliferation.

Measuring electrically charged particle fluxes in space using a fiber optic loop sensor

NASA Technical Reports Server (NTRS)

1992-01-01

The purpose of this program was to demonstrate the potential of a fiber optic loop sensor for the measurement of electrically charged particle fluxes in space. The key elements of the sensor are a multiple turn loop of low birefringence, single mode fiber, with a laser diode light source, and a low noise optical receiver. The optical receiver is designed to be shot noise limited, with this being the limiting sensitivity factor for the sensor. The sensing element is the fiber optic loop. Under a magnetic field from an electric current flowing along the axis of the loop, there is a non-vanishing line integral along the fiber optic loop. This causes a net birefringence producing two states of polarization whose phase difference is correlated to magnetic field strength and thus, current in the optical receiver electronic processing. The objectives in this program were to develop a prototype laser diode powered fiber optic sensor. The performance specification of a minimum detectable current density of 1 (mu)amp/sq m-(radical)Hz, should be at the shot noise limit of the detection electronics. OPTRA has successfully built and tested a 3.2 m diameter loop with 137 turns of low birefringence optical fiber and achieved a minimum detectable current density of 5.4 x 10(exp-5) amps/(radical)Hz. If laboratory space considerations were not an issue, with the length of optical fiber available to us, we would have achieved a minimum detectable current density of 4 x 10(exp -7) amps/(radical)Hz.

Loop conformation and dynamics of the Escherichia coli HPPK apo-enzyme and its binary complex with MgATP.

PubMed

Yang, Rong; Lee, Matthew C; Yan, Honggao; Duan, Yong

2005-07-01

Comparison of the crystallographic and NMR structures of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) suggests that the enzyme may undergo significant conformational change upon binding to its first substrate, ATP. Two of the three surface loops (loop 2 and loop 3) accounting for most of the conformational differences appear to be confined by crystal contacts, raising questions about the putative large-scale induced-fit conformational change of HPPK and the functional roles of the conserved side-chain residues on the loops. To investigate the loop dynamics in crystal-free environment, we carried out molecular dynamics and locally enhanced sampling simulations of the apo-enzyme and the HPPK.MgATP complex. Our simulations showed that the crystallographic B-factors underestimated the loop dynamics considerably. We found that the open-conformation of loop 3 in the binary complex is accessible to the apo-enzyme and is the favored conformation in solution phase. These results revise our previous view of HPPK-substrate interactions and the associated functional mechanism of conformational change. The lessons learned here offer valuable structural insights into the workings of HPPK and should be useful for structure-based drug design.

Loop III region of platelet-derived growth factor (PDGF) B-chain mediates binding to PDGF receptors and heparin.

PubMed Central

Schilling, D; Reid IV, J D; Hujer, A; Morgan, D; Demoll, E; Bummer, P; Fenstermaker, R A; Kaetzel, D M

1998-01-01

Site-directed mutagenesis of the platelet-derived growth factor (PDGF) B-chain was conducted to determine the importance of cationic amino acid residues (Arg160-Lys161-Lys162; RKK) located within the loop III region in mediating the biological and cell-association properties of the molecule. Binding to both PDGF alpha-and beta-receptors was inhibited by the conversion of all three cationic residues into anionic glutamates (RKK-->EEE), whereas an RKK-->SSS mutant also exhibited a modest loss in affinity for beta-receptors. Replacements with serine at either Arg160 (RKK-->SKK) or at all three positions (RKK-->SSS) had little effect on binding to alpha-receptors. Replacements with either glutamic or serine residues at any of the three positions also resulted in significant inhibition of heparin-binding activity. Furthermore, the RKK-->EEE mutant exhibited decreased association with the cell surface and accumulated in the culture medium as 29-32 kDa forms. Stable transfection of U87 astrocytoma cells with RKK-->EEE mutants of either the A-chain or the B-chain inhibited malignant growth in athymic nude mice. Despite altered receptor-binding activities, each of the loop III mutants retained full mitogenic activity when applied to cultured Swiss 3T3 cells. CD spectrophotometric analysis of the RKK-->EEE mutant revealed a secondary structure indistinguishable from the wild type, with a high degree of beta-sheet structure and random coil content (50% and 43% respectively). These findings indicate an important role of the Arg160-Lys161-Lys162 sequence in mediating the biological and cell-associative activities of the PDGF-BB homodimer, and reveal that the mitogenic activity of PDGF-BB is insufficient to mediate its full oncogenic properties. PMID:9677323

REVIEWS OF TOPICAL PROBLEMS: Coronal magnetic loops

NASA Astrophysics Data System (ADS)

Zaitsev, Valerii V.; Stepanov, Alexander V.

2008-11-01

The goal of this review is to outline some new ideas in the physics of coronal magnetic loops, the fundamental structural elements of the atmospheres of the Sun and flaring stars, which are involved in phenomena such as stellar coronal heating, flare energy release, charged particle acceleration, and the modulation of optical, radio, and X-ray emissions. The Alfvén-Carlqvist view of a coronal loop as an equivalent electric circuit allows a good physical understanding of loop processes. Describing coronal loops as MHD-resonators explains various ways in which flaring emissions from the Sun and stars are modulated, whereas modeling them by magnetic mirror traps allows one to describe the dynamics and emission of high-energy particles. Based on these approaches, loop plasma and fast particle parameters are obtained and models for flare energy release and stellar corona heating are developed.

Direct-contact closed-loop heat exchanger

DOEpatents

Berry, G.F.; Minkov, V.; Petrick, M.

1981-11-02

A high temperature heat exchanger is disclosed which has a closed loop and a heat transfer liquid within the loop, the closed loop having a first horizontal channel with inlet and outlet means for providing direct contact of a first fluid at a first temperature with the heat transfer liquid, a second horizontal channel with inlet and outlet means for providing direct contact of a second fluid at a second temperature with the heat transfer liquid, and means for circulating the heat transfer liquid.

Teachers' Attitudes and Perceptions of Looping and the Effect of Looping on Students' Academic Achievement

ERIC Educational Resources Information Center

Williams-Wright, Vera

2013-01-01

The purpose of this research study was two-fold. The first purpose was to investigate the impact of looping on academic achievement of students in selected public schools in Mississippi. The students' results on the 2010 and 2011 Mississippi Curriculum Test, Second Edition (MCT2) were used to determine whether looping students score differently in…

Orthopositronium decay form factors and two-photon correlations

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

Adkins, Gregory S.; Droz, Daniel R.; Rastawicki, Dominik

2010-04-15

We give results for the orthopositronium decay form factors through one-loop order. We use the form factors to calculate momentum correlations of the final-state photons and , including one-loop corrections, for ensembles of initial orthopositronium atoms having arbitrary polarization.

Optimizing the inner loop of the gravitational force interaction on modern processors

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

Warren, Michael S

2010-12-08

We have achieved superior performance on multiple generations of the fastest supercomputers in the world with our hashed oct-tree N-body code (HOT), spanning almost two decades and garnering multiple Gordon Bell Prizes for significant achievement in parallel processing. Execution time for our N-body code is largely influenced by the force calculation in the inner loop. Improvements to the inner loop using SSE3 instructions has enabled the calculation of over 200 million gravitational interactions per second per processor on a 2.6 GHz Opteron, for a computational rate of over 7 Gflops in single precision (700/0 of peak). We obtain optimal performancemore » some processors (including the Cell) by decomposing the reciprocal square root function required for a gravitational interaction into a table lookup, Chebychev polynomial interpolation, and Newton-Raphson iteration, using the algorithm of Karp. By unrolling the loop by a factor of six, and using SPU intrinsics to compute on vectors, we obtain performance of over 16 Gflops on a single Cell SPE. Aggregated over the 8 SPEs on a Cell processor, the overall performance is roughly 130 Gflops. In comparison, the ordinary C version of our inner loop only obtains 1.6 Gflops per SPE with the spuxlc compiler.« less

Protein Loop Structure Prediction Using Conformational Space Annealing.

PubMed

Heo, Seungryong; Lee, Juyong; Joo, Keehyoung; Shin, Hang-Cheol; Lee, Jooyoung

2017-05-22

We have developed a protein loop structure prediction method by combining a new energy function, which we call E PLM (energy for protein loop modeling), with the conformational space annealing (CSA) global optimization algorithm. The energy function includes stereochemistry, dynamic fragment assembly, distance-scaled finite ideal gas reference (DFIRE), and generalized orientation- and distance-dependent terms. For the conformational search of loop structures, we used the CSA algorithm, which has been quite successful in dealing with various hard global optimization problems. We assessed the performance of E PLM with two widely used loop-decoy sets, Jacobson and RAPPER, and compared the results against the DFIRE potential. The accuracy of model selection from a pool of loop decoys as well as de novo loop modeling starting from randomly generated structures was examined separately. For the selection of a nativelike structure from a decoy set, E PLM was more accurate than DFIRE in the case of the Jacobson set and had similar accuracy in the case of the RAPPER set. In terms of sampling more nativelike loop structures, E PLM outperformed E DFIRE for both decoy sets. This new approach equipped with E PLM and CSA can serve as the state-of-the-art de novo loop modeling method.

Environmental impacts of open loop geothermal system on groundwater

NASA Astrophysics Data System (ADS)

Kwon, Koo-Sang; Park, Youngyun; Yun, Sang Woong; Lee, Jin-Yong

2013-04-01

Application of renewable energies such as sunlight, wind, rain, tides, waves and geothermal heat has gradually increased to reduce emission of CO2 which is supplied from combustion of fossil fuel. The geothermal energy of various renewable energies has benefit to be used to cooling and heating systems and has good energy efficiency compared with other renewable energies. However, open loop system of geothermal heat pump system has possibility that various environmental problems are induced because the system directly uses groundwater to exchange heat. This study was performed to collect data from many documents such as papers and reports and to summarize environmental impacts for application of open loop system. The environmental impacts are classified into change of hydrogeological factors such as water temperature, redox condition, EC, change of microbial species, well contamination and depletion of groundwater. The change of hydrogeological factors can induce new geological processes such as dissolution and precipitation of some minerals. For examples, increase of water temperature can change pH and Eh. These variations can change saturation index of some minerals. Therefore, dissolution and precipitation of some minerals such as quartz and carbonate species and compounds including Fe and Mn can induce a collapse and a clogging of well. The well contamination and depletion of groundwater can reduce available groundwater resources. These environmental impacts will be different in each region because hydrogeological properties and scale, operation period and kind of the system. Therefore, appropriate responses will be considered for each environmental impact. Also, sufficient study will be conducted to reduce the environmental impacts and to improve geothermal energy efficiency during the period that a open loop system is operated. This work was supported by the Energy Efficiency and Resources of the Korea Institute of Energy Technology Evaluation and Planning

3D MHD Models of Active Region Loops

NASA Technical Reports Server (NTRS)

Ofman, Leon

2004-01-01

Present imaging and spectroscopic observations of active region loops allow to determine many physical parameters of the coronal loops, such as the density, temperature, velocity of flows in loops, and the magnetic field. However, due to projection effects many of these parameters remain ambiguous. Three dimensional imaging in EUV by the STEREO spacecraft will help to resolve the projection ambiguities, and the observations could be used to setup 3D MHD models of active region loops to study the dynamics and stability of active regions. Here the results of 3D MHD models of active region loops are presented, and the progress towards more realistic 3D MHD models of active regions. In particular the effects of impulsive events on the excitation of active region loop oscillations, and the generation, propagations and reflection of EIT waves are shown. It is shown how 3D MHD models together with 3D EUV observations can be used as a diagnostic tool for active region loop physical parameters, and to advance the science of the sources of solar coronal activity.

EXAMINATION OF Zr AND Ti RECOMBINER LOOP SPECIMENS

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

Rittenhouse, P.L.

1958-12-19

Cold-worked specimens of iodide zirconium, Zircaloy-2, iodide titanium, and A-55 titanium were tested in a high-pressure recombiner loop in an attempt to duplicate anomalous results obtained in a prior recombiner loop. Hydrogen analyses and metallographic examinations were made on all specimens. The titanium materials and Zircaloy-2 picked up major amounts of hydrogen in the cell section. None of the materials tested showed appreciable hydrogen absorption in the recombiner section. Complete recrystallization occurred in all cell specimens while only Zircaloy-2, of the recombiner specimens, showed any degree of recrystallization. No explanation for this behavior can be given. A survnnary of themore » data obtained in previous recombiner loops is compared with the results of this loop. Conclusions were based on the results of three recombiner loops. Primarlly because of the hydrogen absorption data obtained in all three recombiner loops it is recommended that the zirconium and titunium materials tested not be used in environments similar to those encountered in high pressure recombiner loops. (auth)« less

Iterative LQG Controller Design Through Closed-Loop Identification

NASA Technical Reports Server (NTRS)

Hsiao, Min-Hung; Huang, Jen-Kuang; Cox, David E.

1996-01-01

This paper presents an iterative Linear Quadratic Gaussian (LQG) controller design approach for a linear stochastic system with an uncertain open-loop model and unknown noise statistics. This approach consists of closed-loop identification and controller redesign cycles. In each cycle, the closed-loop identification method is used to identify an open-loop model and a steady-state Kalman filter gain from closed-loop input/output test data obtained by using a feedback LQG controller designed from the previous cycle. Then the identified open-loop model is used to redesign the state feedback. The state feedback and the identified Kalman filter gain are used to form an updated LQC controller for the next cycle. This iterative process continues until the updated controller converges. The proposed controller design is demonstrated by numerical simulations and experiments on a highly unstable large-gap magnetic suspension system.

A dual-loop model of the human controller

NASA Technical Reports Server (NTRS)

Hess, R. A.

1977-01-01

A representative model of the human controller in single-axis compensatory tracking tasks that exhibits an internal feedback loop which is not evident in single-loop models now in common use is presented. This hypothetical inner-loop involves a neuromuscular command signal derived from the time rate of change of controlled element output which is due to control activity. It is not contended that the single-loop human controller models now in use are incorrect, but that they contain an implicit but important internal loop closure, which, if explicitly considered, can account for a good deal of the adaptive nature of the human controller in a systematic manner.

Molecular Recognition of 6′-N-5-Hexynoate Kanamyin A and RNA 1×1 Internal Loops Containing CA Mismatches

PubMed Central

Tran, Tuan; Disney, Matthew D.

2011-01-01

In our previous study to identify the RNA internal loops that bind an aminoglycoside derivative, we determined that 6′-N-5-hexynoate kanamycin A prefers to bind 1×1 nucleotide internal loops containing C•A mismatches. In this present study, the molecular recognition between a variety of RNAs that are mutated around the C•A loop and the ligand was investigated. Studies show that both loop nucleotides and loop closing pairs affect binding affinity. Most interestingly, it was shown that there is a correlation between the thermodynamic stability of the C•A internal loops and ligand affinity. Specifically, C•A loops that had relatively high or low stability bound the ligand most weakly whereas loops with intermediate stability bound the ligand most tightly. In contrast, there is no correlation between the likelihood that a loop forms a C-A+ pair at lower pH and ligand affinity. It was also found that a 1×1 nucleotide C•A loop that bound to the ligand with the highest affinity is identical to the consensus site in RNAs that are edited by adenosine deaminases acting on RNA type 2 (ADAR2). These studies provide a detailed investigation of factors affecting small molecule recognition of internal loops containing C•A mismatches, which are present in a variety of RNAs that cause disease. PMID:21207945

Genericness of inflation in isotropic loop quantum cosmology.

PubMed

Date, Ghanashyam; Hossain, Golam Mortuza

2005-01-14

Nonperturbative corrections from loop quantum cosmology (LQC) to the scalar matter sector are already known to imply inflation. We prove that the LQC modified scalar field generates exponential inflation in the small scale factor regime, for all positive definite potentials, independent of initial conditions and independent of ambiguity parameters. For positive semidefinite potentials it is always possible to choose, without fine-tuning, a value of one of the ambiguity parameters such that exponential inflation results, provided zeros of the potential are approached at most as a power law in the scale factor. In conjunction with the generic occurrence of bounce at small volumes, particle horizon is absent, thus eliminating the horizon problem of the standard big bang model.

Tumor-Secreted Autocrine Motility Factor (AMF): Casual Role in a Animal Model of Cachexia

DTIC Science & Technology

2004-08-01

83:526-531 Crown AL, Cottle K, Lightman SL, Falk S, Mohamed-Ali V, Armstrong L, Millar AB, Holly JM (2002). What is the role of the insulin-like growth...Falk S, Mohamed-Ali V, Armstrong L, Millar AB, Holly JM (2002). What is the role of the insulin-like growth factor system in the pathophysiology of...Regulation of lipolysis: natriuretic peptides and the development of cachexia. Int J Cardiol 85:125-132 Kotler DP (2000). Cachexia. Ann Intern Med 133:622-634

Closed-loop fiber optic gyroscope with homodyne detection

NASA Astrophysics Data System (ADS)

Zhu, Yong; Qin, BingKun; Chen, Shufen

1996-09-01

Interferometric fiber optic gyroscope (IFOG) has been analyzed with autocontrol theory in this paper. An open-loop IFOG system is not able to restrain the bias drift, but a closed-loop IFOG system can do it very well using negative feedback in order to suppress zero drift. The result of our theoretic analysis and computer simulation indicate that the bias drift of a closed-loop system is smaller than an open- loop one.

Perception as a closed-loop convergence process.

PubMed

Ahissar, Ehud; Assa, Eldad

2016-05-09

Perception of external objects involves sensory acquisition via the relevant sensory organs. A widely-accepted assumption is that the sensory organ is the first station in a serial chain of processing circuits leading to an internal circuit in which a percept emerges. This open-loop scheme, in which the interaction between the sensory organ and the environment is not affected by its concurrent downstream neuronal processing, is strongly challenged by behavioral and anatomical data. We present here a hypothesis in which the perception of external objects is a closed-loop dynamical process encompassing loops that integrate the organism and its environment and converging towards organism-environment steady-states. We discuss the consistency of closed-loop perception (CLP) with empirical data and show that it can be synthesized in a robotic setup. Testable predictions are proposed for empirical distinction between open and closed loop schemes of perception.

Dynamic loop gain increases upon adopting the supine body position during sleep in patients with obstructive sleep apnoea.

PubMed

Joosten, Simon A; Landry, Shane A; Sands, Scott A; Terrill, Philip I; Mann, Dwayne; Andara, Christopher; Skuza, Elizabeth; Turton, Anthony; Berger, Philip; Hamilton, Garun S; Edwards, Bradley A

2017-11-01

Obstructive sleep apnoea (OSA) is typically worse in the supine versus lateral sleeping position. One potential factor driving this observation is a decrease in lung volume in the supine position which is expected by theory to increase a key OSA pathogenic factor: dynamic ventilatory control instability (i.e. loop gain). We aimed to quantify dynamic loop gain in OSA patients in the lateral and supine positions, and to explore the relationship between change in dynamic loop gain and change in lung volume with position. Data from 20 patients enrolled in previous studies on the effect of body position on OSA pathogenesis were retrospectively analysed. Dynamic loop gain was calculated from routinely collected polysomnographic signals using a previously validated mathematical model. Lung volumes were measured in the awake state with a nitrogen washout technique. Dynamic loop gain was significantly higher in the supine than in the lateral position (0.77 ± 0.15 vs 0.68 ± 0.14, P = 0.012). Supine functional residual capacity (FRC) was significantly lower than lateral FRC (81.0 ± 15.4% vs 87.3 ± 18.4% of the seated FRC, P = 0.021). The reduced FRC we observed on moving to the supine position was predicted by theory to increase loop gain by 10.2 (0.6, 17.1)%, a value similar to the observed increase of 8.4 (-1.5, 31.0)%. Dynamic loop gain increased by a small but statistically significant amount when moving from the lateral to supine position and this may, in part, contribute to the worsening of OSA in the supine sleeping position. © 2017 Asian Pacific Society of Respirology.

Equilibrium models of coronal loops that involve curvature and buoyancy

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

Hindman, Bradley W.; Jain, Rekha, E-mail: hindman@solarz.colorado.edu

2013-12-01

We construct magnetostatic models of coronal loops in which the thermodynamics of the loop is fully consistent with the shape and geometry of the loop. This is achieved by treating the loop as a thin, compact, magnetic fibril that is a small departure from a force-free state. The density along the loop is related to the loop's curvature by requiring that the Lorentz force arising from this deviation is balanced by buoyancy. This equilibrium, coupled with hydrostatic balance and the ideal gas law, then connects the temperature of the loop with the curvature of the loop without resorting to amore » detailed treatment of heating and cooling. We present two example solutions: one with a spatially invariant magnetic Bond number (the dimensionless ratio of buoyancy to Lorentz forces) and the other with a constant radius of the curvature of the loop's axis. We find that the density and temperature profiles are quite sensitive to curvature variations along the loop, even for loops with similar aspect ratios.« less

Digital Filters for Digital Phase-locked Loops

NASA Technical Reports Server (NTRS)

Simon, M.; Mileant, A.

1985-01-01

An s/z hybrid model for a general phase locked loop is proposed. The impact of the loop filter on the stability, gain margin, noise equivalent bandwidth, steady state error and time response is investigated. A specific digital filter is selected which maximizes the overall gain margin of the loop. This filter can have any desired number of integrators. Three integrators are sufficient in order to track a phase jerk with zero steady state error at loop update instants. This filter has one zero near z = 1.0 for each integrator. The total number of poles of the filter is equal to the number of integrators plus two.

Protein-mediated looping of DNA under tension requires supercoiling

PubMed Central

Yan, Yan; Leng, Fenfei; Finzi, Laura; Dunlap, David

2018-01-01

Abstract Protein-mediated DNA looping is ubiquitous in chromatin organization and gene regulation, but to what extent supercoiling or nucleoid associated proteins promote looping is poorly understood. Using the lac repressor (LacI), a paradigmatic loop-mediating protein, we measured LacI-induced looping as a function of either supercoiling or the concentration of the HU protein, an abundant nucleoid protein in Escherichia coli. Negative supercoiling to physiological levels with magnetic tweezers easily drove the looping probability from 0 to 100% in single DNA molecules under slight tension that likely exists in vivo. In contrast, even saturating (micromolar) concentrations of HU could not raise the looping probability above 30% in similarly stretched DNA or 80% in DNA without tension. Negative supercoiling is required to induce significant looping of DNA under any appreciable tension. PMID:29365152

LMFBR with booster pump in pumping loop

DOEpatents

Rubinstein, H.J.

1975-10-14

A loop coolant circulation system is described for a liquid metal fast breeder reactor (LMFBR) utilizing a low head, high specific speed booster pump in the hot leg of the coolant loop with the main pump located in the cold leg of the loop, thereby providing the advantages of operating the main pump in the hot leg with the reliability of cold leg pump operation.

Phase-lock loop frequency control and the dropout problem

NASA Technical Reports Server (NTRS)

Attwood, S.; Kline, A. J.

1968-01-01

Technique automatically sets the frequency of narrow band phase-lock loops within automatic lock-in-range. It presets a phase-lock loop to a desired center frequency with a closed loop electronic frequency discriminator and holds the phase-lock loop to that center frequency until lock is achieved.

Visualizing Active-Site Dynamics in Single Crystals of HePTP: Opening of the WPD Loop Involves Coordinated Movement of the E Loop

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

D Critton; L Tautz; R Page

2011-12-31

Phosphotyrosine hydrolysis by protein tyrosine phosphatases (PTPs) involves substrate binding by the PTP loop and closure over the active site by the WPD loop. The E loop, located immediately adjacent to the PTP and WPD loops, is conserved among human PTPs in both sequence and structure, yet the role of this loop in substrate binding and catalysis is comparatively unexplored. Hematopoietic PTP (HePTP) is a member of the kinase interaction motif (KIM) PTP family. Compared to other PTPs, KIM-PTPs have E loops that are unique in both sequence and structure. In order to understand the role of the E loopmore » in the transition between the closed state and the open state of HePTP, we identified a novel crystal form of HePTP that allowed the closed-state-to-open-state transition to be observed within a single crystal form. These structures, which include the first structure of the HePTP open state, show that the WPD loop adopts an 'atypically open' conformation and, importantly, that ligands can be exchanged at the active site, which is critical for HePTP inhibitor development. These structures also show that tetrahedral oxyanions bind at a novel secondary site and function to coordinate the PTP, WPD, and E loops. Finally, using both structural and kinetic data, we reveal a novel role for E-loop residue Lys182 in enhancing HePTP catalytic activity through its interaction with Asp236 of the WPD loop, providing the first evidence for the coordinated dynamics of the WPD and E loops in the catalytic cycle, which, as we show, is relevant to multiple PTP families.« less

Current systems of coronal loops in 3D MHD simulations

NASA Astrophysics Data System (ADS)

Warnecke, J.; Chen, F.; Bingert, S.; Peter, H.

2017-11-01

Aims: We study the magnetic field and current structure associated with a coronal loop. Through this we investigate to what extent the assumptions of a force-free magnetic field break down and where they might be justified. Methods: We analyze a three-dimensional (3D) magnetohydrodynamic (MHD) model of the solar corona in an emerging active region with the focus on the structure of the forming coronal loops. The lower boundary of this simulation is taken from a model of an emerging active region. As a consequence of the emerging magnetic flux and the horizontal motions at the surface a coronal loop forms self-consistently. We investigate the current density along magnetic field lines inside (and outside) this loop and study the magnetic and plasma properties in and around this loop. The loop is defined as the bundle of field lines that coincides with enhanced emission in extreme UV. Results: We find that the total current along the emerging loop changes its sign from being antiparallel to parallel to the magnetic field. This is caused by the inclination of the loop together with the footpoint motion. Around the loop, the currents form a complex non-force-free helical structure. This is directly related to a bipolar current structure at the loop footpoints at the base of the corona and a local reduction of the background magnetic field (I.e., outside the loop) caused by the plasma flow into and along the loop. Furthermore, the locally reduced magnetic pressure in the loop allows the loop to sustain a higher density, which is crucial for the emission in extreme UV. The action of the flow on the magnetic field hosting the loop turns out to also be responsible for the observed squashing of the loop. Conclusions: The complex magnetic field and current system surrounding it can only be modeled in 3D MHD models where the magnetic field has to balance the plasma pressure. A one-dimensional coronal loop model or a force-free extrapolation cannot capture the current system

Innovative hybrid pile oscillator technique in the Minerve reactor: open loop vs. closed loop

NASA Astrophysics Data System (ADS)

Geslot, Benoit; Gruel, Adrien; Bréaud, Stéphane; Leconte, Pierre; Blaise, Patrick

2018-01-01

Pile oscillator techniques are powerful methods to measure small reactivity worth of isotopes of interest for nuclear data improvement. This kind of experiments has long been implemented in the Mineve experimental reactor, operated by CEA Cadarache. A hybrid technique, mixing reactivity worth estimation and measurement of small changes around test samples is presented here. It was made possible after the development of high sensitivity miniature fission chambers introduced next to the irradiation channel. A test campaign, called MAESTRO-SL, took place in 2015. Its objective was to assess the feasibility of the hybrid method and investigate the possibility to separate mixed neutron effects, such as fission/capture or scattering/capture. Experimental results are presented and discussed in this paper, which focus on comparing two measurements setups, one using a power control system (closed loop) and another one where the power is free to drift (open loop). First, it is demonstrated that open loop is equivalent to closed loop. Uncertainty management and methods reproducibility are discussed. Second, results show that measuring the flux depression around oscillated samples provides valuable information regarding partial neutron cross sections. The technique is found to be very sensitive to the capture cross section at the expense of scattering, making it very useful to measure small capture effects of highly scattering samples.

Effects of two-loop contributions in the pseudofermion functional renormalization group method for quantum spin systems

NASA Astrophysics Data System (ADS)

Rück, Marlon; Reuther, Johannes

2018-04-01

We implement an extension of the pseudofermion functional renormalization group method for quantum spin systems that takes into account two-loop diagrammatic contributions. An efficient numerical treatment of the additional terms is achieved within a nested graph construction which recombines different one-loop interaction channels. In order to be fully self-consistent with respect to self-energy corrections, we also include certain three-loop terms of Katanin type. We first apply this formalism to the antiferromagnetic J1-J2 Heisenberg model on the square lattice and benchmark our results against the previous one-loop plus Katanin approach. Even though the renormalization group (RG) equations undergo significant modifications when including the two-loop terms, the magnetic phase diagram, comprising Néel ordered and collinear ordered phases separated by a magnetically disordered regime, remains remarkably unchanged. Only the boundary position between the disordered and the collinear phases is found to be moderately affected by two-loop terms. On the other hand, critical RG scales, which we associate with critical temperatures Tc, are reduced by a factor of ˜2 indicating that the two-loop diagrams play a significant role in enforcing the Mermin-Wagner theorem. Improved estimates for critical temperatures are also obtained for the Heisenberg ferromagnet on the three-dimensional simple cubic lattice where errors in Tc are reduced by ˜34 % . These findings have important implications for the quantum phase diagrams calculated within the previous one-loop plus Katanin approach which turn out to be already well converged.

Sweeping Arches and Loops [video

NASA Image and Video Library

2014-07-10

Two active regions with their intense magnetic fields produced towering arches and spiraling coils of solar loops above them (June 29 - July 1, 2014) as they rotated into view. When viewed in extreme ultraviolet light, magnetic field lines are revealed by charged particles that travel along them. These active regions appear as dark sunspots when viewed in filtered light. Note the small blast in the upper of the two major active regions, followed by more coils of loops as the region reorganizes itself. The still was taken on June 30 at 10:33 UT. Credit: NASA/Solar Dynamics Observatory Two active regions with their intense magnetic fields produced towering arches and spiraling coils of solar loops above them (June 29 - July 1, 2014) as they rotated into view. When viewed in extreme ultraviolet light, magnetic field lines are revealed by charged particles that travel along them. These active regions appear as dark sunspots when viewed in filtered light. Note the small blast in the upper of the two major active regions, followed by more coils of loops as the region reorganizes itself. The still was taken on June 30 at 10:33 UT. Credit: Solar Dynamics Observatory/NASA.

Feedback loop compensates for rectifier nonlinearity

NASA Technical Reports Server (NTRS)

1966-01-01

Signal processing circuit with two negative feedback loops rectifies two sinusoidal signals which are 180 degrees out of phase and produces a single full-wave rectified output signal. Each feedback loop incorporates a feedback rectifier to compensate for the nonlinearity of the circuit.

Surface NMR imaging with simultaneously energized transmission loops

NASA Astrophysics Data System (ADS)

Irons, T. P.; Kass, A.; Parsekian, A.

2016-12-01

Surface nuclear magnetic resonance (sNMR) is a unique geophysical technique which allows for the direct detection of liquid-phase water. In saturated media the sNMR response also provides estimates of hydrologic properties including porosity and permeability. The most common survey deployment consists of a single coincident loop performing both transmission and receiving. Because the sNMR method is relatively slow, tomography using coincident loops is time-intensive. Surveys using multiple receiver loops (but a single transmitter) provide additional sensitivity; however, they still require iterating transmission over the loops, and do not decrease survey acquisition time. In medical rotating frame imaging, arrays of transmitters are employed in order to decrease acquisition time, whilst optimizing image resolving power-a concept which we extend to earth's field imaging. Using simultaneously energized transmission loops decreases survey time linearly with the number of channels. To demonstrate the efficacy and benefits of multiple transmission loops, we deployed simultaneous sNMR transmission arrays using minimally coupled loops and a specially modified instrument at the Red Buttes Hydrogeophysics Experiment Site-a well-characterized location near Laramie, Wyoming. The proposed survey proved capable of acquiring multiple-channel imaging data with comparable noise levels to figure-eight configurations. Finally, the channels can be combined after acquisition or inverted simultaneously to provide composite datasets and images. This capability leverages the improved near surface resolving power of small loops but retains sensitivity to deep media through the use of synthetic aperature receivers. As such, simultaneously acquired loop arrays provide a great deal of flexibility.

Interleukin-8 (IL-8) over-production and autocrine cell activation are key factors in monomethylarsonous acid [MMA(III)]-induced malignant transformation of urothelial cells

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

Escudero-Lourdes, C., E-mail: cescuder@uaslp.mx; Wu, T.; Camarillo, J.M.

2012-01-01

The association between chronic human exposure to arsenicals and bladder cancer development is well recognized; however, the underlying molecular mechanisms have not been fully determined. We propose that inflammatory responses can play a pathogenic role in arsenic-related bladder carcinogenesis. In previous studies, it was demonstrated that chronic exposure to 50 nM monomethylarsenous acid [MMA(III)] leads to malignant transformation of an immortalized model of urothelial cells (UROtsa), with only 3 mo of exposure necessary to trigger the transformation-related changes. In the three-month window of exposure, the cells over-expressed pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), consistent with the sustained activation of NFKβmore » and AP1/c-jun, ERK2, and STAT3. IL-8 was over-expressed within hours after exposure to MMA(III), and sustained over-expression was observed during chronic exposure. In this study, we profiled IL-8 expression in UROtsa cells exposed to 50 nM MMA(III) for 1 to 5 mo. IL-8 expression was increased mainly in cells after 3 mo MMA(III) exposure, and its production was also found increased in tumors derived from these cells after heterotransplantation in SCID mice. UROtsa cells do express both receptors, CXCR1 and CXCR2, suggesting that autocrine cell activation could be important in cell transformation. Supporting this observation and consistent with IL-8 over-expression, CXCR1 internalization was significantly increased after three months of exposure to MMA(III). The expression of MMP-9, cyclin D1, bcl-2, and VGEF was significantly increased in cells exposed to MMA(III) for 3 mo, but these mitogen-activated kinases were significantly decreased after IL-8 gene silencing, together with a decrease in cell proliferation rate and in anchorage-independent colony formation. These results suggest a relevant role of IL-8 in MMA(III)-induced UROtsa cell transformation. -- Highlights: ► IL-8 is over-expressed in human MMA

A class of optimum digital phase locked loops

NASA Technical Reports Server (NTRS)

Kumar, R.; Hurd, W. J.

1986-01-01

This paper presents a class of optimum digital filters for digital phase locked loops, for the important case in which the maximum update rate of the loop filter and numerically controlled oscillator (NCO) is limited. This case is typical when the loop filter is implemented in a microprocessor. In these situations, pure delay is encountered in the loop transfer function and thus the stability and gain margin of the loop are of crucial interest. The optimum filters designed for such situations are evaluated in terms of their gain margin for stability, dynamic error, and steady-state error performance. For situations involving considerably high phase dynamics an adaptive and programmable implementation is also proposed to obtain an overall optimum strategy.

Functional Loop Dynamics of the Streptavidin-Biotin Complex

PubMed Central

Song, Jianing; Li, Yongle; Ji, Changge; Zhang, John Z. H.

2015-01-01

Accelerated molecular dynamics (aMD) simulation is employed to study the functional dynamics of the flexible loop3-4 in the strong-binding streptavidin-biotin complex system. Conventional molecular (cMD) simulation is also performed for comparison. The present study reveals the following important properties of the loop dynamics: (1) The transition of loop3-4 from open to closed state is observed in 200 ns aMD simulation. (2) In the absence of biotin binding, the open-state streptavidin is more stable, which is consistent with experimental evidences. The free energy (ΔG) difference is about 5 kcal/mol between two states. But with biotin binding, the closed state is more stable due to electrostatic and hydrophobic interactions between the loop3-4 and biotin. (3) The closure of loop3-4 is concerted to the stable binding of biotin to streptavidin. When the loop3-4 is in its open-state, biotin moves out of the binding pocket, indicating that the interactions between the loop3-4 and biotin are essential in trapping biotin in the binding pocket. (4) In the tetrameric streptavidin system, the conformational change of the loop3-4 in each monomer is independent of each other. That is, there is no cooperative binding for biotin bound to the four subunits of the tetramer. PMID:25601277

Damped transverse oscillations of interacting coronal loops

NASA Astrophysics Data System (ADS)

Soler, Roberto; Luna, Manuel

2015-10-01

Damped transverse oscillations of magnetic loops are routinely observed in the solar corona. This phenomenon is interpreted as standing kink magnetohydrodynamic waves, which are damped by resonant absorption owing to plasma inhomogeneity across the magnetic field. The periods and damping times of these oscillations can be used to probe the physical conditions of the coronal medium. Some observations suggest that interaction between neighboring oscillating loops in an active region may be important and can modify the properties of the oscillations. Here we theoretically investigate resonantly damped transverse oscillations of interacting nonuniform coronal loops. We provide a semi-analytic method, based on the T-matrix theory of scattering, to compute the frequencies and damping rates of collective oscillations of an arbitrary configuration of parallel cylindrical loops. The effect of resonant damping is included in the T-matrix scheme in the thin boundary approximation. Analytic and numerical results in the specific case of two interacting loops are given as an application.

Perception as a closed-loop convergence process

PubMed Central

Ahissar, Ehud; Assa, Eldad

2016-01-01

Perception of external objects involves sensory acquisition via the relevant sensory organs. A widely-accepted assumption is that the sensory organ is the first station in a serial chain of processing circuits leading to an internal circuit in which a percept emerges. This open-loop scheme, in which the interaction between the sensory organ and the environment is not affected by its concurrent downstream neuronal processing, is strongly challenged by behavioral and anatomical data. We present here a hypothesis in which the perception of external objects is a closed-loop dynamical process encompassing loops that integrate the organism and its environment and converging towards organism-environment steady-states. We discuss the consistency of closed-loop perception (CLP) with empirical data and show that it can be synthesized in a robotic setup. Testable predictions are proposed for empirical distinction between open and closed loop schemes of perception. DOI: http://dx.doi.org/10.7554/eLife.12830.001 PMID:27159238

A comparative approach to closed-loop computation.

PubMed

Roth, E; Sponberg, S; Cowan, N J

2014-04-01

Neural computation is inescapably closed-loop: the nervous system processes sensory signals to shape motor output, and motor output consequently shapes sensory input. Technological advances have enabled neuroscientists to close, open, and alter feedback loops in a wide range of experimental preparations. The experimental capability of manipulating the topology-that is, how information can flow between subsystems-provides new opportunities to understand the mechanisms and computations underlying behavior. These experiments encompass a spectrum of approaches from fully open-loop, restrained preparations to the fully closed-loop character of free behavior. Control theory and system identification provide a clear computational framework for relating these experimental approaches. We describe recent progress and new directions for translating experiments at one level in this spectrum to predictions at another level. Operating across this spectrum can reveal new understanding of how low-level neural mechanisms relate to high-level function during closed-loop behavior. Copyright © 2013 Elsevier Ltd. All rights reserved.

Two AFC Loops For Low CNR And High Dynamics

NASA Technical Reports Server (NTRS)

Hinedi, Sami M.; Aguirre, Sergio

1992-01-01

Two alternative digital automatic-frequency-control (AFC) loops proposed to acquire (or reacquire) and track frequency of received carrier radio signal. Intended for use where carrier-to-noise ratios (CNR's) low and carrier frequency characterized by high Doppler shift and Doppler rate because of high relative speed and acceleration, respectively, between transmitter and receiver. Either AFC loops used in place of phase-locked loop. New loop concepts integrate ideas from classical spectrum-estimation, digital-phase-locked-loop, and Kalman-Filter theories.

Shortening a loop can increase protein native state entropy.

PubMed

Gavrilov, Yulian; Dagan, Shlomi; Levy, Yaakov

2015-12-01

Protein loops are essential structural elements that influence not only function but also protein stability and folding rates. It was recently reported that shortening a loop in the AcP protein may increase its native state conformational entropy. This effect on the entropy of the folded state can be much larger than the lower entropic penalty of ordering a shorter loop upon folding, and can therefore result in a more pronounced stabilization than predicted by polymer model for loop closure entropy. In this study, which aims at generalizing the effect of loop length shortening on native state dynamics, we use all-atom molecular dynamics simulations to study how gradual shortening a very long or solvent-exposed loop region in four different proteins can affect their stability. For two proteins, AcP and Ubc7, we show an increase in native state entropy in addition to the known effect of the loop length on the unfolded state entropy. However, for two permutants of SH3 domain, shortening a loop results only with the expected change in the entropy of the unfolded state, which nicely reproduces the observed experimental stabilization. Here, we show that an increase in the native state entropy following loop shortening is not unique to the AcP protein, yet nor is it a general rule that applies to all proteins following the truncation of any loop. This modification of the loop length on the folded state and on the unfolded state may result with a greater effect on protein stability. © 2015 Wiley Periodicals, Inc.

MULTI-STRAND CORONAL LOOP MODEL AND FILTER-RATIO ANALYSIS

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

Bourouaine, Sofiane; Marsch, Eckart, E-mail: bourouaine@mps.mpg.d

2010-01-10

We model a coronal loop as a bundle of seven separate strands or filaments. Each of the loop strands used in this model can independently be heated (near their left footpoints) by Alfven/ion-cyclotron waves via wave-particle interactions. The Alfven waves are assumed to penetrate the strands from their footpoints, at which we consider different wave energy inputs. As a result, the loop strands can have different heating profiles, and the differential heating can lead to a varying cross-field temperature in the total coronal loop. The simulation of Transition Region and Coronal Explorer (TRACE) observations by means of this loop modelmore » implies two uniform temperatures along the loop length, one inferred from the 171:195 filter ratio and the other from the 171:284 ratio. The reproduced flat temperature profiles are consistent with those inferred from the observed extreme-ultraviolet coronal loops. According to our model, the flat temperature profile is a consequence of the coronal loop consisting of filaments, which have different temperatures but almost similar emission measures in the cross-field direction. Furthermore, when we assume certain errors in the simulated loop emissions (e.g., due to photometric uncertainties in the TRACE filters) and use the triple-filter analysis, our simulated loop conditions become consistent with those of an isothermal plasma. This implies that the use of TRACE or EUV Imaging Telescope triple filters for observation of a warm coronal loop may not help in determining whether the cross-field isothermal assumption is satisfied or not.« less

Man-in-the-control-loop simulation of manipulators

NASA Technical Reports Server (NTRS)

Chang, J. L.; Lin, Tsung-Chieh; Yae, K. Harold

1989-01-01

A method to achieve man-in-the-control-loop simulation is presented. Emerging real-time dynamics simulation suggests a potential for creating an interactive design workstation with a human operator in the control loop. The recursive formulation for multibody dynamics simulation is studied to determine requirements for man-in-the-control-loop simulation. High speed computer graphics techniques provides realistic visual cues for the simulator. Backhoe and robot arm simulations are implemented to demonstrate the capability of man-in-the-control-loop simulation.

On the nature of fast sausage waves in coronal loops

NASA Astrophysics Data System (ADS)

Bahari, Karam

2018-05-01

The effect of the parameters of coronal loops on the nature of fast sausage waves are investigated. To do this three models of the coronal loop considered, a simple loop model, a current-carrying loop model and a model with radially structured density called "Inner μ" profile. For all the models the Magnetohydrodynamic (MHD) equations solved analytically in the linear approximation and the restoring forces of oscillations obtained. The ratio of the magnetic tension force to the pressure gradient force obtained as a function of the distance from the axis of the loop. In the simple loop model for all values of the loop parameters the fast sausages wave have a mixed nature of Alfvénic and fast MHD waves, in the current-carrying loop model with thick annulus and low density contrast the fast sausage waves can be considered as purely Alfvénic wave in the core region of the loop, and in the "Inner μ" profile for each set of the parameters of the loop the wave can be considered as a purely Alfvénic wave in some regions of the loop.

Spring control of wire harness loops

NASA Technical Reports Server (NTRS)

Curcio, P. J.

1979-01-01

Negator spring control guides wire harness between movable and fixed structure. It prevents electrical wire harness loop from jamming or being severed as wire moves in response to changes in position of aircraft rudder. Spring-loaded coiled cable controls wire loop regardless of rudder movement.

Loop corrections to primordial non-Gaussianity

NASA Astrophysics Data System (ADS)

Boran, Sibel; Kahya, E. O.

2018-02-01

We discuss quantum gravitational loop effects to observable quantities such as curvature power spectrum and primordial non-Gaussianity of cosmic microwave background (CMB) radiation. We first review the previously shown case where one gets a time dependence for zeta-zeta correlator due to loop corrections. Then we investigate the effect of loop corrections to primordial non-Gaussianity of CMB. We conclude that, even with a single scalar inflaton, one might get a huge value for non-Gaussianity which would exceed the observed value by at least 30 orders of magnitude. Finally we discuss the consequences of this result for scalar driven inflationary models.

System identification from closed-loop data with known output feedback dynamics

NASA Technical Reports Server (NTRS)

Phan, Minh; Juang, Jer-Nan; Horta, Lucas G.; Longman, Richard W.

1992-01-01

This paper presents a procedure to identify the open loop systems when it is operating under closed loop conditions. First, closed loop excitation data are used to compute the system open loop and closed loop Markov parameters. The Markov parameters, which are the pulse response samples, are then used to compute a state space representation of the open loop system. Two closed loop configurations are considered in this paper. The closed loop system can have either a linear output feedback controller or a dynamic output feedback controller. Numerical examples are provided to illustrate the proposed closed loop identification method.

Radiation Enhanced Absorption of Frank Loops by Nanovoids in Cu

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

Chen, Youxing; Zhang, Xinghang; Wang, Jian

Neutron and heavy ion irradiation generally induces voids in metallic materials, and continuous radiations typically result in void swelling and mechanical failure of the irradiated materials. Recent experiments showed that nanovoids in nanotwinned copper could act as sinks for radiation-induced Frank loops, significantly mitigating radiation damage [Y. Chen et al., Nat. Commun. 6:7036 (2015)]. In this paper, we report on structural evolution of Frank loops under cascades and address the role of nanovoids in absorbing Frank loops in detail by using molecular dynamics simulations. Results show that a stand-alone Frank loop is stable under cascades. When Frank loops are adjacentmore » to nanovoids, the diffusion of a group of atoms from the loop into nanovoids is accomplished via the formation and propagation of dislocation loops. The loop-nanovoid interactions result in the shrinkage of the nanovoids and the Frank loops.« less

Radiation Enhanced Absorption of Frank Loops by Nanovoids in Cu

DOE PAGES

Chen, Youxing; Zhang, Xinghang; Wang, Jian

2016-11-01

Neutron and heavy ion irradiation generally induces voids in metallic materials, and continuous radiations typically result in void swelling and mechanical failure of the irradiated materials. Recent experiments showed that nanovoids in nanotwinned copper could act as sinks for radiation-induced Frank loops, significantly mitigating radiation damage [Y. Chen et al., Nat. Commun. 6:7036 (2015)]. In this paper, we report on structural evolution of Frank loops under cascades and address the role of nanovoids in absorbing Frank loops in detail by using molecular dynamics simulations. Results show that a stand-alone Frank loop is stable under cascades. When Frank loops are adjacentmore » to nanovoids, the diffusion of a group of atoms from the loop into nanovoids is accomplished via the formation and propagation of dislocation loops. The loop-nanovoid interactions result in the shrinkage of the nanovoids and the Frank loops.« less

Browns Ferry-1 single-loop operation tests

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

March-Leuba, J.; Wood, R.T.; Otaduy, P.J.

1985-09-01

This report documents the results of the stability tests performed on February 9, 1985, at the Browns Ferry Nuclear Power Plant Unit 1 under single-loop operating conditions. The observed increase in neutron noise during single-loop operation is solely due to an increase in flow noise. The Browns Ferry-1 reactor has been found to be stable in all modes of operation attained during the present tests. The most unstable test plateau corresponded to minimum recirculation pump speed in single-loop operation (test BFTP3). This operating condition had the minimum flow and maximum power-to-flow ratio. The estimated decay ratio in this plateau ismore » 0.53. The decay ratio decreased as the flow was increased during single-loop operation (down to 0.34 for test plateau BFTP6). This observation implies that the core-wide reactor stability follows the same trends in single-loop as it does in two-loop operation. Finally, no local or higher mode instabilities were found in the data taken from local power range monitors. The decay ratios estimated from the local power range monitors were not significantly different from those estimated from the average power range monitors.« less

Thumb-loops up for catalysis: a structure/function investigation of a functional loop movement in a GH11 xylanase

PubMed Central

Paës, Gabriel; Cortés, Juan; Siméon, Thierry; O'Donohue, Michael J.; Tran, Vinh

2012-01-01

Dynamics is a key feature of enzyme catalysis. Unfortunately, current experimental and computational techniques do not yet provide a comprehensive understanding and description of functional macromolecular motions. In this work, we have extended a novel computational technique, which combines molecular modeling methods and robotics algorithms, to investigate functional motions of protein loops. This new approach has been applied to study the functional importance of the so-called thumb-loop in the glycoside hydrolase family 11 xylanase from Thermobacillus xylanilyticus (Tx-xyl). The results obtained provide new insight into the role of the loop in the glycosylation/deglycosylation catalytic cycle, and underline the key importance of the nature of the residue located at the tip of the thumb-loop. The effect of mutations predicted in silico has been validated by in vitro site-directed mutagenesis experiments. Overall, we propose a comprehensive model of Tx-xyl catalysis in terms of substrate and product dynamics by identifying the action of the thumb-loop motion during catalysis. PMID:24688637

Transequatorial loops interconnecting McMath regions 12472 and 12474

NASA Technical Reports Server (NTRS)

Svestka, Z.; Krieger, A. S.; Chase, R. C.; Howard, R.

1977-01-01

The paper reviews the life history of one transequatorial loop in a system observed in soft X-rays for at least 1.5 days and which interconnected a newly born active region with an old region. The birth of the selected loop is discussed along with properties of the interconnected active regions, sharpening and brightening of the loop, decay of the loop system, and physical relations between the interconnected regions. It is concluded that: (1) the loop was most probably born via reconnection of magnetic-field lines extending from the two active regions toward the equator, which occurred later than 33 hr after the younger region was born; (2) the fully developed interconnection was composed of several loops, all of which appeared to be rooted in a spotless magnetic hill of preceding northern polarity but were spread over two separate spotty regions of southern polarity in the magnetically complex new region; (3) the loop electron temperature increased from 2.1 million to 3.1 million K in one to three hours when the loop system brightened; and (4) the loops became twisted during the brightening, possibly due to their rise in the corona while remaining rooted in moving magnetic features in the younger region.

Markovian modeling of classical thermal noise in two inductively coupled wire loops

NASA Astrophysics Data System (ADS)

Gillespie, Daniel T.

1997-03-01

Continuous Markov process theory is used to model classical thermal noise in two wire loops of resistances R1 and R2 , self-inductances L1 and L2 , and absolute temperature T, which are coupled through their mutual inductance M. It is shown that even though the currents I1 (t) and I2 (t) in the two loops become progressively noisier as M increases from 0 toward its upper bound (L1 L2 )1/2 , the fluctuation-dissipation, Nyquist, and conductance formulas all remain unchanged. But changes do occur in the spectral density functions of the currents Ii (t). Exact formulas for those functions are developed, and two special cases are examined in detail. (i) In the identical loop case (R1 =R2 =R and L1 =L2 =L), the M=0 'knee' at frequency R/2πL in the spectral density function of Ii (t), below which that function has slope 0 and above which it has slope -2, is found to split when M>0 into two knees at frequencies R/[2π(L+/-M)]. The noise remains white, but surprisingly slightly suppressed, at frequencies below R/[2π(L+M)], and it remains 1/f2 at frequencies above R/[2π(L-M)]. In between the two knee frequencies a rough '1/f-type' noise behavior is exhibited. The sum and difference currents I+/- (t)≡I1 (t)+/-I2 (t) are found to behave like thermal currents in two uncoupled loops with resistances R, self-inductances (L+/-M), and temperatures 2T. In the limit M-->L, I+ (t) approaches the thermal current in a loop of resistance R and self-inductance L at temperature T, while I- (t) approaches (4kT/R)1/2 times Gaussian white noise. (ii) In the weakly coupled highly dissimilar loop case (R1 <loop 1. But the spectral density function of I1 (t) is found to be enhanced for frequencies ν<factor (1+αν2 ), where α=(2πM)2 /R1 R2 . A concomitant enhancement, by an approximate factor of (1+2M2 R2 /L2 R1 )1/2 , is found in the high

Harwell high pressure heat transfer loop

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

Bennett, A.W.; Keeys, R.K.F.

1967-12-15

A detailed description is presented of the Harwell (Chemical Engineering and Process Technology Division) high pressure, steam-water heat transfer loop; this description is aimed at supplementing the information given in reports on individual experiments. The operating instructions for the loop are given in an appendix. (auth)

Structures of apo IRF-3 and IRF-7 DNA binding domains: effect of loop L1 on DNA binding

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

De Ioannes, Pablo; Escalante, Carlos R.; Aggarwal, Aneel K.

2013-11-20

Interferon regulatory factors IRF-3 and IRF-7 are transcription factors essential in the activation of interferon-{beta} (IFN-{beta}) gene in response to viral infections. Although, both proteins recognize the same consensus IRF binding site AANNGAAA, they have distinct DNA binding preferences for sites in vivo. The X-ray structures of IRF-3 and IRF-7 DNA binding domains (DBDs) bound to IFN-{beta} promoter elements revealed flexibility in the loops (L1-L3) and the residues that make contacts with the target sequence. To characterize the conformational changes that occur on DNA binding and how they differ between IRF family members, we have solved the X-ray structures ofmore » IRF-3 and IRF-7 DBDs in the absence of DNA. We found that loop L1, carrying the conserved histidine that interacts with the DNA minor groove, is disordered in apo IRF-3 but is ordered in apo IRF-7. This is reflected in differences in DNA binding affinities when the conserved histidine in loop L1 is mutated to alanine in the two proteins. The stability of loop L1 in IRF-7 derives from a unique combination of hydrophobic residues that pack against the protein core. Together, our data show that differences in flexibility of loop L1 are an important determinant of differential IRF-DNA binding.« less

Dynamical behaviour in coronal loops

NASA Technical Reports Server (NTRS)