Effects of Human Recombinant PEDF Protein and PEDF-Derived Peptide 34-mer on Choroidal Neovascularization

PubMed Central

Amaral, Juan

2010-01-01

Purpose. Pigment epithelium-derived factor (PEDF) is a serpin with antiangiogenic properties. Previously, the authors showed that PEDF injected into the subconjunctiva reaches the choroid. Here, they examined the effects of PEDF polypeptide fragments on vessel sprouting and on choroidal neovascularization (CNV) after subconjunctival administration. Methods. Recombinant human PEDF (rhuPEDF) was cleaved at its serpin-exposed loop by limited chymotrypsin proteolysis. Synthetic PEDF peptides 34-mer (Asp44-Asn77) and 44-mer (Val78-Thr121) were used. Ex vivo chick aortic vessel sprouting assays were performed. CNV was induced in rats by laser injury of Bruch's membrane. Daily subconjunctival injections (0.01–10 pmol/d protein) were performed for 5 days starting at day of injury or at the seventh day after injury. New vessel volumes were quantified using optical sections of choroid/RPE flat-mounts labeled with isolectin-Ib4. PEDF distribution was evaluated by immunofluorescence of choroid/RPE/retina cross-sections. Results. Full-length rhuPEDF, cleaved rhuPEDF, or peptide 34-mer exhibited ex vivo antiangiogenic activity, but peptide 44-mer was inefficient. PEDF immunostaining around CNV lesions diminished after laser injury. Subconjunctival administration of rhuPEDF or 34-mer at 0.1 pmol/d decreased CNV lesion volumes by 52% and 47%, respectively, whereas those of 44-mer were similar to vehicle injections. Doses of 0.1 and 1 pmol/d rhuPEDF decreased fully developed CNV complex volumes by 45% and 50%, respectively, compared with vehicle injections. Conclusions. A functional region for the inhibition of vessel sprouting and CNV resides within the 34-mer region of PEDF. Furthermore, subconjunctival administration of optimal range dosages of rhuPEDF or 34-mer can suppress and regress rat CNV lesions, demonstrating that these agents reach the choroid/RPE complex as functionally active molecules. PMID:19850839

Role of pigment epithelium-derived factor in the reproductive system.

PubMed

Chuderland, Dana; Ben-Ami, Ido; Bar-Joseph, Hadas; Shalgi, Ruth

2014-10-01

The physiological function of the female reproductive organs is hormonally controlled. In each cycle, the reproductive organs undergo tissue modifications that are accompanied by formation and destruction of blood vessels. Proper angiogenesis requires an accurate balance between stimulatory and inhibitory signals, provided by pro- and anti-angiogenic factors. As with many other tissues, vascular endothelial growth factor (VEGF) appears to be one of the major pro-angiogenic factors in the female reproductive organs. Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic activity that negates VEGF activity. The role of PEDF in decreasing abnormal neovascularization by exerting its anti-angiogenic effect that inhibits pro-angiogenic factors, including VEGF, has been investigated mainly in the eye and in cancer. This review summarizes the function of PEDF in the reproductive system, showing its hormonal regulation and its anti-angiogenic activity. Furthermore, some pathologies of the female reproductive organs, including endometriosis, ovarian hyperstimulation syndrome, polycystic ovary syndrome, and others, are associated with a faulty angiogenic process. This review illuminates the role of PEDF in their pathogenesis and treatment. Collectively, we can conclude that although PEDF seems to play an essential role in the physiology and pathophysiology of the reproductive system, its full role and mechanism of action still need to be elucidated. © 2014 Society for Reproduction and Fertility.

Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs

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

Chen Haibing; Department of Ophthalmology, Anhui Provincial Hospital, Hefei; Jia Weiping

2008-05-02

Poly(ADP-ribose)polymerase (PARP) inhibitors decrease angiogenesis through reducing vascular endothelium growth factor (VEGF) induced proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In contrast to VEGF, pigment epithelium-derived factor (PEDF) has been demonstrated to act as a strong endogenous inhibitor of angiogenesis. Here, we show that PARP inhibition with a specific inhibitor PJ-34 or specific PARP antisense oligonucleotide upregulates hyperglycemia-induced PEDF expression in HUVECs in a dose-dependent manner. This results in the retard of activation of p38 MAP kinase and the concomitant decrease in cell apoptosis. These results give the first direct demonstration that PEDF might representmore » a target for PARP inhibition treatment and the effects of PEDF on endothelial cells growth are context dependent.« less

Defects in subventricular zone pigmented epithelium-derived factor niche signaling in the senescence-accelerated mouse prone-8.

PubMed

Castro-Garcia, Paola; Díaz-Moreno, María; Gil-Gas, Carmen; Fernández-Gómez, Francisco J; Honrubia-Gómez, Paloma; Álvarez-Simón, Carmen Belén; Sánchez-Sánchez, Francisco; Cano, Juan Carlos Castillo; Almeida, Francisco; Blanco, Vicente; Jordán, Joaquín; Mira, Helena; Ramírez-Castillejo, Carmen

2015-04-01

We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model. © FASEB.

Cell and Molecular Biology Underpinning the Effects of PEDF on Cancers in General and Osteosarcoma in Particular

PubMed Central

Chandolu, Vijay; Dass, Crispin R.

2012-01-01

Cancer is becoming an increasingly common disease in which abnormal cells aggressively grow, invade, and metastasize. In this paper, we review the biological functions of PEDF (pigmented epithelium-derived factor) against cancer, with a focus on a particular type of bone cancer called osteosarcoma. PEDF is a 50 kDa glycoprotein and is a potent inhibitor of angiogenesis, via its ability to decrease proliferation and migration of endothelial cells. This paper critically examines the anticancer activities of PEDF via its role in antiangiogenesis, apoptosis-mediated tumor suppression, and increased tumor cell differentiation. Recently, an orthotopic model of osteosarcoma was used to show that treatment with PEDF had the greatest impact on metastases, warranting an evaluation of PEDF efficacy in other types of cancers. PMID:22690122

Pigment Epithelium Derived Factor Peptide Protects Murine Hepatocytes from Carbon Tetrachloride-Induced Injury

PubMed Central

Shih, Shou-Chuan; Ho, Tsung-Chuan; Chen, Show-Li; Tsao, Yeou-Ping

2016-01-01

Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl4). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl4, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl4-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl4 caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl4 injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl4 injury. This protective effect may stem from strengthening the counter oxidative stress capacity and induction of hepatoprotective factors. PMID:27384427

Pigment epithelium-derived factor upregulates collagen I and downregulates matrix metalloproteinase 2 in osteosarcoma cells, and colocalises to collagen I and heat shock protein 47 in fetal and adult bone.

PubMed

Alcantara, Marice B; Nemazannikova, Natalie; Elahy, Mina; Dass, Crispin R

2014-11-01

Pigment epithelium-derived factor (PEDF) has proven anti-osteosarcoma activity. However, the mechanism(s) underpinning its ability to reduce primary bone tumour (osteosarcoma) metastasis is unknown. Adult and fetal murine bone were immunostained for PEDF, collagen I (major protein in bone) and its processing proteins, heat shock protein 47 (HSP47, a chaperone protein for collagen I), membrane type I matrix metalloproteinase (MT1-MMP, a collagenase), and matrix metalloproteinase 2 (MMP-2, which is activated by MT1-MMP). Immunoblotting and immunocytochemistry were used to observe levels of the above biomarkers when human osteosarcoma cells were treated with PEDF. Immunohistochemical staining in adult and fetal bone mirrors collagen I. PEDF localised to ridges of trabecular bone in tibial cortex and to megakaryocytes within bone marrow. Second, we observed that PEDF upregulates collagen I, HSP47 and MT1-MMP, while downregulating MMP-2 in osteosarcoma cells in vitro. PEDF is a promising antagonist to osteosarcoma cell metastasis via downregulation of MMP-2, and can induce tumour cells to further adopt differentiative properties, thereby possibly reducing their aggressive growth in vitro and in vivo. © 2014 Royal Pharmaceutical Society.

Pigment Epithelium-Derived Factor Blocks Tumor Extravasation by Suppressing Amoeboid Morphology and Mesenchymal Proteolysis12

PubMed Central

Ladhani, Omar; Sánchez-Martinez, Cristina; Orgaz, Jose L; Jimenez, Benilde; Volpert, Olga V

2011-01-01

Metastatic melanoma cells are highly adaptable to their in vivo microenvironment and can switch between protease-dependent mesenchymal and protease-independent amoeboid invasion to facilitate metastasis. Such adaptability can be visualized in vitro, when cells are cultured in conditions that recapitulate three-dimensional microenvironments. Using thick collagen layers in cell culture and in vivo extravasation assays, we found that pigment epithelium-derived factor (PEDF) suppressed lung extravasation of aggressive melanoma by coordinated regulation of cell shape and proteolysis. In cells grown on a thick collagen bed, PEDF overexpression and exogenous PEDF blocked the rapidly invasive, rounded morphology, and promoted an elongated, mesenchymal-like phenotype associated with reduced invasion. These changes in cell shape depended on decreased RhoA and increased Rac1 activation and were mediated by the up-regulation of Rac1-GEF, DOCK3 and down-regulation of Rac1-GAP, ARHGAP22. Surprisingly, we found that PEDF overexpression also blocked the trafficking of membrane-tethered, MT1-MMP to the cell surface through RhoA inhibition and Rac1 activation. In vivo, knockdown of Rac1 and DOCK3 or overexpression of MT1-MMP was sufficient to reverse the inhibitory effect of PEDF on extravasation. Using functional studies, we demonstrated that PEDF suppressed the rounded morphology and MT1-MMP surface localization through its antiangiongenic, 34-mer epitope and the recently identified PEDF receptor candidate, PNPLA2. Our findings unveil the coordinated regulation of cell shape and proteolysis and identify an unknown mechanism for PEDF's antimetastatic activity. PMID:21750657

Pigment epithelium-derived factor blocks tumor extravasation by suppressing amoeboid morphology and mesenchymal proteolysis.

PubMed

Ladhani, Omar; Sánchez-Martinez, Cristina; Orgaz, Jose L; Jimenez, Benilde; Volpert, Olga V

2011-07-01

Metastatic melanoma cells are highly adaptable to their in vivo microenvironment and can switch between protease-dependent mesenchymal and protease-independent amoeboid invasion to facilitate metastasis. Such adaptability can be visualized in vitro, when cells are cultured in conditions that recapitulate three-dimensional microenvironments. Using thick collagen layers in cell culture and in vivo extravasation assays, we found that pigment epithelium-derived factor (PEDF) suppressed lung extravasation of aggressive melanoma by coordinated regulation of cell shape and proteolysis. In cells grown on a thick collagen bed, PEDF overexpression and exogenous PEDF blocked the rapidly invasive, rounded morphology, and promoted an elongated, mesenchymal-like phenotype associated with reduced invasion. These changes in cell shape depended on decreased RhoA and increased Rac1 activation and were mediated by the up-regulation of Rac1-GEF, DOCK3 and down-regulation of Rac1-GAP, ARHGAP22. Surprisingly, we found that PEDF overexpression also blocked the trafficking of membrane-tethered, MT1-MMP to the cell surface through RhoA inhibition and Rac1 activation. In vivo, knockdown of Rac1 and DOCK3 or overexpression of MT1-MMP was sufficient to reverse the inhibitory effect of PEDF on extravasation. Using functional studies, we demonstrated that PEDF suppressed the rounded morphology and MT1-MMP surface localization through its antiangiongenic, 34-mer epitope and the recently identified PEDF receptor candidate, PNPLA2. Our findings unveil the coordinated regulation of cell shape and proteolysis and identify an unknown mechanism for PEDF's antimetastatic activity.

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

PubMed Central

Wietecha, Mateusz S.; Król, Mateusz J.; Michalczyk, Elizabeth R.; Chen, Lin; Gettins, Peter G.

2015-01-01

During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis. Mechanisms guiding wound resolution are poorly understood; one candidate regulator is pigment epithelium-derived factor (PEDF), a secreted glycoprotein. PEDF is a potent antiangiogenic in models of pathological angiogenesis and a promising cancer and cardiovascular disease therapeutic, but little is known about its physiological function. To examine the roles of PEDF in physiological wound repair, we used a reproducible model of excisional skin wound healing in BALB/c mice. We show that PEDF is abundant in unwounded and healing skin, is produced primarily by dermal fibroblasts, binds to resident microvascular endothelial cells, and accumulates in dermal ECM and epidermis. PEDF transcript and protein levels were low during the inflammatory and proliferative phases of healing but increased in quantity and colocalization with microvasculature during wound resolution. Local antibody inhibition of endogenous PEDF delayed vessel regression and collagen maturation during the remodeling phase. Treatment of wounds with intradermal injections of exogenous, recombinant PEDF inhibited nascent angiogenesis by repressing endothelial proliferation, promoted vascular integrity and function, and increased collagen maturity. These results demonstrate that PEDF contributes to the resolution of healing wounds by causing regression of immature blood vessels and stimulating maturation of the vascular microenvironment, thus promoting a return to tissue homeostasis after injury. PMID:26163443

PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells.

PubMed

Ho, Tsung-Chuan; Chiang, Yi-Pin; Chuang, Chih-Kuang; Chen, Show-Li; Hsieh, Jui-Wen; Lan, Yu-Wen; Tsao, Yeou-Ping

2015-08-01

In response injury, intrinsic repair mechanisms are activated in skeletal muscle to replace the damaged muscle fibers with new muscle fibers. The regeneration process starts with the proliferation of satellite cells to give rise to myoblasts, which subsequently differentiate terminally into myofibers. Here, we investigated the promotion effect of pigment epithelial-derived factor (PEDF) on muscle regeneration. We report that PEDF and a synthetic PEDF-derived short peptide (PSP; residues Ser(93)-Leu(112)) induce satellite cell proliferation in vitro and promote muscle regeneration in vivo. Extensively, soleus muscle necrosis was induced in rats by bupivacaine, and an injectable alginate gel was used to release the PSP in the injured muscle. PSP delivery was found to stimulate satellite cell proliferation in damaged muscle and enhance the growth of regenerating myofibers, with complete regeneration of normal muscle mass by 2 wk. In cell culture, PEDF/PSP stimulated C2C12 myoblast proliferation, together with a rise in cyclin D1 expression. PEDF induced the phosphorylation of ERK1/2, Akt, and STAT3 in C2C12 myoblasts. Blocking the activity of ERK, Akt, or STAT3 with pharmacological inhibitors attenuated the effects of PEDF/PSP on the induction of C2C12 cell proliferation and cyclin D1 expression. Moreover, 5-bromo-2'-deoxyuridine pulse-labeling demonstrated that PEDF/PSP stimulated primary rat satellite cell proliferation in myofibers in vitro. In summary, we report for the first time that PSP is capable of promoting the regeneration of skeletal muscle. The signaling mechanism involves the ERK, AKT, and STAT3 pathways. These results show the potential utility of this PEDF peptide for muscle regeneration. Copyright © 2015 the American Physiological Society.

Human adipose-derived mesenchymal stromal cell pigment epithelium-derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells.

PubMed

Zolochevska, Olga; Shearer, Joseph; Ellis, Jayne; Fokina, Valentina; Shah, Forum; Gimble, Jeffrey M; Figueiredo, Marxa L

2014-03-01

Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells. ASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epithelium-derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture-conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer-focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays. ASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs. These results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Pigment epithelium-derived factor stimulates skeletal muscle glycolytic activity through NADPH oxidase-dependent reactive oxygen species production.

PubMed

Carnagarin, Revathy; Carlessi, Rodrigo; Newsholme, Philip; Dharmarajan, Arun M; Dass, Crispin R

2016-09-01

Pigment epithelium-derived factor is a multifunctional serpin implicated in insulin resistance in metabolic disorders. Recent evidence suggests that exposure of peripheral tissues such as skeletal muscle to PEDF has profound metabolic consequences with predisposition towards chronic conditions such as obesity, type 2 diabetes, metabolic syndrome and polycystic ovarian syndrome. Chronic inflammation shifts muscle metabolism towards increased glycolysis and decreased oxidative metabolism. In the present study, we demonstrate a novel effect of PEDF on cellular metabolism in mouse cell line (C2C12) and human primary skeletal muscle cells. PEDF addition to skeletal muscle cells induced enhanced phospholipase A2 activity. This was accompanied with increased production of reactive oxygen species in a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent manner that triggered a shift towards a more glycolytic phenotype. Extracellular flux analysis and glucose consumption assays demonstrated that PEDF treatment resulted in enhanced glycolysis but did not change mitochondrial respiration. Our results demonstrate that skeletal muscle cells express a PEDF-inducible oxidant generating system that enhances glycolysis but is sensitive to antioxidants and NADPH oxidase inhibition. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration.

PubMed

Wang, Yujuan; Subramanian, Preeti; Shen, Defen; Tuo, Jingsheng; Becerra, S Patricia; Chan, Chi-Chao

2013-11-26

AMD (age-related macular degeneration) is a neurodegenerative disease causing irreversible central blindness in the elderly. Apoptosis and inflammation play important roles in AMD pathogenesis. PEDF (pigment epithelium-derived factor) is a potent neurotrophic and anti-inflammatory glycoprotein that protects the retinal neurons and photoreceptors against cell death caused by pathological insults. We studied the effects of PEDF on focal retinal lesions in DKO rd8 (Ccl2(-/-)/Cx3cr1(-/-) on C57BL/6N [Crb1(rd8)]) mice, a model for progressive, focal rd (retinal degeneration). First, we found a significant decrease in PEDF transcript expression in DKO rd8 mouse retina and RPE (retinal pigment epithelium) than WT (wild-type, C57BL/6N). Next, cultured DKO rd8 RPE cells secreted lower levels of PEDF protein in the media than WT. Then the right eyes of DKO rd8 mice were injected intravitreously with recombinant human PEDF protein (1 μg), followed by a subconjunctival injection of PEDF (3 μg) 4 weeks later. The untreated left eyes served as controls. The effect of PEDF was assessed by fundoscopy, ocular histopathology and A2E {[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium} levels, as well as apoptotic and inflammatory molecules. The PEDF-treated eyes showed slower progression or attenuation of the focal retinal lesions, fewer and/or smaller photoreceptor and RPE degeneration, and significantly lower A2E, relative to the untreated eyes. In addition, lower expression of apoptotic and inflammatory molecules were detected in the PEDF-treated than untreated eyes. Our results establish that PEDF potently stabilizes photoreceptor degeneration via suppression of both apoptotic and inflammatory pathways. The multiple beneficial effects of PEDF represent a novel approach for potential AMD treatment.

Pigment epithelium-derived factor protects retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction

PubMed Central

Tian, Shu-Wei; Ren, Yuan; Pei, Jin-Zhi; Ren, Bai-Chao; He, Yuan

2017-01-01

AIM To investigate the potential of pigment epithelium-derived factor (PEDF) to protect the immortalized rat retinal ganglion cells-5 (RGC-5) exposed to CoCl2-induced chemical hypoxia. METHODS After being differentiated with staurosporine (SS), RGC-5 cells were cultured in four conditions: control group cells cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum, 100 µmol/mL streptomycin and penicillin (named as normal conditions); hypoxia group cells cultured in DMEM containing 300 µmol/mL CoCl2; cells in the group protected by PEDF were first pretreated with 100 ng/mL PEDF for 2h and then cultured in the same condition as hypoxia group cells; and PEDF group cells that were cultured in the presence of 100 ng/mL PEDF under normal conditions. The cell viability was assessed by MTT assay, the percentage of apoptotic cells was quantified using Annexin V-FITC apoptosis kit, and intra-cellar reactive oxygen species (ROS) was measured by dichloro-dihydro-fluorescein diacetate (DCFH-DA) probe. The mitochondria-mediated apoptosis was also examined to further study the underlying mechanism of the protective effect of PEDF. The opening of mitochondrial permeability transition pores (mPTPs) and membrane potential (Δψm) were tested as cellular adenosine triphosphate (ATP) level and glutathione (GSH). Also, the expression and distribution of Cyt C and apoptosis inducing factor (AIF) were observed. RESULTS SS induced differentiation of RGC-5 cells resulting in elongation of their neurites and establishing contacts between outgrowths. Exposure to 300 µmol/mL CoCl2 triggered death of 30% of the total cells in cultures within 24h. At the same time, pretreatment with 100 ng/mL PEDF significantly suppressed the cell death induced by hypoxia (P<0.05). The apoptosis induced by treatment of CoCl2 was that induced cell death accompanied with increasing intra-cellar ROS and decreasing GSH and ATP level. PEDF pre-treatment suppressed these effects (P<0.05). Additionally, PEDF treatment inhibited the opening of mPTPs and suppressed decreasing of Δψm in RGC-5 cells, resulting in blocking of the mitochondrial apoptotic pathway. CONCLUSION Pretreatment of RGC-5 cells with 100 ng/mL PEDF significantly decreases the extent of apoptosis. PEDF inhibits the opening of mPTPs and suppresses decreasing of Δψm. Moreover, PEDF also reduces ROS production and inhibits cellular ATP level's reduction. Cyt C and AIF activation in PEDF-pretreated cultures are also reduced. These results demonstrate the potential for PEDF to protect RGCs against hypoxic damage in vitro by preventing mitochondrial dysfunction. PMID:28730105

PEDF Is Associated with the Termination of Chondrocyte Phenotype and Catabolism of Cartilage Tissue.

PubMed

Klinger, P; Lukassen, S; Ferrazzi, F; Ekici, A B; Hotfiel, T; Swoboda, B; Aigner, T; Gelse, K

2017-01-01

Objective. To investigate the expression and target genes of pigment epithelium-derived factor (PEDF) in cartilage and chondrocytes, respectively. Methods. We analyzed the expression pattern of PEDF in different human cartilaginous tissues including articular cartilage, osteophytic cartilage, and fetal epiphyseal and growth plate cartilage, by immunohistochemistry and quantitative real-time (qRT) PCR. Transcriptome analysis after stimulation of human articular chondrocytes with rhPEDF was performed by RNA sequencing (RNA-Seq) and confirmed by qRT-PCR. Results. Immunohistochemically, PEDF could be detected in transient cartilaginous tissue that is prone to undergo endochondral ossification, including epiphyseal cartilage, growth plate cartilage, and osteophytic cartilage. In contrast, PEDF was hardly detected in healthy articular cartilage and in the superficial zone of epiphyses, regions that are characterized by a permanent stable chondrocyte phenotype. RNA-Seq analysis and qRT-PCR demonstrated that rhPEDF significantly induced the expression of a number of matrix-degrading factors including SAA1, MMP1, MMP3, and MMP13. Simultaneously, a number of cartilage-specific genes including COL2A1, COL9A2, COMP, and LECT were among the most significantly downregulated genes. Conclusions. PEDF represents a marker for transient cartilage during all neonatal and postnatal developmental stages and promotes the termination of cartilage tissue by upregulation of matrix-degrading factors and downregulation of cartilage-specific genes. These data provide the basis for novel strategies to stabilize the phenotype of articular cartilage and prevent its degradation.

Osteopontin and Other Regulators of Angiogenesis and Fibrogenesis in the Vitreous from Patients with Proliferative Vitreoretinal Disorders

PubMed Central

Abu El-Asrar, Ahmed M.; Imtiaz Nawaz, Mohd; Kangave, Dustan; Siddiquei, Mohammed Mairaj; Geboes, Karel

2012-01-01

The aim of this study was to determine the levels of the angiogenic and fibrogenic factors osteopontin (OPN), high-mobility group box-1 (HMGB1), and connective tissue growth factor (CTGF) and the antiangiogenic and antifibrogenic pigment epithelium-derived factor (PEDF) in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and rhegmatogenous retinal detachment with no PVR (RD). Vitreous samples from 48 PDR, 17 PVR and 30 RD patients were studied by enzyme-linked immunosorbent assay. OPN, HMGB1, CTGF, and PEDF levels were significantly higher in PDR patients than in RD patients (P < 0.001; 0.002; <0.001; <0.001, resp.). CTGF and PEDF levels were significantly higher in PVR patients than in RD patients (P < 0.001; 0.004, resp.). Exploratory logistic regression analysis identified significant associations between PDR and high levels of HMGB1, CTGF and PEDF, between PDR with active neovascularization and high levels of CTGF and PEDF, and between PDR with traction retinal detachment and high levels of HMGB1. In patients with PDR, there were significant correlations between the levels of PEDF and the levels of OPN (r = 0.544, P = 0.001), HMGB1 (r = 0.719, P < 0.001), and CTGF (r = 0.715, P < 0.001). In patients with PVR, there were significant correlations between the levels of OPN and the levels of HMGB1 (r = 0.484, P = 0.049) and PEDF (r = 0.559, P = 0.02). Our findings suggest that OPN, HMGB1, and CTGF contribute to the pathogenesis of proliferative vitreoretinal disorders and that increased levels of PEDF may be a response to counterbalance the activity of angiogenic and fibrogenic factors in PDR and PVR. PMID:23055574

Opposing Effects of Pigment Epithelium-Derived Factor on Breast Cancer Cell versus Neuronal Survival: Implication for Brain Metastasis and Metastasis-Induced Brain Damage

PubMed Central

Fitzgerald, Daniel P.; Subramanian, Preeti; Deshpande, Monika; Graves, Christian; Gordon, Ira; Qian, Yongzhen; Snitkovsky, Yeva; Liewehr, David J.; Steinberg, Seth M.; Paltán-Ortiz, José D.; Herman, Mary M.; Camphausen, Kevin; Palmieri, Diane; Becerra, S. Patricia; Steeg, Patricia S.

2011-01-01

Brain metastases are a significant cause of cancer patient morbidity and mortality, yet preventative and therapeutic options remain an unmet need. The cytokine PEDF is downregulated in resected human brain metastases of breast cancer compared to primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a pro-survival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish that PEDF as both a metastatic suppressor and a neuroprotectant in the the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences. PMID:22215693

PEDF attenuates insulin-dependent molecular pathways of glucose homeostasis in skeletal myocytes.

PubMed

Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

2016-02-15

Pigment epithelium-derived factor (PEDF) is an anti-angiogenic serpin associated with insulin resistance in metabolic disorders such as diabetes, metabolic syndrome, obesity and polycystic ovarian syndrome. While the mechanism of PEDF induced-insulin resistance of metabolic disorders has been attributed to its inflammatory and lipolytic effects, little evidence exists to support a direct role of PEDF in mediating insulin resistance. Here, we seminally provide evidence that PEDF can inhibit insulin signal transduction governing glucose homeostasis from the receptor to the effector phosphorylation through Akt/PKB-dependent and -independent pathways in mouse and human skeletal muscle cell lines. PEDF attenuates the insulin-dependent molecular axes of glucose metabolism. Exposure of skeletal myocytes to PEDF attenuates insulin-dependent insulin receptor autophosphorylation, tyrosine phosphorylation of insulin receptor substrate 1, and dual loop phosphorylation-activation of Akt. PEDF significantly inhibits the downstream effector - glycogen synthase kinase (and thereby the glycogenic axis of insulin signalling). PEDF turned off both the molecular switches of GLUT4 translocation: IRS-Akt/PKB-AS160 mediated and IR-pCbl-dependent GLUT4 translocation (the molecular axis of glucose uptake). These findings implicate a direct effect of PEDF on multiple insulin-dependent molecular mechanisms of glucose homeostasis in skeletal muscle cells, thereby enabling it to contribute to peripheral insulin resistance at the cellular level. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A dock derived compound against laminin receptor (37 LR) exhibits anti-cancer properties in a prostate cancer cell line model.

PubMed

Umbaugh, Charles Samuel; Diaz-Quiñones, Adriana; Neto, Manoel Figueiredo; Shearer, Joseph J; Figueiredo, Marxa L

2018-01-19

Laminin receptor (67 LR) is a 67 kDa protein derived from a 37 kDa precursor (37 LR). 37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transduce physiochemical and mechanosensing signals in endothelial cells and modulate angiogenesis. Recently, it was demonstrated that 37/67 LR modulates the anti-angiogenic potential of the secreted glycoprotein pigment epithelium-derived factor (PEDF). Restoration of PEDF balance is a desirable therapeutic outcome, and we sought to identify a small molecule that could recapitulate known signaling properties of PEDF but without the additional complications of peptide formulation or gene delivery safety validation. We used an in silico drug discovery approach to target the interaction interface between PEDF and 37 LR. Following cell based counter screening and binding validation, we characterized a hit compound's anti-viability, activation of PEDF signaling-related genes, anti-wound healing, and anti-cancer signaling properties. This hit compound has potential for future development as a lead compound for treating tumor growth and inhibiting angiogenesis.

Efficacy of Continuously Administered PEDF-Derived Synthetic Peptides against Osteosarcoma Growth and Metastasis

PubMed Central

Broadhead, Matthew L.; Choong, Peter F. M.; Dass, Crispin R.

2012-01-01

The potent antiangiogenic pigment epithelium-derived factor (PEDF) has shown promise against osteosarcoma, a tumour that originates in the bone and metastasises to the lungs. Neurotrophic, antiangiogenic, antiproliferative, and antimetastatic properties of PEDF have been attributed to a number of functional epitopes on the PEDF glycoprotein. StVOrth-2 (residues 78–102) and StVOrth-3 (residues 90–114) are two PEDF-derived peptides based on these functional epitopes. StVOrth-2 has previously been shown to inhibit osteosarcoma cell proliferation, while StVOrth-3 increased osteosarcoma cell adhesion to collagen I in vitro. In this paper, we have evaluated systemically and continuously delivered StVOrth-2 and StVOrth-3 using a clinically relevant murine model of osteosarcoma with spontaneous metastasis. Treatment with StVOrth-2 or StVOrth-3 with microosmotic pumps was initiated after primary osteosarcoma was established in the tibia. While treatment with StVOrth-2 and StVOrth-3 did not appear to affect local tumour invasion, tumour necrosis or apoptosis, StVOrth-2 predominantly restricted the growth of primary tumours, while StVOrth-3 restricted the burden of pulmonary metastatic disease. No peptide caused gross toxicity in mouse tissues as assessed by measuring weight of animals, serum biochemistry, and gross tissue observation. The differential effects exhibited by StVOrth-2 and StVOrth-3 in this orthotopic model of osteosarcoma may be related to the functional epitopes on the PEDF glycoprotein that they represent. PMID:22701300

Cigarette Smoke-Related Hydroquinone Dysregulates MCP-1, VEGF and PEDF Expression in Retinal Pigment Epithelium in Vitro and in Vivo

PubMed Central

Pons, Marianne; Marin-Castaño, Maria E.

2011-01-01

Background Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly population. Debris (termed drusen) below the retinal pigment epithelium (RPE) have been recognized as a risk factor for dry AMD and its progression to wet AMD, which is characterized by choroidal neovascularization (CNV). The underlying mechanism of how drusen might elicit CNV remains undefined. Cigarette smoking, oxidative damage to the RPE and inflammation are postulated to be involved in the pathophysiology of the disease. To better understand the cellular mechanism(s) linking oxidative stress and inflammation to AMD, we examined the expression of pro-inflammatory monocyte chemoattractant protein-1 (MCP-1), pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial derived factor (PEDF) in RPE from smoker patients with AMD. We also evaluated the effects of hydroquinone (HQ), a major pro-oxidant in cigarette smoke on MCP-1, VEGF and PEDF expression in cultured ARPE-19 cells and RPE/choroids from C57BL/6 mice. Principal Findings MCP-1, VEGF and PEDF expression was examined by real-time PCR, Western blot, and ELISA. Low levels of MCP-1 protein were detected in RPE from AMD smoker patients relative to controls. Both MCP-1 mRNA and protein were downregulated in ARPE-19 cells and RPE/choroids from C57BL/6 mice after 5 days and 3 weeks of exposure to HQ-induced oxidative injury. VEGF protein expression was increased and PEDF protein expression was decreased in RPE from smoker patients with AMD versus controls resulting in increased VEGF/PEDF ratio. Treatment with HQ for 5 days and 3 weeks increased the VEGF/PEDF ratio in vitro and in vivo. Conclusion We propose that impaired RPE-derived MCP-1-mediated scavenging macrophages recruitment and phagocytosis might lead to incomplete clearance of proinflammatory debris and infiltration of proangiogenic macrophages which along with increased VEGF/PEDF ratio favoring angiogenesis might promote drusen accumulation and progression to CNV in smoker patients with dry AMD. PMID:21386905

Serum levels of pigment epithelium-derived factor (PEDF) are positively associated with acanthosis nigricans in obese adolescents.

PubMed

Galhardo, J; Hunt, L P; Shield, J P H

2012-07-01

Circulating pigment epithelium-derived factor, or serine protease inhibitor F1, is upregulated during adipogenesis, contributing to obesity-induced insulin resistance. Furthermore, pigment epithelium-derived factor is abundant in stage I melanosomes and has been reported to increase pigment granules and the appearance of mature melanosomes in retinal pigment epithelium. As acanthosis nigricans is a well-recognized clinical marker of insulin resistance, we hypothesized that increased pigment epithelium-derived factor might be associated with the generation of acanthosis nigricans. Acanthosis nigricans, anthropometric measurements, circulating total PEDF and metabolic profiles were assessed in 28 obese adolescents in a hospital-based obesity clinic. Subjects with acanthosis nigricans (n = 10) showed greater plasma levels of pigment epithelium-derived factor (PEDF) than those without [geometric mean 23.55 (range 15.2-40.2) vs. 9.01 (range 5.5-18.7) μg/ml; P < 0.001]. Although pigment epithelium-derived factor was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.779, P < 0.001; 95% CI 0.573-0.892), as previously reported, for the same degree of insulin resistance, those with acanthosis nigricans exhibited a 2.1-fold (95%CI 2.0-2.3) higher level of pigment epithelium-derived factor. While acanthosis nigricans is undoubtedly associated with insulin resistance, its appearance is not ubiquitous in patients at any given level of HOMA-IR. The higher levels of pigment epithelium-derived factor in those with acanthosis nigricans compared with those without, with similar levels of resistance, suggest that pigment epithelium-derived factor levels are associated with acanthosis nigricans. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Insulin antagonises pigment epithelium-derived factor (PEDF)-induced modulation of lineage commitment of myocytes and heterotrophic ossification.

PubMed

Carnagarin, Revathy; Elahy, Mina; Dharmarajan, Arun M; Dass, Crispin R

2017-12-16

Extensive bone defects arising as a result of trauma, infection and tumour resection and other bone pathologies necessitates the identification of effective strategies in the form of tissue engineering, gene therapy and osteoinductive agents to enhance the bone repair process. PEDF is a multifunctional glycoprotein which plays an important role in regulating osteoblastic differentiation and bone formation. PEDF treatment of mice and human skeletal myocytes at physiological concentration inhibited myogenic differentiation and activated Erk1/2 MAPK- dependent osteogenic transdifferentiation of myocytes. In mice, insulin, a promoter of bone regeneration, attenuated PEDF-induced expression of osteogenic markers such as osteocalcin, alkaline phosphatase and mineralisation for bone formation in the muscle and surrounding adipose tissue. These results provide new insights into the molecular aspects of the antagonising effect of insulin on PEDF-dependent modulation of the differentiation commitment of musculoskeletal environment into osteogenesis, and suggest that PEDF may be developed as an effective clinical therapy for bone regeneration as its heterotopic ossification can be controlled via co-administration of insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study

PubMed Central

Ryan, K M; Glaviano, A; O'Donovan, S M; Kolshus, E; Dunne, R; Kavanagh, A; Jelovac, A; Noone, M; Tucker, G M; Dunn, M J; McLoughlin, D M

2017-01-01

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression. PMID:28350398

Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study.

PubMed

Ryan, K M; Glaviano, A; O'Donovan, S M; Kolshus, E; Dunne, R; Kavanagh, A; Jelovac, A; Noone, M; Tucker, G M; Dunn, M J; McLoughlin, D M

2017-03-28

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression.

Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration.

PubMed

Yu, Ting; Xu, Bei; He, Lili; Xia, Shan; Chen, Yan; Zeng, Jun; Liu, Yongmei; Li, Shuangzhi; Tan, Xiaoyue; Ren, Ke; Yao, Shaohua; Song, Xiangrong

2016-01-01

Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely used as systemic gene vectors.

Subconjunctival Bevacizumab Injection Impairs Corneal Innervations and Epithelial Wound Healing in Mice.

PubMed

Dong, Muchen; Di, Guohu; Zhang, Xiaoping; Zhou, Qingjun; Shi, Weiyun

2017-03-01

To investigate the effects of subconjunctival bevacizumab injection on the corneal nerve, sensitivity, and epithelial wound healing in mice. Adult C57BL/6 mice were treated with subconjunctival injection of 1, 2, 5, or 25 mg/mL bevacizumab. The corneal nerve was observed with whole-mount anti-β3-tubulin fluorescence staining. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer. The protein levels of pigment epithelium-derived factor (PEDF), nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were measured by ELISA. The corneal epithelial wound-healing rate was evaluated by fluorescein staining. The recovery of impaired mouse corneal innervations and epithelial wound-healing rate following bevacizumab injection was evaluated with the co-injection of PEDF, NGF, or CNTF. Subconjunctival bevacizumab injection caused apparent corneal nerve degeneration, attenuated corneal sensitivity, and delayed corneal epithelial wound healing and nerve regeneration in normal mice, which was more significant with increased concentration and times of the bevacizumab injection. However, the corneal nerve and sensitivity gradually improved and recovered in mice with a single injection of 1 to 5 mg/mL bevacizumab. Moreover, the bevacizumab injection significantly decreased the corneal PEDF, NGF, and CNTF content, whereas exogenous PEDF, NGF, or CNTF supplement attenuated impairment of the corneal nerve, sensitivity, and epithelial wound healing after subconjunctival bevacizumab injection. Subconjunctival bevacizumab injection impairs corneal innervations, epithelial wound healing, and nerve regeneration in normal mice, which may be caused by the reduction of neurotrophic factor content in the cornea.

Alginate Bead-Encapsulated PEDF Induces Ectopic Bone Formation In Vivo in the Absence of Co-Administered Mesenchymal Stem Cells.

PubMed

Elahy, Mina; Doschak, Michael R; Hughes, Jeffery D; Baindur-Hudson, Swati; Dass, Crispin R

2018-01-01

Bone defects can be severely debilitating and reduce quality of life. Osteoregeneration can alleviate some of the complications in bony defects. For therapeutic use in future, a single factor that can cause potent bone regeneration is highly preferred as it will be more costeffective, any off-target effects will be more easily monitored and potentially managed, and for ease of administration which would lead to better patient compliance and satisfaction. We demonstrate that pigment epithelium-derived factor (PEDF), one such factor that is known to be potent against angiogenesis, promotes osteoblastogenesis in mesenchymal stem cells in vitro, but does not need co-encapsulation of cells in alginate bead scaffolds for osteogeneration in vivo. Osteogenic differentiation by PEDF in vitro was confirmed with immunoblotting and immunocytochemical staining for bone markers (alkaline phosphatase, osteocalcin, osteopontin, collagen I), calcified mineral deposition, and assay for alkaline phosphatase activity. PEDF-mediated bone formation in a muscle pocket in vivo model was confirmed by microcomputed tomography (microCT), histology (haematoxylin and eosin, Alcian blue staining), immunostaining for bone markers and for collagen I-processing proteins (heat shock protein 47 and membrane type I matrix metalloproteinase). PEDF therefore presents itself as a promising biological for osteogeneration. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Retinal pigment epithelium, age-related macular degeneration and neurotrophic keratouveitis.

PubMed

Bianchi, Enrica; Scarinci, Fabio; Ripandelli, Guido; Feher, Janos; Pacella, Elena; Magliulo, Giuseppe; Gabrieli, Corrado Balacco; Plateroti, Rocco; Plateroti, Pasquale; Mignini, Fiorenzo; Artico, Marco

2013-01-01

Age-related macular degeneration (AMD) is the leading cause of impaired vision and blindness in the aging population. The aims of our studies were to identify qualitative and quantitative alterations in mitochondria in human retinal pigment epithelium (RPE) from AMD patients and controls and to test the protective effects of pigment epithelium-derived factor (PEDF), a known neurotrophic and antiangiogenic substance, against neurotrophic keratouveitis. Histopathological alterations were studied by means of morphometry, light and electron microscopy. Unexpectedly, morphometric data showed that the RPE alterations noted in AMD may also develop in normal aging, 10-15 years later than appearing in AMD patients. Reduced tear secretion, corneal ulceration and leukocytic infiltration were found in capsaicin (CAP)-treated rats, but this effect was significantly attenuated by PEDF. These findings suggest that PEDF accelerated the recovery of tear secretion and also prevented neurotrophic keratouveitis and vitreoretinal inflammation. PEDF may have a clinical application in inflammatory and neovascular diseases of the eye.

Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.

PubMed

Böhm, Anja; Ordelheide, Anna-Maria; Machann, Jürgen; Heni, Martin; Ketterer, Caroline; Machicao, Fausto; Schick, Fritz; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich; Staiger, Harald

2012-01-01

Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.

A novel in vivo model of focal light emitting diode-induced cone-photoreceptor phototoxicity: neuroprotection afforded by brimonidine, BDNF, PEDF or bFGF.

PubMed

Ortín-Martínez, Arturo; Valiente-Soriano, Francisco Javier; García-Ayuso, Diego; Alarcón-Martínez, Luis; Jiménez-López, Manuel; Bernal-Garro, José Manuel; Nieto-López, Leticia; Nadal-Nicolás, Francisco Manuel; Villegas-Pérez, María Paz; Wheeler, Larry A; Vidal-Sanz, Manuel

2014-01-01

We have investigated the effects of light-emitting diode (LED)-induced phototoxicity (LIP) on cone-photoreceptors and their protection with brimonidine (BMD), brain-derived neurotrophic factor (BDNF), pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF) or basic fibroblast growth factor (bFGF). In anesthetized, dark adapted, adult albino rats a blue (400 nm) LED was placed perpendicular to the cornea (10 sec, 200 lux) and the effects were investigated using Spectral Domain Optical Coherence Tomography (SD-OCT) and/or analysing the retina in oriented cross-sections or wholemounts immune-labelled for L- and S-opsin and counterstained with the nuclear stain DAPI. The effects of topical BMD (1%) or, intravitreally injected BDNF (5 µg), PEDF (2 µg), CNTF (0.4 µg) or bFGF (1 µg) after LIP were examined on wholemounts at 7 days. SD-OCT showed damage in a circular region of the superotemporal retina, whose diameter varied from 1,842.4±84.5 µm (at 24 hours) to 1,407.7±52.8 µm (at 7 days). This region had a progressive thickness diminution from 183.4±5 µm (at 12 h) to 114.6±6 µm (at 7 d). Oriented cross-sections showed within the light-damaged region of the retina massive loss of rods and cone-photoreceptors. Wholemounts documented a circular region containing lower numbers of L- and S-cones. Within a circular area (1 mm or 1.3 mm radius, respectively) in the left and in its corresponding region of the contralateral-fellow-retina, total L- or S-cones were 7,118±842 or 661±125 for the LED exposed retinas (n = 7) and 14,040±1,860 or 2,255±193 for the fellow retinas (n = 7), respectively. BMD, BDNF, PEDF and bFGF but not CNTF showed significant neuroprotective effects on L- or S-cones. We conclude that LIP results in rod and cone-photoreceptor loss, and is a reliable, quantifiable model to study cone-photoreceptor degeneration. Intravitreal BDNF, PEDF or bFGF, or topical BMD afford significant cone neuroprotection in this model.

The Emerging Role of PEDF in Stem Cell Biology

PubMed Central

Elahy, Mina; Baindur-Hudson, Swati; Dass, Crispin R.

2012-01-01

Encoded by a single gene, PEDF is a 50 kDa glycoprotein that is highly conserved and is widely expressed among many tissues. Most secreted PEDF deposits within the extracellular matrix, with cell-type-specific functions. While traditionally PEDF is known as a strong antiangiogenic factor, more recently, as this paper highlights, PEDF has been linked with stem cell biology, and there is now accumulating evidence demonstrating the effects of PEDF in a variety of stem cells, mainly in supporting stem cell survival and maintaining multipotency. PMID:22675247

A Novel In Vivo Model of Focal Light Emitting Diode-Induced Cone-Photoreceptor Phototoxicity: Neuroprotection Afforded by Brimonidine, BDNF, PEDF or bFGF

PubMed Central

García-Ayuso, Diego; Alarcón-Martínez, Luis; Jiménez-López, Manuel; Bernal-Garro, José Manuel; Nieto-López, Leticia; Nadal-Nicolás, Francisco Manuel; Villegas-Pérez, María Paz; Wheeler, Larry A.; Vidal-Sanz, Manuel

2014-01-01

We have investigated the effects of light-emitting diode (LED)-induced phototoxicity (LIP) on cone-photoreceptors and their protection with brimonidine (BMD), brain-derived neurotrophic factor (BDNF), pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF) or basic fibroblast growth factor (bFGF). In anesthetized, dark adapted, adult albino rats a blue (400 nm) LED was placed perpendicular to the cornea (10 sec, 200 lux) and the effects were investigated using Spectral Domain Optical Coherence Tomography (SD-OCT) and/or analysing the retina in oriented cross-sections or wholemounts immune-labelled for L- and S-opsin and counterstained with the nuclear stain DAPI. The effects of topical BMD (1%) or, intravitreally injected BDNF (5 µg), PEDF (2 µg), CNTF (0.4 µg) or bFGF (1 µg) after LIP were examined on wholemounts at 7 days. SD-OCT showed damage in a circular region of the superotemporal retina, whose diameter varied from 1,842.4±84.5 µm (at 24 hours) to 1,407.7±52.8 µm (at 7 days). This region had a progressive thickness diminution from 183.4±5 µm (at 12 h) to 114.6±6 µm (at 7 d). Oriented cross-sections showed within the light-damaged region of the retina massive loss of rods and cone-photoreceptors. Wholemounts documented a circular region containing lower numbers of L- and S-cones. Within a circular area (1 mm or 1.3 mm radius, respectively) in the left and in its corresponding region of the contralateral-fellow-retina, total L- or S-cones were 7,118±842 or 661±125 for the LED exposed retinas (n = 7) and 14,040±1,860 or 2,255±193 for the fellow retinas (n = 7), respectively. BMD, BDNF, PEDF and bFGF but not CNTF showed significant neuroprotective effects on L- or S-cones. We conclude that LIP results in rod and cone-photoreceptor loss, and is a reliable, quantifiable model to study cone-photoreceptor degeneration. Intravitreal BDNF, PEDF or bFGF, or topical BMD afford significant cone neuroprotection in this model. PMID:25464513

Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction.

PubMed

Moskowitz-Kassai, Eliza; Mackelaite, Lina; Chen, Jun; Patel, Kaushal; Dadhania, Darshana M; Gross, Steven S; Chander, Praveen; Delaney, Vera; Deng, Luqin; Chen, Ligong; Cui, Xiangqin; Suthanthiran, Manikkam; Goligorsky, Michael S

2012-02-01

We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD). Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium-derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD. In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD-0 was diagnosed based on clinical criteria. In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti-angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD.

Evaluation of pigment epithelium-derived factor and complement factor I polymorphisms as a cause of choroidal neovascularization in highly myopic eyes.

PubMed

Miyake, Masahiro; Yamashiro, Kenji; Nakanishi, Hideo; Nakata, Isao; Akagi-Kurashige, Yumiko; Kumagai, Kyoko; Oishi, Maho; Tsujikawa, Akitaka; Moriyama, Muka; Ohno-Matsui, Kyoko; Mochizuki, Manabu; Yoshimura, Nagahisa

2013-06-19

A case-control study in a relatively large cohort of highly myopic patients was conducted to explore the genetic background of the occurrence of choroidal neovascularization (CNV) secondary to high myopia. We evaluated three single nucleotide polymorphisms (SNPS) from two candidate genes: pigment epithelium-derived factor (PEDF) and complement factor I (CFI). The SNPs were selected based on previous reports. A total of 1082 unrelated highly myopic (i.e., axial length ≥ 26 mm in at least one eye) Japanese individuals with CNV (n = 478) and without CNV (n = 557) who were 50 years of age and older were genotyped by using an SNP assay. Multivariable logistic regression was conducted to adjust for age, sex, and axial length. compared with individuals without CNV, subjects with CNV were significantly older (P 0.01) and more likely to be female (P 0.01), but they did not have a significantly different axial length (P = 0.50). We did not find an association between the three SNPS and the occurrence of CNV. However, a subanalysis using extremely myopic patients (case: control = 284:317) revealed a marginal association of rs12603825 in the PEDF gene (P = 0.045). The contribution of rs1136287 in CFI was not found in any analysis. We demonstrated a marginal association of the PEDF SNP, rs12603825, with myopic CNV in extremely myopic patients. A further study using a larger cohort might elucidate a significant association; rs1136287 in CFI is less likely to be associated in Japanese individuals.

Comparison of the effects of letrozole and cabergoline on vascular permeability, ovarian diameter, ovarian tissue VEGF levels, and blood PEDF levels, in a rat model of ovarian hyperstimulation syndrome.

PubMed

Şahin, Nur; Apaydın, Nesin; Töz, Emrah; Sivrikoz, Oya Nermin; Genç, Mine; Turan, Gülüzar Arzu; Cengiz, Hakan; Eskicioğlu, Fatma

2016-05-01

To evaluate the effects of letrozole and cabergoline in a rat model of ovarian hyperstimulation syndrome (OHSS). In this prospective, controlled experimental study, the 28 female Wistar rats were divided into four subgroups (one non-stimulated control and three OHSS-positive groups: placebo, letrozole, and cabergoline). To induce OHSS, rats were injected with 10 IU of pregnant mare serum gonadotropin from day 29 to day 32 of life, followed by subcutaneous injection of 30 IU hCG on day 33. Letrozole rats received with a single dose of 0.1 mg/kg letrozole via oral gavage, on the hCG day. Cabergoline rats received with a single dose of 100 µg/kg cabergoline via oral gavage, on the hCG day. All animals were compared in terms of body weight, vascular permeability (VP), ovarian diameter, ovarian tissue VEGF expression (assessed via immunohistochemical staining), and blood pigment epithelium-derived growth factor (PEDF) levels. The OHSS-positive placebo group (group 2) exhibited the highest VP, ovarian diameter, extent of VEGF staining, and lowest PEDF level, as expected. No significant difference was evident between the letrozole and cabergoline groups in terms of any of body weight; VP; PEDF level; ovarian diameter; or the staining intensity of, or percentage staining for, VEGF in ovarian tissues. Letrozole and cabergoline were equally effective to prevent OHSS, reducing the ovarian diameter, VP, and PEDF and VEGF levels to similar extents.

Serum PEDF levels are decreased in a spontaneous animal model for human autoimmune uveitis.

PubMed

Zipplies, Johanna K; Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Ueffing, Marius; Deeg, Cornelia A

2009-02-01

Identification of biomarkers is of critical relevance toward improving diagnosis and therapy of autoimmune disorders. Serum markers are a desirable choice as sera are easily accessible and the development of assays for routine clinical detection prompts feasible. Autoimmune uveitis, a recurrent disease affecting the eye, is characterized by returning inflammatory attacks of the inner eye followed by variable periods of quiescent stages. Spontaneous equine recurrent uveitis (ERU) is the equine equivalent and serves as a model for the human disease. To identify potential biomarker candidates, we first systematically compared the proteomes of individual ERU cases with healthy controls by proteomic profiling using 2-D difference-gel-electrophoresis (2-D DIGE) followed by tandem mass spectrometry. A total of seven differentially expressed proteins were identified. Besides the upregulation of IgG and the significant lower expression of albumin, Antithrombin III, and Vitamin D binding protein, we found complement components C1q and C4, to be downregulated in uveitic state. Interestingly, Pigment epithelium-derived factor (PEDF), a marker already detected by 2DE differential proteome analysis in ERU target tissues, vitreous and retina, was found to be also significantly downregulated in sera. The lower expression of PEDF in sera of horses with uveitis could be verified in a cohort of 116 ERU cases and 115 healthy controls. Our findings of a significant lower PEDF expression in ERU cases also in the periphery of the eye proves PEDF as a promising uveitis biomarker.

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

PubMed Central

Farnoodian, Mitra; Halbach, Caroline; Slinger, Cassidy; Pattnaik, Bikash R.; Sorenson, Christine M.

2016-01-01

Defects in the outer blood-retinal barrier have significant impact on the pathogenesis of diabetic retinopathy and macular edema. However, the detailed mechanisms involved remain largely unknown. This is, in part, attributed to the lack of suitable animal and cell culture models, including those of mouse origin. We recently reported a method for the culture of retinal pigment epithelial (RPE) cells from wild-type and transgenic mice. The RPE cells are responsible for maintaining the integrity of the outer blood-retinal barrier whose dysfunction during diabetes has a significant impact on vision. Here we determined the impact of high glucose on the function of RPE cells. We showed that high glucose conditions resulted in enhanced migration and increased the level of oxidative stress in RPE cells, but minimally impacted their rate of proliferation and apoptosis. High glucose also minimally affected the cell-matrix and cell-cell interactions of RPE cells. However, the expression of integrins and extracellular matrix proteins including pigment epithelium-derived factor (PEDF) were altered under high glucose conditions. Incubation of RPE cells with the antioxidant N-acetylcysteine under high glucose conditions restored normal migration and PEDF expression. These cells also exhibited increased nuclear localization of the antioxidant transcription factor Nrf2 and ZO-1, reduced levels of β-catenin and phagocytic activity, and minimal effect on production of vascular endothelial growth factor, inflammatory cytokines, and Akt, MAPK, and Src signaling pathways. Thus high glucose conditions promote RPE cell migration through increased oxidative stress and expression of PEDF without a significant effect on the rate of proliferation and apoptosis. PMID:27440660

γ-Secretase Inhibition of Murine Choroidal Neovascularization Is Associated with Reduction of Superoxide and Proinflammatory Cytokines

PubMed Central

Qi, Xiaoping; Cai, Jun; Ruan, Qing; Liu, Li; Boye, Sanford L.; Chen, Zhijuan; Hauswirth, William W.; Ryals, Renee C.; Shaw, Lynn; Caballero, Sergio; Grant, Maria B.

2012-01-01

Purpose. This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. Methods. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angiogenesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. Results. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. Conclusions. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression during CNV. PMID:22205609

The Antibiotic-free pFAR4 Vector Paired with the Sleeping Beauty Transposon System Mediates Efficient Transgene Delivery in Human Cells.

PubMed

Pastor, Marie; Johnen, Sandra; Harmening, Nina; Quiviger, Mickäel; Pailloux, Julie; Kropp, Martina; Walter, Peter; Ivics, Zoltán; Izsvák, Zsuzsanna; Thumann, Gabriele; Scherman, Daniel; Marie, Corinne

2018-06-01

The anti-angiogenic and neurogenic pigment epithelium-derived factor (PEDF) demonstrated a potency to control choroidal neovascularization in age-related macular degeneration (AMD) patients. The goal of the present study was the development of an efficient and safe technique to integrate, ex vivo, the PEDF gene into retinal pigment epithelial (RPE) cells for later transplantation to the subretinal space of AMD patients to allow continuous PEDF secretion in the vicinity of the affected macula. Because successful gene therapy approaches require efficient gene delivery and stable gene expression, we used the antibiotic-free pFAR4 mini-plasmid vector to deliver the hyperactive Sleeping Beauty transposon system, which mediates transgene integration into the genome of host cells. In an initial study, lipofection-mediated co-transfection of HeLa cells with the SB100X transposase gene and a reporter marker delivered by pFAR4 showed a 2-fold higher level of genetically modified cells than when using the pT2 vectors. Similarly, with the pFAR4 constructs, electroporation-mediated transfection of primary human RPE cells led to 2.4-fold higher secretion of recombinant PEDF protein, which was still maintained 8 months after transfection. Thus, our results show that the pFAR4 plasmid is a superior vector for the delivery and integration of transgenes into eukaryotic cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Heterogeneity of Metastatic Melanoma:  Correlation of MITF With Its Transcriptional Targets MLSN1, PEDF, HMB-45, and MART-1.

PubMed

Zand, Sarvenaz; Buzney, Elizabeth; Duncan, Lyn M; Dadras, Soheil S

2016-09-01

Histologic and molecular heterogeneity is well recognized in malignant melanoma; however, the diversity of expression of new and classic melanoma markers has not been correlated in serial sections of metastases. We examined and correlated the expression of microphthalmia transcription factor (MITF) with its transcriptional targets, including melastatin (MLSN1/TRPM1), pigment epithelium-derived factor (SERPINF1/PEDF), SILV/PMEL17/GP100 (human melanoma black 45 [HMB-45]), and melanoma antigen recognized by T cells 1 (MART-1)/MLANA, in 13 melanoma metastases in lymph nodes of 13 patients. The expression levels and patterns of marker expression were recorded by a semiquantitative, 4-point ordinal reactivity method. Our results showed a consistently robust and diffuse expression of MITF protein in 12 (92%) of 13 metastatic tumors compared with variable expression of MLSN1 (46%) messenger RNA or PEDF (75%), HMB-45 (54%), and MART-1 (46%) proteins. Overall, in melanoma lymph node metastases, MITF protein expression was not tightly correlated with its gene targets. Moreover, the immunoreactivity for MITF, compared with MART-1 and HMB-45, was retained, supporting immunohistochemical detection of MITF as a more sensitive method of detecting metastatic melanoma. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The VEGF and PEDF levels in the follicular fluid of patients co- treated with LETROZOLE and gonadotropins during the stimulation cycle.

PubMed

Haas, Jigal; Bassil, Rawad; Gonen, Noa; Meriano, Jim; Jurisicova, Andrea; Casper, Robert F

2018-05-29

Previous studies have shown that androgens, in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. Recent studies have shown that aromatase inhibitor, letrozole, improves ovarian response to FSH in normal and poor responder patients, possibly by increasing intraovarian androgen levels. Studies in mice also showed an effect of letrozole to increase pigment epithelium-derived factor (PEDF) and to lower vascular epithelial growth factor (VEGF), which might be expected to reduce the risk of ovarian hyperstimulation syndrome (OHSS) with stimulation. The aim of this study was to compare the VEGF and PEDF levels in the follicular fluids of normal responders treated with letrozole and gonadotropins during the ovarian stimulation with patients treated with gonadotropins only. A single center, prospective clinical trial. We collected follicular fluid from 26 patients, on a GnRH antagonist protocol, dual triggered with hCG and GnRH agonist. The patients in one group were co-treated with letrozole and gonadotropins during the ovarian stimulation and the patients in the other group were treated with gonadotropins only. VEGF, PEDF, estrogen, progesterone and testosterone levels were measured by ELISA kits. The age of the patients, the total dose of gonadotropins and the number of oocytes were comparable between the two groups. In the follicular fluid, the estrogen levels (2209 nmol/l vs. 3280 nmol/l, p = 0.02) were significantly decreased, and the testosterone levels (246.5 nmol/l vs. 40.7 nmol/l, p < 0.001) were significantly increased in the letrozole group compared to the gonadotropin only group. The progesterone levels (21.4 μmol/l vs. 17.5 p = NS) were comparable between the two groups. The VEGF levels (2992 pg/ml vs. 1812 pg/ml p = 0.02) were significantly increased and the PEDF levels (9.7 ng/ml vs 17.3 ng/ml p < 0.001) were significantly decreased in the letrozole group. Opposite to observations in the mouse, we found that VEGF levels were increased and PEDF levels were decreased in the follicular fluid in patients treated with letrozole during the stimulation cycles. Further investigation is required to determine if patients treated with letrozole during the IVF stimulation protocol are at increased risk for developing OHSS as a result of these findings.

Nerves and neovessels inhibit each other in the cornea.

PubMed

Ferrari, Giulio; Hajrasouliha, Amir R; Sadrai, Zahra; Ueno, Hiroki; Chauhan, Sunil K; Dana, Reza

2013-01-28

To evaluate the regulatory cross-talk of the vascular and neural networks in the cornea. b-FGF micropellets (80 ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day 7, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation, corneas were harvested for ELISA (VEGFR3 and pigment epithelium-derived factor [PEDF]) and for quantitative RT-PCR (VEGFR3, PEDF, and CD45). PEDF, VEGFR3, beta-3 tubulin, CD45, CD11b, and F4/80 expression in the cornea were evaluated using immunostaining. No nerves were detected in the areas subject to corneal neovascularization, whereas they persisted in the areas that were neovessel-free. Conversely, 7 days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 in the corneal epithelial layer. Finally, an inflammatory cell infiltrate, including macrophages, was observed. Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far-reaching implications in understanding angiogenesis.

Osteogenesis Imperfecta Type VI in Individuals from Northern Canada.

PubMed

Ward, Leanne; Bardai, Ghalib; Moffatt, Pierre; Al-Jallad, Hadil; Trejo, Pamela; Glorieux, Francis H; Rauch, Frank

2016-06-01

Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis.

Nerves and Neovessels Inhibit Each Other in the Cornea

PubMed Central

Ferrari, Giulio; Hajrasouliha, Amir R.; Sadrai, Zahra; Ueno, Hiroki; Chauhan, Sunil K.; Dana, Reza

2013-01-01

Purpose. To evaluate the regulatory cross-talk of the vascular and neural networks in the cornea. Methods. b-FGF micropellets (80 ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day 7, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation, corneas were harvested for ELISA (VEGFR3 and pigment epithelium-derived factor [PEDF]) and for quantitative RT-PCR (VEGFR3, PEDF, and CD45). PEDF, VEGFR3, beta-3 tubulin, CD45, CD11b, and F4/80 expression in the cornea were evaluated using immunostaining. Results. No nerves were detected in the areas subject to corneal neovascularization, whereas they persisted in the areas that were neovessel-free. Conversely, 7 days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 in the corneal epithelial layer. Finally, an inflammatory cell infiltrate, including macrophages, was observed. Conclusion. Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far-reaching implications in understanding angiogenesis. PMID:23307967

Promising Nanocarriers for PEDF Gene Targeting Delivery to Cervical Cancer Cells Mediated by the Over-expressing FRα.

PubMed

Yang, Yuhan; He, Lili; Liu, Yongmei; Xia, Shan; Fang, Aiping; Xie, Yafei; Gan, Li; He, Zhiyao; Tan, Xiaoyue; Jiang, Chunling; Tong, Aiping; Song, Xiangrong

2016-08-31

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer.

Promising Nanocarriers for PEDF Gene Targeting Delivery to Cervical Cancer Cells Mediated by the Over-expressing FRα

PubMed Central

Yang, Yuhan; He, Lili; Liu, Yongmei; Xia, Shan; Fang, Aiping; Xie, Yafei; Gan, Li; He, Zhiyao; Tan, Xiaoyue; Jiang, Chunling; Tong, Aiping; Song, Xiangrong

2016-01-01

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer. PMID:27576898

On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion.

PubMed

Rodríguez-Piñeiro, A M; Blanco-Prieto, S; Sánchez-Otero, N; Rodríguez-Berrocal, F J; de la Cadena, M Páez

2010-06-16

The current imperative need for new biomarkers of non-small cell lung cancer (NSCLC) prompted us to compare the proteome of serum and pleural effusion samples from cancer patients with those with benign lung diseases as pneumonia or tuberculosis. Samples were prefractionated through affinity chromatography prior to 2D-DIGE to detect proteins with altered expression in cancer patients. Overall, we identified more potential biomarkers in pleural effusion, which is closer to the affected organ, than in serum. Nevertheless, in both cases principal component analysis demonstrated that the pattern of significantly altered proteins discriminates between disease groups. The biomarker candidates comprise proteins increased in malignant pleural effusions as gelsolin and the metalloproteinase inhibitor 2, and others with lower levels as S100-A8 and S100-A9. The most interesting protein was the pigment epithelium-derived factor (PEDF), which is related to angiogenesis inhibition, and was significantly overexpressed both in serum and pleural effusion from NSCLC patients. More than 12 PEDF isoforms were specifically immunodetected in both fluids in 2-D blots, most of them overexpressed in NSCLC. Thus, further validation would be ideally directed to quantify individual PEDF isoforms, as it may be only one or some of them the ones altered in the cancer process. Copyright 2010 Elsevier B.V. All rights reserved.

[The correlation between the concentrations of VEGF and PEDF and Ca2+-PKC signaling pathways in human retinal pigment epithelial cells cultured in vitro after exposuring to blue light].

PubMed

Wang, Limin; Cai, Shanjun; Wu, Zhipeng; Gong, Xin; Lyu, Jianping; Su, Gang; Wang, Lili

2015-11-01

To investigate the concentrations of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), inositol triphosphate (IP3) and diacylglycerol (DAG) in human retinal pigment epithelium (RPE) cells after exposuring to blue light, and to explore the relationship with Ca2+-PKC signaling pathways, to evaluate the role of Ca2+-PKC signaling pathways of blue-light irradiation induced apoptosis in RPE cells. The fourth generation human RPE cells in vitro were exposured to blue light (2000±500 lux) for 6 hours, 24 hours prolongation of post-exposure culture. The concentrations of VEGF, PEDF, IP3 and DAG were assayed by enzyme linked immunosorbent assay (ELISA). Cells were randomly divided into 6 groups, group A (control), group B (exposure to blue light), group C (exposure to blue light+PMA), group D (exposure to blue light+Calphostin C), group E (exposure to blue light+Nifedipine), group F (exposure to blue light+Calphostin C+Nifedipine). Flow cytometry was used to detect the apoptosis rate of human RPE cells in A, B and F group. Comparing with group A (584.38±10.66), the concentration of VEGF in group B (700.70±5.88), group C (698.21±6.66) and group E (648.30±4.91) was higher, the difference was statistically significant (P=0.002, 0.002, 0.016). Comparing with group B (700.70±5.88), the concentration of VEGF in Group D (623.87±3.12) and E (648.30±4.91) was lower (P=0.001, 0.002). Comparing with group A (75.96±1.70), the concentration of PEDF in Group B (71.82±1.67) and C (72.43±0.58) was lower (P=0.004, 0.011), but the concentration of PEDF in Group D (86.31±1.35) and E (93.72±1.24) was higher (P=0.000, 0.000). Comparing with group B (71.82±1.67), the concentration of PEDF in Group D (86.31±1.35) and E (93.72±1.24) was higher (P=0.000, 0.000). Comparing with group A (7.70±0.29), the ratio of VEGF to PEDF in Group B (9.85±0.34) and Croup C (9.64±0.02) was higher (P=0.008, 0.027) Comparing with group B, The ratio of VEGF to PEDF in Group D (7.23±0.08) and E (6.92±0.06) was lower (P=0.016, 0.015). Comparing with group A (108.42±0.75, 995.47± 13.61), the concentration of IP3 and DAG in Group B (117.24±1.06, 1070.10±10.07), C (137.12±2.71, 1046.40±7.90), D (139.17±1.40, 1041.13±9.76) and E (149.61±0.77, 1273.14±10.89) was higher, the difference was statistically significant (P=0.003, 0.007, 0.000, 0.000, 0.000, 0.000, 0.000, 0.000). Comparing with group B, the concentration of IP3 in Group C, D and E was higher (P=0.011, 0.000, 0.000). Comparing with group B, the concentration of DAG in Group C and D was lower (P=0.021, 0.007). Comparing with group B, the concentration of DAG in Group E was higher (P=0.000). Comparing with group A (10.27±1.88), the apoptosis rate of RPE cells in Group B(25.07±2.66) and F(19.37±3.23) was higher, the difference was statistically significant (P=0.001, 0.009). Comparing with group B (25.07±2.66), the apoptosis rate of RPE cells in Group F (19.37±3.23) was lower (P=0.038). (1) After exposuring to blue light, the concentrations of VEGF, IP3 and DAG are increased and the ratio of VEGF to PEDF is also increased and the concentration of PEDF is decreased in human RPE cells. (2) L-Type Calcium Channels and Ca2+-PKC signaling pathways may be regulate the concentrations of VEGF, PEDF, IP3 and DAG in RPE cells after exposuring to blue light by feedback regulation. (3) The application of Calphostin C combined with Nifedipine may be restrain the apoptosis of RPE cells after exposuring to blue light.

Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatitis c virus-associated insulin resistance.

PubMed

Kawaguchi, T; Yamagishi, S; Sata, M

2009-01-01

Recent clinical studies have shown that patients with chronic liver disease are insulin resistant. Of all etiologies of chronic liver disease including non-alcoholic fatty liver disease, the one that causes the most sever insulin resistance is hepatitis C virus (HCV) infection. Since insulin resistance promotes inflammatory and fibrogenic reactions in the liver, thus leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC) in patients with HCV infection, amelioration of insulin sensitivity may inhibit the progression of HCV-associated liver disease, and could improve the survival of these patients. HCV directly causes insulin resistance through HCV core protein-elicited proteasomal degradation of insulin receptor substrates and subsequent inactivation of intracellular insulin signaling molecules such as Akt. Furthermore, tumor necrosis factor-alpha (TNF-alpha) and/or triglyceride accumulation-induced nuclear factor-kappaB (NF-kappaB) activation in the liver is shown to play a role in insulin resistance in patients with HCV-related chronic liver disease as well. We, along with others, have recently found that branched-chain amino acids (BCAAs) and pigment epithelium-derived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-kappaB and preservation of insulin signaling pathway. In this review, we discuss the mechanisms for the actions of BCAAs and PEDF, and their clinical implications in insulin resistance of chronic liver disease in patients with HCV infection. We also discuss here which chemical structures could contribute to insulin-sensitization in patients with HCV infection.

Biological Modulation of Mouse RPE Cells in Response to Subthreshold Diode Micropulse Laser Treatment.

PubMed

Li, Zhouyue; Song, Yanping; Chen, Xiao; Chen, Zhongshan; Ding, Qin

2015-11-01

Many clinical trials have demonstrated the effectiveness of subthreshold phototherapy with no visible damage in retinal vascular diseases, such as diabetic retinopathy. We aimed primarily to investigate the effect of subthreshold diode micropulse laser (SDM) treatment on mouse retinal pigmented epithelium (RPE) cells. The expression of angiogenesis-modulating cytokines in response to SDM was also explored. The least toxic laser dose was selected by measuring cell viability with MTT assay and 5 % duty cycle (DC) was chosen for use in further experiments. RPE cells were treated with laser-induced radiation ranging from 0 to 400 mW for 24 h. The apoptotic rate of RPE cells was assessed by flow cytometry. Expressions of vascular endothelial growth factor A (VEGF-A), transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF), and pigment epithelium-derived factor (PEDF) were determined by Western Blotting and real-time PCR, respectively. After 24 h of laser irradiation, cell viability was reduced dose dependently and the effect was significant compared to the controls (P < 0.05). In addition, laser treatment with intensities of 100 and 200 mW with DC of 5 % produced no significant effect on cell viability and apoptosis as compared with the control group (P > 0.05). The protein and mRNA expressions of angiogenic stimulators (VEGF-A, TGF-β, and bFGF) were significantly down-regulated (P < 0.05), whereas those of the angiogenic inhibitor (PEDF) were up-regulated (P < 0.05). No significant difference was found between the cells treated with different intensities of laser radiation (P > 0.05). Our results showed that SDM treatment of the RPE cells suppressed the expression of choroid neovasculization-promoting cytokines and up-regulated the angiogenic inhibitor, PEDF without damaging the cells. Further investigation is needed to understand the mechanism and to optimize the use of SDM as a novel method of treatment for retinal vascular diseases.

Dietary Weight Loss and Exercise Effects on Serum Biomarkers of Angiogenesis in Overweight Postmenopausal Women: A Randomized Controlled Trial.

PubMed

Duggan, Catherine; Tapsoba, Jean de Dieu; Wang, Ching-Yun; McTiernan, Anne

2016-07-15

Obese and sedentary persons have an increased risk for cancer, but underlying mechanisms are poorly understood. Angiogenesis is common to adipose tissue formation and remodeling, and to tumor vascularization. A total of 439 overweight/obese, healthy, postmenopausal women [body mass index (BMI) > 25 kg/m(2)] ages 50-75 years, recruited between 2005 and 2008 were randomized to a 4-arm 12-month randomized controlled trial, comparing a caloric restriction diet arm (goal: 10% weight loss, N = 118), aerobic exercise arm (225 minutes/week of moderate-to-vigorous activity, N = 117), a combined diet + exercise arm (N = 117), or control (N = 87) on circulating levels of angiogenic biomarkers. VEGF, plasminogen activator inhibitor-1 (PAI-1), and pigment epithelium-derived factor (PEDF) were measured by immunoassay at baseline and 12 months. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity. Participants randomized to the diet + exercise arms had statistically significantly greater reductions in PAI-1 at 12 months compared with controls (-19.3% vs. +3.48%, respectively, P < 0.0001). Participants randomized to the diet and diet + exercise arms had statistically significantly greater reductions in PEDF (-9.20%, -9.90%, respectively, both P < 0.0001) and VEGF (-8.25%, P = 0.0005; -9.98%, P < 0.0001, respectively) compared with controls. There were no differences in any of the analytes in participants randomized to the exercise arm compared with controls. Increasing weight loss was statistically significantly associated with linear trends of greater reductions in PAI-1, PEDF, and VEGF. Weight loss is significantly associated with reduced circulating VEGF, PEDF, and PAI-1, and could provide incentive for reducing weight as a cancer prevention method in overweight and obese individuals. Cancer Res; 76(14); 4226-35. ©2016 AACR. ©2016 American Association for Cancer Research.

Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration.

PubMed

Ioanna, Zygoula; Christian, Schori; Christian, Grimm; Daniel, Barthelmes

2018-02-01

Various hypoxia-related proteins are differentially expressed in the retina and secreted to the vitreous and/or aqueous humor of patients affected by dry or neovascular age-related macular degeneration (nAMD). To determine whether these conditions alter concentrations of cytokines also in the systemic circulation, we measured plasma levels of six hypoxia-related proteins. Plasma was prepared from EDTA blood that was collected from patients affected by dry AMD (n = 5), nAMD (n = 11), proliferative diabetic retinopathy (PDR; n = 9), and patients with an epiretinal membrane (ERM; n = 11). ERM samples served as negative controls, PDR samples as positive controls. Protein concentrations of vascular endothelial growth factor (VEGF), erythropoietin (EPO), angiopoietin-like 4 (ANGPTL4), placental growth factor (PlGF), tumor necrosis factor alpha (TNF-α), and pigment epithelium-derived factor (PEDF) were determined by enzyme-linked immunosorbent assay (ELISA). The concentration of PlGF was significantly increased in plasma of patients affected by nAMD. Although no statistically significant differences were found for EPO, ANGPTL4, PlGF, TNF-α, and PEDF, the mean concentration of VEGF was lowest in the nAMD group. Plasma concentrations of the six factors did not correlate with gender or age of patients. nAMD may increase plasma concentrations of PlGF, making it a candidate as a biomarker for the neovascular form of AMD. Other factors, however, were not differentially regulated, suggesting that their systemic concentrations are not generally increased in hypoxia-related retinal diseases.

Prospectives for Gene Therapy of Retinal Degenerations

PubMed Central

Thumann, Gabriele

2012-01-01

Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness. Retinal degenerations can be divided into two groups, a group in which the defect has been linked to a specific gene and a second group that has a complex etiology that includes environmental and genetic influences. The first group encompasses a number of relatively rare diseases with the most prevalent being Retinitis pigmentosa that affects approximately 1 million individuals worldwide. Attempts have been made to correct the defective gene by transfecting the appropriate cells with the wild-type gene and while these attempts have been successful in animal models, human gene therapy for these inherited retinal degenerations has only begun recently and the results are promising. To the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). These retinal degenerations have a genetic component since they occur more often in families with affected probands but they are also linked to environmental factors, specifically elevated intraocular pressure, age and high blood sugar levels respectively. The economic and medical impact of these three diseases can be assessed by the number of individuals affected; AMD affects over 30 million, DR over 40 million and glaucoma over 65 million individuals worldwide. The basic defect in these diseases appears to be the relative lack of a neurogenic environment; the neovascularization that often accompanies these diseases has suggested that a decrease in pigment epithelium-derived factor (PEDF), at least in part, may be responsible for the neurodegeneration since PEDF is not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularization. In the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell growth factors (VEGF), have been used to prevent the neovascularization that accompanies AMD and DR resulting in the amelioration of vision in a significant number of patients. In animal models it has been shown that transfection of RPE cells with the gene for PEDF and other growth factors can prevent or slow degeneration. A limited number of studies in humans have also shown that transfection of RPE cells in vivo with the gene for PEDF is effective in preventing degeneration and restore vision. Most of these studies have used virally mediated gene delivery with all its accompanying side effects and have not been widely used. New techniques using non-viral protocols that allow efficient delivery and permanent integration of the transgene into the host cell genome offer novel opportunities for effective treatment of retinal degenerations. PMID:23372421

Long-Term Effects of Weight Loss and Exercise on Biomarkers Associated with Angiogenesis.

PubMed

Duggan, Catherine; Tapsoba, Jean de Dieu; Wang, Ching-Yun; Schubert, Karen E Foster; McTiernan, Anne

2017-12-01

Background: We tested the effect of weight loss on circulating levels of the angiogenic factors VEGF and pigment epithelium-derived factor (PEDF) in postmenopausal overweight/obese women, 18 months after completing a year-long 4-arm randomized controlled trial of behavioral weight loss and/or exercise versus control (i.e., 30 months postrandomization). Methods: The 439 overweight/obese, postmenopausal women, ages 50 to 75 years, were randomized to: diet (goal: 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), diet + exercise ( N = 117), or control ( N = 87). At 12 months, 399 women gave a blood sample; 156 returned at 30 months. Biomarkers were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity. Results: Participants randomized to diet, exercise, and diet + exercise arms had greater reductions in VEGF at 30 months (-14.1% P = 0.02; -19.7% P = 0.003; -14.5% P = 0.002, respectively) versus controls (-4.5%). There were no statistically significant changes in PEDF in any intervention arm. Participants maintaining ≥10% of baseline weight loss at 30 months had greater reductions in VEGF versus those who gained weight/had no weight change (-22.3% vs. -10.2% respectively, P = 0.002). Participants maintaining any weight loss had significantly lower levels of PEDF at 30 months versus those who gained weight/no weight change. Conclusions: Sustained weight loss via diet and/or exercise results in reductions in angiogenic factors, and can be maintained up to 30-month follow-up. Limitations include relatively small numbers, and possible bias toward more successful weight loss among women who returned at 30 months. Impact: Maintaining weight loss can achieve long-term reductions in biomarkers of angiogenesis that can persist up to 18 months after completion of a weight loss intervention. Cancer Epidemiol Biomarkers Prev; 26(12); 1788-94. ©2017 AACR . ©2017 American Association for Cancer Research.

PEDF as an anticancer drug and new treatment methods following the discovery of its receptors: A patent perspective

PubMed Central

Manalo, Katrina B.; Choong, Peter F.M.; Becerra, S. Patricia; Dass, Crispin R.

2014-01-01

Background Traditional forms of cancer therapy, which includes chemotherapy, have largely been overhauled due to the significant degree of toxicity they pose to normal, otherwise healthy tissue. It is hoped that use of biological agents, most of which are endogenously present in the body, will lead to safer treatment outcomes, without sacrificing efficacy. Objective The finding that PEDF, a naturally-occurring protein, was a potent angiogenesis inhibitor became the basis for studying the role of PEDF in tumours that are highly resistant to chemotherapy. The determination of the direct role of PEDF against cancer paved the way for understanding and developing PEDF as a novel drug. This review focuses on the patent applications behind testing the anticancer therapeutic effect of PEDF via its receptors as an antiangiogenic agent and as a direct anticancer agent. Conclusions The majority of the PEDF patents describe its and/or its fragments’ antiangiogenic ability and the usage of recombinant vectors as the mode of treatment delivery. PEDF’s therapeutic potential against different diseases and the discovery of its receptors opens possibilities for improving PEDF-based peptide design and drug delivery modes. PMID:21204726

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment.

PubMed

Smitka, Kvido; Marešová, Dana

2015-01-01

Adipose tissue is recognized as an active endocrine organ that produces a number of endocrine substances referred to as "adipokines" including leptin, adiponectin, adipolin, visfatin, omentin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), resistin, pigment epithelium-derived factor (PEDF), and progranulin (PGRN) which play an important role in the food intake regulation and significantly influence insulin sensitivity and in some cases directly affect insulin resistance in skeletal muscle, liver, and adipose tissue. The review summarizes current knowledge about adipose tissue-derived hormones and their influence on energy homeostasis regulation. The possible therapeutic potential of these adipokines in the treatment of insulin resistance, endothelial dysfunction, a pro-inflammatory response, obesity, eating disorders, progression of atherosclerosis, type 1 diabetes, and type 2 diabetes is discussed.

Differential expression of anti-angiogenic factors and guidance genes in the developing macula.

PubMed

Kozulin, Peter; Natoli, Riccardo; O'Brien, Keely M Bumsted; Madigan, Michele C; Provis, Jan M

2009-01-01

The primate retina contains a specialized, cone-rich macula, which mediates high acuity and color vision. The spatial resolution provided by the neural retina at the macula is optimized by stereotyped retinal blood vessel and ganglion cell axon patterning, which radiate away from the macula and reduce shadowing of macular photoreceptors. However, the genes that mediate these specializations, and the reasons for the vulnerability of the macula to degenerative disease, remain obscure. The aim of this study was to identify novel genes that may influence retinal vascular patterning and definition of the foveal avascular area. We used RNA from human fetal retinas at 19-20 weeks of gestation (WG; n=4) to measure differential gene expression in the macula, a region nasal to disc (nasal) and in the surrounding retina (surround) by hybridization to 12 GeneChip microarrays (HG-U133 Plus 2.0). The raw data was subjected to quality control assessment and preprocessing, using GC-RMA. We then used ANOVA analysis (Partek) Genomic Suite 6.3) and clustering (DAVID website) to identify the most highly represented genes clustered according to "biological process." The neural retina is fully differentiated at the macula at 19-20 WG, while neuronal progenitor cells are present throughout the rest of the retina. We therefore excluded genes associated with the cell cycle, and markers of differentiated neurons, from further analyses. Significantly regulated genes (p<0.01) were then identified in a second round of clustering according to molecular/reaction (KEGG) pathway. Genes of interest were verified by quantitative PCR (QRT-PCR), and 2 genes were localized by in situ hybridization. We generated two lists of differentially regulated genes: "macula versus surround" and "macula versus nasal." KEGG pathway clustering of the filtered gene lists identified 25 axon guidance-related genes that are differentially regulated in the macula. Furthermore, we found significant upregulation of three anti-angiogenic factors in the macula: pigment epithelium derived factor (PEDF), natriuretic peptide precurusor B (NPPB), and collagen type IValpha2. Differential expression of several members of the ephrin and semaphorin axon guidance gene families, PEDF, and NPPB was verified by QRT-PCR. Localization of PEDF and Eph-A6 mRNAs in sections of macaque retina shows expression of both genes concentrates in the ganglion cell layer (GCL) at the developing fovea, consistent with an involvement in definition of the foveal avascular area. Because the axons of macular ganglion cells exit the retina from around 8 WG, we suggest that the axon guidance genes highly expressed at the macula at 19-20 WG are also involved in vascular patterning, along with PEDF and NPPB. Localization of both PEDF and Eph-A6 mRNAs to the GCL of the developing fovea supports this idea. It is possible that specialization of the macular vessels, including definition of the foveal avascular area, is mediated by processes that piggyback on axon guidance mechanisms in effect earlier in development. These findings may be useful to understand the vulnerability of the macula to degeneration and to develop new therapeutic strategies to inhibit neovascularization.

Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta

PubMed Central

Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A.; Hoischen, Alexander; Netzer, Christian

2011-01-01

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis. PMID:21353196

Sutureless Fixation of Amniotic Membrane for Therapy of Ocular Surface Disorders

PubMed Central

Kotomin, Ilya; Valtink, Monika; Hofmann, Kai; Frenzel, Annika; Morawietz, Henning; Werner, Carsten; Funk, Richard H. W.; Engelmann, Katrin

2015-01-01

Amniotic membrane is applied to the diseased ocular surface to stimulate wound healing and tissue repair, because it releases supportive growth factors and cytokines. These effects fade within about a week after application, necessitating repeated application. Generally, amniotic membrane is fixed with sutures to the ocular surface, but surgical intervention at the inflamed or diseased site can be detrimental. Therefore, we have developed a system for the mounting of amniotic membrane between two rings for application to a diseased ocular surface without surgical intervention (sutureless amniotic membrane transplantation). With this system, AmnioClip, amniotic membrane can be applied like a large contact lens. First prototypes were tested in an experiment on oneself for wearing comfort. The final system was tested on 7 patients in a pilot study. A possible influence of the ring system on the biological effects of amniotic membrane was analyzed by histochemistry and by analyzing the expression of vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF 2) and pigment epithelium-derived factor (PEDF) from amniotic membranes before and after therapeutic application. The final product, AmnioClip, showed good tolerance and did not impair the biological effects of amniotic membrane. VEGF-A and PEDF mRNA was expressed in amniotic membrane after storage and mounting before transplantation, but was undetectable after a 7-day application period. Consequently, transplantation of amniotic membranes with AmnioClip provides a sutureless and hence improved therapeutic strategy for corneal surface disorders. Trial Registration ClinicalTrials.gov NCT02168790 PMID:25955359

Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors.

PubMed

Michalski, Dominik; Pitsch, Roman; Pillai, Deepu R; Mages, Bianca; Aleithe, Susanne; Grosche, Jens; Martens, Henrik; Schlachetzki, Felix; Härtig, Wolfgang

2017-01-01

Current stroke therapy is focused on recanalizing strategies, but neuroprotective co-treatments are still lacking. Modern concepts of the ischemia-affected neurovascular unit (NVU) and surrounding penumbra emphasize the complexity during the transition from initial damaging to regenerative processes. While early treatment with neurotrophic factors was shown to result in lesion size reduction and blood-brain barrier (BBB) stabilization, cellular consequences from these treatments are poorly understood. This study explored delayed cellular responses not only to ischemic stroke, but also to an early treatment with neurotrophic factors. Rats underwent 60 minutes of focal cerebral ischemia. Fluorescence labeling was applied to sections from brains perfused 7 days after ischemia. Analyses focused on NVU constituents including the vasculature, astrocytes and microglia in the ischemic striatum, the border zone and the contralateral hemisphere. In addition to histochemical signs of BBB breakdown, a strong up-regulation of collagen IV and microglia activation occurred within the ischemic core with simultaneous degradation of astrocytes and their endfeet. Activated astroglia were mainly depicted at the border zone in terms of a glial scar formation. Early treatment with pigment epithelium-derived factor (PEDF) resulted in an attenuation of the usually up-regulated collagen IV-immunoreactivity. However, glial activation was not influenced by treatment with PEDF or the epidermal growth factor (EGF). In conclusion, these data on ischemia-induced cellular reactions within the NVU might help to develop treatments addressing the transition from injury towards regeneration. Thereby, the integrity of the vasculature in close relation to neighboring structures like astrocytes appears as a promising target.

Differential expression of anti-angiogenic factors and guidance genes in the developing macula

PubMed Central

Kozulin, Peter; Natoli, Riccardo; O’Brien, Keely M. Bumsted; Madigan, Michele C.

2009-01-01

Purpose The primate retina contains a specialized, cone-rich macula, which mediates high acuity and color vision. The spatial resolution provided by the neural retina at the macula is optimized by stereotyped retinal blood vessel and ganglion cell axon patterning, which radiate away from the macula and reduce shadowing of macular photoreceptors. However, the genes that mediate these specializations, and the reasons for the vulnerability of the macula to degenerative disease, remain obscure. The aim of this study was to identify novel genes that may influence retinal vascular patterning and definition of the foveal avascular area. Methods We used RNA from human fetal retinas at 19–20 weeks of gestation (WG; n=4) to measure differential gene expression in the macula, a region nasal to disc (nasal) and in the surrounding retina (surround) by hybridization to 12 GeneChip® microarrays (HG-U133 Plus 2.0). The raw data was subjected to quality control assessment and preprocessing, using GC-RMA. We then used ANOVA analysis (Partek® Genomic Suite™ 6.3) and clustering (DAVID website) to identify the most highly represented genes clustered according to “biological process.” The neural retina is fully differentiated at the macula at 19–20 WG, while neuronal progenitor cells are present throughout the rest of the retina. We therefore excluded genes associated with the cell cycle, and markers of differentiated neurons, from further analyses. Significantly regulated genes (p<0.01) were then identified in a second round of clustering according to molecular/reaction (KEGG) pathway. Genes of interest were verified by quantitative PCR (QRT–PCR), and 2 genes were localized by in situ hybridization. Results We generated two lists of differentially regulated genes: “macula versus surround” and “macula versus nasal.” KEGG pathway clustering of the filtered gene lists identified 25 axon guidance-related genes that are differentially regulated in the macula. Furthermore, we found significant upregulation of three anti-angiogenic factors in the macula: pigment epithelium derived factor (PEDF), natriuretic peptide precurusor B (NPPB), and collagen type IVα2. Differential expression of several members of the ephrin and semaphorin axon guidance gene families, PEDF, and NPPB was verified by QRT–PCR. Localization of PEDF and Eph-A6 mRNAs in sections of macaque retina shows expression of both genes concentrates in the ganglion cell layer (GCL) at the developing fovea, consistent with an involvement in definition of the foveal avascular area. Conclusions Because the axons of macular ganglion cells exit the retina from around 8 WG, we suggest that the axon guidance genes highly expressed at the macula at 19–20 WG are also involved in vascular patterning, along with PEDF and NPPB. Localization of both PEDF and Eph-A6 mRNAs to the GCL of the developing fovea supports this idea. It is possible that specialization of the macular vessels, including definition of the foveal avascular area, is mediated by processes that piggyback on axon guidance mechanisms in effect earlier in development. These findings may be useful to understand the vulnerability of the macula to degeneration and to develop new therapeutic strategies to inhibit neovascularization. PMID:19145251

Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats

PubMed Central

Özdemir, G; Ergün, Y; Bakariş, S; Kılınç, M; Durdu, H; Ganiyusufoğlu, E

2014-01-01

Purpose To evaluate the role of melatonin, an antioxidant agent, in diabetic oxidative stress and vascular damage. Methods Diabetes was induced in 21 male Wistar rats by intraperitoneal (IP) administration of streptozotocin and then the rats were equally and randomly allocated to diabetic, melatonin, and vehicle groups. Seven healthy normal rats with similar features comprised the control group as the fourth group. All animals were followed for 12 weeks. The melatonin group received IP melatonin daily and the vehicle group received 2.5% ethanol IP at the last month. At the end of 12 weeks, the rats were killed and retinas were harvested. The retinas were investigated for the existence of hypoxia-inducible factor 1-α (HIF-1α), vascular endothelial growth factor A (VEGF-A), and pigment epithelium-derived factor (PEDF) by ELISA. Retinal oxidative stress is quantitated by measuring nitrotyrosine and malondialdehyde levels. Retinal immunohistochemistry with antibody against CD31 antigen was carried out on retinal cross-sections. For statistics, ANOVA test was used for multiple comparisons. Results Hyperglycemia increased retinal oxidation as measured through levels of nitrotyrosine and malondialdehyde. Diabetic retinas are also associated with abnormal vascular changes such as dilatation and deformation. HIF-1α, VEGF-A, and PEDF were all increased because of diabetic injury. Melatonin showed a potential beneficial effect on retinopathy in diabetic rats. It decreased retinal nitrotyrosine and malondialdehyde levels, showing an antioxidative support. The vasculomodulator cytokines are decreased accordingly by melatonin therapy. Melatonin normalized retinal vascular changes as well. Conclusion Melatonin may show some advantage on diabetic vascular changes through decreasing oxidative stress and vessel-related cytokines. PMID:24924441

Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

PubMed

Shen, Weiyong; Chung, Sook H; Irhimeh, Mohammad R; Li, Shiying; Lee, So-Ra; Gillies, Mark C

2014-01-01

Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats. Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34(+) cells and mobilization of CD34(+)/VEGF-R2(+) cells as well as recruitment of CD34(+) cells into the retina were examined after EPO treatment. RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+) cells along with effective mobilization of CD34(+)/VEGF-R2(+) cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and microglia, inhibition of p75NTR-pro-NT3 signaling together with stimulation of production and mobilization of bone marrow derived cells.

Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

PubMed Central

Shen, Weiyong; Chung, Sook H.; Irhimeh, Mohammad R.; Li, Shiying; Lee, So-Ra; Gillies, Mark C.

2014-01-01

Objective Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats. Methods Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34+ cells and mobilization of CD34+/VEGF-R2+ cells as well as recruitment of CD34+ cells into the retina were examined after EPO treatment. Results RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34+ cells along with effective mobilization of CD34+/VEGF-R2+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. Conclusions Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and microglia, inhibition of p75NTR-pro-NT3 signaling together with stimulation of production and mobilization of bone marrow derived cells. PMID:25119659

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

PubMed

Nishimon, Shohei; Ohnuma, Tohru; Takebayashi, Yuto; Katsuta, Narimasa; Takeda, Mayu; Nakamura, Toru; Sannohe, Takahiro; Higashiyama, Ryoko; Kimoto, Ayako; Shibata, Nobuto; Gohda, Tomohito; Suzuki, Yusuke; Yamagishi, Sho-Ichi; Tomino, Yasuhiko; Arai, Heii

2017-06-02

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore.

PubMed

Moh, Mei Chung; Sum, Chee Fang; Tavintharan, Subramaniam; Pek, Sharon Li Ting; Yeoh, Lee Ying; Ng, Xiaowei; Lee, Simon Biing Ming; Tang, Wern Ee; Lim, Su Chi

2017-07-01

This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease. The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications. Copyright © 2016. Published by Elsevier Inc.

[Elucidating the molecular mechanism of prostate cancer progression under chronic hypoxia and development of the novel therapeutic approach].

PubMed

Nomura, Takeo; Yamasaki, Mutsushi; Mimata, Hiromitsu

2014-12-01

Cancer cells encounter a hypoxic microenvironment during tumor growth and progression. In addition, androgen-deprivation therapy against prostate cancer can develop secondary to a hypoxic condition caused by drastic blood supply reduction because androgen drives angiogenic inducers including vascular endothelial growth factor (VEGF) and inhibits angiogenesis inhibitor prostatic pigment epithelium-derived factor (PEDF). Extreme hypoxic conditions are not suitable for cancer survival, however, cancer cells soon adapt to a hypoxic environment and survive. We established a prostate cancer cell line cultured under chronic hypoxia and analyzed a castration-resistant phenotype. Here, the Vav3 was identified as a key oncogenic molecule associated with castration-resistance under chronic hypoxia. We analyzed the functions of Vav3 and Vav3-mediated signaling to establish a novel therapeutic target for castration-resistant prostate cancer.

Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and Native American women with diabetes mellitus.

PubMed

Teague, April M; Fields, David A; Aston, Christopher E; Short, Kevin R; Lyons, Timothy J; Chernausek, Steven D

2015-06-26

Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women. We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates. DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort. Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

VR-10 Thrombospondin-1 Synthetic Polypeptide's Impact on Rhesus Choroid-Retinal Endothelial Cells.

PubMed

Tian, Run; Han, Fang; Yang, Jun; Zhao, Hai-Yan; Mei, Yan; Deng, Ai-Ping; Fang, Lin; Zhang, Xi-Rui

2018-01-01

This study aimed to investigate the effects of the VR-10 TSP-1 synthetic polypeptide on cytokines and the proliferation and migration of endothelial cells, as well as exploring a new method for anti-ocular neoangiogenesis. We measured the proliferation of RF/6A cells by an MTT assay and investigated the migration of RF/6A cells by a Transwell chamber assay. We examined the mRNA transcript levels of TGF-β2, VEGF, PEDF, Bcl-2 and FasL in RF/6A cells by RT-PCR and evaluated the expression of Fas and caspase-3 proteins in RF/6A cells by western blot analysis. 1. TSP-1 (1 µg/ml) and synthetic peptide VR-10 (0.1 µg/ml, 1 µg/ml and 10 µg/ml) inhibited the proliferation of RF/6A cells in a time and dose-dependent way. 2. TSP-1 and synthetic peptide VR-10 could inhibit the migration of RF/6A cells in a Transwell chamber (P < 0.001). It was demonstrated that 10 µg/ml synthetic peptide VR-10 had the strongest effect. 3. The expression of TGF-β2 mRNA in RF/6A cells increased after treatment with 1 µg/ml TSP-1 (P < 0.0001). However, there was no significant difference between the synthetic peptide VR-10 and the control group (P > 0.05). Expression of PEDF mRNA in RF/6A cells was increased after treatment with 1 µg/ml TSP-1 and synthetic peptide VR-10. We demonstrated that 10 µg/ml synthetic peptide VR-10 had the strongest effect (P < 0.001). There were significant differences between groups (P < 0.001). Expression of TGF-β2 mRNA in RF/6A cells increased after treatment with 1 µg/ml TSP-1 (P = 0.000). There was no significant difference between the synthetic peptide VR-10 and the control group (P > 0.05). PEDF mRNA expression in RF/6A cells decreased after 1 µg/ml TSP-1 and synthetic peptide VR-10 therapy, among which 10 µg/ml synthetic peptide VR-10 demonstrated the strongest effect (P < 0.001). There were significant differences between groups (P < 0.001), except for the 1 µg/ml synthetic peptide VR-10 and 1 µg/ml synthetic peptide VR-10 groups (P = 0.615). 4. Compared with the control group, FasL mRNA expression was significantly increased in the 10 µg/ml synthetic peptide VR-10 treatment group; however, Bcl-2 mRNA expression was decreased. 5. Western blotting showed that RF/6A cells in the control group mainly expressed the 32 kD procaspase-3 forms. For the 10 µg/ml synthetic peptide, VR-10 treatment group, it showed decreased expression of procaspase-3 (32 kD) and concomitant increased expression of its shorter pro apoptotic forms (20 kD). Compared with the control group, Fas protein expression significantly increased in the 10 µg/ml synthetic peptide VR-10 treatment group. Synthetic peptide VR-10 had an inhibitory action on the proliferation and migration of RF/6A cells. VR-10 inhibited angiogenesis by its combined actions, which included up-regulating the expression of an anti-angiogenesis gene, namely, pigment epithelium-derived factor (PEDF), down-regulating the expression of the pro-angiogenic vascular endothelial growth factor (VEGF), and mediated endothelial cell apoptosis. © 2018 The Author(s). Published by S. Karger AG, Basel.

A Review: Proteomics in Retinal Artery Occlusion, Retinal Vein Occlusion, Diabetic Retinopathy and Acquired Macular Disorders.

PubMed

Cehofski, Lasse Jørgensen; Honoré, Bent; Vorum, Henrik

2017-04-28

Retinal artery occlusion (RAO), retinal vein occlusion (RVO), diabetic retinopathy (DR) and age-related macular degeneration (AMD) are frequent ocular diseases with potentially sight-threatening outcomes. In the present review we discuss major findings of proteomic studies of RAO, RVO, DR and AMD, including an overview of ocular proteome changes associated with anti-vascular endothelial growth factor (VEGF) treatments. Despite the severe outcomes of RAO, the proteome of the disease remains largely unstudied. There is also limited knowledge about the proteome of RVO, but proteomic studies suggest that RVO is associated with remodeling of the extracellular matrix and adhesion processes. Proteomic studies of DR have resulted in the identification of potential therapeutic targets such as carbonic anhydrase-I. Proliferative diabetic retinopathy is the most intensively studied stage of DR. Proteomic studies have established VEGF, pigment epithelium-derived factor (PEDF) and complement components as key factors associated with AMD. The aim of this review is to highlight the major milestones in proteomics in RAO, RVO, DR and AMD. Through large-scale protein analyses, proteomics is bringing new important insights into these complex pathological conditions.

Angiogenesis is inhibitory for mammalian digit regeneration

PubMed Central

Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D.; Leininger, Eric; Han, Manjong

2014-01-01

Abstract The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID:27499862

Differential protein expression in Tree Shrew sclera during development of lens-induced myopia and recovery

PubMed Central

Norton, Thomas T.

2007-01-01

Purpose The tree shrew model of refractive development is particularly useful because, like humans, tree shrews have a fibrous sclera. Selective changes in some candidate extracellular matrix proteins and mRNAs have been found in the sclera during the development of, and recovery from, induced myopia. We undertook a more neutral proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry to identify scleral proteins that are differentially expressed during the development of, and recovery from, lens-induced myopia. Methods Five tree shrews (Tupaia glis belangeri) wore a monocular –5 D lens for 4 days, starting 24 days after natural eye opening. At the end of this time, all treated eyes had partially compensated for the lens and were –3.5±0.7 D (mean ± SEM) myopic relative to the untreated fellow control eyes. An additional five animals wore a –5 D lens for 11–13 days, followed by 4 days of recovery without the –5 D lens. The amount of recovery was 1.6±0.4 D. Scleral proteins from both groups were then isolated and resolved by two-dimensional gel electrophoresis and spots that were differentially expressed were identified by mass spectrometry. Results The scleral protein profile typically displayed ~700 distinct protein spots within the pH 5–8 range. Comparison of the treated-eye and control-eye scleras of the lens-compensation animals revealed five spots that were significantly differentially expressed in all five pairs of eyes; all were downregulated 1.2 to 1.7 fold in the treated eye. These proteins were identified as: pigment epithelium-derived factor (PEDF), procollagen I α1, procollagen I α2, and thrombospondin I (two spots). In the recovering eyes, the two thrombospondin I spots remained lower in abundance while PEDF and the procollagens were no longer downregulated. In addition, 78 kDa glucose-regulated protein (GRP 78), a member of the heat shock protein 70 family, was slightly upregulated 1.3 fold. Conclusions We found consistent results across animals that were of a magnitude consistent with the physiologically small changes to the focal plane of these eyes. Changes in collagen confirm previous findings, but downregulation of thrombospondin I adds detail to our understanding of the chain of signals that regulates scleral creep rate. The differential changes in PEDF and GRP 78 were not expected, based on previous studies, and demonstrate the utility of the proteomic approach in tree shrew sclera. PMID:17893659

A Review: Proteomics in Retinal Artery Occlusion, Retinal Vein Occlusion, Diabetic Retinopathy and Acquired Macular Disorders

PubMed Central

Cehofski, Lasse Jørgensen; Honoré, Bent; Vorum, Henrik

2017-01-01

Retinal artery occlusion (RAO), retinal vein occlusion (RVO), diabetic retinopathy (DR) and age-related macular degeneration (AMD) are frequent ocular diseases with potentially sight-threatening outcomes. In the present review we discuss major findings of proteomic studies of RAO, RVO, DR and AMD, including an overview of ocular proteome changes associated with anti-vascular endothelial growth factor (VEGF) treatments. Despite the severe outcomes of RAO, the proteome of the disease remains largely unstudied. There is also limited knowledge about the proteome of RVO, but proteomic studies suggest that RVO is associated with remodeling of the extracellular matrix and adhesion processes. Proteomic studies of DR have resulted in the identification of potential therapeutic targets such as carbonic anhydrase-I. Proliferative diabetic retinopathy is the most intensively studied stage of DR. Proteomic studies have established VEGF, pigment epithelium-derived factor (PEDF) and complement components as key factors associated with AMD. The aim of this review is to highlight the major milestones in proteomics in RAO, RVO, DR and AMD. Through large-scale protein analyses, proteomics is bringing new important insights into these complex pathological conditions. PMID:28452939

KRAS Mutation and Epithelial-Macrophage Interplay in Pancreatic Neoplastic Transformation.

PubMed

Bishehsari, Faraz; Zhang, Lijuan; Barlass, Usman; Preite, Nailliw; Turturro, Sanja; Najor, Matthew S; Shetuni, Brandon B; Zayas, Janet P; Mahdavinia, Mahboobeh; Abukhdeir, Abde M; Keshavarzian, Ali

2018-05-14

Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased i) ductal to acinar gene expression ratios, ii) epithelial cells proliferation, and iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a pro-tumorigenic phenotype in macrophages. Altered macrophages decreased epithelial Pigment Epithelial Derived Factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) as well as in our human PDA specimens. Epithelium-macrophage cross talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a pro-tumorigenic phenotype in macrophages, in turn augmenting neoplastic growth. This article is protected by copyright. All rights reserved. © 2018 UICC.

Contacting co-culture of human retinal microvascular endothelial cells alters barrier function of human embryonic stem cell derived retinal pigment epithelial cells.

PubMed

Skottman, H; Muranen, J; Lähdekorpi, H; Pajula, E; Mäkelä, K; Koivusalo, L; Koistinen, A; Uusitalo, H; Kaarniranta, K; Juuti-Uusitalo, K

2017-10-01

Here we evaluated the effects of human retinal microvascular endothelial cells (hREC) on mature human embryonic stem cell (hESC) derived retinal pigment epithelial (RPE) cells. The hESC-RPE cells (Regea08/017, Regea08/023 or Regea11/013) and hREC (ACBRI 181) were co-cultured on opposite sides of transparent membranes for up to six weeks. Thereafter barrier function, small molecule permeability, localization of RPE and endothelial cell marker proteins, cellular fine structure, and growth factor secretion of were evaluated. After co-culture, the RPE specific CRALBP and endothelial cell specific von Willebrand factor were appropriately localized. In addition, the general morphology, pigmentation, and fine structure of hESC-RPE cells were unaffected. Co-culture increased the barrier function of hESC-RPE cells, detected both with TEER measurements and cumulative permeability of FD4 - although the differences varied among the cell lines. Co-culturing significantly altered VEGF and PEDF secretion, but again the differences were cell line specific. The results of this study showed that co-culture with hREC affects hESC-RPE functionality. In addition, co-culture revealed drastic cell line specific differences, most notably in growth factor secretion. This model has the potential to be used as an in vitro outer blood-retinal barrier model for drug permeability testing. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibitory effects of polysaccharide extract from Spirulina platensis on corneal neovascularization

PubMed Central

Yang, Lingling; Wang, Yao; Zhou, Qingjun; Chen, Peng; Wang, Yiqiang; Wang, Ye; Liu, Ting

2009-01-01

Purpose To assess the effects of polysaccharide extract from Spirulina platensis (PSP) on corneal neovascularization (CNV) in vivo and in vitro. Methods PSP was extracted from dry powder of Spirulina platensis. Its anti-angiogenic activity was evaluated in the mouse corneal alkali burn model after topical administration of PSP four times daily for up to seven days. Corneal samples were processed for histochemical, immunohistochemical, and gene expression analyses. The effects of PSP on proliferation, migration, tube formation, and serine threonine kinase (AKT) and extracellular regulated kinase1/2 (ERK1/2) signaling levels in vascular endothelial cells were determined using 3-(4,5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) and carboxyfluorescein succinimidyl ester (CFSE) labeling assays, wound healing assay, Matrigel tube formation assay, and western blot. Results Topical application of PSP significantly inhibited CNV caused by alkali burn. Corneas treated with PSP showed reduced levels of platelet endothelial cell adhesion molecule (CD31) and stromal cell-derived factor 1 (SDF1) proteins, reduced levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-9 (MMP9), SDF1, and tumor necrosis factor-alpha (TNF-α) mRNAs, and an increased level of pigment epithelium-derived factor (PEDF) mRNA. These are parameters that have all been related to CNV and/or inflammation. In human vascular endothelial cells, PSP significantly inhibited proliferation, migration, and tube formation in a dose-dependent manner. Furthermore, PSP also decreased the levels of activated AKT and ERK 1/2. Conclusions These data suggest that polysaccharide extract from Spirulina platensis is a potent inhibitor of CNV and that it may be of benefit in the therapy of corneal diseases involving neovascularization and inflammation. PMID:19784394

A Bruch's membrane substitute fabricated from silk fibroin supports the function of retinal pigment epithelial cells in vitro.

PubMed

Shadforth, Audra M A; Suzuki, Shuko; Theodoropoulos, Christina; Richardson, Neil A; Chirila, Traian V; Harkin, Damien G

2017-06-01

Silk fibroin provides a promising biomaterial for ocular tissue reconstruction, including the damaged outer blood-retinal barrier of patients afflicted with age-related macular degeneration (AMD). The aim of the present study was to evaluate the function of retinal pigment epithelial (RPE) cells in vitro, when grown on fibroin membranes manufactured to a thickness similar to that of Bruch's membrane (3 µm). Confluent cultures of RPE cells (ARPE-19) were established on fibroin membranes and maintained under conditions designed to promote maturation over 4 months. Control cultures were grown on polyester cell culture well inserts (Transwell ® ). Cultures established on either material developed a cobblestone morphology, with partial pigmentation, within 12 weeks. Immunocytochemistry at 16 weeks revealed a similar distribution pattern between cultures for F-actin, ZO-1, ezrin, cytokeratin pair 8/18, RPE-65 and Na + /K + -ATPase. Electron microscopy revealed that cultures grown on fibroin displayed a rounder apical surface with a more dense distribution of microvilli. Both cultures avidly ingested fluorescent microspheres coated with vitronectin and bovine serum albumin (BSA), but not controls coated with BSA alone. VEGF and PEDF were detected in the conditioned media collected from above and below the two membrane types. Levels of PEDF were significantly higher than for VEGF on both membranes and a trend was observed towards larger amounts of PEDF in apical compartments. These findings demonstrated that RPE cell functions on fibroin membranes are equivalent to those observed for standard test materials (polyester membranes). As such, these studies support advancement to studies of RPE cell implantation on fibroin membranes in a preclinical model. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

The ethanol extract of Zingiber zerumbet rhizomes mitigates vascular lesions in the diabetic retina.

PubMed

Hong, Tang-Yao; Tzeng, Thing-Fong; Liou, Shorong-Shii; Liu, I-Min

2016-01-01

Diabetic retinopathy (DR) is a common diabetic eye disease which is well-known as the result of microvascular retinal changes. Although the ethanol extract from Zingiber zerumbet (L.) Smith rhizome (EEZZR) has been indicated to ameliorate hyperglycemia in diabetes, its protective effect on DR remains unclear. The aim of this study was to determine the effects of EEZZR on DR in streptozotocin (STZ) diabetic rats. Diabetic rats were treated orally with EEZZR (200, 300 mg/kg per day) or calcium dobesilate (CD; 500 mg/kg per day) for 12 weeks. EEZZR displayed similar characteristics to CD in reducing blood-retinal barrier permeability in diabetic rats. Retinal histopathological observation showed that retinal vessels were decreased in EEZZR-treated diabetic rats. EEZZR decreased the increased retinal expression of vascular endothelial growth factor (VEGF) and upregulate the expressions of renal pigment epithelium-derived factor (PEDF) in diabetic rats. Retinal mRNA expression of tumor necrosis factor-α, interleukin (IL)-1, IL-6, monocyte chemotactic proteins-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were all decreased in EEZZR-treated diabetic rats. Moreover, EEZZR could attenuate phosphorylation of nuclear factor Kappa B (NF-κB) p65 and extracellular signal-regulated kinase (ERK)1/2 as well as inhibit the nuclear translocation of pNF-κB p65 induced by diabetes. In conclusion, restoring the balance between stimulators and inhibitors of angiogenesis may be associated with the protective effect of EEZZR on DR. In addition, EEZZR can ameliorate retinal inflammation via transrepression of NF-κB and inhibition of ERK1/2 signaling pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Loss of PEDF: A Novel Mechanism of Antihormone Resistance in Breast Cancer

DTIC Science & Technology

2013-08-01

phosphorylated ERa, Akt, and RET in these tumors. Discussion Resistance to endocrine therapy presents a major chal- lenge in the management of ERa-positive... Drury S, Dowsett M, Martin LA, Isacke CM: Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals

Experiences with New Approach to Use of Information Technologies in Education

ERIC Educational Resources Information Center

Kostolányová, Katerina

2008-01-01

Paper describes approach of Department of Information and Communication technologies (KIK) on Pedagogical Faculty of University of Ostrava in Ostrava (PedF OU) to development of information knowledge and skills of students of OU with the aid of modern methods and education technologies with support of information technologies (IT). It surveys the…

Loss of PEDF: A Novel Mechanism of Antihormone Resistance in Breast Cancer

DTIC Science & Technology

2014-08-01

major chal- lenge in the management of ERa-positive breast cancer and is an area under intense investigation. While many studies point towards the cross...I, Morandi A, Robertson D, Pancholi S, Drury S, Dowsett M, Martin LA, Isacke CM: Targeting the receptor tyrosine kinase RET sensitizes breast cancer

Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis.

PubMed

Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Gerhards, Hartmut; Ueffing, Marius; Deeg, Cornelia A

2007-06-01

Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Although retinal-autoantigen specific T-helper 1 cells have been demonstrated to trigger disease progression and relapses, the molecular processes leading to retinal degeneration and consequent blindness remain unknown. To elucidate such processes, we studied changes in the total retinal proteome of ERU-diseased horses compared to healthy controls. Severe changes in the retinal proteome were found for several markers for blood-retinal barrier breakdown and whose emergence depended upon disease severity. Additionally, uveitic changes in the retina were accompanied by upregulation of aldose 1-epimerase, selenium-binding protein 1, alpha crystallin A chain, phosphatase 2A inhibitor (SET), and glial fibrillary acidic protein (GFAP), the latter indicating an involvement of retinal Mueller glial cells (RMG) in disease process. To confirm this, we screened for additional RMG-specific markers and could demonstrate that, in uveitic retinas, RMG concomitantly upregulate vimentin and GFAP and downregulate glutamine synthetase. These expression patterns suggest for an activated state of RMG, which further downregulate the expression of pigment epithelium-derived factor (PEDF) and begin expressing interferon-gamma, a pro-inflammatory cytokine typical for T-helper 1 cells. We thus propose that RMG may play a fatal role in uveitic disease progression by directly triggering inflammatory processes through the expression and secretion of interferon-gamma.

Comparison of genome-wide gene expression in suture- and alkali burn-induced murine corneal neovascularization

PubMed Central

Jia, Changkai; Zhu, Wei; Ren, Shengwei; Xi, Haijie; Li, Siyuan

2011-01-01

Purpose Suture placement and alkali burn to the cornea are often used to induce inflammatory corneal neovascularization (CorNV) models in animals. This study compares the changes in genome-wide gene expression under these two CorNV conditions in mice. Methods CorNV were induced in Balb/c mice by three interrupted 10–0 sutures placed at sites about 1 mm from the corneal apex, or by alkali burns that were 2 mm in size in the central area of the cornea. At the points in time when neovascularization progressed most quickly, some eyeballs were subjected to histological staining to examine CorNV and inflammatory cells infiltration, and some corneas were harvested to extract mRNA for microarray assay. After normalization and filtering, the microarray data were subject to statistical analysis using Significance Analysis of Microarray software, and interested genes were annotated using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) program. The expression change of classical proangiogenic molecule like vascular endothelial growth factor (VEGF) and antiangiogenic molecule like pigment epithelium-derived factor (PEDF) was further verified using western blotting. Results Suture placement induced CorNV in the areas between the suture and limbus, but did not affect the transparency of the yet unvasuclarized areas of the corneas. In contrast, alkali burn caused edema and total loss of transparency of the whole cornea. Histology showed that sutures only caused localized epithelial loss and inflammatory infiltration between the suture and limbus, but chemical burn depleted the whole epithelial layer of the central cornea and caused heavy cellular infiltration of the whole cornea. At day 5 after suture placement, 1,055 differentially expressed probes were identified, out of which 586 probes were upregulated and 469 probes were downregulated. At a comparable time point, namely on day 6 after the alkali burn to the corneas, 472 probes were upregulated and 389 probes were downregulated. Among these differentially expressed probes, a significant portion (530 probes in total, including 286 upregulated and 244 downregulated probes) showed a similar pattern of change in both models. Annotation (using DAVID) of the overlapping differential genes revealed that the significant enrichment gene ontology terms were “chemotaxis” and “immune response” for the upregulated genes, and “oxidation reduction” and “programmed cell death” for the downregulated genes. Some genes or gene families (e.g., S100A family or α-, β-, or γ-crystallin family) that had not been related to corneal pathogenesis or neovascularization were also revealed to be involved in CorNV. VEGF was upregulated and PEDF was stable as shown with western blotting. Conclusions Sutures and alkali burn to the corneas produced types of damage that affected transparency differentially, but gene profiling revealed similar patterns of changes in gene expression in these two CorNV models. Further studies of the primary genes found to be involved in CorNV will supplement current understanding about the pathogenesis of neovascularization diseases. PMID:21921991

Genetic variants in pigment epithelium-derived factor influence response of polypoidal choroidal vasculopathy to photodynamic therapy.

PubMed

Nakata, Isao; Yamashiro, Kenji; Yamada, Ryo; Gotoh, Norimoto; Nakanishi, Hideo; Hayashi, Hisako; Tsujikawa, Akitaka; Otani, Atsushi; Ooto, Sotaro; Tamura, Hiroshi; Saito, Masaaki; Saito, Kuniharu; Iida, Tomohiro; Oishi, Akio; Kurimoto, Yasuo; Matsuda, Fumihiko; Yoshimura, Nagahisa

2011-07-01

To investigate whether photodynamic therapy (PDT) outcomes of polypoidal choroidal vasculopathy (PCV) are related to baseline clinical characteristics, smoking history, or genetic factors by analyzing the retreatment-free period after the first PDT. Retrospective cohort study. The study consisted of 167 patients with PCV who underwent PDT as their first treatment. We targeted 638 single nucleotide polymorphisms (SNPs) in 42 possible susceptible genes for age-related macular degeneration to evaluate their relation to the effectiveness of PDT for PCV. For this evaluation, we used 2 methods: (1) survival analysis, with the retreatment-free period as the target; and (2) logistic regression test between the need for additional therapy within 3 months after the first PDT and the genotypes, with age, gender, smoking status, and greatest linear dimension (GLD) at baseline as covariates. The contributions of smoking status and GLD at baseline for the retreatment-free period also were evaluated. Contributions of these factors to visual prognosis were evaluated for 1 year after PDT. Retreatment-free period after the first PDT for PCV. Secondary outcome measures included correlation of the susceptible factor to the retreatment requirement within the 3-month follow-up and the mean visual acuity change. In survival analyses, SERPINF1 rs12603825 showed a significant association with the retreatment-free period after the first PDT; those patients homozygous for the minor allele A of rs12603825 received additional treatment after PDT within significantly shorter times than those with other genotypes (P = 0.0038). There was no significant difference in the retreatment-free period between baseline GLD and smoking status. Retreatment within 3 months was required significantly more in patients with the AA genotype, even after taking into consideration the effect of clinical characteristics (age, gender), baseline PCV lesion size, and smoking status (P = 0.0027). Furthermore, patients with the AA genotype showed significantly worse visual prognosis after PDT (P = 0.013). Pigment epithelium-derived factor (SERPINF1 or PEDF) polymorphisms may influence the initial response to and visual prognosis after PDT for PCV. Our findings may lead to understanding the pathogenesis of PCV and modification of the effects of PDT. Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Proteomics-Derived Cerebrospinal Fluid Markers of Autopsy-Confirmed Alzheimer’s Disease

PubMed Central

Roher, Alex E.; Maarouf, Chera L.; Sue, Lucia I.; Hu, Yiran; Wilson, Jeffrey; Beach, Thomas G.

2010-01-01

The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers of neuropathologically-confirmed Alzheimer’s disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial 2-dimensional gel electrophoresis studies or by literature review. Markers selected by the former method included apolipoprotein A-1 (ApoA1), hemopexin (HPX), transthyretin (TTR) and pigment epithelium-derived factor (PEDF) while markers identified from the literature included Aβ1–40, Aβ1–42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). Ventricular CSF concentrations of the markers were measured by ELISA. The concentrations of Aβ1–42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. Logistic regression analysis for the diagnostic discrimination of AD from ND found that Aβ1–42, ApoA1 and HPX each had significant and independent associations with diagnosis. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1–42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1–42 was significantly related to diagnosis, with a sensitivity of 58%, specificity of 86% and 86% correctly classified. The results indicate that for the discrimination of AD from ND control subjects, measurement of a set of markers including Aβ1–42, ApoA1 and HPX improved diagnostic performance over that obtained by measurement of Aβ1–42 alone. For the discrimination of AD from NADD subjects, measurement of Aβ1–42 alone was superior. PMID:19863188

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

Takada, Michiya; Ban, Yoshiyuki, E-mail: yshyban@yahoo.co.jp; Yamamoto, Gou

Research highlights: {yields} In proliferative membrane and epiretinal membrane specimens, the numbers of proteins are 225 and 154, respectively, and 123 proteins are common to both. {yields} Periostin and thrombospondin-1 proteins are unique to the proliferative membrane specimens. {yields} The expression of periostin is significantly up-regulated in proliferative membrane specimens. -- Abstract: Diabetes can lead to serious microvascular complications including proliferative diabetic retinopathy (PDR), the leading cause of blindness in adults. Recent studies using gene array technology have attempted to apply a hypothesis-generating approach to elucidate the pathogenesis of PDR, but these studies rely on mRNA differences, which may ormore » may not be related to significant biological processes. To better understand the basic mechanisms of PDR and to identify potential new biomarkers, we performed shotgun liquid chromatography (LC)/tandem mass spectrometry (MS/MS) analysis on pooled protein extracts from neovascular membranes obtained from PDR specimens and compared the results with those from non-vascular epiretinal membrane (ERM) specimens. We detected 226 distinct proteins in neovascular membranes and 154 in ERM. Among these proteins, 102 were specific to neovascular membranes and 30 were specific to ERM. We identified a candidate marker, periostin, as well as several known PDR markers such as pigment epithelium-derived factor (PEDF). We then performed RT-PCR using these markers. The expression of periostin was significantly up-regulated in proliferative membrane specimens. Periostin induces cell attachment and spreading and plays a role in cell adhesion. Proteomic analysis by LC/MS/MS, which permits accurate quantitative comparison, was useful in identifying new candidates such as periostin potentially involved in the pathogenesis of PDR.« less

Will PEDF Therapy Reverse Chronic Demyelination and Prevent Axon Loss in a Murine Model of Progressive Multiple Sclerosis

DTIC Science & Technology

2015-12-01

Multiple Sclerosis ? PRINCIPAL INVESTIGATOR: David Pleasure MD CONTRACTING ORGANIZATION: University of California Davis, CA 95618 REPORT DATE...Murine Model of Progressive Multiple Sclerosis ? 5b. GRANT NUMBER W81XWH-12-1-0566 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David Pleasure MD 5d...enhance central nervous system (CNS) remyelination and preserve CNS axons in mouse models of multiple sclerosis models. After determining the dosage of

Angiogenic and angiostatic factors in the molecular control of angiogenesis.

PubMed

Distler, J H W; Hirth, A; Kurowska-Stolarska, M; Gay, R E; Gay, S; Distler, O

2003-09-01

The vascular system that ensures an adequate blood flow is required to provide the cells with sufficient supply of nutrients and oxygen. Two different mechanisms of the formation of new vessels can be distinguished: vasculogenesis, the formation of the first primitive vascular plexus de novo and angiogenesis, the formation of new vessels from preexisting ones. Both processes are regulated by a delicate balance of pro- and anti-angiogenic factors. Physiologically, angiostatic mediators outweigh the angiogenic molecules and angiogenesis does not occur. Under certain conditions such as tumor formation or wound healing, the positive regulators of angiogenesis predominate and the endothelium becomes activated. Angiogenesis is initiated by vasodilatation and an increased permeability. After destabilization of the vessel wall, endothelial cells proliferate, migrate and form a tube, which is finally stabilized by pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases as well as extracellular matrix proteins and adhesion molecules strictly control this multi-step process. The properties and interactions of angiogenic molecules such as VEGFs, FGFs, angiopoietins, PDGF, angiogenin, angiotropin, HGF, CXC chemokines with ELR motif, PECAM-1, integrins and VE-cadherin as well as angiostatic key players such as angiostatin, endostatin, thrombospondin, CXC chemokines without ELR motif, PEDF are discussed in this review with respect to their molecular impact on angiogenesis.

Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation.

PubMed

Marini, Joan C; Reich, Adi; Smith, Simone M

2014-08-01

Osteogenesis imperfecta or 'brittle bone disease' has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for osteogenesis imperfecta as a collagen-related disorder, where most cases are due to autosomal dominant type I collagen defects, while rare, mostly recessive, forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development, and future of this paradigm shift in the understanding of osteogenesis imperfecta. Bone-restricted interferon-induced transmembrane (IFITM)-like protein (BRIL) and pigment epithelium-derived factor (PEDF) defects cause types V and VI osteogenesis imperfecta via defective bone mineralization, while defects in cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CYPB) cause types VII-IX osteogenesis imperfecta via defective collagen post-translational modification. Heat shock protein 47 (HSP47) and FK506-binding protein-65 (FKBP65) defects cause types X and XI osteogenesis imperfecta via aberrant collagen crosslinking, folding, and chaperoning, while defects in SP7 transcription factor, wingless-type MMTV integration site family member 1 (WNT1), trimeric intracellular cation channel type b (TRIC-B), and old astrocyte specifically induced substance (OASIS) disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase bone morphogenetic protein 1 (BMP1) causes type XII osteogenesis imperfecta due to altered collagen maturation/processing. Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of osteogenesis imperfecta types by shared mechanism to simplify current nosology, and has prodded investigations into common pathways in osteogenesis imperfecta. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients.

Secretome analysis of rat osteoblasts during icariin treatment induced osteogenesis

PubMed Central

Qian, Weiqing; Su, Yan; Zhang, Yajie; Yao, Nianwei; Gu, Nin; Zhang, Xu; Yin, Hong

2018-01-01

Osteoporosis is a serious public health problem and icariin (ICA) is the active component of the Epimedium sagittatum, a traditional Chinese medicinal herb. The present study aimed to investigate the effects and underlying mechanisms of ICA as a potential therapy for osteoporosis. Calvaria osteoblasts were isolated from newborn rats and treated with ICA. Cell viability, apoptosis, alkaline phosphatase activity and calcium deposition were analyzed. Bioinformatics analyses were performed to identify differentially expressed proteins (DEPs) in response to ICA treatment. Western blot analysis was performed to validate the expression of DEPs. ICA administration promoted osteoblast viability, alkaline phosphatase activity, calcium deposition and inhibited osteoblast apoptosis. Secretome analysis of ICA-treated cells was performed using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A total of 56 DEPs were identified, including serpin family F member 1 (PEDF), protein disulfide isomerase family A, member 3 (PDIA3), nuclear protein, co-activator of histone transcription (NPAT), c-Myc and heat shock protein 70 (HSP70). These proteins were associated with signaling pathways, including Fas and p53. Bioinformatics and western blot analyses confirmed that the expression levels of the six DEPs were upregulated following ICA treatment. These genes may be directly or indirectly involved in ICA-mediated osteogenic differentiation and osteogenesis. It was demonstrated that ICA treatment promoted osteogenesis by modulating the expression of PEDF, PDIA3, NPAT and HSP70 through signaling pathways, including Fas and p53. PMID:29532868

Adenovirally transduced bone marrow stromal cells differentiate into pigment epithelial cells and induce rescue effects in RCS rats.

PubMed

Arnhold, Stefan; Heiduschka, Peter; Klein, Helmut; Absenger, Yvonne; Basnaoglu, Serkan; Kreppel, Florian; Henke-Fahle, Sylvia; Kochanek, Stefan; Bartz-Schmidt, Karl-Ulrich; Addicks, Klaus; Schraermeyer, Ulrich

2006-09-01

To determine the potential of adenovirally transduced bone marrow stromal cells (BMSCs) to differentiate into retinal pigment epithelial-like cells and to evaluabe possible rescue effects after transplantation into the retinas of Royal College of Surgeons (RCS) rats. Through a high-capacity adenoviral vector expressing either green fluorescent protein (GFP) or pigment epithelial-derived factor (PEDF), rat MSCs were transduced in vitro before subretinal transplantation into Wistar rats or, alternatively, RCS rats. Two months after cell injection, the rats were killed and the eyes enucleated. The eyes were then investigated light microscopically or processed for electron microscopic investigations. Cell differentiation and integration were analyzed immunocytochemically using antibodies against cytokeratin and the tight junction protein ZO-1. Electroretinography was performed 16 days after injection of cells, to check whether a functional rescue could be detected. In vitro experiments in cocultured human MSCs and human RPE cells showed that MSCs adopted RPE-like characteristics. In grafting experiments, some rat MSCs integrate into the host RPE cell layer of Wistar and RCS rats, indicated by their hexagonal morphology. Subretinally transplanted cells express the epithelial marker cytokeratin and establish tight junctions with the host RPE cells. Furthermore, rescue effects can be demonstrated after grafting of vector-transduced and nontransduced MSCs in semithin sections of dystrophic retinas. Ultrastructurally, MSCs can be detected on top of host RPE and in close contact with photoreceptor outer segments phagocytosing rod outer segments. Taken together, these results raise the possibility that MSCs have the potency to replace diseased RPE cells and deliver therapeutic proteins into the subretinal space to protect photoreceptor cells from degeneration.

Loss of PEDF: A Novel Mechanism of Antihormone Resistance in Breast Cancer

DTIC Science & Technology

2015-10-01

positive control. After overnight incubation at 37°C in 5% CO2, the media-containing virus was removed and replaced with 2 ml complete culture media. After...potently restricts entry and infections by a number of highly pathogenic viruses , including HIV-1, filovirus, and SARS coronavirus [30]. More recently...and MCF-7:5C cells were pretreated with 5 μg/mL anti-IFNAR1/2/MMHAR2 from Millipore, Temecula, CA, USA ( cat # MAB1155) for four hours and then treated

Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury.

PubMed

Tong, Nianting; Zhang, Zhenzhen; Zhang, Wei; Qiu, Yating; Gong, Yuanyuan; Yin, Lili; Qiu, Qinghua; Wu, Xingwei

2013-01-01

Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R) injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG) just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB) extravasation was determined to assess blood-retinal barrier (BRB) disruption and the structure of tight junctions (TJ) was examined by transmission electron microscopy. Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1) and occludin protein expression and decreased VEGF/PEDF ratio. Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio.

The small tellurium-based compound SAS suppresses inflammation in human retinal pigment epithelium

PubMed Central

Livnat, Tami; Halpert, Gilad; Jawad, Shayma; Nisgav, Yael; Azar-Avivi, Shirley; Liu, Baoying; Nussenblatt, Robert B.; Weinberger, Dov; Sredni, Benjamin

2016-01-01

Purpose Pathological angiogenesis and chronic inflammation greatly contribute to the development of choroidal neovascularization (CNV) in chorioretinal diseases involving abnormal contact between retinal pigment epithelial (RPE) and endothelial cells (ECs), associated with Bruch’s membrane rupture. We explored the ability of the small organotellurium compound octa-O-bis-(R,R)-tartarate ditellurane (SAS) to mitigate inflammatory processes in human RPE cells. Methods Cell adhesion assays and analyses of gene and protein expression were used to examine the effect of SAS on ARPE-19 cells or primary human RPE cells that were grown alone or in an RPE-EC co-culture. Results Adhesion assays showed that SAS inhibited αv integrins expressed on RPE cells. Co-cultures of RPE cells with ECs significantly reduced the gene expression of PEDF, as compared to RPE cells cultured alone. Both SAS and the anti-αvβ3 antibody LM609 significantly enhanced the production of PEDF at both mRNA and protein levels in RPE cells. RPE cells co-cultured with EC exhibited increased gene expression of CXCL5, COX1, MMP2, IGF1, and IL8, all of which are involved in both angiogenesis and inflammation. The enhanced expression of these genes was greatly suppressed by SAS, but interestingly, remained unaffected by LM609. Zymography assay showed that SAS reduced the level of MMP-2 activity in RPE cells. We also found that SAS significantly suppressed IL-1β-induced IL-6 expression and secretion from RPE cells by reducing the protein levels of phospho-IkappaBalpha (pIκBα). Conclusions Our results suggest that SAS is a promising anti-inflammatory agent in RPE cells, and may be an effective therapeutic approach for controlling chorioretinal diseases. PMID:27293373

The small tellurium-based compound SAS suppresses inflammation in human retinal pigment epithelium.

PubMed

Dardik, Rima; Livnat, Tami; Halpert, Gilad; Jawad, Shayma; Nisgav, Yael; Azar-Avivi, Shirley; Liu, Baoying; Nussenblatt, Robert B; Weinberger, Dov; Sredni, Benjamin

2016-01-01

Pathological angiogenesis and chronic inflammation greatly contribute to the development of choroidal neovascularization (CNV) in chorioretinal diseases involving abnormal contact between retinal pigment epithelial (RPE) and endothelial cells (ECs), associated with Bruch's membrane rupture. We explored the ability of the small organotellurium compound octa-O-bis-(R,R)-tartarate ditellurane (SAS) to mitigate inflammatory processes in human RPE cells. Cell adhesion assays and analyses of gene and protein expression were used to examine the effect of SAS on ARPE-19 cells or primary human RPE cells that were grown alone or in an RPE-EC co-culture. Adhesion assays showed that SAS inhibited αv integrins expressed on RPE cells. Co-cultures of RPE cells with ECs significantly reduced the gene expression of PEDF, as compared to RPE cells cultured alone. Both SAS and the anti-αvβ3 antibody LM609 significantly enhanced the production of PEDF at both mRNA and protein levels in RPE cells. RPE cells co-cultured with EC exhibited increased gene expression of CXCL5, COX1, MMP2, IGF1, and IL8, all of which are involved in both angiogenesis and inflammation. The enhanced expression of these genes was greatly suppressed by SAS, but interestingly, remained unaffected by LM609. Zymography assay showed that SAS reduced the level of MMP-2 activity in RPE cells. We also found that SAS significantly suppressed IL-1β-induced IL-6 expression and secretion from RPE cells by reducing the protein levels of phospho-IkappaBalpha (pIκBα). Our results suggest that SAS is a promising anti-inflammatory agent in RPE cells, and may be an effective therapeutic approach for controlling chorioretinal diseases.

Comparison of human bone marrow stromal cells cultured in human platelet growth factors and fetal bovine serum.

PubMed

Ren, Jiaqiang; Ward, Dawn; Chen, Steven; Tran, Katherine; Jin, Ping; Sabatino, Marianna; Robey, Pamela G; Stroncek, David F

2018-03-14

Bone marrow stromal cells (BMSCs) have classically been cultured in media supplemented with fetal bovine serum (FBS). As an alternative to FBS, pooled solvent detergent apheresis platelets, HPGF-C18, was evaluated for BMSC culture. A comparison of passage 2 BMSC growth revealed that 10% HPGF-C18 produced similar cell numbers as 20% FBS. Marrow aspirates from 5 healthy subjects were cultured for 4 passages in 10% HPGF-C18 or 20% FBS and were analyzed for proliferation, colony formation efficiency (CFE), surface marker expression, suppression of mixed lymphocyte reactions (MLRs), global gene and microRNA expression analysis. BMSC supernatant cytokine and growth factor concentrations were also compared. Primary cultures of marrow aspirates in 10% HPGF-C18 and 20% FBS yielded similar numbers and CFE. After 4 passages, 10% HPGF-C18 and 20% FBS yielded similar numbers of BMSCs, surface marker expression patterns and immunosuppression effects. Gene and microRNA expression analysis revealed that BMSCs cultured under the two conditions had distinct expression profiles. Gene Set Enrichment Analysis (GSEA) revealed HPGF-C18-cultured BMSCs were enriched in metabolic processing and biosynthetic pathways, cell proliferation and cell cycle pathways, and immune response pathways. FBS-cultured BMSCs were enriched in MAPK signaling, TGF-beta signaling, cell adhesion and extracellular matrix pathways. Differently expressed microRNAs were related to the osteogenesis of BMSCs. The supernatant of HPGF-C18 BMSCs had higher levels of PEDF and TGFB1 and lower levels of IL6, VEGF, SDF1 and PLGF. Traditional measures, expansion, surface marker expression and inhibition of MLRs suggest that BMSC cultured in HPGF-C18 and FBS were similar, but analysis at the molecular level revealed many differences. BMSCs cultured in HPGF-C18 should be assessed in specific functional assays that reflect application-specific potency before substituting FBS with HPGF-C18.

Pharmacologic Approaches Against Advanced Glycation End Products (AGEs) in Diabetic Cardiovascular Disease.

PubMed

Nenna, Antonio; Nappi, Francesco; Avtaar Singh, Sanjeet Singh; Sutherland, Fraser W; Di Domenico, Fabio; Chello, Massimo; Spadaccio, Cristiano

2015-05-01

Advanced Glycation End-Products (AGEs) are signaling proteins associated to several vascular and neurological complications in diabetic and non-diabetic patients. AGEs proved to be a marker of negative outcome in both diabetes management and surgical procedures in these patients. The reported role of AGEs prompted the development of pharmacological inhibitors of their effects, giving rise to a number of both preclinical and clinical studies. Clinical trials with anti-AGEs drugs have been gradually developed and this review aimed to summarize most relevant reports. Evidence acquisition process was performed using PubMed and ClinicalTrials.gov with manually checked articles. Pharmacological approaches in humans include aminoguanidine, pyridoxamine, benfotiamine, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statin, ALT-711 (alagebrium) and thiazolidinediones. The most recent promising anti-AGEs agents are statins, alagebrium and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical settings and these newer anti-AGEs drugs would undergo clinical evaluation in the next years. Compounds with anti-AGEs activity but still not available for clinical scenarios are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF. Despite most studies confirm the efficacy of these pharmacological approaches, other reports produced conflicting evidences; in almost any case, these drugs were well tolerated. At present, AGEs measurement has still not taken a precise role in clinical practice, but its relevance as a marker of disease has been widely shown; therefore, it is important for clinicians to understand the value of new cardiovascular risk factors. Findings from the current and future clinical trials may help in determining the role of AGEs and the benefits of anti-AGEs treatment in cardiovascular disease.

MK2 inhibitor reduces alkali burn-induced inflammation in rat cornea

PubMed Central

Chen, Yanfeng; Yang, Wenzhao; Zhang, Xiaobo; Yang, Shu; Peng, Gao; Wu, Ting; Zhou, Yueping; Huang, Caihong; Reinach, Peter S.; Li, Wei; Liu, Zuguo

2016-01-01

MK2 activation by p38 MAPK selectively induces inflammation in various diseases. We determined if a MK2 inhibitor (MK2i), improves cornea wound healing by inhibiting inflammation caused by burning rat corneas with alkali. Our study, for the first time, demonstrated that MK2i inhibited alkali burn-induced MK2 activation as well as rises in inflammation based on: a) blunting rises in inflammatory index, inflammatory cell infiltration, ED1+ macrophage and PMN+ neutrophil infiltration; b) suppressing IL-6 and IL-1β gene expression along with those of macrophage inflammatory protein-1α (MIP-1α), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1); c) reducing angiogenic gene expression levels and neovascularization (NV) whereas anti-angiogenic PEDF levels increased. In addition, this study found that MK2i did not affect human corneal epithelial cell (HCEC) proliferation and migration and had no detectable side effects on ocular surface integrity. Taken together, MK2i selectively inhibited alkali burn-induced corneal inflammation by blocking MK2 activation, these effects have clinical relevance in the treatment of inflammation related ocular surface diseases. PMID:27329698

Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families

PubMed Central

Moldenhauer Minillo, Renata; Sobreira, Nara; de Fatima de Faria Soares, Maria; Jurgens, Julie; Ling, Hua; Hetrick, Kurt N.; Doheny, Kimberly F.; Valle, David; Brunoni, Decio; Alvarez Perez, Ana B.

2014-01-01

Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed. PMID:25565926

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

PubMed

Nomura, T; Honmou, O; Harada, K; Houkin, K; Hamada, H; Kocsis, J D

2005-01-01

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

PubMed

Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu; Hsiung, Shu-Chi; Liu, Yan; Simpson, Norman R; Bakalian, Mihran J; Rosoklija, Gorazd B; Dwork, Andrew J; Arango, Victoria; Mann, J John

2018-06-01

Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect.

PubMed

Mathijssen, Natascha C J; Masereeuw, Rosalinde; Holme, Pal Andre; van Kraaij, Marian G J; Laros-van Gorkom, Britta A P; Peyvandi, Flora; van Heerde, Waander L

2013-08-01

Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study. Ten factor VII deficient patients were treated with either recombinant activated (20 μg/kg) or plasma-derived (25 IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points. Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236 ml/kg; 175 ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206 ml/kg; 64 ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII. Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products. Copyright © 2013 Elsevier Ltd. All rights reserved.

Agomelatine Increases BDNF Serum Levels in Depressed Patients in Correlation with the Improvement of Depressive Symptoms

PubMed Central

Pettorruso, Mauro; De Berardis, Domenico; Varasano, Paola Annunziata; Lucidi Pressanti, Gabriella; De Remigis, Valeria; Valchera, Alessandro; Ricci, Valerio; Di Nicola, Marco; Janiri, Luigi; Biggio, Giovanni; Di Giannantonio, Massimo

2016-01-01

Background: Agomelatine modulates brain-derived neurotrophic factor expression via its interaction with melatonergic and serotonergic receptors and has shown promising results in terms of brain-derived neurotrophic factor increase in animal models. Methods: Twenty-seven patients were started on agomelatine (25mg/d). Venous blood was collected and brain-derived neurotrophic factor serum levels were measured at baseline and after 2 and 8 weeks along with a clinical assessment, including Hamilton Depression Rating Scale and Snaith-Hamilton Pleasure Scale. Results: Brain-derived neurotrophic factor serum concentration increased after agomelatine treatment. Responders showed a significant increase in brain-derived neurotrophic factor levels after 2 weeks of agomelatine treatment; no difference was observed in nonresponders. Linear regression analysis showed that more prominent brain-derived neurotrophic factor level variation was associated with lower baseline BDNF levels and greater anhedonic features at baseline. Conclusions: Patients affected by depressive disorders showed an increase of brain-derived neurotrophic factor serum concentration after a 2-week treatment with agomelatine. The increase of brain-derived neurotrophic factor levels was found to be greater in patients with lower brain-derived neurotrophic factor levels and marked anhedonia at baseline. PMID:26775293

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

PubMed

Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

1999-01-01

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Platelet-derived growth factor inhibits platelet activation in heparinized whole blood.

PubMed

Selheim, F; Holmsen, H; Vassbotn, F S

1999-08-15

We previously have demonstrated that human platelets have functionally active platelet-derived growth factor alpha-receptors. Studies with gel-filtered platelets showed that an autocrine inhibition pathway is transduced through this tyrosine kinase receptor during platelet activation. The physiological significance of this inhibitory effect of platelet-derived growth factor on gel-filtered platelets activation is, however, not known. In the present study, we investigated whether platelet-derived growth factor inhibits platelet activation under more physiological conditions in heparinized whole blood, which represents a more physiological condition than gel-filtered platelets. Using flow cytometric assays, we demonstrate here that platelet-derived growth factor inhibits thrombin-, thrombin receptor agonist peptide SFLLRN-, and collagen-induced platelet aggregation and shedding of platelet-derived microparticles from the platelet plasma membrane during platelet aggregation in stirred heparinized whole blood. The inhibitory effect of platelet-derived growth factor was dose dependent. However, under nonaggregating conditions (no stirring), we could not demonstrate any significant effect of platelet-derived growth factor on thrombin- and thrombin receptor agonist peptide-induced platelet surface expression of P-selectin. Our results demonstrate that platelet-derived growth factor appears to be a true antithrombotic agent only under aggregating conditions in heparinized whole blood.

Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair.

PubMed

Tilokee, Everad L; Latham, Nicholas; Jackson, Robyn; Mayfield, Audrey E; Ye, Bin; Mount, Seth; Lam, Buu-Khanh; Suuronen, Erik J; Ruel, Marc; Stewart, Duncan J; Davis, Darryl R

2016-07-01

First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal-cell derived factor 1α, which opens the prospect of maximizing up-front paracrine-mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal-cell derived factor 1α. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal-cell derived factor 1α over-expression prevented lv-mediated "loss of cytokines" through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal-cell derived factor 1α enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal-cell derived factor 1α enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal-cell derived factor 1α content paralleled reductions in myocyte apoptosis but did not influence long-term engraftment or the fate of transplanted cells. Transplantation of stromal-cell derived factor 1α transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction. Stem Cells 2016;34:1826-1835. © 2016 AlphaMed Press.

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases

PubMed Central

Alvarez, Irene; Iglesias, Olalla; Crespo, Ignacio; Figueroa, Jesus; Aleixandre, Manuel; Linares, Carlos; Granizo, Elias; Garcia-Fantini, Manuel; Marey, Jose; Masliah, Eliezer; Winter, Stefan; Muresanu, Dafin; Moessler, Herbert

2016-01-01

Background: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer’s disease. Methods: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer’s disease patients. Results: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. Conclusion: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer’s disease cases with apolipoprotein E epsilon-4 allele. PMID:27207906

Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

PubMed Central

Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

2013-01-01

Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance. PMID:25206547

Serum Brain-Derived Neurotrophic Factors in Taiwanese Patients with Drug-Naïve First-Episode Major Depressive Disorder: Effects of Antidepressants.

PubMed

Chiou, Yu-Jie; Huang, Tiao-Lai

2017-03-01

Brain-derived neurotrophic factors are known to be related to the psychopathology of major depressive disorder. However, studies focusing on drug-naïve first-episode patients are still rare. Over a 6-year period, we examined the serum brain-derived neurotrophic factors levels in patients with first-episode drug-naïve major depressive disorder and compared them with sex-matched healthy controls. We also investigated the relationships between serum brain-derived neurotrophic factors levels, suicidal behavior, and Hamilton Depression Rating Scale scores before and after a 4-week antidepressant treatment. The baseline serum brain-derived neurotrophic factors levels of 71 patients were significantly lower than those of the controls (P=.017), and the Hamilton Depression Rating Scale scores in 71 patients did not correlate with brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor levels were significantly lower in 13 suicidal major depressive disorder patients than in 58 nonsuicidal major depressive disorder patients (P=.038). Among 41 followed-up patients, there was no alteration in serum brain-derived neurotrophic factors levels after treatment with antidepressants (P=.126). In receiver operating characteristic curve analysis of using pretreatment brain-derived neurotrophic factors to estimate the response to treatment, the area under the curve was 0.684. The most suitable cut-off point was 6.1 ng/mL (sensitivity=78.6%, specificity = 53.8%). Our data support the serum brain-derived neurotrophic factor levels in patients with drug-naïve first-episode major depressive disorder were lower than those in the healthy controls, and patients with pretreatment brain-derived neurotrophic factors >6.1 ng/mL were more likely to be responders. Although the relationship of our results to the mechanism of drug action and pathophysiology of depression remains unclear, the measure may have potential use as a predictor of response to treatment. In the future, it needs a large sample to prove these results. © The Author 2016. Published by Oxford University Press on behalf of CINP.

[Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor].

PubMed

Toscano-Garibay, Julia Dolores; Quiroz-Mercado, Hugo; Espitia-Pinzón, Clara; Gil-Carrasco, Félix; Flores-Estrada, José Javier

2014-01-01

Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium-derived factor. Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days).

BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

PubMed

Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten

2016-04-01

One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Changes in compressed neurons from dogs with acute and severe cauda equina constrictions following intrathecal injection of brain-derived neurotrophic factor-conjugated polymer nanoparticles☆

PubMed Central

Tan, Junming; Shi, Jiangang; Shi, Guodong; Liu, Yanling; Liu, Xiaohong; Wang, Chaoyang; Chen, Dechun; Xing, Shunming; Shen, Lianbing; Jia, Lianshun; Ye, Xiaojian; He, Hailong; Li, Jiashun

2013-01-01

This study established a dog model of acute multiple cauda equina constriction by experimental constriction injury (48 hours) of the lumbosacral central processes in dorsal root ganglia neurons. The repair effect of intrathecal injection of brain-derived neurotrophic factor with 15 mg encapsulated biodegradable poly(lactide-co-glycolide) nanoparticles on this injury was then analyzed. Dorsal root ganglion cells (L7) of all experimental dogs were analyzed using hematoxylin-eosin staining and immunohistochemistry at 1, 2 and 4 weeks following model induction. Intrathecal injection of brain-derived neurotrophic factor can relieve degeneration and inflammation, and elevate the expression of brain-derived neurotrophic factor in sensory neurons of compressed dorsal root ganglion. Simultaneously, intrathecal injection of brain-derived neurotrophic factor obviously improved neurological function in the dog model of acute multiple cauda equina constriction. Results verified that sustained intraspinal delivery of brain-derived neurotrophic factor encapsulated in biodegradable nanoparticles promoted the repair of histomorphology and function of neurons within the dorsal root ganglia in dogs with acute and severe cauda equina syndrome. PMID:25206593

Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells.

PubMed Central

Gauldie, J; Richards, C; Harnish, D; Lansdorp, P; Baumann, H

1987-01-01

One of the oldest and most preserved of the homeostatic responses of the body to injury is the acute phase protein response associated with inflammation. The liver responds to hormone-like mediators by the increased synthesis of a series of plasma proteins called acute phase reactants. In these studies, we examined the relationship of hepatocyte-stimulating factor derived from peripheral blood monocytes to interferon beta 2 (IFN-beta 2), which has been cloned. Antibodies raised against fibroblast-derived IFN-beta having neutralizing activity against both IFN-beta 1 and -beta 2 inhibited the major hepatocyte-stimulating activity derived from monocytes. Fibroblast-derived mediator elicited the identical stimulated response in human HepG2 cells and primary rat hepatocytes as the monocyte cytokine. Finally, recombinant-derived human B-cell stimulatory factor type 2 (IFN-beta 2) from Escherichia coli induced the synthesis of all major acute phase proteins studied in human hepatoma HepG2 and primary rat hepatocyte cultures. These data demonstrate that monocyte-derived hepatocyte-stimulating factor and IFN-beta 2 share immunological and functional identity and that IFN-beta 2, also known as B-cell stimulatory factor and hybridoma plasmacytoma growth factor, has the hepatocyte as a major physiologic target and thereby is essential in controlling the hepatic acute phase response. Images PMID:2444978

PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.

PubMed

Guru, Sameer Ahmad; Mir, Rashid; Bhat, Musadiq; Najar, Imtiyaz; Zuberi, Mariyam; Sumi, Mamta; Masroor, Mirza; Gupta, Naresh; Saxena, Alpana

2017-10-01

Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2 -Δct ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p < 0.0001). Moreover, +68GA del/del and ins/del genotypes in imatinib-treated chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an allele dose-dependent manner. Platelet-derived growth factor receptor-α -909AA genotype is also associated with lower expression of platelet-derived growth factor receptor-α. The downregulation of platelet-derived growth factor receptor-α expression may play a causative role in imatinib-induced thrombocytopenia, a common side effect, in the subset of chronic myeloid leukemia patients with platelet-derived growth factor receptor-α +68 GA ins/del, +68 GA del/del, and -909C/A genotypes.

Biomimetic hybrid porous scaffolds immobilized with platelet derived growth factor-BB promote cellularization and vascularization in tissue engineering.

PubMed

Murali, Ragothaman; Ponrasu, Thangavel; Cheirmadurai, Kalirajan; Thanikaivelan, Palanisamy

2016-02-01

Development of hybrid scaffolds with synergistic combination of growth factor is a promising approach to promote early in vivo wound repair and tissue regeneration. Here, we show the rapid wound healing in Wistar albino rats using biomimetic collagen-poly(dialdehyde) guar gum based hybrid porous scaffolds covalently immobilized with platelet derived growth factor-BB. The immobilized platelet derived growth factor in the hybrid scaffolds not only enhance the total protein, collagen, hexosamine, and uronic acid contents in the granulation tissue but also provide stronger tissues. The wound closure analysis reveal that the complete epithelialization period is 15.4 ± 0.9 days for collagen-poly(dialdehyde) guar gum-platelet derived growth factor hybrid scaffolds, whereas it is significantly higher for control, collagen, collagen- poly(dialdehyde) guar gum and povidine-iodine treated groups. Further, the histological evaluation shows that the immobilized platelet derived growth factor in the hybrid scaffolds induced a more robust cellular and vascular response in the implanted site. Hence, we demonstrate that the collagen-poly(dialdehyde) guar gum hybrid scaffolds loaded with platelet derived growth factor stimulates chemotactic effects in the implanted site to promote rapid tissue regeneration and wound repair without the assistance of antibacterial agents. © 2015 Wiley Periodicals, Inc.

Plasma brain-derived neurotrophic factor in women after bariatric surgery: a pilot study.

PubMed

Merhi, Zaher O; Minkoff, Howard; Lambert-Messerlian, Geralyn M; Macura, Jerzy; Feldman, Joseph; Seifer, David B

2009-04-01

Eighteen morbidly obese women had plasma brain-derived neurotrophic factor (BDNF) measured before bariatric surgery and 3 months postoperatively. We analyzed plasma BDNF levels in all the participants then subdivided according to menopausal status and type of surgery. Brain-derived neurotrophic factor decreased significantly in all the participants and in the premenopausal group when looked at in isolation.

Protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion.

PubMed

Zhai, S-Q; Guo, W; Hu, Y-Y; Yu, N; Chen, Q; Wang, J-Z; Fan, M; Yang, W-Y

2011-05-01

To explore the protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion. Recombinant adenovirus brain-derived neurotrophic factor vector, recombinant adenovirus LacZ and artificial perilymph were prepared. Guinea pigs with audiometric auditory brainstem response thresholds of more than 75 dB SPL, measured seven days after four hours of noise exposure at 135 dB SPL, were divided into three groups. Adenovirus brain-derived neurotrophic factor vector, adenovirus LacZ and perilymph were infused into the cochleae of the three groups, variously. Eight weeks later, the cochleae were stained immunohistochemically and the spiral ganglion cells counted. The auditory brainstem response threshold recorded before and seven days after noise exposure did not differ significantly between the three groups. However, eight weeks after cochlear perfusion, the group receiving brain-derived neurotrophic factor had a significantly decreased auditory brainstem response threshold and increased spiral ganglion cell count, compared with the adenovirus LacZ and perilymph groups. When administered via cochlear infusion following noise damage, brain-derived neurotrophic factor appears to improve the auditory threshold, and to have a protective effect on the spiral ganglion cells.

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

PubMed Central

Sun, Wei-Lun; Eisenstein, Sarah A.; Zelek-Molik, Agnieszka

2015-01-01

Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. PMID:25522393

Intraspinal Rewiring of the Corticospinal Tract Requires Target-Derived Brain-Derived Neurotrophic Factor and Compensates Lost Function after Brain Injury

ERIC Educational Resources Information Center

Ueno, Masaki; Hayano, Yasufumi; Nakagawa, Hiroshi; Yamashita, Toshihide

2012-01-01

Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery…

Theoretical Bound of CRLB for Energy Efficient Technique of RSS-Based Factor Graph Geolocation

NASA Astrophysics Data System (ADS)

Kahar Aziz, Muhammad Reza; Heriansyah; Saputra, EfaMaydhona; Musa, Ardiansyah

2018-03-01

To support the increase of wireless geolocation development as the key of the technology in the future, this paper proposes theoretical bound derivation, i.e., Cramer Rao lower bound (CRLB) for energy efficient of received signal strength (RSS)-based factor graph wireless geolocation technique. The theoretical bound derivation is crucially important to evaluate whether the energy efficient technique of RSS-based factor graph wireless geolocation is effective as well as to open the opportunity to further innovation of the technique. The CRLB is derived in this paper by using the Fisher information matrix (FIM) of the main formula of the RSS-based factor graph geolocation technique, which is lied on the Jacobian matrix. The simulation result shows that the derived CRLB has the highest accuracy as a bound shown by its lowest root mean squared error (RMSE) curve compared to the RMSE curve of the RSS-based factor graph geolocation technique. Hence, the derived CRLB becomes the lower bound for the efficient technique of RSS-based factor graph wireless geolocation.

Genetic engineering approach to develop next-generation reagents for endotoxin quantification.

PubMed

Mizumura, Hikaru; Ogura, Norihiko; Aketagawa, Jun; Aizawa, Maki; Kobayashi, Yuki; Kawabata, Shun-Ichiro; Oda, Toshio

2017-02-01

The bacterial endotoxin test, which uses amebocyte lysate reagents of horseshoe crab origin, is a sensitive, reproducible and simple assay to measure endotoxin concentration. To develop sustainable raw materials for lysate reagents that do not require horseshoe crabs, three recombinant protease zymogens (factor C, derived from mammalian cells; factor B; and the proclotting enzyme derived from insect cells) were prepared using a genetic engineering technique. Recombinant cascade reagents (RCRs) were then prepared to reconstruct the reaction cascade in the amebocyte lysate reagent. The protease activity of the RCR containing recombinant factor C was much greater than that of recombinant factor C alone, indicating the efficiency of signal amplification in the cascade. Compared with the RCR containing the insect cell-derived factor C, those containing mammalian cell-derived factor C, which features different glycosylation patterns, were less susceptible to interference by the injectable drug components. The standard curve of the RCR containing mammalian cell-derived recombinant factor C had a steeper slope than the curves for those containing natural lysate reagents, suggesting a greater sensitivity to endotoxin. The present study supports the future production of recombinant reagents that do not require the use of natural resources.

Genetic engineering approach to develop next-generation reagents for endotoxin quantification

PubMed Central

Ogura, Norihiko; Aketagawa, Jun; Aizawa, Maki; Kobayashi, Yuki; Kawabata, Shun-ichiro; Oda, Toshio

2016-01-01

The bacterial endotoxin test, which uses amebocyte lysate reagents of horseshoe crab origin, is a sensitive, reproducible and simple assay to measure endotoxin concentration. To develop sustainable raw materials for lysate reagents that do not require horseshoe crabs, three recombinant protease zymogens (factor C, derived from mammalian cells; factor B; and the proclotting enzyme derived from insect cells) were prepared using a genetic engineering technique. Recombinant cascade reagents (RCRs) were then prepared to reconstruct the reaction cascade in the amebocyte lysate reagent. The protease activity of the RCR containing recombinant factor C was much greater than that of recombinant factor C alone, indicating the efficiency of signal amplification in the cascade. Compared with the RCR containing the insect cell-derived factor C, those containing mammalian cell-derived factor C, which features different glycosylation patterns, were less susceptible to interference by the injectable drug components. The standard curve of the RCR containing mammalian cell-derived recombinant factor C had a steeper slope than the curves for those containing natural lysate reagents, suggesting a greater sensitivity to endotoxin. The present study supports the future production of recombinant reagents that do not require the use of natural resources. PMID:27913792

Hypoxia enhances the protective effects of placenta-derived mesenchymal stem cells against scar formation through hypoxia-inducible factor-1α.

PubMed

Du, Lili; Lv, Runxiao; Yang, Xiaoyi; Cheng, Shaohang; Xu, Jing; Ma, Tingxian

2016-06-01

To explore the effect of placenta-derived mesenchymal stem cells on scar formation as well as the underlying mechanism. The isolated placenta-derived mesenchymal stem cells from mice were distributed in the wounded areas of scalded mouse models, attenuated inflammatory responses and decreased the deposition of collagens, thus performing a beneficial effect against scar formation. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells and hypoxia-inducible factor-1α was involved in the protective effect of placenta-derived mesenchymal stem cells in hypoxic condition. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells through hypoxia-inducible factor-1α and PMSCs may have a potential application in the treatment of wound.

Stability-Derivative Determination from Flight Data

NASA Technical Reports Server (NTRS)

Holowicz, Chester H.; Holleman, Euclid C.

1958-01-01

A comprehensive discussion of the various factors affecting the determination of stability and control derivatives from flight data is presented based on the experience of the NASA High-Speed Flight Station. Factors relating to test techniques, determination of mass characteristics, instrumentation, and methods of analysis are discussed. For most longitudinal-stability-derivative analyses simple equations utilizing period and damping have been found to be as satisfactory as more comprehensive methods. The graphical time-vector method has been the basis of lateral-derivative analysis, although simple approximate methods can be useful If applied with caution. Control effectiveness has been generally obtained by relating the peak acceleration to the rapid control input, and consideration must be given to aerodynamic contributions if reasonable accuracy is to be realized.. Because of the many factors involved In the determination of stability derivatives, It is believed that the primary stability and control derivatives are probably accurate to within 10 to 25 percent, depending upon the specific derivative. Static-stability derivatives at low angle of attack show the greatest accuracy.

Light-cone singularities and transverse-momentum-dependent factorization at twist-3

NASA Astrophysics Data System (ADS)

Chen, A. P.; Ma, J. P.

2017-05-01

We study transverse-momentum-dependent factorization at twist-3 for Drell-Yan processes. The factorization can be derived straightforwardly at leading order of αs. But at this order we find that light-cone singularities already exist and effects of soft gluons are not correctly factorized. We regularize the singularities with gauge links off the light-cone and introduce a soft factor to factorize the effects of soft gluons. Interestingly, the soft factor must be included in the definition of subtracted TMD parton distributions to correctly factorize the effects of soft gluons. We derive the Collins-Soper equation for one of twist-3 TMD parton distributions. The equation can be useful for resummation of large logarithms terms appearing in the corresponding structure function in collinear factorization. However, the derived equation is nonhomogeneous. This will make the resummation complicated.

76 FR 33752 - Notice of Availability of the External Review Draft of the Guidance for Applying Quantitative...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-09

... External Review Draft of the Guidance for Applying Quantitative Data To Develop Data-Derived Extrapolation... Applying Quantitative Data to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies... Applying Quantitative Data to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies...

Cost function approach for estimating derived demand for composite wood products

Treesearch

T. C. Marcin

1991-01-01

A cost function approach was examined for using the concept of duality between production and input factor demands. A translog cost function was used to represent residential construction costs and derived conditional factor demand equations. Alternative models were derived from the translog cost function by imposing parameter restrictions.

In vitro comparison of the efficacy of TGF-β1 and PDGF-BB in combination with freeze-dried bone allografts for induction of osteogenic differentiation in MG-63 osteoblast-like cells.

PubMed

Vahabi, Surena; Torshabi, Maryam; Esmaeil Nejad, Azadeh

2016-12-01

Predictable regeneration of alveolar bone defects has always been a challenge in implant dentistry. Bone allografts are widely used bone substitutes with controversial osteoinductive activity. This in vitro study aimed to assess the osteogenic potential of some commercially available freeze-dried bone allografts supplemented with human recombinant platelet-derived growth factor-BB and transforming growth factor beta-1. Cell viability, mineralization, and osteogenic gene expression of MG-63 osteoblast-like cells were compared among the allograft alone, allograft/platelet-derived growth factor-BB, allograft/transforming growth factor beta-1, and allograft/platelet-derived growth factor-BB/transforming growth factor beta-1 groups. The methyl thiazol tetrazolium assay, real-time quantitative reverse transcription polymerase chain reaction and alizarin red staining were performed, respectively, for assessment of cell viability, differentiation, and mineralization at 24-72 h post treatment. The allograft with greater cytotoxic effect on MG-63 cells caused the lowest differentiation among the groups. In comparison with allograft alone, allograft/transforming growth factor beta-1, and allograft/transforming growth factor beta-1/platelet-derived growth factor-BB caused significant upregulation of bone sialoprotein and osteocalcin osteogenic mid-late marker genes, and resulted in significantly higher amounts of calcified nodules especially in mineralized non-cytotoxic allograft group. Supplementation of platelet-derived growth factor-BB alone in 5 ng/mL concentration had no significant effect on differentiation or mineralization markers. According to the results, transforming growth factor beta-1 acts synergistically with bone allografts to enhance the osteogenic differentiation potential. Therefore, this combination may be useful for rapid transformation of undifferentiated cells into bone-forming cells for bone regeneration. However, platelet-derived growth factor-BB supplementation did not support this synergistic ability to enhance osteogenic differentiation and thus, further investigations are required.

On geometric factors for neutral particle analyzers

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

Stagner, L.; Heidbrink, W. W.

2014-11-15

Neutral particle analyzers (NPA) detect neutralized energetic particles that escape from plasmas. Geometric factors relate the counting rate of the detectors to the intensity of the particle source. Accurate geometric factors enable quick simulation of geometric effects without the need to resort to slower Monte Carlo methods. Previously derived expressions [G. R. Thomas and D. M. Willis, “Analytical derivation of the geometric factor of a particle detector having circular or rectangular geometry,” J. Phys. E: Sci. Instrum. 5(3), 260 (1972); J. D. Sullivan, “Geometric factor and directional response of single and multi-element particle telescopes,” Nucl. Instrum. Methods 95(1), 5–11 (1971)]more » for the geometric factor implicitly assume that the particle source is very far away from the detector (far-field); this excludes applications close to the detector (near-field). The far-field assumption does not hold in most fusion applications of NPA detectors. We derive, from probability theory, a generalized framework for deriving geometric factors that are valid for both near and far-field applications as well as for non-isotropic sources and nonlinear particle trajectories.« less

Activated partial thromboplastin time derivative curves: helpful diagnostic tool in mixing test interpretation.

PubMed

Esmedere Eren, Sevim; Karakukcu, Cigdem; Ciraci, Mehmet Z; Ustundag, Yasemin; Karakukcu, Musa

2018-06-01

: The mixing test is used to evaluate whether prolonged activated partial thromboplastin time (APTT) is due to an inhibitor or a factor deficiency. The coagulation reaction is demonstrated with APTT derivative curves on the ACL TOP series. We aimed to determine the utility of APTT derivative curves in the mixing test process. The plasma of a patient was mixed with normal plasma in a 1 : 1 ratio and APTT assay was performed with SynthASil reagent. We observed roughness, biphasic and shoulder patterns in derivative curves during the mixing test. An extended laboratory investigation revealed a positive lupus anticoagulant, low factors XI and IX activities. Along with mixing test cut-off limits, we recommend analysing changes in APTT derivative curves to minimize erroneous interpretations of the mixing test. Derivative curves display either a normalizing pattern in factor deficiencies or an atypical pattern in the presence of lupus anticoagulant.

The effect of choosing three different C factor formulae derived from NDVI on a fully raster-based erosion modelling

NASA Astrophysics Data System (ADS)

Sulistyo, Bambang

2016-11-01

The research was aimed at studying the efect of choosing three different C factor formulae derived from NDVI on a fully raster-based erosion modelling of The USLE using remote sensing data and GIS technique. Methods applied was by analysing all factors affecting erosion such that all data were in the form of raster. Those data were R, K, LS, C and P factors. Monthly R factor was evaluated based on formula developed by Abdurachman. K factor was determined using modified formula used by Ministry of Forestry based on soil samples taken in the field. LS factor was derived from Digital Elevation Model. Three C factors used were all derived from NDVI and developed by Suriyaprasit (non-linear) and by Sulistyo (linear and non-linear). P factor was derived from the combination between slope data and landcover classification interpreted from Landsat 7 ETM+. Another analysis was the creation of map of Bulk Density used to convert erosion unit. To know the model accuracy, model validation was done by applying statistical analysis and by comparing Emodel with Eactual. A threshold value of ≥ 0.80 or ≥ 80% was chosen to justify. The research result showed that all Emodel using three formulae of C factors have coeeficient of correlation value of > 0.8. The results of analysis of variance showed that there was significantly difference between Emodel and Eactual when using C factor formula developed by Suriyaprasit and Sulistyo (non-linear). Among the three formulae, only Emodel using C factor formula developed by Sulistyo (linear) reached the accuracy of 81.13% while the other only 56.02% as developed by Sulistyo (nonlinear) and 4.70% as developed by Suriyaprasit, respectively.

Hyperbaric Oxygen Therapy Alleviates Carbon Monoxide Poisoning-Induced Delayed Memory Impairment by Preserving Brain-Derived Neurotrophic Factor-Dependent Hippocampal Neurogenesis.

PubMed

Liu, Wen-Chung; Yang, San-Nan; Wu, Chih-Wei J; Chen, Lee-Wei; Chan, Julie Y H

2016-01-01

To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute carbon monoxide poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor in the hippocampus. Laboratory animal experiments. University/Medical center research laboratory. Adult, male Sprague-Dawley rats. Rats were divided into five groups: (1) non-carbon monoxide-treated control, (2) acute carbon monoxide poisoning, (3) acute carbon monoxide poisoning followed by 7-day hyperbaric oxygen treatment, (4) carbon monoxide + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute carbon monoxide poisoning followed by intracerebroventricular infusion of brain-derived neurotrophic factor. Acute carbon monoxide poisoning was achieved by exposing the rats to carbon monoxide at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after carbon monoxide poisoning. Recombinant human TrkB-Fc chimera or brain-derived neurotrophic factor was infused into the lateral ventricle via the implanted osmotic minipump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of brain-derived neurotrophic factor was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze. Acute carbon monoxide poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67⁺, and doublecortin⁺ cells in the subgranular zone of the dentate gyrus. This suppression of adult neurogenesis by the carbon monoxide poisoning was appreciably alleviated by early treatment of hyperbaric oxygen. The hyperbaric oxygen treatment also promoted a sustained increase in hippocampal brain-derived neurotrophic factor level. Blockade of hippocampal brain-derived neurotrophic factor signaling with intracerebroventricular infusion of recombinant human TrkB-Fc chimera significantly blunted the protection by the hyperbaric oxygen on hippocampal neurogenesis; whereas intracerebroventricular infusion of brain-derived neurotrophic factor mimicked the action of hyperbaric oxygen and preserved hippocampal neurogenesis after acute carbon monoxide poisoning. Furthermore, acute carbon monoxide poisoning resulted in a delayed impairment of cognitive function. The hyperbaric oxygen treatment notably restored the cognitive impairment in a brain-derived neurotrophic factor-dependent manner. The early hyperbaric oxygen treatment may alleviate delayed memory impairment after acute carbon monoxide poisoning by preserving adult neurogenesis via an increase in hippocampal brain-derived neurotrophic factor content.

Adult hippocampus derived soluble factors induce a neuronal-like phenotype in mesenchymal stem cells.

PubMed

Rivera, Francisco J; Sierralta, Walter D; Minguell, Jose J; Aigner, Ludwig

2006-10-02

Bone marrow-derived mesenchymal stem cells (MSCs) are not restricted in their differentiation fate to cells of the mesenchymal lineage. They acquire a neural phenotype in vitro and in vivo after transplantation in the central nervous system. Here we investigated whether soluble factors derived from different brain regions are sufficient to induce a neuronal phenotype in MSCs. We incubated bone marrow-derived MSCs in conditioned medium (CM) derived from adult hippocampus (HCM), cortex (CoCM) or cerebellum (CeCM) and analyzed the cellular morphology and the expression of neuronal and glial markers. In contrast to muscle derived conditioned medium, which served as control, conditioned medium derived from the different brain regions induced a neuronal morphology and the expression of the neuronal markers GAP-43 and neurofilaments in MSCs. Hippocampus derived conditioned medium had the strongest activity. It was independent of NGF or BDNF; and it was restricted to the neuronal differentiation fate, since no induction of the astroglial marker GFAP was observed. The work indicates that soluble factors present in the brain are sufficient to induce a neuronal phenotype in MSCs.

REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER RNA LEVELS IN AVIAN HYPOTHALAMIC SLICE CULTURES. (R825294)

EPA Science Inventory

Mechanisms regulating the expression of brain-derived neurotrophic factor, a member of the neurotrophin family, have been extensively studied in the rat cerebral cortex, hippocampus and cerebellum. In contrast, little is known regarding the regulation of this growth factor in ...

Effects of Non-Collagenous Proteins, TGF-β1, and PDGF-BB on Viability and Proliferation of Dental Pulp Stem Cells

PubMed Central

Tabatabaei, Fahimeh Sadat

2016-01-01

ABSTRACT Objectives The dentin matrix servers as a reservoir of growth factors, sequestered during dentinogenesis. The aim of this study was to assess the viability and proliferation of dental pulp stem cells in the presence of dentin matrix-derived non-collagenous proteins and two growth factors; platelet-derived growth factor BB and transforming growth factor beta 1. Material and Methods The dental pulp cells were isolated and cultured. The dentin proteins were extracted and purified. The MTT assay was performed for assessment of cell viability and proliferation in the presence of different concentrations of dentin proteins and growth factors during 24 - 72 h post-treatment. Results The cells treated with 250 ng/mL dentin proteins had the best viability and proliferation ability in comparison with other concentrations (P < 0.05). The MTT assay demonstrated that cells cultured with 5 ng/mL platelet-derived growth factor BB had the highest viability at each time point as compared to other groups (P < 0.05). However, in presence of platelet-derived growth factor BB alone and in combination with transforming growth factor beta 1 and dentin proteins (10 ng/mL), significant higher viability was seen at all time points (P < 0.05). The least viability and proliferation at each growth factor concentration was seen in cells treated with combination of transforming growth factor beta 1 and dentin proteins at 72 h (P < 0.05). Conclusions The results indicated that the triple combination of growth factors and matrix-derived non-collagenous proteins (especially at 10 ng/mL concentration) has mitogenic effect on dental pulp stem cells. PMID:27099698

The Influence of Platelet-Derived Growth Factor and Fibroblast Growth Factor 2 on Oligodendrocyte Development and Remyelination

DTIC Science & Technology

2004-01-01

OLIGODENDROCYTE DEVELOPMENT AND REMYELINATION 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e...Z39-18 ABSTRACT Title: THE INFLUENCE OF PLATELET-DERIVED GROWTH FACTOR AND FIBROBLAST GROWTH FACTOR 2 ON OLIGODENDROCYTE DEVELOPMENT AND...GROWTH FACTOR 2 ON OLIGODENDROCYTE DEVELOPMENT AND REMYELINATION by Joshua C. Murtie Thesis/dissertation submitted to the

Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder☆

PubMed Central

Wang, Hongyan; Zhang, Yingquan; Qiao, Mingqi

2013-01-01

The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression. PMID:25206732

N-acetylcysteine does not influence the activity of endothelium-derived relaxing factor in vivo.

PubMed

Creager, M A; Roddy, M A; Boles, K; Stamler, J S

1997-02-01

Nitric oxide forms complexes with an array of biomolecular carriers that retain biological activity. This reactivity of nitric oxide in physiological systems has led to some dispute as to whether endothelium-derived relaxing factors nitric oxide or a closely related adduct thereof, such as a nitrosothiol. In vitro bioassays used to address this question are limited by the exclusion of biological thiols that are requisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing factor in vivo. We reasoned that if endothelium-derived relaxing factor in nitric oxide, infusion of physiological concentrations of thiol would potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used venous-occlusion plethysmography to study forearm blood flow in normal subjects. Methacholine (0.3 to 10 micrograms/min) and nitroglycerin (1 to 30 micrograms/min) were infused via the brachial artery to elicit endothelium-dependent and endothelium-independent vasodilation, respectively. Dose-response determinations were made for each drug before and after an intra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methacholine increased forearm blood flow in a dose-dependent manner. Infusion of N-acetylcysteine did not change the sensitivity (ED50, 1.7 versus 1.7 micrograms/min, P = NS) or maximal response to methacholine. In contrast, thiol increased the sensitivity to nitroglycerin (ED50, 4.7 versus 2.8 micrograms/min, P < .01). Thus, conflicting with reports in vitro, thiol does not modulate endothelium-derived relaxing factor responses in vivo. These data indicate that sulfhydryl groups are not a limiting factor for endothelium-derived relaxing factor responses in forearm resistance vessels in normal humans and are in keeping with reports that nitrosothiol contributes to endothelium-derived relaxing factor bioactivity in plasma and vascular smooth muscle. Potentiation of the effects of nitroglycerin by N-acetylcysteine can be attributed to its enhanced biotransformation to an endothelium-derived relaxing factor equivalent, such as nitrosothiol. These observations support the notion of an equilibrium between nitric oxide and nitrosothiol in biological systems that may be influenced by redox state.

A Histologically Distinctive Interstitial Pneumonia Induced by Overexpression of the Interleukin 6, Transforming Growth Factor β1, or Platelet-Derived Growth Factor B Gene

NASA Astrophysics Data System (ADS)

Yoshida, Mitsuhiro; Sakuma, Junko; Hayashi, Seiji; Abe, Kin'ya; Saito, Izumu; Harada, Shizuko; Sakatani, Mitsunoir; Yamamoto, Satoru; Matsumoto, Norinao; Kaneda, Yasufumi; Kishmoto, Tadamitsu

1995-10-01

Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor β1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor β1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

Acoustic fill factors for a 120 inch diameter fairing

NASA Technical Reports Server (NTRS)

Lee, Y. Albert

1992-01-01

Data from the acoustic test of a 120-inch diameter payload fairing were collected and an analysis of acoustic fill factors were performed. Correction factors for obtaining a weighted spatial average of the interior sound pressure level (SPL) were derived based on this database and a normalized 200-inch diameter fairing database. The weighted fill factors were determined and compared with statistical energy analysis (VAPEPS code) derived fill factors. The comparison is found to be reasonable.

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

PubMed Central

Kode, Aruna; Mosialou, Ioanna; Silva, Barbara C.; Rached, Marie-Therese; Zhou, Bin; Wang, Ji; Townes, Tim M.; Hen, Rene; DePinho, Ronald A.; Guo, X. Edward; Kousteni, Stavroula

2012-01-01

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element–binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID:22945629

Influential Observations in Principal Factor Analysis.

ERIC Educational Resources Information Center

Tanaka, Yutaka; Odaka, Yoshimasa

1989-01-01

A method is proposed for detecting influential observations in iterative principal factor analysis. Theoretical influence functions are derived for two components of the common variance decomposition. The major mathematical tool is the influence function derived by Tanaka (1988). (SLD)

Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

ERIC Educational Resources Information Center

Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

2013-01-01

Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

THE RELATIONSHIP OF THE CHEMOTACTIC BEHAVIOR OF THE COMPLEMENT-DERIVED FACTORS, C3a, C5a, AND C567, AND A BACTERIAL CHEMOTACTIC FACTOR TO THEIR ABILITY TO ACTIVATE THE PROESTERASE 1 OF RABBIT POLYMORPHONUCLEAR LEUKOCYTES

PubMed Central

Becker, Elmer L.

1972-01-01

The inhibition profiles obtained when a series of p-nitrophenyl ethyl alkylphosphonates and of p-nitrophenyl ethyl chloroalkylphosphonates were used to interfere with the chemotactic activity of polymorphonuclear leukocytes stimulated by C3a, C5a, and bacterial factor were the same as found previously when C567 was the chemotactic agent. This indicates that as in the chemotactic activity induced by C567, an obligatory step in the chemotaxis caused by C3a, C5a, and bacterial factor is the activation of proesterase 1 of the rabbit polymorphonuclear leukocyte. C5a and C3a activate proesterase 1 of peripheral blood polymophonuclear leukocytes as measured by the increase of acetyl DL-phenylalanine β-naphthyl esterase activity. Attempts to detect in a like manner the proesterase 1 of the same leukocytes using bacterial factor under varying circumstances have consistently failed. It is concluded that bacterial factor, for unknown reasons, is unable to activate proesterase 1 to the same extent as the complement-derived chemotactic factors. The hypothesis of there being a quantitative difference in the ability of bacterial factor to activate proesterase 1 compared with the complement-derived factors explains the previous observations that bacterial factor can not deactivate to itself or to the complement-derived factors, although these latter factors can deactivate to themselves, to each other, and to the bacterial factor. The quantitative difference in the ability of bacterial factor to activate proesterase 1 compared to the complement-derived factors is also associated with and explains the finding that the maximal chemotactic activity attainable when bacterial factor is the chemotactic agent is distinctly less than that obtained using either C3a, C5a, or C567. These results indicate that the activation of proesterase 1 is a general requirement for the chemotactic activity of rabbit polymorphonuclear leukocytes with known macromolecular chemotactic agents and suggest that under several different circumstances the level of chemotactic activity attained is related to the degree of such activation. PMID:4551218

Prognostic impact of a compartment-specific angiogenic marker profile in patients with pancreatic cancer.

PubMed

Kahlert, Christoph; Fiala, Maria; Musso, Gabriel; Halama, Niels; Keim, Sophia; Mazzone, Massimiliano; Lasitschka, Felix; Pecqueux, Mathieu; Klupp, Fee; Schmidt, Thomas; Rahbari, Nuh; Schölch, Sebastian; Pilarsky, Christian; Ulrich, Alexis; Schneider, Martin; Weitz, Juergen; Koch, Moritz

2014-12-30

Pancreatic cancer consists of a heterogenous bulk of tumor cells and stroma cells which contribute to tumor progression by releasing angiogenic factors. Those factors can be detected as circulating serum factors. We performed a compartment-specific analysis of tumor-derived and stroma-derived angiogenic factors to identify biomarkers and molecular targets for the treatment of pancreatic cancer. Kryo-frozen tissue from primary ductal adenocarcinomas (n = 51) was laser-microdissected to isolate tumor and stroma tissue. Expression of 17 angiogenic factors (angiopoietin-2, follistatin, GCSF, HGF, interleukin-8, leptin, PDGF-BB, PECAM-1, VEGF, matrix metalloproteinase -1, -2, -3, -7, -9, -10, -12, and -13) was analyzed using a multiplex elisa assay for tissue-derived proteins and corresponding serum. Our study reveals a compartment-specific expression profile for several angiogenic factors and matrix metalloproteinases. ROC analysis of corresponding serum samples reveals MMP-7 and MMP-12 as strong classifiers for the diagnosis of patients with pancreatic cancer vs. healthy control donors. High expression of tumor-derived PDGF-BB and MMP-1 correlates with prolonged survival in univariate and multivariate analysis. In conclusion, a distinct expression patterns for angiogenic cytokines and MMPs in pancreatic cancer and surrounding stroma may implicate them as novel targets for cancer treatment. Tumor-derived PDGF-BB and MMP-1 are significant and independent prognostic markers for poor survival.

Platelet factor 4 (CXCL4) facilitates human macrophage infection with HIV-1 and potentiates virus replication.

PubMed

Schwartzkopff, Franziska; Grimm, Tobias A; Lankford, Carla S R; Fields, Karen; Wang, Jiun; Brandt, Ernst; Clouse, Kathleen A

2009-12-01

Platelet factor 4 (CXCL4), a member of the CXC chemokine subfamily released in high amounts by activated platelets, has been identified as a monocyte survival factor that induces monocyte differentiation into macrophages. Although CXCL4 has been shown to have biological effects unique to chemokines, nothing is known about the role of CXCL4-derived human macrophages or CXCL4 in human immunodeficiency virus (HIV) disease. In this study, CXCL4-derived macrophages are compared with macrophage-colony stimulating factor (M-CSF)-derived macrophages for their ability to support HIV-1 replication. We show that CXCL4-derived macrophages can be infected with macrophage-tropic HIV-1 that uses either CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4) as a co-receptor for viral entry. We also find that M-CSF and the chemokines, monocyte chemoattractant protein 1 (MCP-1; CCL2) and macrophage-inflammatory-protein-1-alpha (MIP-1alpha; CCL3) are produced upon R5- and X4-tropic HIV-1 replication in both M-CSF- and CXCL4-derived human macrophages. In addition, CXCL4 added to M-CSF-derived macrophages after virus adsorption and maintained throughout the infection enhances HIV-1 replication. We thus propose a novel role for CXCL4 in HIV disease.

Differentiation of Mesenchymal Stem Cells Towards Nephrogenic Lineage and Their Enhanced Resistance to Oxygen Peroxide-induced Oxidative Stress.

PubMed

Tayyeb, Asima; Shahzad, Naveed; Ali, Gibran

2017-07-01

Mesenchymal stem cells (MSCs) have been publicized to ameliorate kidney injury both in vitro and in vivo. However, very less is known if MSCs can be differentiated towards renal lineages and their further application potential in kidney injuries. The present study developed a conditioning system of growth factors fibroblast growth factor 2, transforming growth factor-β2, and leukemia inhibitory factor for in vitro differentiation of MSCs isolated from different sources towards nephrogenic lineage. Less invasively isolated adipose-derived MSCs were also compared to bone marrow-derived MSCs for their differentiation potential to induce renal cell. Differentiated MSCs were further evaluated for their resistance to oxidative stress induced by oxygen peroxide. A combination of growth factors successfully induced differentiation of MSCs. Both types of differentiated cells showed significant expression of pronephrogenic markers (Wnt4, Wt1, and Pax2) and renal epithelial markers (Ecad and ZO1). In contrast, expression of mesenchymal stem cells marker Oct4 and Vim were downregulated. Furthermore, differentiated adipose-derived MSCs and bone marrow-derived MSCs showed enhanced and comparable resistance to oxygen peroxide-induced oxidative stress. Adipose-derived MSC provides a promising alternative to bone marrow-derived MSC as a source of autologous stem cells in human kidney injuries. In addition, differentiated MSCs with further in vivo investigations may serve as a cell source for tissue engineering or cell therapy in different renal ailments.

Noncultured Autologous Adipose-Derived Stem Cells Therapy for Chronic Radiation Injury

PubMed Central

Akita, Sadanori; Akino, Kozo; Hirano, Akiyoshi; Ohtsuru, Akira; Yamashita, Shunichi

2010-01-01

Increasing concern on chronic radiation injuries should be treated properly for life-saving improvement of wound management and quality of life. Recently, regenerative surgical modalities should be attempted with the use of noncultured autologous adipose-derived stem cells (ADSCs) with temporal artificial dermis impregnated and sprayed with local angiogenic factor such as basic fibroblast growth factor, and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Autologous adipose-derived stem cells, together with angiogenic and mitogenic factor of basic fibroblast growth factor and an artificial dermis, were applied over the excised irradiated skin defect and tested for Patients who were uneventfully healed with minimal donor-site morbidity, which lasts more than 1.5 years. PMID:21151652

Origins and Properties of Dental, Thymic, and Bone Marrow Mesenchymal Cells and Their Stem Cells

PubMed Central

Komada, Yukiya; Yamane, Toshiyuki; Kadota, Daiji; Isono, Kana; Takakura, Nobuyuki; Hayashi, Shin-Ichi; Yamazaki, Hidetoshi

2012-01-01

Mesenchymal cells arise from the neural crest (NC) or mesoderm. However, it is difficult to distinguish NC-derived cells from mesoderm-derived cells. Using double-transgenic mouse systems encoding P0-Cre, Wnt1-Cre, Mesp1-Cre, and Rosa26EYFP, which enabled us to trace NC-derived or mesoderm-derived cells as YFP-expressing cells, we demonstrated for the first time that both NC-derived (P0- or Wnt1-labeled) and mesoderm-derived (Mesp1-labeled) cells contribute to the development of dental, thymic, and bone marrow (BM) mesenchyme from the fetal stage to the adult stage. Irrespective of the tissues involved, NC-derived and mesoderm-derived cells contributed mainly to perivascular cells and endothelial cells, respectively. Dental and thymic mesenchyme were composed of either NC-derived or mesoderm-derived cells, whereas half of the BM mesenchyme was composed of cells that were not derived from the NC or mesoderm. However, a colony-forming unit-fibroblast (CFU-F) assay indicated that CFU-Fs in the dental pulp, thymus, and BM were composed of NC-derived and mesoderm-derived cells. Secondary CFU-F assays were used to estimate the self-renewal potential, which showed that CFU-Fs in the teeth, thymus, and BM were entirely NC-derived cells, entirely mesoderm-derived cells, and mostly NC-derived cells, respectively. Colony formation was inhibited drastically by the addition of anti-platelet–derived growth factor receptor-β antibody, regardless of the tissue and its origin. Furthermore, dental mesenchyme expressed genes encoding critical hematopoietic factors, such as interleukin-7, stem cell factor, and cysteine-X-cysteine (CXC) chemokine ligand 12, which supports the differentiation of B lymphocytes and osteoclasts. Therefore, the mesenchymal stem cells found in these tissues had different origins, but similar properties in each organ. PMID:23185234

The effects of adolescent methylphenidate exposure on the behavioral and brain-derived neurotrophic factor response to nicotine.

PubMed

Cummins, Elizabeth D; Leedy, Kristen K; Dose, John M; Peterson, Daniel J; Kirby, Seth L; Hernandez, Liza J; Brown, Russell W

2017-01-01

This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain-derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a "school day" regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45-P63 and tested after a three-day drug washout on the forced swim stress task on P67-P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44-P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre-exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent.

[Prognostic factors of mortality in the malignant biliary obstruction unresectable after the insertion of an endoscopic stent].

PubMed

Hernández Guerrero, Angélica; Sánchez del Monte, Julio; Sobrino Cossío, Sergio; Alonso Lárraga, Octavio; Delgado de la Cruz, Lourdes; Frías Mendívil, M Mauricio; Frías Mendívil, C Mauricio

2006-01-01

To determine the factors prognostics of early mortality in the malignant billary estenosis after the endoscopic derivation. The surgical, percutaneous or endoscopic derivation is the alternative of palliative treatment in the biliary obstruction unresectable. The factors prognostic the early mortality after surgical derivation are: hemoglobin < 10 g/dL, serum bilirubin > 10 mg/dL and serum albumin < 2.5 g/dL; for the percutaneous derivation they are the sanguineous urea more of 4.3 mmol/L and hemoglobin < 10.9 g/dL; whereas in the single endoscopic derivation type 3 of Bismuth and the infectious complications after the endoscopic colangiography and the absence of the clinical success were factors prognoses of early mortality. Descriptive and retrospective analysis of 97 cases with malignant biliary obstruction. The factors were evaluated prognoses of early mortality. Univariated and bivaried analysis and of survival by the method of Kaplan-Meier was made curved. 97 cases were included that presented/displayed unresectable disease and had a biochemical control subsequent to the drainage. They were 58 women and 39 men. More frequent symptoms: ictericia, pain and prurito. 61 cases of distal obstruction and 36 with proximal obstruction. Twenty deaths (25.9%) happened within the 30 later days to the treatment. The bilirubin > 14 mg/dL and the proximal location were like predicting of early mortality. The obstruction biliary more frequent is located in choledocho distal and is of pancreatic origin. The main factors associated to early mortality are: the bilirubin > of 14 mg/dL and the proximal location reason why is important the suitable selection of patient candidates to endoscopic derivation. The survival is better in the distal obstruction.

SU-E-T-469: A Practical Approach for the Determination of Small Field Output Factors Using Published Monte Carlo Derived Correction Factors

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

Calderon, E; Siergiej, D

2014-06-01

Purpose: Output factor determination for small fields (less than 20 mm) presents significant challenges due to ion chamber volume averaging and diode over-response. Measured output factor values between detectors are known to have large deviations as field sizes are decreased. No set standard to resolve this difference in measurement exists. We observed differences between measured output factors of up to 14% using two different detectors. Published Monte Carlo derived correction factors were used to address this challenge and decrease the output factor deviation between detectors. Methods: Output factors for Elekta's linac-based stereotactic cone system were measured using the EDGE detectormore » (Sun Nuclear) and the A16 ion chamber (Standard Imaging). Measurements conditions were 100 cm SSD (source to surface distance) and 1.5 cm depth. Output factors were first normalized to a 10.4 cm × 10.4 cm field size using a daisy-chaining technique to minimize the dependence of field size on detector response. An equation expressing the relation between published Monte Carlo correction factors as a function of field size for each detector was derived. The measured output factors were then multiplied by the calculated correction factors. EBT3 gafchromic film dosimetry was used to independently validate the corrected output factors. Results: Without correction, the deviation in output factors between the EDGE and A16 detectors ranged from 1.3 to 14.8%, depending on cone size. After applying the calculated correction factors, this deviation fell to 0 to 3.4%. Output factors determined with film agree within 3.5% of the corrected output factors. Conclusion: We present a practical approach to applying published Monte Carlo derived correction factors to measured small field output factors for the EDGE and A16 detectors. Using this method, we were able to decrease the percent deviation between both detectors from 14.8% to 3.4% agreement.« less

Controllable Syntheses of MOF-Derived Materials.

PubMed

Zou, Kang-Yu; Li, Zuo-Xi

2018-05-02

Metal-organic frameworks (MOFs), as an important kind of porous inorganic-organic hybrid materials with inherent outstanding physicochemistry characteristics, can be widely applied as versatile precursors for the facile preparation of functional MOF-derived materials. However, there are plenty of sophisticated factors during the synthetic process, which is far from reaching the goal of effectively controlling the nature of MOF-derived materials (such as the composition, morphology and surface area). Therefore, it is urgently necessary to develop regular protocols and concepts for controllable syntheses of MOF-derived materials. In this minireview, we mainly summarize and analyze complicated factors in the fabrication of MOF-derived materials according to recently reported literatures, and this provides a new insight into the rational design and syntheses of MOF-derived materials. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vitro effects of three blood derivatives on human corneal epithelial cells.

PubMed

Freire, Vanesa; Andollo, Noelia; Etxebarria, Jaime; Durán, Juan A; Morales, María-Celia

2012-08-15

We compared the effects of three blood derivatives, autologous serum (AS), platelet-rich plasma (PRP), and serum derived from plasma rich in growth factors (PRGF), on a human corneal epithelial (HCE) cell line to evaluate their potential as an effective treatment for corneal epithelial disorders. The concentrations of epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and fibronectin were quantified by ELISA. The proliferation and viability of HCE cells were measured by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay. Cell morphology was assessed by phase-contrast microscopy. The patterns of expression of several connexin, involucrin, and integrin α6 genes were analyzed by real-time RT-PCR. We found significantly higher levels of EGF in PRGF compared to AS and PRP. However, AS and PRGF induced robust proliferation of HCE cells. In addition, PRGF cultured cells grew as heterogeneous colonies, exhibiting differentiated and non-differentiated cell phenotypes, whereas AS- and PRP-treated cultures exhibited quite homogeneous colonies. Finally, PRGF upregulated the expression of several genes associated with communication and cell differentiation, in comparison to AS or PRP. PRGF promotes biological processes required for corneal epithelialization, such as proliferation and differentiation. Since PRGF effects are similar to those associated with routinely used blood derivatives, the present findings warrant further research on PRGF as a novel alternative treatment for ocular surface diseases.

Association Between Brain-Derived Neurotrophic Factor Genotype and Upper Extremity Motor Outcome After Stroke.

PubMed

Chang, Won Hyuk; Park, Eunhee; Lee, Jungsoo; Lee, Ahee; Kim, Yun-Hee

2017-06-01

The identification of intrinsic factors for predicting upper extremity motor outcome could aid the design of individualized treatment plans in stroke rehabilitation. The aim of this study was to identify prognostic factors, including intrinsic genetic factors, for upper extremity motor outcome in patients with subacute stroke. A total of 97 patients with subacute stroke were enrolled. Upper limb motor impairment was scored according to the upper limb of Fugl-Meyer assessment score at 3 months after stroke. The prediction of upper extremity motor outcome at 3 months was modeled using various factors that could potentially influence this impairment, including patient characteristics, baseline upper extremity motor impairment, functional and structural integrity of the corticospinal tract, and brain-derived neurotrophic factor genotype. Multivariate ordinal logistic regression models were used to identify the significance of each factor. The independent predictors of motor outcome at 3 months were baseline upper extremity motor impairment, age, stroke type, and corticospinal tract functional integrity in all stroke patients. However, in the group with severe motor impairment at baseline (upper limb score of Fugl-Meyer assessment <25), the number of Met alleles in the brain-derived neurotrophic factor genotype was also an independent predictor of upper extremity motor outcome 3 months after stroke. Brain-derived neurotrophic factor genotype may be a potentially useful predictor of upper extremity motor outcome in patients with subacute stroke with severe baseline motor involvement. © 2017 American Heart Association, Inc.

Comparison of fibrin clots derived from peripheral blood and bone marrow.

PubMed

Shoji, Takeshi; Nakasa, Tomoyuki; Yoshizuka, Masaaki; Yamasaki, Takuma; Yasunaga, Yuji; Adachi, Nobuo; Ochi, Mitsuo

2017-03-01

Autologous fibrin clots derived from peripheral blood (pb-fibrin clot) and bone marrow (bm-fibrin clot) are thought to be effective for tissue regeneration. However, there is no report detailing the amount of growth factors in pb-/bm-fibrin clot. In this study we evaluated the amount of growth factors in human pb-/bm-fibrin clot, and prove the validity of fibrin clot for clinical use. Human pb-/bm-fibrin clots were obtained during surgery. In the first experiment, enzyme-linked immunosorbent assay (ELISA) was performed for detecting the amount of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor basic (bFGF), hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-β), platelet derived-growth factors-AB (PDGF-AB), and stromal cell-derived factor-1 (SDF-1). In the second experiment, the efficacy of fibrin clot on the osteogenic differentiation and fibroblast proliferation was evaluated. Pb-/bm-fibrin clots were incubated in human osteoblast derived from mesenchymal stromal cells (MSCs) or human skin fibroblast. Alizarin red staining and real-time PCR (COL1A1, RUNX2) were performed for the detection of osteogenic potential. Cell-growth assay (WST-8) and real-time PCR (COL1A1) were also performed for the detection of the potential of fibroblast proliferation. ELISA analysis revealed that the amount of VEGF, HGF, bFGF, IGF-1, and SDF-1 of bm-fibrin clot group is higher than that of pb-fibrin clot group with statistical differences. Besides, we confirmed that bm-fibrin clot has much potential for the osteogenic differentiation and fibroblast proliferation. The positive outcomes confirm the efficacy of pb-/bm-fibrin clot, and bm-fibrin clot was proved to have much potential for tissue regeneration compared with pb-fibrin clot. The current study showed the potential of a strategy for regenerative medicine using bm-fibrin clot.

N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

PubMed

Stamler, J; Mendelsohn, M E; Amarante, P; Smick, D; Andon, N; Davies, P F; Cooke, J P; Loscalzo, J

1989-09-01

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

On the derivation of the areal reduction factor of storms

NASA Astrophysics Data System (ADS)

Bacchi, Baldassare; Ranzi, Roberto

A stochastic derivation of the areal reduction factor (ARF) of the storm intensity is presented: it is based on the analysis of the crossing properties of the rainfall process aggregated in space and time. As a working hypothesis, the number of crossings of high rainfall intensity levels is assumed to be Poisson-distributed and a hyperbolic tail of the probability of exceedances of rainfall intensity has been adopted. These hypotheses are supported by the analysis of radar maps during an intense storm event which occurred in Northern Italy. The reduction factor derived from this analysis shows a power-law decay with respect to the area of integration and the duration of the storm. The areal reduction results as a function of the storm duration and of its frequency. A weak, but significant decrease of the areal reduction factor with respect to the return period is shown by the functions derived, and this result is consistent with that of some recent studies on this topic. The results derived, although preliminary, may find useful applications for the definition of the design storm in urban catchments of a size greater than some square kilometres and with duration of some hours.

Interactions of Indole Derivatives with β-Cyclodextrin: A Quantitative Structure-Property Relationship Study

PubMed Central

Šoškić, Milan; Porobić, Ivana

2016-01-01

Retention factors for 31 indole derivatives, most of them with auxin activity, were determined by high-performance liquid chromatography, using bonded β-cyclodextrin as a stationary phase. A three-parameter QSPR (quantitative structure-property relationship) model, based on physico-chemical and structural descriptors was derived, which accounted for about 98% variations in the retention factors. The model suggests that the indole nucleus occupies the relatively apolar cavity of β-cyclodextrin while the carboxyl group of the indole -3-carboxylic acids makes hydrogen bonds with the hydroxyl groups of β-cyclodextrin. The length and flexibility of the side chain containing carboxyl group strongly affect the binding of these compounds to β-cyclodextrin. Non-acidic derivatives, unlike the indole-3-carboxylic acids, are poorly retained on the column. A reasonably well correlation was found between the retention factors of the indole-3-acetic acids and their relative binding affinities for human serum albumin, a carrier protein in the blood plasma. A less satisfactory correlation was obtained when the retention factors of the indole derivatives were compared with their affinities for auxin-binding protein 1, a plant auxin receptor. PMID:27124734

Differential effect of extracellular matrix derived from papillary and reticular fibroblasts on epidermal development in vitro.

PubMed

Janson, David; Rietveld, Marion; Mahé, Christian; Saintigny, Gaëlle; El Ghalbzouri, Abdoelwaheb

2017-06-01

Papillary and reticular fibroblasts have different effects on keratinocyte proliferation and differentiation. The aim of this study was to investigate whether these effects are caused by differential secretion of soluble factors or by differential generation of extracellular matrix from papillary and reticular fibroblasts. To study the effect of soluble factors, keratinocyte monolayer cultures were grown in papillary or reticular fibroblast-conditioned medium. To study the effect of extracellular matrix, keratinocytes were grown on papillary or reticular-derived matrix. Conditioned medium from papillary or reticular fibroblasts did not differentially affect keratinocyte viability or epidermal development. However, keratinocyte viability was increased when grown on matrix derived from papillary, compared with reticular, fibroblasts. In addition, the longevity of the epidermis was increased when cultured on papillary fibroblast-derived matrix skin equivalents compared with reticular-derived matrix skin equivalents. The findings indicate that the matrix secreted by papillary and reticular fibroblasts is the main causal factor to account for the differences in keratinocyte growth and viability observed in our study. Differences in response to soluble factors between both populations were less significant. Matrix components specific to the papillary dermis may account for the preferential growth of keratinocytes on papillary dermis.

Alterations of Growth Factors in Autism and Attention-Deficit/Hyperactivity Disorder

PubMed Central

Galvez-Contreras, Alma Y.; Campos-Ordonez, Tania; Gonzalez-Castaneda, Rocio E.; Gonzalez-Perez, Oscar

2017-01-01

Growth factors (GFs) are cytokines that regulate the neural development. Recent evidence indicates that alterations in the expression level of GFs during embryogenesis are linked to the pathophysiology and clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). In this concise review, we summarize the current evidence that supports the role of brain-derived neurotrophic factor, insulin-like growth factor 2, hepatocyte growth factor (HGF), glial-derived neurotrophic factor, nerve growth factor, neurotrophins 3 and 4, and epidermal growth factor in the pathogenesis of ADHD and ASD. We also highlight the potential use of these GFs as clinical markers for diagnosis and prognosis of these neurodevelopmental disorders. PMID:28751869

SKF83959 Produces Antidepressant Effects in a Chronic Social Defeat Stress Model of Depression through BDNF-TrkB Pathway

PubMed Central

Jiang, Bo; Wang, Fang; Yang, Si; Fang, Peng; Deng, Zhi-Fang; Xiao, Jun-Li; Hu, Zhuang-Li

2015-01-01

Background: SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca2+/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects. Methods: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959. Results: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects. Conclusion: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway. PMID:25522427

Osteogenesis Imperfecta due to Mutations in Non-Collagenous Genes-Lessons in the Biology of Bone Formation

PubMed Central

Marini, Joan C.; Reich, Adi; Smith, Simone M.

2014-01-01

Purpose of Review Osteogenesis imperfecta (OI), or “brittle bone disease”, has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for OI as a collagen-related disorder, where autosomal dominant type I collagen defects cause most cases, while rare, mostly recessive forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development and future of this paradigm shift in the understanding of OI. Recent Findings BRIL and PEDF defects cause types V and VI OI via defective bone mineralization, while defects in CRTAP, P3H1 and CyPB cause types VII-IX via defective collagen post-translational modification. Hsp47 and FKBP65 defects cause types X and XI OI via aberrant collagen crosslinking, folding and chaperoning, while defects in SP7, WNT1, TRIC-B and OASIS disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase BMP1 causes type XII OI due to altered collagen maturation/processing. Summary Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of OI types by shared mechanism to simplify current nosology, and should prod investigations into common pathways in OI. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients. PMID:25007323

An accelerated subspace iteration for eigenvector derivatives

NASA Technical Reports Server (NTRS)

Ting, Tienko

1991-01-01

An accelerated subspace iteration method for calculating eigenvector derivatives has been developed. Factors affecting the effectiveness and the reliability of the subspace iteration are identified, and effective strategies concerning these factors are presented. The method has been implemented, and the results of a demonstration problem are presented.

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4).

PubMed

Bertling, Anne; Brodde, Martin F; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C; Kelsch, Reinhard; Kehrel, Beate E

2017-09-01

Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.

A Bilayer Construct Controls Adipose-Derived Stem Cell Differentiation into Endothelial Cells and Pericytes without Growth Factor Stimulation

DTIC Science & Technology

2011-01-01

A Bilayer Construct Controls Adipose-Derived Stem Cell Differentiation into Endothelial Cells and Pericytes Without Growth Factor Stimulation...Ph.D.3 This work describes the differentiation of adipose-derived mesenchymal stem cells (ASC) in a composite hy- drogel for use as a vascularized...tissue from a single population of ASC. This work underscores the importance of the extracellular matrix in controlling stem cell phenotype. It is our

Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

EPA Science Inventory

Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

Characterization of male-derived factors inhibiting female sexual receptivity in Lygus hesperus

USDA-ARS?s Scientific Manuscript database

Newly mated females of the plant bug, Lygus hesperus Knight, enter a refractory period during which their sexual receptivity to courting males is greatly reduced for several days. This behavioral change appears to be induced by male-derived factors delivered in the spermatophore during copulation. T...

BOREAS RSS-2 Extracted Reflectance Factors Derived from ASAS Imagery

NASA Technical Reports Server (NTRS)

Russell, C.; Hall, Forrest G. (Editor); Nickerson, Jaime (Editor); Dabney, P.; Kovalick, W.; Graham, D.; Bur, Michael; Irons, James R.; Tierney, M.

2000-01-01

The BOREAS RSS-2 team derived atmospherically corrected bidirectional reflectance factor means from multispectral, multiangle ASAS imagery for small homogeneous areas near several BOREAS sites. The ASAS imagery was acquired from the C-130 aircraft platform in 1994 and 1996. The data are stored in tabular ASCII files.

Examining the effects of anthropogenic emissions on isoprene-derived secondary organic aerosol formation during the 2013 Southern Oxidant and Aerosol Study (SOAS) at the Look Rock, Tennessee ground site

NASA Astrophysics Data System (ADS)

Budisulistiorini, S. H.; Li, X.; Bairai, S. T.; Renfro, J.; Liu, Y.; Liu, Y. J.; McKinney, K. A.; Martin, S. T.; McNeill, V. F.; Pye, H. O. T.; Nenes, A.; Neff, M. E.; Stone, E. A.; Mueller, S.; Knote, C.; Shaw, S. L.; Zhang, Z.; Gold, A.; Surratt, J. D.

2015-08-01

A suite of offline and real-time gas- and particle-phase measurements was deployed at Look Rock, Tennessee (TN), during the 2013 Southern Oxidant and Aerosol Study (SOAS) to examine the effects of anthropogenic emissions on isoprene-derived secondary organic aerosol (SOA) formation. High- and low-time-resolution PM2.5 samples were collected for analysis of known tracer compounds in isoprene-derived SOA by gas chromatography/electron ionization-mass spectrometry (GC/EI-MS) and ultra performance liquid chromatography/diode array detection-electrospray ionization-high-resolution quadrupole time-of-flight mass spectrometry (UPLC/DAD-ESI-HR-QTOFMS). Source apportionment of the organic aerosol (OA) was determined by positive matrix factorization (PMF) analysis of mass spectrometric data acquired on an Aerodyne Aerosol Chemical Speciation Monitor (ACSM). Campaign average mass concentrations of the sum of quantified isoprene-derived SOA tracers contributed to ~ 9 % (up to 28 %) of the total OA mass, with isoprene-epoxydiol (IEPOX) chemistry accounting for ~ 97 % of the quantified tracers. PMF analysis resolved a factor with a profile similar to the IEPOX-OA factor resolved in an Atlanta study and was therefore designated IEPOX-OA. This factor was strongly correlated (r2 > 0.7) with 2-methyltetrols, C5-alkene triols, IEPOX-derived organosulfates, and dimers of organosulfates, confirming the role of IEPOX chemistry as the source. On average, IEPOX-derived SOA tracer mass was ~ 26 % (up to 49 %) of the IEPOX-OA factor mass, which accounted for 32 % of the total OA. A low-volatility oxygenated organic aerosol (LV-OOA) and an oxidized factor with a profile similar to 91Fac observed in areas where emissions are biogenic-dominated were also resolved by PMF analysis, whereas no primary organic aerosol (POA) sources could be resolved. These findings were consistent with low levels of primary pollutants, such as nitric oxide (NO ~ 0.03 ppb), carbon monoxide (CO ~ 116 ppb), and black carbon (BC ~ 0.2 μg m-3). Particle-phase sulfate is fairly correlated (r2 ~ 0.3) with both methacrylic acid epoxide (MAE)/hydroxymethyl-methyl-α-lactone (HMML)- (henceforth called methacrolein (MACR)-derived SOA tracers) and IEPOX-derived SOA tracers, and more strongly correlated (r2 ~ 0.6) with the IEPOX-OA factor, in sum suggesting an important role of sulfate in isoprene SOA formation. Moderate correlation between the MACR-derived SOA tracer 2-methylglyceric acid with sum of reactive and reservoir nitrogen oxides (NOy; r2 = 0.38) and nitrate (r2 = 0.45) indicates the potential influence of anthropogenic emissions through long-range transport. Despite the lack of a clear association of IEPOX-OA with locally estimated aerosol acidity and liquid water content (LWC), box model calculations of IEPOX uptake using the simpleGAMMA model, accounting for the role of acidity and aerosol water, predicted the abundance of the IEPOX-derived SOA tracers 2-methyltetrols and the corresponding sulfates with good accuracy (r2 ~ 0.5 and ~ 0.7, respectively). The modeling and data combined suggest an anthropogenic influence on isoprene-derived SOA formation through acid-catalyzed heterogeneous chemistry of IEPOX in the southeastern US. However, it appears that this process was not limited by aerosol acidity or LWC at Look Rock during SOAS. Future studies should further explore the extent to which acidity and LWC as well as aerosol viscosity and morphology becomes a limiting factor of IEPOX-derived SOA, and their modulation by anthropogenic emissions.

Mesenchymal Stem Cells Suppress Chronic Rejection in Heterotopic Small Intestine Transplant Rat Models Via Inhibition of CD68, Transforming Growth Factor- β1, and Platelet-Derived Growth Factor Expression.

PubMed

Li, Fuxin; Cao, Jisen; Zhao, Zhicheng; Li, Chuan; Qi, Feng; Liu, Tong

2017-04-01

Mesenchymal stem cells are easy to obtain and expand, with characteristics of low immunogenicity and strong tissue repair capacity. In this study, our aim was to investigate the role of mesenchymal stem cells in chronic immune rejection of heterotopic small intestine transplant in rats. After successfully constructing a rat chronic immune rejection model of heterotopic small intestine transplant, we infused mesenchymal stem cells into the animal recipients. We observed mesenchymal stem cell location in the recipients, recipient survival, pathology changes, and the expression of CD68, transforming growth factor β1, and platelet-derived growth factor C in the donor intestine. Mesenchymal stem cells inhibited the lymphocyte proliferation caused by concanavalin A in vitro. After stem cells were infused into recipients, they were mainly located in the donor intestine, as well as in the spleen and thymus. Recovery after transplant and pathology changes of the donor intestine in rats with stem cell infusion were better than in the control group; however, we observed no differences in survival time, accompanied by downregulated expression of CD68, transforming growth factor β1, and platelet-derived growth factor C. Mesenchymal stem cells, to a certain extent, could inhibit the process of chronic rejection. The mechanisms may include the inhibited function of these cells on lymphocyte proliferation, reduced infiltration of macrophages, and reduced expression of transforming growth factor β1 and platelet-derived growth factor C.

Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor.

PubMed

Hung, Pi-Lien; Huang, Chao-Ching; Huang, Hsiu-Mei; Tu, Dom-Gene; Chang, Ying-Chao

2013-08-01

Low level of thyroid hormone is a strong independent risk factor for white matter (WM) injury, a major cause of cerebral palsy, in preterm infants. Thyroxin upregulates brain-derived neurotrophic factor during development. We hypothesized that thyroxin protected against preoligodendrocyte apoptosis and WM injury in the immature brain via upregulation of brain-derived neurotrophic factor. Postpartum (P) day-7 male rat pups were exposed to hypoxic ischemia (HI) and intraperitoneally injected with thyroxin (T4; 0.2 mg/kg or 1 mg/kg) or normal saline immediately after HI at P9 and P11. WM damage was analyzed for myelin formation, axonal injury, astrogliosis, and preoligodendrocyte apoptosis. Neurotrophic factor expression was assessed by real-time polymerase chain reaction and immunohistochemistry. Neuromotor functions were measured using open-field locomotion (P11 and P21), inclined plane climbing (P11), and beam walking (P21). Intracerebroventricular injection of TrkB-Fc or systemic administration of 7,8-dihydroxyflavone was performed. On P11, the HI group had significantly lower blood T4 levels than the controls. The HI group showed ventriculomegaly and marked reduction of myelin basic protein immunoreactivities in the WM. T4 (1 mg/kg) treatment after HI markedly attenuated axonal injury, astrocytosis, and microgliosis, and increased preoligodendrocyte survival. In addition, T4 treatment significantly increased myelination and selectively upregulated brain-derived neurotrophic factor expression in the WM, and improved neuromotor deficits after HI. The protective effect of T4 on WM myelination and neuromotor performance after HI was significantly attenuated by TrkB-Fc. Systemic 7,8-dihydroxyflavone treatment ameliorated hypomyelination after HI injury. T4 protects against WM injury at both pathological and functional levels via upregulation of brain-derived neurotrophic factor-TrkB signaling in the immature brain.

Lower Bounds to the Reliabilities of Factor Score Estimators.

PubMed

Hessen, David J

2016-10-06

Under the general common factor model, the reliabilities of factor score estimators might be of more interest than the reliability of the total score (the unweighted sum of item scores). In this paper, lower bounds to the reliabilities of Thurstone's factor score estimators, Bartlett's factor score estimators, and McDonald's factor score estimators are derived and conditions are given under which these lower bounds are equal. The relative performance of the derived lower bounds is studied using classic example data sets. The results show that estimates of the lower bounds to the reliabilities of Thurstone's factor score estimators are greater than or equal to the estimates of the lower bounds to the reliabilities of Bartlett's and McDonald's factor score estimators.

Quantitative Tractography and Volumetric MRI in Blast and Blunt Force TBI: Predictors of Neurocognitive and Behavioral Outcome

DTIC Science & Technology

2016-10-01

are related to mechanism of injury as well as white matter integrity using diffusion tensor imaging (DTI). We are also collecting and analyzing...APOE ε4] and brain-derived neurotrophic factor [BDNF]) to brain integrity , neuropsychological functioning, and neurobehavioral outcome. 15. SUBJECT...contribution of genetic factors (Apolipoprotein-E ε-4 [APOE ε4] and brain-derived neurotrophic factor [BDNF]) to brain integrity , neuropsychological

Small field detector correction factors kQclin,Qmsr (fclin,fmsr) for silicon-diode and diamond detectors with circular 6 MV fields derived using both empirical and numerical methods.

PubMed

O'Brien, D J; León-Vintró, L; McClean, B

2016-01-01

The use of radiotherapy fields smaller than 3 cm in diameter has resulted in the need for accurate detector correction factors for small field dosimetry. However, published factors do not always agree and errors introduced by biased reference detectors, inaccurate Monte Carlo models, or experimental errors can be difficult to distinguish. The aim of this study was to provide a robust set of detector-correction factors for a range of detectors using numerical, empirical, and semiempirical techniques under the same conditions and to examine the consistency of these factors between techniques. Empirical detector correction factors were derived based on small field output factor measurements for circular field sizes from 3.1 to 0.3 cm in diameter performed with a 6 MV beam. A PTW 60019 microDiamond detector was used as the reference dosimeter. Numerical detector correction factors for the same fields were derived based on calculations from a geant4 Monte Carlo model of the detectors and the Linac treatment head. Semiempirical detector correction factors were derived from the empirical output factors and the numerical dose-to-water calculations. The PTW 60019 microDiamond was found to over-respond at small field sizes resulting in a bias in the empirical detector correction factors. The over-response was similar in magnitude to that of the unshielded diode. Good agreement was generally found between semiempirical and numerical detector correction factors except for the PTW 60016 Diode P, where the numerical values showed a greater over-response than the semiempirical values by a factor of 3.7% for a 1.1 cm diameter field and higher for smaller fields. Detector correction factors based solely on empirical measurement or numerical calculation are subject to potential bias. A semiempirical approach, combining both empirical and numerical data, provided the most reliable results.

Endocytosis of exogenous factor V by ex-vivo differentiated megakaryocytes from patients with severe parahaemophilia.

PubMed

Radu, Claudia M; Spiezia, Luca; Bulato, Cristiana; Gavasso, Sabrina; Campello, Elena; Sartorello, Francesca; Castoldi, Elisabetta; Simioni, Paolo

2016-11-01

Although human megakaryocytes can synthesize factor V (FV), platelet FV derives largely from endocytosis of plasma FV. Recently, it has been shown that plasma transfusions can replenish the platelet FV pool in parahaemophilic patients. Here we corroborate this finding by showing FV endocytosis by ex vivo differentiated megakaryocytes derived from patients with inherited parahaemophilia. Mononuclear stem cells isolated from peripheral blood of healthy subjects and of three patients with severe parahaemophilia were cultured in the presence of thrombopoietin and interleukin-3 and differentiated into CD41-positive polynucleated megakaryocytes. Exogenous purified FV was added to the culture medium to evaluate FV endocytosis. Immunofluorescence staining revealed abundant FV expression in megakaryocytes derived from healthy donors, but no FV expression in those derived from patients with severe parahaemophilia. However, after the addition of purified FV to the culture medium, megakaryocytes from parahaemophilia patients became positive upon FV immunostaining, suggesting endocytosis of exogenous FV. Endocytosed FV retained factor Xa-co-factor activity as assessed by a prothrombin time-based functional test in megakaryocyte lysates. Addition of exogenous FV to culture medium can restore the FV content of megakaryocytes derived from patients with severe FV defects. This rescue mechanism can have important clinical implications in the management of parahaemophilia patients. © 2016 John Wiley & Sons Ltd.

Vitreous Microparticle Shedding in Retinal Detachment: A Prospective Comparative Study.

PubMed

Tumahai, Perle; Saas, Philippe; Ricouard, Fanny; Biichlé, Sabéha; Puyraveau, Marc; Laheurte, Caroline; Delbosc, Bernard; Saleh, Maher

2016-01-01

Microparticles (MPs) are membrane-derived vesicles measuring less than 1 μm in diameter. They are shed from nearly every activated or preapoptotic cell and may exhibit biologic activities in inflammation or apoptosis settings. The main purpose of this study was to determine whether MP shedding was higher in the vitreous of patients with retinal detachment (RD). This was a prospective, comparative study. Levels of vitreous MPs (including phosphatidylserine [PS]-expressing MPs, photoreceptor cell-derived MPs, and photoreceptor cell-derived MPs expressing PS) and soluble proinflammatory factors (i.e., monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and IL-6) were analyzed by flow cytometry. Samples were obtained from 49 eyes undergoing RD surgery and 41 control eyes. Vitreous levels of all the MPs studied were significantly increased in the RD group. Vitreous MP levels were correlated with levels of at least one proinflammatory factor depending on MP subsets. Concerning clinical parameters, vitreous PS-expressing MP and PS-expressing photoreceptor cell-derived MP levels were higher depending on the duration of RD at surgery, the detached retina surface, and the macula status and were found more sensitive than proinflammatory factors only for the duration of RD at surgery. Vitreous concentrations of MPs (mainly derived from photoreceptor cells) are higher after rhegmatogenous RD and found to be correlated with soluble proinflammatory factors.

Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

USDA-ARS?s Scientific Manuscript database

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

USDA-ARS?s Scientific Manuscript database

In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis

ERIC Educational Resources Information Center

Saghazadeh, Amene; Rezaei, Nima

2017-01-01

Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity. Altered blood BDNF levels have been frequently identified in people with autism spectrum disorders (ASD). There are however wide discrepancies in the evidence. Therefore, we performed the present systematic review and meta-analysis aimed at…

Factors Affecting the Acquisition and Retention of College Faculty. Final Report.

ERIC Educational Resources Information Center

Balyeat, Ralph E.

Employment satisfactions and dissatisfactions, with the accompanying levels of faculty morale and motivation, may be classified into 2 groups: those derived from the basic salary, and those derived from factors, practices and conditions not related to the salary, or so-called fringe benefits. This study was designed to identify and to…

Immunohistochemical examination of effects of kefir, koumiss and commercial probiotic capsules on platelet derived growth factor-c and platelet derived growth factor receptor-alpha expression in mouse liver and kidney.

PubMed

Bakir, B; Sari, E K; Aydin, B D; Yildiz, S E

2015-04-01

We investigated using immunohistochemistry the effects of kefir, koumiss and commercial probiotic capsules on the expression of platelet derived growth factor-c (PDGF-C) and platelet derived growth factor receptor-alpha (PDGFR-α) in mouse liver and kidney. Mice were assigned to four groups: group 1 was given commercial probiotic capsules, group 2 was given kefir, group 3 was given koumiss and group 4 was untreated. After oral administration for 15 days, body weights were recorded and liver and kidney tissue samples were obtained. Hematoxylin and eosin staining was used to examine histology. PDGF-C and PDGFR-α in liver and kidney were localized using the streptavidin-biotin peroxidase complex method (ABC). We found that the weights of the mice in the kefir, koumiss and commercial probiotic capsules groups increased compared to the control group. No differences in liver and kidney histology were observed in any of the experimental groups. Kefir, koumiss and the commercial probiotic preparation increased PDGF-C and PDGFR-α expression.

Immortalized prairie vole-derived fibroblasts (VMF-K4DTs) can be transformed into pluripotent stem cells and provide a useful tool with which to determine optimal reprogramming conditions

PubMed Central

KATAYAMA, Masafumi; HIRAYAMA, Takashi; KIYONO, Tohru; ONUMA, Manabu; TANI, Tetsuya; TAKEDA, Satoru; NISHIMORI, Katsuhiko; FUKUDA, Tomokazu

2017-01-01

The cellular conditions required to establish induced pluripotent stem cells (iPSCs), such as the number of reprogramming factors and/or promoter selection, differ among species. The establishment of iPSCs derived from cells of previously unstudied species therefore requires the extensive optimization of programming conditions, including promoter selection and the optimal number of reprogramming factors, through a trial-and-error approach. While the four Yamanaka factors Oct3/4, Sox2, Klf4, and c-Myc are sufficient for iPSC establishment in mice, we reported previously that six reprogramming factors were necessary for the creation of iPSCs from primary prairie vole-derived cells. Further to this study, we now show detailed data describing the optimization protocol we developed in order to obtain iPSCs from immortalized prairie vole-derived fibroblasts. Immortalized cells can be very useful tools in the optimization of cellular reprogramming conditions, as cellular senescence is known to dramatically decrease the efficiency of iPSC establishment. The immortalized prairie vole cells used in this optimization were designated K4DT cells as they contained mutant forms of CDK4, cyclin D, and telomerase reverse transcriptase (TERT). We show that iPSCs derived from these immortalized cells exhibit the transcriptional silencing of exogenous reprogramming factors while maintaining pluripotent cell morphology. There were no observed differences between the iPSCs derived from primary and immortalized prairie vole fibroblasts. Our data suggest that cells that are immortalized with mutant CDK4, cyclin D, and TERT provide a useful tool for the determination of the optimal conditions for iPSC establishment. PMID:28331164

Immortalized prairie vole-derived fibroblasts (VMF-K4DTs) can be transformed into pluripotent stem cells and provide a useful tool with which to determine optimal reprogramming conditions.

PubMed

Katayama, Masafumi; Hirayama, Takashi; Kiyono, Tohru; Onuma, Manabu; Tani, Tetsuya; Takeda, Satoru; Nishimori, Katsuhiko; Fukuda, Tomokazu

2017-06-21

The cellular conditions required to establish induced pluripotent stem cells (iPSCs), such as the number of reprogramming factors and/or promoter selection, differ among species. The establishment of iPSCs derived from cells of previously unstudied species therefore requires the extensive optimization of programming conditions, including promoter selection and the optimal number of reprogramming factors, through a trial-and-error approach. While the four Yamanaka factors Oct3/4, Sox2, Klf4, and c-Myc are sufficient for iPSC establishment in mice, we reported previously that six reprogramming factors were necessary for the creation of iPSCs from primary prairie vole-derived cells. Further to this study, we now show detailed data describing the optimization protocol we developed in order to obtain iPSCs from immortalized prairie vole-derived fibroblasts. Immortalized cells can be very useful tools in the optimization of cellular reprogramming conditions, as cellular senescence is known to dramatically decrease the efficiency of iPSC establishment. The immortalized prairie vole cells used in this optimization were designated K4DT cells as they contained mutant forms of CDK4, cyclin D, and telomerase reverse transcriptase (TERT). We show that iPSCs derived from these immortalized cells exhibit the transcriptional silencing of exogenous reprogramming factors while maintaining pluripotent cell morphology. There were no observed differences between the iPSCs derived from primary and immortalized prairie vole fibroblasts. Our data suggest that cells that are immortalized with mutant CDK4, cyclin D, and TERT provide a useful tool for the determination of the optimal conditions for iPSC establishment.

The Baade-Wesselink projection factor of the δ-Scuti stars AI Vel and β Cas

NASA Astrophysics Data System (ADS)

Guiglion, G.; Nardetto, N.; Domiciano de Souza, A.; Mathias, P.; Mourard, D.; Poretti, E.

2012-12-01

The Baade-Wesselink method of distance determination is based on the oscillations of pulsating stars. After determining the angular diameter and the linear radius variations, the distance is derived by a simple ratio. The linear radius variation is measured by integrating the pulsation velocity (hereafter V_{puls}) over one pulsating cycle. However, from observations we have only access to the radial velocity (V_{rad}) because of the projection along the line-of-sight. The projection factor, used to convert the radial velocity into the pulsation velocity, is defined by: p = V_{puls} / V_{rad}. We aim to derive the projection factor for two δ-Scuti stars, the high amplitude pulsator AI Vel and the fast rotator β Cas. The geometric component of the projection factor is derived using a limb-darkening model of the intensity distribution of AI Vel, and a fast rotator model for β Cas. Then, by comparing the radial velocity curves of several spectral lines forming at different levels in the atmosphere, we derive directly the velocity gradient (in a part of the atmosphere of the star) using SOPHIE/OHP data for β Cas and HARPS/ESO data for AI Vel, which is used to derive a dynamical projection factor for both stars. We find p = 1.44 ± 0.05 for AI Vel and p = 1.41 ± 0.25 for β Cas. By comparing Cepheids and δ-Scuti stars, these results bring valuable insights into the dynamical structure of pulsating star atmospheres.

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4)

PubMed Central

Bertling, Anne; Brodde, Martin F.; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C.; Kelsch, Reinhard; Kehrel, Beate E.

2017-01-01

Background Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Methods Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Results Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Conclusion Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress. PMID:29070980

Consistency and Generalizability of Dietary Patterns in a Multiethnic Working Population.

PubMed

Eng, Jui-Yee; Moy, Foong-Ming; Bulgiba, Awang; Rampal, Sanjay

2018-03-31

Dietary pattern analysis is a complementary method to nutrient analysis in evaluating overall diet-disease hypotheses. Although studies have been conducted to derive dietary patterns among Malaysians, their consistency across subgroups has not been examined. The study aimed to derive dietary patterns empirically and to examine the consistency and generalizability of patterns across sex, ethnicity, and urban status in a working population. This was a cross-sectional study using data from the Clustering of Lifestyle Risk Factors and Understanding its Association with Stress on Health and Well-Being among School Teachers in Malaysia study collected between August 2014 and November 2015. Dietary intake was assessed using a food frequency questionnaire, and dietary patterns were derived using factor analysis. Participants were teachers from selected public schools from three states in Peninsular Malaysia (n=4,618). Dietary patterns derived using factor analysis. Separate factor analysis was conducted by sex, ethnicity, and urban status to identify dietary patterns. Eigenvalue >2, scree plot, Velicer's minimum average partial analysis, and Horn's parallel analysis were used to determine the number of factors to retain. The interpretability of each dietary pattern was evaluated. The consistency and generalizability of dietary patterns across subgroups were assessed using the Tucker congruence coefficient. There was no subgroup-specific dietary pattern found. Thus, dietary patterns were derived using the pooled sample in the final model. Two dietary patterns (Western and Prudent) were derived. The Western dietary pattern explained 15.4% of total variance, characterized by high intakes of refined grains, animal-based foods, added fat, and sugar-sweetened beverages as well as fast food. The Prudent dietary pattern explained 11.1% of total variance and was loaded with pulses, legumes, vegetables, and fruits. The derived Western and Prudent dietary patterns were consistent and generalizable across subgroups of sex, ethnicity, and urban status. Further research is needed to explore associations between these dietary patterns and chronic diseases. Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Neurotrophic and neuroprotective potential of human limbus-derived mesenchymal stromal cells.

PubMed

Liang, Chang-Min; Weng, Shao-Ju; Tsai, Tung-Han; Li, I-Hsun; Lu, Pin-Hui; Ma, Kuo-Hsing; Tai, Ming-Cheng; Chen, Jiann-Torng; Cheng, Cheng-Yi; Huang, Yuahn-Sieh

2014-10-01

The purpose of this study was to examine neurotrophic and neuroprotective effects of limbus stroma-derived mesenchymal stromal cells (L-MSCs) on cortical neurons in vitro and in vivo. Cultured L-MSCs were characterized by flow cytometry and immunofluorescence through the use of specific MSC marker antibodies. Conditioned media were collected from normoxia- and hypoxia-treated L-MSCs to assess neurotrophic effects. Neuroprotective potentials were evaluated through the use of in vitro hypoxic cortical neuron culture and in vivo rat focal cerebral ischemia models. Neuronal morphology was confirmed by immunofluorescence with the use of anti-MAP2 antibody. Post-ischemic infarct volume and motor behavior were assayed by means of triphenyltetrazolium chloride staining and open-field testing, respectively. Human growth antibody arrays and enzyme-linked immunoassays were used to analyze trophic/growth factors contained in conditioned media. Isolated human L-MSCs highly expressed CD29, CD90 and CD105 but not CD34 and CD45. Mesenchymal lineage cell surface expression pattern and differentiation capacity were identical to MSCs derived form human bone marrow and adipose tissue. The L-MSC normoxic and hypoxic conditioned media both promoted neurite outgrowth in cultured cortical neurons. Hypoxic conditioned medium showed superior neurotrophic function and neuroprotective potential with reduced ischemic brain injury and improved functional recovery in rat focal cerebral ischemia models. Human growth factor arrays and enzyme-linked immunoassays measurements showed neuroprotective and growth-associated cytokines (vascular endothelial growth factor [VEGF], VEGFR3, brain-derived neurotrophic factor, insulin-like growth factor -2 and hepatocyte growth factor) contained in conditioned media. Hypoxic exposure caused VEGF and brain-derived neurotrophic factor upregulation, possibly contributing to neurotrophic and neuroprotective effects. L-MSCs can secrete various neurotrophic factors stimulating neurite outgrowth and protecting neurons against brain ischemic injury through paracrine mechanism. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

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 treatment and future derivation of patient-specific embryonic stem cells.

Recombinant Human Acidic Fibroblast Growth Factor (aFGF) Expressed in Nicotiana benthamiana Potentially Inhibits Skin Photoaging.

PubMed

Ha, Jang-Ho; Kim, Ha-Neul; Moon, Ki-Beom; Jeon, Jae-Heung; Jung, Dai-Hyun; Kim, Su-Jung; Mason, Hugh S; Shin, Seo-Yeon; Kim, Hyun-Soon; Park, Kyung-Mok

2017-07-01

Responding to the need for recombinant acidic fibroblast growth factor in the pharmaceutical and cosmetic industries, we established a scalable expression system for recombinant human aFGF using transient and a DNA replicon vector expression in Nicotiana benthamiana . Recombinant human-acidic fibroblast growth factor was recovered following Agrobacterium infiltration of N. benthamiana . The optimal time point at which to harvest recombinant human acidic fibroblast growth factor expressing leaves was found to be 4 days post-infiltration, before necrosis was evident. Commassie-stained SDS-PAGE gels of His-tag column eluates, concentrated using a 10 000 molecular weight cut-off column, showed an intense band at the expected molecular weight for recombinant human acidic fibroblast growth factor. An immunoblot confirmed that this band was recombinant human acidic fibroblast growth factor. Up to 10 µg recombinant human-acidic fibroblast growth factor/g of fresh leaves were achieved by a simple affinity purification protocol using protein extract from the leaves of agroinfiltrated N. benthamiana . The purified recombinant human acidic fibroblast growth factor improved the survival rate of UVB-irradiated HaCaT and CCD-986sk cells approximately 89 and 81 %, respectively. N. benthamiana -derived recombinant human acidic fibroblast growth factor showed similar effects on skin cell proliferation and UVB protection compared to those of Escherichia coli -derived recombinant human acidic fibroblast growth factor. Additionally, N. benthamiana- derived recombinant human acidic fibroblast growth factor increased type 1 procollagen synthesis up to 30 % as well as reduced UVB-induced intracellular reactive oxygen species generation in fibroblast (CCD-986sk) cells.UVB is a well-known factor that causes various types of skin damage and premature aging. Therefore, the present study demonstrated that N. benthamiana -derived recombinant human acidic fibroblast growth factor effectively protects skin cell from UVB, suggesting its potential use as a cosmetic or therapeutic agent against skin photoaging. Georg Thieme Verlag KG Stuttgart · New York.

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

PubMed Central

Akimoto, Keiko; Kimura, Kenichi; Nagano, Masumi; Takano, Shingo; To'a Salazar, Georgina; Yamashita, Toshiharu

2013-01-01

Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms—promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application. PMID:23231075

Examining the effects of anthropogenic emissions on isoprene-derived secondary organic aerosol formation during the 2013 Southern Oxidant and Aerosol Study (SOAS) at the Look Rock, Tennessee, ground site

NASA Astrophysics Data System (ADS)

Budisulistiorini, S. H.; Li, X.; Bairai, S. T.; Renfro, J.; Liu, Y.; Liu, Y. J.; McKinney, K. A.; Martin, S. T.; McNeill, V. F.; Pye, H. O. T.; Nenes, A.; Neff, M. E.; Stone, E. A.; Mueller, S.; Knote, C.; Shaw, S. L.; Zhang, Z.; Gold, A.; Surratt, J. D.

2015-03-01

A suite of offline and real-time gas- and particle-phase measurements was deployed at Look Rock, Tennessee (TN), during the 2013 Southern Oxidant and Aerosol Study (SOAS) to examine the effects of anthropogenic emissions on isoprene-derived secondary organic aerosol (SOA) formation. High- and low-time resolution PM2.5 samples were collected for analysis of known tracer compounds in isoprene-derived SOA by gas chromatography/electron ionization-mass spectrometry (GC/EI-MS) and ultra performance liquid chromatography/diode array detection-electrospray ionization-high-resolution quadrupole time-of-flight mass spectrometry (UPLC/DAD-ESI-HR-QTOFMS). Source apportionment of the organic aerosol (OA) was determined by positive matrix factorization (PMF) analysis of mass spectrometric data acquired on an Aerodyne Aerosol Chemical Speciation Monitor (ACSM). Campaign average mass concentrations of the sum of quantified isoprene-derived SOA tracers contributed to ~9% (up to 26%) of the total OA mass, with isoprene-epoxydiol (IEPOX) chemistry accounting for ~97% of the quantified tracers. PMF analysis resolved a factor with a profile similar to the IEPOX-OA factor resolved in an Atlanta study and was therefore designated IEPOX-OA. This factor was strongly correlated (r2>0.7) with 2-methyltetrols, C5-alkene triols, IEPOX-derived organosulfates, and dimers of organosulfates, confirming the role of IEPOX chemistry as the source. On average, IEPOX-derived SOA tracer mass was ~25% (up to 47%) of the IEPOX-OA factor mass, which accounted for 32% of the total OA. A low-volatility oxygenated organic aerosol (LV-OOA) and an oxidized factor with a profile similar to 91Fac observed in areas where emissions are biogenic-dominated were also resolved by PMF analysis, whereas no primary organic aerosol (POA) sources could be resolved. These findings were consistent with low levels of primary pollutants, such as nitric oxide (NO~0.03ppb), carbon monoxide (CO~116 ppb), and black carbon (BC~0.2 μg m-3). Particle-phase sulfate is fairly correlated (r2~0.3) with both MAE- and IEPOX-derived SOA tracers, and more strongly correlated (r2~0.6) with the IEPOX-OA factor, in sum suggesting an important role of sulfate in isoprene SOA formation. Moderate correlation between the methacrylic acid epoxide (MAE)-derived SOA tracer 2-methylglyceric acid with sum of reactive and reservoir nitrogen oxides (NOy; r2=0.38) and nitrate (r2=0.45) indicates the potential influence of anthropogenic emissions through long-range transport. Despite the lack of a~clear association of IEPOX-OA with locally estimated aerosol acidity and liquid water content (LWC), box model calculations of IEPOX uptake using the simpleGAMMA model, accounting for the role of acidity and aerosol water, predicted the abundance of the IEPOX-derived SOA tracers 2-methyltetrols and the corresponding sulfates with good accuracy (r2~0.5 and ~0.7, respectively). The modeling and data combined suggest an anthropogenic influence on isoprene-derived SOA formation through acid-catalyzed heterogeneous chemistry of IEPOX in the southeastern US. However, it appears that this process was not limited by aerosol acidity or LWC at Look Rock during SOAS. Future studies should further explore the extent to which acidity and LWC becomes a limiting factor of IEPOX-derived SOA, and their modulation by anthropogenic emissions.

Initial Biochemical Characterization of Cells Derived from Human Periodontium and Their In vitro Response to Platelet-Derived Growth Factor, Epidermal Growth Factor and Transforming Growth Factor-Beta

DTIC Science & Technology

1988-05-01

Periodontal disease is characterized by a loss of connective tissue...obtained for bone cells and fibroblasts. • " S,. O. ipr’ 0 II. LITERATURE REVIEW A . Periodontal Regeneration Periodontal disease is characterized by a ...fracture are felt to involve a similar sequence of cellular events. Since periodontal disease also involves the loss of soft tissue structures, such

Corallocins A-C, Nerve Growth and Brain-Derived Neurotrophic Factor Inducing Metabolites from the Mushroom Hericium coralloides.

PubMed

Wittstein, Kathrin; Rascher, Monique; Rupcic, Zeljka; Löwen, Eduard; Winter, Barbara; Köster, Reinhard W; Stadler, Marc

2016-09-23

Three new natural products, corallocins A-C (1-3), along with two known compounds were isolated from the mushroom Hericium coralloides. Their benzofuranone and isoindolinone structures were elucidated by spectral methods. All corallocins induced nerve growth factor and/or brain-derived neurotrophic factor expression in human 1321N1 astrocytes. Furthermore, corallocin B showed antiproliferative activity against HUVEC and human cancer cell lines MCF-7 and KB-3-1.

Effect of platelet-derived β-thromboglobulins on coagulation.

PubMed

Egan, Karl; van Geffen, Johanna P; Ma, Hui; Kevane, Barry; Lennon, Aine; Allen, Seamus; Neary, Elaine; Parsons, Martin; Maguire, Patricia; Wynne, Kieran; O' Kennedy, Richard; Heemskerk, Johan W M; Áinle, Fionnuala Ní

2017-06-01

β-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived β-thromboglobulins (βTG) share 70% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of βTG on coagulation is unknown. Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified βTG on coagulation. In normal pooled plasma, βTG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, βTG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when βTG was incubated with factor X, suggesting a direct interaction between βTG and factor X. Using SPR, βTG were found to bind to immobilised factor X in a dose dependent manner. βTG modulate coagulation in vitro via an interaction with factor X. Copyright © 2017 Elsevier Ltd. All rights reserved.

Expression, purification, crystallization and preliminary X-ray crystallographic analysis of a resuscitation-promoting factor from Mycobacterium tuberculosis

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

Ruggiero, Alessia; Tizzano, Barbara; Geerlof, Arie

2007-10-01

The first crystallization of a resuscitation-promoting factor has been performed. Multiwavelength anomalous dispersion experiments have been carried out to obtain experimental phases using data at 2.9 Å resolution from a selenomethionine derivative. The resuscitation-promoting factor RpfB, the most complex of the five resuscitation-promoting factors produced by M. tuberculosis, is devoted to bacterial reactivation from the dormant state. RpfB consists of 362 residues predicted to form five domains. An RpfB fragment containing the protein catalytic domain and a G5 domain has been successfully crystallized using vapour-diffusion methods. This is the first crystallographic study of a resuscitation-promoting factor. Crystals of this proteinmore » belong to space group I422, with unit-cell parameters a = 97.63, b = 97.63, c = 114.87 Å. Diffraction data have also been collected from a selenomethionine derivative at 2.9 Å resolution. Model building using the phases derived from the multiwavelength anomalous dispersion experiment is in progress.« less

Factorization and resummation of Higgs boson differential distributions in soft-collinear effective theory

NASA Astrophysics Data System (ADS)

Mantry, Sonny; Petriello, Frank

2010-05-01

We derive a factorization theorem for the Higgs boson transverse momentum (pT) and rapidity (Y) distributions at hadron colliders, using the soft-collinear effective theory (SCET), for mh≫pT≫ΛQCD, where mh denotes the Higgs mass. In addition to the factorization of the various scales involved, the perturbative physics at the pT scale is further factorized into two collinear impact-parameter beam functions (IBFs) and an inverse soft function (ISF). These newly defined functions are of a universal nature for the study of differential distributions at hadron colliders. The additional factorization of the pT-scale physics simplifies the implementation of higher order radiative corrections in αs(pT). We derive formulas for factorization in both momentum and impact parameter space and discuss the relationship between them. Large logarithms of the relevant scales in the problem are summed using the renormalization group equations of the effective theories. Power corrections to the factorization theorem in pT/mh and ΛQCD/pT can be systematically derived. We perform multiple consistency checks on our factorization theorem including a comparison with known fixed-order QCD results. We compare the SCET factorization theorem with the Collins-Soper-Sterman approach to low-pT resummation.

Macrophage Control of Phagocytosed Mycobacteria Is Increased by Factors Secreted by Alveolar Epithelial Cells through Nitric Oxide Independent Mechanisms

PubMed Central

Freidl, Raphaela; Fernández, Carmen

2014-01-01

Tissue-resident macrophages are heterogeneous with tissue-specific and niche-specific functions. Thus, simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo. We focus here on the respiratory tract and ask whether factors secreted by alveolar epithelial cells (AEC) can influence the functionality of resident pulmonary macrophages (PuM). We have previously reported that factors secreted by AEC increase control of intracellular growth of BCG in macrophages. In the current study, we also aimed to investigate possible mechanisms by which AEC-derived factors increase intracellular control of BCG in both primary murine interstitial macrophages, and bone marrow-derived macrophages and characterize further the effect of these factors on macrophage differentiation. We show that; a) in contrast to other macrophage types, IFN-γ did not increase intracellular growth control of Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) by interstitial pulmonary macrophages although the same macrophages could be activated by factors secreted by AEC; b) the lack of response of pulmonary macrophages to IFN-γ was apparently regulated by suppressor of cytokine signaling (SOCS)1; c) AEC-derived factors did not induce pro-inflammatory pathways induced by IFN-γ e.g. expression of inducible nitric oxide synthase (iNOS), secretion of nitric oxide (NO), or IL-12, d) in contrast to IFN-γ, intracellular bacterial destruction induced by AEC-derived factors was not dependent on iNOS transcription and NO production. Collectively, our data show that PuM were restricted in inflammatory responses mediated by IFN-γ through SOCS1 and that factors secreted by AEC- enhanced the microbicidal capacities of macrophages by iNOS independent mechanisms. PMID:25089618

Engineered living blood vessels: functional endothelia generated from human umbilical cord-derived progenitors.

PubMed

Schmidt, Dörthe; Asmis, Lars M; Odermatt, Bernhard; Kelm, Jens; Breymann, Christian; Gössi, Matthias; Genoni, Michele; Zund, Gregor; Hoerstrup, Simon P

2006-10-01

Tissue-engineered living blood vessels (TEBV) with growth capacity represent a promising new option for the repair of congenital malformations. We investigate the functionality of TEBV with endothelia generated from human umbilical cord blood-derived endothelial progenitor cells. Tissue-engineered living blood vessels were generated from human umbilical cord-derived myofibroblasts seeded on biodegradable vascular scaffolds, followed by endothelialization with differentiated cord blood-derived endothelial progenitor cells. During in vitro maturation the TEBV were exposed to physiologic conditioning in a flow bioreactor. For functional assessment, a subgroup of TEBV was stimulated with tumor necrosis factor-alpha. Control vessels endothelialized with standard vascular endothelial cells were treated in parallel. Analysis of the TEBV included histology, immunohistochemistry, biochemistry (extracellular matrix analysis, DNA), and biomechanical testing. Endothelia were analyzed by flow cytometry and immunohistochemistry (CD31, von Willebrand factor, thrombomodulin, tissue factor, endothelial nitric oxide synthase). Histologically, a three-layered tissue organization of the TEBV analogous to native vessels was observed, and biochemistry revealed the major matrix constituents (collagen, proteoglycans) of blood vessels. Biomechanical properties (Young's modulus, 2.03 +/- 0.65 MPa) showed profiles resembling those of native tissue. Endothelial progenitor cells expressed typical endothelial cell markers CD31, von Willebrand factor, and endothelial nitric oxide synthase comparable to standard vascular endothelial cells. Stimulation with tumor necrosis factor-alpha resulted in physiologic upregulation of tissue factor and downregulation of thrombomodulin expression. These results indicate that TEBV with tissue architecture and functional endothelia similar to native blood vessels can be successfully generated from human umbilical cord progenitor cells. Thus, blood-derived progenitor cells obtained before or at birth may enable the clinical realization of tissue engineering constructs for pediatric applications.

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

PubMed Central

van Beers, Eduard J.; Schaap, Marianne C.L.; Berckmans, René J.; Nieuwland, Rienk; Sturk, Augueste; van Doormaal, Frederiek F.; Meijers, Joost C.M.; Biemond, Bart J.

2009-01-01

Background Sickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived microparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease. Design and Methods In the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease. Results The majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived microparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=−0.58, p<0.001) and lactate dehydrogenase (r=0.59, p<0.001), von Willebrand factor as a marker of platelet/endothelial activation (r=0.44, p<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52, p<0.001 and r=0.59, p<0.001, respectively) as markers of fibrinolysis and coagulation activation. Thrombin generation depended on the total number of microparticles (r=0.63, p<0.001). Anti-human factor XI inhibited thrombin generation by about 50% (p<0.001), whereas anti-human factor VII was ineffective (p>0.05). The extent of factor XI inhibition was associated with erythrocyte-derived microparticles (r=0.50, p=0.023). Conclusions We conclude that the procoagulant state in sickle cell disease is partially explained by the factor XI-dependent procoagulant properties of circulating erythrocyte-derived microparticles. PMID:19815831

Evaluation of the rat bladder-derived relaxant factor by coaxial bioassay system.

PubMed

Bozkurt, Turgut Emrah; Sahin-Erdemli, Inci

2004-07-14

The release of bladder-derived relaxant factor in a coaxial bioassay system and the effects of reactive oxygen species were studied. After precontraction with phenylephrine (10(-6)-3x10(-6)) or 50 mM K+, acetylcholine (10(-8)-10(-3) M) induced relaxation in rat anococcygeus muscle mounted within rat bladder in a tissue bath. This relaxation was not altered by the removal of the urothelium or incubation with tetrodotoxin (10(-6) M). However, bupivacaine (10(-4) M) and lidocaine (3 x 10(-4) M) inhibited this response after raising the pH of the nutrient solution to 7.8, and oxybuprocaine (10(-4) M) exerted inhibitory effect at both physiological pH (7.4) and at pH 7.8. Exposure to electrolysis-generated reactive oxygen species or incubation with hydrogen peroxide and pyrogallol did not alter the acetylcholine response. Present results indicate that the bladder-derived relaxant factor does not behave like endothelium-derived hyperpolarizing factor, but its release may be associated with tetrodotoxin-resistant Na+ channels, which are probably in the neurons of the bladder rather than in the urothelium or detrusor muscle. Furthermore, reactive oxygen species do not interact with this relaxing factor, the exact nature and the physiological importance of which, however, remains to be established.

Differential Regulation of Brain-Derived Neurotrophic Factor Transcripts during the Consolidation of Fear Learning

ERIC Educational Resources Information Center

Ressler, Kerry J.; Rattiner, Lisa M.; Davis, Michael

2004-01-01

Brain-derived neurotrophic factor (BDNF) has been implicated as a molecular mediator of learning and memory. The BDNF gene contains four differentially regulated promoters that generate four distinct mRNA transcripts, each containing a unique noncoding 5[prime]-exon and a common 3[prime]-coding exon. This study describes novel evidence for the…

Isolation and Characterization of Rat Pituitary Endothelial Cells

PubMed Central

Chaturvedi, Kirti; Sarkar, Dipak K.

2010-01-01

Most previous studies that determined the effect of estradiol on angiogenesis used endothelial cells from nonpituitary sources. Because pituitary tumor tissue receives its blood supply via portal and arterial circulation, it is important to use pituitary-derived endothelial cells in studying pituitary angiogenesis. We have developed a magnetic separation technique to isolate endothelial cells from pituitary tissues and have characterized these cells in primary cultures. Endothelial cells of the pituitary showed the existence of endothelial cell marker, CD31, and of von Willebrand factor protein. These cells in cultures also showed immunore-activity of estrogen receptors alpha and beta. The angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, significantly increased proliferation and migration of the pituitary-derived endothelial cells in primary cultures. These results suggest that a magnetic separation technique can be used for enrichment of pituitary-derived endothelial cells for determination of cellular mechanisms governing the vascularization in the pituitary. PMID:17028416

Approximate method of variational Bayesian matrix factorization/completion with sparse prior

NASA Astrophysics Data System (ADS)

Kawasumi, Ryota; Takeda, Koujin

2018-05-01

We derive the analytical expression of a matrix factorization/completion solution by the variational Bayes method, under the assumption that the observed matrix is originally the product of low-rank, dense and sparse matrices with additive noise. We assume the prior of a sparse matrix is a Laplace distribution by taking matrix sparsity into consideration. Then we use several approximations for the derivation of a matrix factorization/completion solution. By our solution, we also numerically evaluate the performance of a sparse matrix reconstruction in matrix factorization, and completion of a missing matrix element in matrix completion.

Human umbilical cord derived matrix: A scaffold suitable for tissue engineering application.

PubMed

Dan, Pan; Velot, Émilie; Mesure, Benjamin; Groshenry, Guillaume; Bacharouche, Jalal; Decot, Véronique; Menu, Patrick

2017-01-01

Human tissue derived natural extracellular matrix (ECM) has great potential in tissue engineering. We sought to isolate extracellular matrix derived from human umbilical cord and test its potential in tissue engineering. An enzymatic method was applied to isolate and solubilized complete human umbilical cord derived matrix (hUCM). The obtained solution was analyzed for growth factors, collagen and residual DNA contents, then used to coat 2D and 3D surfaces for cell culture application. The hUCM was successfully isolated with trypsin digestion to acquire a solution containing various growth factors and collagen but no residual DNA. This hUCM solution can form a coating on 2D and 3D substrates suitable cell culture. We developed a new matrix derived from human source that can be further used in tissue engineering.

A note on derivations of Murray-von Neumann algebras.

PubMed

Kadison, Richard V; Liu, Zhe

2014-02-11

A Murray-von Neumann algebra is the algebra of operators affiliated with a finite von Neumann algebra. In this article, we first present a brief introduction to the theory of derivations of operator algebras from both the physical and mathematical points of view. We then describe our recent work on derivations of Murray-von Neumann algebras. We show that the "extended derivations" of a Murray-von Neumann algebra, those that map the associated finite von Neumann algebra into itself, are inner. In particular, we prove that the only derivation that maps a Murray-von Neumann algebra associated with a factor of type II1 into that factor is 0. Those results are extensions of Singer's seminal result answering a question of Kaplansky, as applied to von Neumann algebras: The algebra may be noncommutative and may even contain unbounded elements.

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

PubMed

Puy, Cristina; Tucker, Erik I; Ivanov, Ivan S; Gailani, David; Smith, Stephanie A; Morrissey, James H; Gruber, András; McCarty, Owen J T

2016-01-01

Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma. Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP.

Endothelial-derived GM-CSF influences expression of oncostatin M

USDA-ARS?s Scientific Manuscript database

During and following transendothelial migration, neutrophils undergo a number of phenotypic changes resulting from encounters with endothelial-derived factors. This report uses an in vitro model with HUVEC and isolated human neutrophils to examine the effects of two locally-derived cytokines, granul...

Control of Human Endometrial Stromal Cell Motility by PDGF-BB, HB-EGF and Trophoblast-Secreted Factors

PubMed Central

Schwenke, Maren; Knöfler, Martin; Velicky, Philipp; Weimar, Charlotte H. E.; Kruse, Michelle; Samalecos, Annemarie; Wolf, Anja; Macklon, Nick S.; Bamberger, Ana-Maria; Gellersen, Birgit

2013-01-01

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site. PMID:23349855

The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.

PubMed

Dankovic, D A; Naumann, B D; Maier, A; Dourson, M L; Levy, L S

2015-01-01

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process.

Perceived key injury risk factors in World Cup alpine ski racing—an explorative qualitative study with expert stakeholders

PubMed Central

Spörri, Jörg; Kröll, Josef; Amesberger, Günter; Blake, Ollie M; Müller, Erich

2012-01-01

Background There is limited knowledge about key injury risk factors in alpine ski racing, particularly for World Cup (WC) athletes. Objective This study was undertaken to compile and explore perceived intrinsic and extrinsic risk factors for severe injuries in WC alpine ski racing. Methods Qualitative study. Interviews were conducted with 61 expert stakeholders of the WC ski racing community. Experts’ statements were collected, paraphrased and loaded into a database with inductively derived risk factor categories (Risk Factor Analysis). At the end of the interviews, experts were asked to name those risk factors they believed to have a high potential impact on injury risk and to rank them according to their priority of impact (Risk Factor Rating). Results In total, 32 perceived risk factors categories were derived from the interviews within the basic categories Athlete, Course, Equipment and Snow. Regarding their perceived impact on injury risk, the experts’ top five categories were: system ski, binding, plate and boot; changing snow conditions; physical aspects of the athletes; speed and course setting aspects and speed in general. Conclusions Severe injuries in WC alpine ski racing can have various causes. This study compiled a list of perceived intrinsic and extrinsic risk factors and explored those factors with the highest believed impact on injury risk. Hence, by using more detailed hypotheses derived from this explorative study, further studies should verify the plausibility of these factors as true risk factors for severe injuries in WC alpine ski racing. PMID:22872684

Derivation of Sky-View Factors from LIDAR Data

NASA Technical Reports Server (NTRS)

Kidd, Christopher; Chapman, Lee

2013-01-01

The use of Lidar (Light Detection and Ranging), an active light-emitting instrument, is becoming increasingly common for a range of potential applications. Its ability to provide fine resolution spatial and vertical resolution elevation data makes it ideal for a wide range of studies. This paper demonstrates the capability of Lidar data to measure sky view factors (SVF). The Lidar data is used to generate a spatial map of SVFs which are then compared against photographically-derived SVF at selected point locations. At each location three near-surface elevations measurements were taken and compared with collocated Lidar-derived estimated. It was found that there was generally good agreement between the two methodologies, although with decreasing SVF the Lidar-derived technique tended to overestimate the SVF: this can be attributed in part to the spatial resolution of the Lidar sampling. Nevertheless, airborne Lidar systems can map sky view factors over a large area easily, improving the utility of such data in atmospheric and meteorological models.

On the derivation of flow rating curves in data-scarce environments

NASA Astrophysics Data System (ADS)

Manfreda, Salvatore

2018-07-01

River monitoring is a critical issue for hydrological modelling that relies strongly on the use of flow rating curves (FRCs). In most cases, these functions are derived by least-squares fitting which usually leads to good performance indices, even when based on a limited range of data that especially lack high flow observations. In this context, cross-section geometry is a controlling factor which is not fully exploited in classical approaches. In fact, river discharge is obtained as the product of two factors: 1) the area of the wetted cross-section and 2) the cross-sectionally averaged velocity. Both factors can be expressed as a function of the river stage, defining a viable alternative in the derivation of FRCs. This makes it possible to exploit information about cross-section geometry limiting, at least partially, the uncertainty in the extrapolation of discharge at higher flow values. Numerical analyses and field data confirm the reliability of the proposed procedure for the derivation of FRCs.

Damping factor estimation using spin wave attenuation in permalloy film

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

Manago, Takashi, E-mail: manago@fukuoka-u.ac.jp; Yamanoi, Kazuto; Kasai, Shinya

2015-05-07

Damping factor of a Permalloy (Py) thin film is estimated by using the magnetostatic spin wave propagation. The attenuation lengths are obtained by the dependence of the transmission intensity on the antenna distance, and decrease with increasing magnetic fields. The relationship between the attenuation length, damping factor, and external magnetic field is derived theoretically, and the damping factor was determined to be 0.0063 by fitting the magnetic field dependence of the attenuation length, using the derived equation. The obtained value is in good agreement with the general value of Py. Thus, this estimation method of the damping factor using spinmore » waves attenuation can be useful tool for ferromagnetic thin films.« less

Dynamics of competitive systems with a single common limiting factor.

PubMed

Kon, Ryusuke

2015-02-01

The concept of limiting factors (or regulating factors) succeeded in formulating the well-known principle of competitive exclusion. This paper shows that the concept of limiting factors is helpful not only to formulate the competitive exclusion principle, but also to obtain other ecological insights. To this end, by focusing on a specific community structure, we study the dynamics of Kolmogorov equations and show that it is possible to derive an ecologically insightful result only from the information about interactions between species and limiting factors. Furthermore, we find that the derived result is a generalization of the preceding work by Shigesada, Kawasaki, and Teramoto (1984), who examined a certain Lotka-Volterra equation in a different context.

Brain-Derived Neurotrophic Factor Gene Expression in Pediatric Bipolar Disorder: Effects of Treatment and Clinical Response

ERIC Educational Resources Information Center

Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Dwivedi, Yogesh; Pavuluri, Mani N.

2008-01-01

The study determines the gene expression of brain-derived neurotrophic factor (BDNF) in the lymphocytes of subjects with pediatric bipolar disorder (PBD) before and during treatment with mood stabilizers and in drug-free normal control subjects. Results indicate the potential of BDNF levels as a biomarker for PBD and as a treatment predictor and…

Brain-derived neurotrophic factor and its receptors in Bergmann glia cells.

PubMed

Poblete-Naredo, Irais; Guillem, Alain M; Juárez, Claudia; Zepeda, Rossana C; Ramírez, Leticia; Caba, Mario; Hernández-Kelly, Luisa C; Aguilera, José; López-Bayghen, Esther; Ortega, Arturo

2011-12-01

Brain-derived neurotrophic factor is an abundant and widely distributed neurotrophin expressed in the Central Nervous System. It is critically involved in neuronal differentiation and survival. The expression of brain-derived neurotrophic factor and that of its catalytic active cognate receptor (TrkB) has been extensively studied in neuronal cells but their expression and function in glial cells is still controversial. Despite of this fact, brain-derived neurotrophic factor is released from astrocytes upon glutamate stimulation. A suitable model to study glia/neuronal interactions, in the context of glutamatergic synapses, is the well-characterized culture of chick cerebellar Bergmann glia cells. Using, this system, we show here that BDNF and its functional receptor are present in Bergmann glia and that BDNF stimulation is linked to the activation of the phosphatidyl-inositol 3 kinase/protein kinase C/mitogen-activated protein kinase/Activator Protein-1 signaling pathway. Accordingly, reverse transcription-polymerase chain reaction (RT-PCR) experiments predicted the expression of full-length and truncated TrkB isoforms. Our results suggest that Bergmann glia cells are able to express and respond to BDNF stimulation favoring the notion of their pivotal role in neuroprotection. Copyright © 2011 Elsevier B.V. All rights reserved.

Generation of fibrosarcomas in vivo by a retrovirus that expresses the normal B chain of platelet-derived growth factor and mimics the alternative splice pattern of the v-sis oncogene

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

Pech, M.; Gazit, A.; Arnstein, P.

1989-04-01

A retrovirus containing the entire human platelet-derived growth factor B-chain (PDGF-B) gene was constructed in order to investigate the in vivo biological activity of its encoded growth factor. When this virus was introduced into newborn mice, it reproducibly generated fibrosarcomas at the site of inoculation. Proviruses in each fibrosarcoma analyzed had lost 149 nucleotides downstream of the PDGF-B coding region. This deletion originated from an alternative or aberrant splice event that occurred within exon 7 of the PDGF-B gene and mimicked the v-sis oncogene. Thus, deletion of this region may be necessary for efficient retrovirus replication or for more potentmore » transforming function. Evidence that the normal growth factor coding sequence was unaltered derived from RNase protection studies and immunoprecipitation analysis. Tumors were generally polyclonal but demonstrated clonal subpopulations. Moreover, tumor-derived cell lines became monoclonal within a few tissue culture passages and rapidly formed tumors in vivo. These findings argue that overexpression of the normal human PDGF-B gene product under retrovirus control can induce the fully malignant phenotype.« less

Platelet-Rich Plasma Peptides: Key for Regeneration

PubMed Central

Sánchez-González, Dolores Javier; Méndez-Bolaina, Enrique; Trejo-Bahena, Nayeli Isabel

2012-01-01

Platelet-derived Growth Factors (GFs) are biologically active peptides that enhance tissue repair mechanisms such as angiogenesis, extracellular matrix remodeling, and cellular effects as stem cells recruitment, chemotaxis, cell proliferation, and differentiation. Platelet-rich plasma (PRP) is used in a variety of clinical applications, based on the premise that higher GF content should promote better healing. Platelet derivatives represent a promising therapeutic modality, offering opportunities for treatment of wounds, ulcers, soft-tissue injuries, and various other applications in cell therapy. PRP can be combined with cell-based therapies such as adipose-derived stem cells, regenerative cell therapy, and transfer factors therapy. This paper describes the biological background of the platelet-derived substances and their potential use in regenerative medicine. PMID:22518192

Platelet-rich plasma derived growth factors contribute to stem cell differentiation in musculoskeletal regeneration

NASA Astrophysics Data System (ADS)

Qian, Yun; Han, Qixin; Chen, Wei; Song, Jialin; Zhao, Xiaotian; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

2017-10-01

Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of platelet-rich plasma derived growth factors with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.

Method to determine the position-dependant metal correction factor for dose-rate equivalent laser testing of semiconductor devices

DOEpatents

Horn, Kevin M.

2013-07-09

A method reconstructs the charge collection from regions beneath opaque metallization of a semiconductor device, as determined from focused laser charge collection response images, and thereby derives a dose-rate dependent correction factor for subsequent broad-area, dose-rate equivalent, laser measurements. The position- and dose-rate dependencies of the charge-collection magnitude of the device are determined empirically and can be combined with a digital reconstruction methodology to derive an accurate metal-correction factor that permits subsequent absolute dose-rate response measurements to be derived from laser measurements alone. Broad-area laser dose-rate testing can thereby be used to accurately determine the peak transient current, dose-rate response of semiconductor devices to penetrating electron, gamma- and x-ray irradiation.

Factorization and resummation of Higgs boson differential distributions in soft-collinear effective theory

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

Mantry, Sonny; Petriello, Frank

We derive a factorization theorem for the Higgs boson transverse momentum (p{sub T}) and rapidity (Y) distributions at hadron colliders, using the soft-collinear effective theory (SCET), for m{sub h}>>p{sub T}>>{Lambda}{sub QCD}, where m{sub h} denotes the Higgs mass. In addition to the factorization of the various scales involved, the perturbative physics at the p{sub T} scale is further factorized into two collinear impact-parameter beam functions (IBFs) and an inverse soft function (ISF). These newly defined functions are of a universal nature for the study of differential distributions at hadron colliders. The additional factorization of the p{sub T}-scale physics simplifies themore » implementation of higher order radiative corrections in {alpha}{sub s}(p{sub T}). We derive formulas for factorization in both momentum and impact parameter space and discuss the relationship between them. Large logarithms of the relevant scales in the problem are summed using the renormalization group equations of the effective theories. Power corrections to the factorization theorem in p{sub T}/m{sub h} and {Lambda}{sub QCD}/p{sub T} can be systematically derived. We perform multiple consistency checks on our factorization theorem including a comparison with known fixed-order QCD results. We compare the SCET factorization theorem with the Collins-Soper-Sterman approach to low-p{sub T} resummation.« less

5'-adenosine monophosphate is the neutrophil-derived paracrine factor that elicits chloride secretion from T84 intestinal epithelial cell monolayers.

PubMed Central

Madara, J L; Patapoff, T W; Gillece-Castro, B; Colgan, S P; Parkos, C A; Delp, C; Mrsny, R J

1993-01-01

Neutrophil transmigration across intestinal epithelia is thought to contribute to epithelial dysfunction and characterizes many inflammatory intestinal diseases. Neutrophils activated by factors, normally present in the lumen, release a neutrophil-derived secretagogue activity to which intestinal epithelia respond with an electrogenic chloride secretion, the transport event which underlies secretory diarrhea. Using sequential ultrafiltration, column chromatographic, and mass and Raman spectroscopic techniques, neutrophil-derived secretagogue was identified as 5'-AMP. Additional studies suggested that neutrophil-derived 5'-AMP is subsequently converted to adenosine at the epithelial cell surface by ecto-5'-nucleotidase and that adenosine subsequently activates intestinal secretion through adenosine receptors on the apical membrane of target intestinal epithelial cells. These findings suggest that this ATP metabolite may serve as a neutrophil-derived paracrine mediator that contributes to secretory diarrhea in states of intestinal inflammation. PMID:8486793

A note on the velocity derivative flatness factor in decaying HIT

NASA Astrophysics Data System (ADS)

Djenidi, L.; Danaila, L.; Antonia, R. A.; Tang, S.

2017-05-01

We develop an analytical expression for the velocity derivative flatness factor, F, in decaying homogenous and isotropic turbulence (HIT) starting with the transport equation of the third-order moment of the velocity increment and assuming self-preservation. This expression, fully consistent with the Navier-Stokes equations, relates F to the product between the second-order pressure derivative (∂2p /∂x2) and second-order moment of the longitudinal velocity derivative ((∂u/∂x ) 2), highlighting the role the pressure plays in the scaling of the fourth-order moment of the longitudinal velocity derivative. It is also shown that F has an upper bound which follows the integral of k*4Ep*(k* ) where Ep and k are the pressure spectrum and the wavenumber, respectively (the symbol * represents the Kolmogorov normalization). Direct numerical simulations of forced HIT suggest that this integral converges toward a constant as the Reynolds number increases.

Synthesizing Risk from Summary Evidence Across Multiple Risk Factors.

PubMed

Shrier, Ian; Colditz, Graham A; Steele, Russell J

2018-07-01

Although meta-analyses provide summary effect estimates that help advise patient care, patients often want to compare their overall health to the general population. The Harvard Cancer Risk Index was published in 2004 and uses risk ratio estimates and prevalence estimates from original studies across many risk factors to provide an answer to this question. However, the published version of the formula only uses dichotomous risk factors and its derivation was not provided. The objective of this brief report was to provide the derivation of a more general form of the equation that allows the incorporation of risk factors with three or more levels.

Development of ground-water vulnerability database for the U.S. Environmental protection agency's hazard ranking system using a geographic information system

USGS Publications Warehouse

Clarke, John S.; Sorensen, Jerry W.; Strickland, Henry G.; Collins, George

1992-01-01

Geographic information system (GIS) methods were applied to the U.S. Environmental Protection Agency's (EPA) hazard ranking system (HRS) to evaluate the vulnerability of ground water to contamination from actual or potential releases of hazardous materials from waste-disposal sites. Computerized maps of four factors influencing ground-water vulnerability - hydraulic conductivity, sorptive capacity, depth to water, and net precipitation - were derived for the Southeastern United States from digitized copies of published maps and from computerized databases, including the U.S. Geological Survey's (USGS) national water information system. To test the accuracy of the derived data coverages used to assess ground-water vulnerability, GIS-derived values for hydraulic conductivity, depth to water, and net precipitation were compared to corresponding values assigned by EPA's field investigation teams (FIT) at 28 hazardous waste sites. For each factor, site data were divided into three physiographic groupings: (1) Coastal Plain, (2) Valley and Ridge-Interior Low Plateaus, and (3) Piedmont-Blue Ridge. The best correlation between the paired data sets was for the net precipitation factor, where most GIS-derived values were within 0 to 40% of the FIT data, and 79% were within the same HRS scoring range. For the hydraulic conductivity factor, the best correlation between GIS and FIT data was for values derived from a published surficial deposits map, where most of the values were within one order of magnitude of the FIT data, and on the average were within 1.24 orders of magnitude of the FIT data. For this map, the best match between data sets was in the Coastal Plain province, where the difference in order to magnitude averaged 0.92. For the depth-to-water factor, most of the GIS derived values were within 51 to 100% of the FIT data, and only 44 to 50% of the sites were within a common scoring range. The best correlation for depth to water was in the Coastal Plain where GIS derived values were within 8 to 100% of the FIT data.

Combining uncertainty factors in deriving human exposure levels of noncarcinogenic toxicants.

PubMed

Kodell, R L; Gaylor, D W

1999-01-01

Acceptable levels of human exposure to noncarcinogenic toxicants in environmental and occupational settings generally are derived by reducing experimental no-observed-adverse-effect levels (NOAELs) or benchmark doses (BDs) by a product of uncertainty factors (Barnes and Dourson, Ref. 1). These factors are presumed to ensure safety by accounting for uncertainty in dose extrapolation, uncertainty in duration extrapolation, differential sensitivity between humans and animals, and differential sensitivity among humans. The common default value for each uncertainty factor is 10. This paper shows how estimates of means and standard deviations of the approximately log-normal distributions of individual uncertainty factors can be used to estimate percentiles of the distribution of the product of uncertainty factors. An appropriately selected upper percentile, for example, 95th or 99th, of the distribution of the product can be used as a combined uncertainty factor to replace the conventional product of default factors.

Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

EPA Science Inventory

Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

Temperament in the developmental course: a longitudinal comparison of New York Longitudinal Study-derived dimensions with the Junior Temperament and Character Inventory.

PubMed

Pitzer, Martina; Esser, Guenter; Schmidt, Martin H; Laucht, Manfred

2007-01-01

Despite theoretical discrepancies between different concepts of temperament, some core dimensions are thought to be common to the various models. We compared temperamental traits derived from the New York Longitudinal Study (NYLS) model and the Cloninger dimensions in the developmental course and investigated the associations of temperament with sex as well as with obstetric risks or psychosocial risks present at birth. Participants were 151 boys and 157 girls born at differing degrees of obstetric and psychosocial risk from a longitudinal study on a high-risk community sample. In infancy and childhood, NYLS-derived temperamental characteristics were assessed by a highly structured parent interview and standardized behavioral observations. At age 15 years, the Junior Temperament and Character Inventory/12-18 was administered. Moderate correlations were found between Junior Temperament and Character Inventory scales in adolescence and NYLS-derived factors in childhood. The psychosocial risk load seemed to influence the expression of novelty seeking or corresponding NYLS-derived factors, whereas the obstetric risks did not contribute to variation in temperament. Our findings further support highly sex-specific gene x environment interactions on temperament in the developmental course. The content of our NYLS-derived factors and the specific type of association across different temperament constructs fit into the increasing consensus regarding a small number of higher-order temperamental traits.

75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-14

... Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and (2) labeling of blood and blood components and plasma-derived products, including plasma-derived albumin and products..., the Committee will hear informational presentations related to FDA's geographic donor deferral policy...

EPO improved neurologic outcome in rat pups late after traumatic brain injury.

PubMed

Schober, Michelle E; Requena, Daniela F; Rodesch, Christopher K

2018-05-01

In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Bone-Derived Stem Cells Repair the Heart after Myocardial Infarction Through Transdifferentiation and Paracrine Signaling Mechanisms

PubMed Central

Duran, Jason M.; Makarewich, Catherine A.; Sharp, Thomas E.; Starosta, Timothy; Fang, Zhu; Hoffman, Nicholas E.; Chiba, Yumi; Madesh, Muniswamy; Berretta, Remus M.; Kubo, Hajime; Houser, Steven R.

2013-01-01

Rationale Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is key toward improving clinical outcomes. Objective To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results Cortical bone stem cells (CBSCs) and cardiac-derived stem cells (CDCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=67), CDCs (n=36) or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to CDC- or saline-treated MI controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle and endothelial cells could be identified in CBSC- but not in CDC-treated animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP- myocytes. Conclusions CBSCs improve survival, cardiac function, and attenuate remodeling through two mechanisms:1) secretion of pro-angiogenic factors that stimulate endogenous neovascularization, and 2) differentiation into functional adult myocytes and vascular cells. PMID:23801066

Mitochondria Are Critical for BDNF-Mediated Synaptic and Vascular Plasticity of Hippocampus following Repeated Electroconvulsive Seizures.

PubMed

Chen, Fenghua; Ardalan, Maryam; Elfving, Betina; Wegener, Gregers; Madsen, Torsten M; Nyengaard, Jens R

2018-03-01

Electroconvulsive therapy is a fast-acting and efficient treatment of depression used in the clinic. The underlying mechanism of its therapeutic effect is still unclear. However, recovery of synaptic connections and synaptic remodeling is thought to play a critical role for the clinical efficacy obtained from a rapid antidepressant response. Here, we investigated the relationship between synaptic changes and concomitant nonneuronal changes in microvasculature and mitochondria and its relationship to brain-derived neurotrophic factor level changes after repeated electroconvulsive seizures, an animal model of electroconvulsive therapy. Electroconvulsive seizures or sham treatment was given daily for 10 days to rats displaying a genetically driven phenotype modelling clinical depression: the Flinders Sensitive and Resistant Line rats. Stereological principles were employed to quantify numbers of synapses and mitochondria, and the length of microvessels in the hippocampus. The brain-derived neurotrophic factor protein levels were quantified with immunohistochemistry. In untreated controls, a lower number of synapses and mitochondria was accompanied by shorter microvessels of the hippocampus in "depressive" phenotype (Flinders Sensitive Line) compared with the "nondepressed" phenotype (Flinders Resistant Line). Electroconvulsive seizure administration significantly increased the number of synapses and mitochondria, and length of microvessels both in Flinders Sensitive Line-electroconvulsive seizures and Flinders Resistant Line-electroconvulsive seizures rats. In addition, the amount of brain-derived neurotrophic factor protein was significantly increased in Flinders Sensitive Line and Flinders Resistant Line rats after electroconvulsive seizures. Furthermore, there was a significant positive correlation between brain-derived neurotrophic factor level and mitochondria/synapses. Our results indicate that rapid and efficient therapeutic effect of electroconvulsive seizures may be related to synaptic plasticity, accompanied by brain-derived neurotrophic factor protein level elevation and mitochondrial and vascular support. © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Z-Guggulsterone Produces Antidepressant-Like Effects in Mice through Activation of the BDNF Signaling Pathway

PubMed Central

Liu, Feng-Guo; Hu, Wen-Feng; Wang, Ji-Li; Wang, Peng; Gong, Yu; Tong, Li-Juan; Jiang, Bo; Zhang, Wei; Qin, Yi-Bin; Chen, Zhuo

2017-01-01

Abstract Background: Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression. Methods: The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone. Results: Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone. Conclusions: Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis. PMID:28339691

Brain-derived neurotrophic factor and its clinical implications

PubMed Central

Bathina, Siresha

2015-01-01

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus. PMID:26788077

A Brief History of the Philosophical Foundations of Exploratory Factor Analysis.

ERIC Educational Resources Information Center

Mulaik, Stanley A.

1987-01-01

Exploratory factor analysis derives its key ideas from many sources, including Aristotle, Francis Bacon, Descartes, Pearson and Yule, and Kant. The conclusions of exploratory factor analysis are never complete without subsequent confirmatory factor analysis. (Author/GDC)

Factor analysis of rock, soil and water geochemical data from Salem magnesite mines and surrounding area, Salem, southern India

NASA Astrophysics Data System (ADS)

Satyanarayanan, M.; Eswaramoorthi, S.; Subramanian, S.; Periakali, P.

2017-09-01

Geochemical analytical data of 15 representative rock samples, 34 soil samples and 55 groundwater samples collected from Salem magnesite mines and surrounding area in Salem, southern India, were subjected to R-mode factor analysis. A maximum of three factors account for 93.8 % variance in rock data, six factors for 84 % variance in soil data, five factors for 71.2 % in groundwater data during summer and six factors for 73.7 % during winter. Total dissolved solids are predominantly contributed by Mg, Na, Cl and SO4 ions in both seasons and are derived from the country rock and mining waste by dissolution of minerals like magnesite, gypsum, halite. The results also show that groundwater is enriched in considerable amount of minor and trace elements (Fe, Mn, Ni, Cr and Co). Nickel, chromium and cobalt in groundwater and soil are derived from leaching of huge mine dumps deposited by selective magnesite mining activity. The factor analysis on trivalent, hexavalent and total Cr in groundwater indicates that most of the Cr in summer is trivalent and in winter hexavalent. The gradational decrease in topographical elevation from northern mine area to the southern residential area, combined regional hydrogeological factors and distribution of ultramafic rocks in the northern part of the study area indicate that these toxic trace elements in water were derived from mine dumps.

Smart home design and operation preferences of Americans and Koreans.

PubMed

Jeong, Kyeong-Ah; Salvendy, Gavriel; Proctor, Robert W

2010-05-01

The purpose of the present study was to generate both culture-specific and universal design and operational guidelines for smart homes. Questionnaire surveys were performed in the USA and South Korea to collect data on preferences for various aspects of the design and operation of smart homes. The factors that the survey participants considered most important were derived through factor analyses of the survey data and the responses of Americans and Koreans were compared to generate culture-specific guidelines. The five factors derived were: 1) environmental connection and control; 2) smart devices (appliances) and their control; 3) physical safety and security concerns; 4) comfort and relaxation issues; 5) control restriction issues. The two cultures showed different preference structures with statistical significance for all five factors. Prediction capability of the derived factors was also examined through multiple regressions for buying intention, interest, self-vision of living, moving intention, living satisfaction and perceived time and effort savings. 'Environmental connection and control' and 'smart devices (appliances) and their control' seemed to be the most influential factors for Americans and Koreans, respectively. STATEMENT OF RELEVANCE: Analysis of a survey of design and operational preferences for smart homes yielded five factors on which US and South Korean respondents differed. These factors form the basis for culture-specific guidelines, which, along with universal guidelines, should be followed in design of user-centred smart homes.

Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells

PubMed Central

Choi, Nahyun; Shin, Soyoung; Song, Sun U.; Sung, Jong-Hyuk

2018-01-01

Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal–regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration. PMID:29495622

Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells.

PubMed

Choi, Nahyun; Shin, Soyoung; Song, Sun U; Sung, Jong-Hyuk

2018-02-28

Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration.

On the derivation of the semiclassical approximation to the quantum propagator

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

Fischer, Stefan G., E-mail: stefan.fischer@physik.uni-freiburg.de; Buchleitner, Andreas

2015-07-15

In order to rigorously derive the amplitude factor of the semiclassical approximation to the quantum propagator, we extend an existing method originally devised to evaluate Gaussian path-integral expressions. Using a result which relates the determinant of symmetric block-tridiagonal matrices to the determinants of their blocks, two difference equations are obtained. The first one allows to establish the connection of the amplitude factor to Jacobi’s accessory equations in the continuous-time limit, while the second one leads to an additional factor which, however, contributes to the final result only in exceptional cases. In order to demonstrate the wide applicability of these differencemore » equations, we treat explicitly the case where the time-sliced Lagrangian is written in generalized coordinates, for which a general derivation has so far been unavailable.« less

Role of Endogenous Microbiota, Probiotics and Their Biological Products in Human Health

PubMed Central

Howarth, Gordon S.; Wang, Hanru

2013-01-01

Although gut diseases such as inflammatory bowel disease, mucositis and the alimentary cancers share similar pathogenetic features, further investigation is required into new treatment modalities. An imbalance in the gut microbiota, breached gut integrity, bacterial invasion, increased cell apoptosis to proliferation ratio, inflammation and impaired immunity may all contribute to their pathogenesis. Probiotics are defined as live bacteria, which when administered in sufficient amounts, exert beneficial effects to the gastrointestinal tract. More recently, probiotic-derived factors including proteins and other molecules released from living probiotics, have also been shown to exert beneficial properties. In this review we address the potential for probiotics, with an emphasis on probiotic-derived factors, to reduce the severity of digestive diseases and further discuss the known mechanisms by which probiotics and probiotic-derived factors exert their physiological effects. PMID:23306189

The role of Foxi family transcription factors in otic placode and neural crest cell development

PubMed Central

Edlund, Renée K.; Birol, Onur; Groves, Andrew K.

2015-01-01

The mammalian outer, middle and inner ears have different embryonic origins and evolved at different times in the vertebrate lineage. The outer ear is derived from first and second branchial arch ectoderm and mesoderm, the middle ear ossicles are derived from neural crest mesenchymal cells that invade the first and second branchial arches, whereas the inner ear and its associated vestibule-acoustic (VIIIth) ganglion are derived from the otic placode. In this review, we discuss recent findings in the development of these structures and describe the contributions of members of a Forkhead transcription factor family, the Foxi family to their formation. Foxi transcription factors are critical for formation of the otic placode, survival of the branchial arch neural crest, and developmental remodeling of the branchial arch ectoderm. PMID:25662269

Establishment of two new scirrhous gastric cancer cell lines: analysis of factors associated with disseminated metastasis.

PubMed Central

Yashiro, M.; Chung, Y. S.; Nishimura, S.; Inoue, T.; Sowa, M.

1995-01-01

Determination of the differences between cell lines which are derived from a primary tumour and a disseminated metastatic lesion from the same patient may aid in elucidating the factors associated with disseminated metastases. We report on the establishment and characterisation of two new scirrhous gastric cancer cell lines, designated OCUM-2M and OCUM-2D, derived from a 49-year-old female. OCUM-2M was derived from a primary gastric tumour, and OCUM-2D was derived from a sample of disseminated metastasis. The two cell lines were derived from the same patient. We investigated biological differences between the two cell lines to study mechanisms involved in disseminated metastasis. The growth activity of OCUM-2D cells as determined by doubling time and tumorigenicity was greater than that of OCUM-2M cells. The level of epidermal growth factor receptor (EGFR) expression in OCUM-2D cells was about twice that of OCUM-2M cells and the growth of OCUM-2D cells was stimulated more by epidermal growth factor (EGF) than that of OCUM-2M cells. The invasive activity of OCUM-2D cells was higher than that of OCUM-2M cells and was increased after addition of transforming growth factor-beta 1 (TGF-beta 1). An increase in the number of attached and spreading cells was found following the addition of 10 ng ml-1 TGF-beta 1. These findings suggest that high growth and invasive activity may play an important role in disseminated metastasis and that EGF and TGF-beta 1, which affect the growth and invasive activity of OCUM-2D cells, might be factors associated with metastasis in scirrhous gastric carcinoma. The two cell lines OCUM-2M and OCUM-2D should be beneficial for analysing mechanisms of tumour progression. Images Figure 1 Figure 5 Figure 6 Figure 7 Figure 10 PMID:7577468

Serum brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels in children with attention-deficit/hyperactivity disorder.

PubMed

Bilgiç, Ayhan; Toker, Aysun; Işık, Ümit; Kılınç, İbrahim

2017-03-01

It has been suggested that neurotrophins are involved in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate whether there are differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) levels between children with ADHD and healthy controls. A total of 110 treatment-naive children with the combined presentation of ADHD and 44 healthy controls aged 8-18 years were enrolled in this study. The severity of ADHD symptoms was determined by scores on the Conners' Parent Rating Scale-Revised Short and Conners' Teacher Rating Scale-Revised Short. The severity of depression and anxiety symptoms of the children were evaluated by the self-report inventories. Serum levels of neurotrophins were measured using commercial enzyme-linked immunosorbent assay kits. The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the levels of serum neurotrophins, an effect that was independent of age, sex, and the severity of the depression and anxiety. The analysis of covariance (ANCOVA) indicated that the mean serum GDNF and NTF3 levels of ADHD patients were significantly higher than that of controls. However, serum BDNF and NGF levels did not show any significant differences between groups. No correlations between the levels of serum neurotrophins and the severity of ADHD were observed. These results suggest that elevated serum GDNF and NTF3 levels may be related to ADHD in children.

Conditioned Medium Derived from Neural Progenitor Cells Induces Long-term Post-ischemic Neuroprotection, Sustained Neurological Recovery, Neurogenesis, and Angiogenesis.

PubMed

Doeppner, Thorsten R; Traut, Viktorija; Heidenreich, Alexander; Kaltwasser, Britta; Bosche, Bert; Bähr, Mathias; Hermann, Dirk M

2017-03-01

Adult neural progenitor cells (NPCs) induce post-ischemic long-term neuroprotection and brain remodeling by releasing of survival- and plasticity-promoting mediators. To evaluate whether secreted factors may mimic neuroprotective and restorative effects of NPCs, we exposed male C57BL6 mice to focal cerebral ischemia and intravenously applied conditioned medium (CM) derived from subventricular zone NPCs. CM dose-dependently reduced infarct volume and brain leukocyte infiltration after 48 h when delivered up to 12 h after focal cerebral ischemia. Neuroprotection persisted in the post-acute stroke phase yielding enhanced neurological recovery that lasted throughout the 28-day observation period. Increased Bcl-2, phosphorylated Akt and phosphorylated STAT-3 abundance, and reduced caspase-3 activity and Bax abundance were noted in ischemic brains of CM-treated mice at 48 h post-stroke, indicative of enhanced cell survival signaling. Long-term neuroprotection was associated with increased brain glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) concentrations at 28 days resulting in increased neurogenesis and angiogenesis. The observation that NPC-derived CM induces sustained neuroprotection and neurological recovery suggests that cell transplantation may be dispensable when secreted factors are instead administered.

Conjugation in Escherichia coli

PubMed Central

Boyer, Herbert

1966-01-01

Boyer, Herbert (Yale University, New Haven, Conn.). Conjugation in Escherichia coli. J. Bacteriol. 91:1767–1772. 1966.—The sex factor of Escherichia coli K-12 was introduced into an E. coli B/r strain by circumventing the host-controlled modification and restriction incompatibilities known to exist between these closely related strains. The sexual properties of the constructed F+ B strain and its Hfr derivatives were examined. These studies showed that the E. coli strain B/r F+ and Hfr derivatives are similar to the E. coli strain K-12 F+ and Hfr derivatives. However, the site of sex factor integration was found to be dependent on the host genome. PMID:5327905

Clinical Applications of Platelet-Rich Plasma in Patellar Tendinopathy

PubMed Central

Jeong, D. U.; Lee, C.-R.; Lee, J. H.; Pak, J.; Kang, L.-W.; Jeong, B. C.

2014-01-01

Platelet-rich plasma (PRP), a blood derivative with high concentrations of platelets, has been found to have high levels of autologous growth factors (GFs), such as transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), fibroblastic growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). These GFs and other biological active proteins of PRP can promote tissue healing through the regulation of fibrosis and angiogenesis. Moreover, PRP is considered to be safe due to its autologous nature and long-term usage without any reported major complications. Therefore, PRP therapy could be an option in treating overused tendon damage such as chronic tendinopathy. Here, we present a systematic review highlighting the clinical effectiveness of PRP injection therapy in patellar tendinopathy, which is a major cause of athletes to retire from their respective careers. PMID:25136568

The factor structure and reliability of the Illness Attitude Scales in a student and a patient sample

PubMed Central

Crössmann, Alexander; Pauli, Paul

2006-01-01

Background The Illness Attitude Scales (IAS), designed by Kellner in 1986, assesses fears, beliefs, and attitudes associated with hypochondriasis and abnormal illness behaviour. However, its factor structure is, especially for translations of the IAS, not sufficiently explored. Thus, the present Study aimed to analyse the factor structure of the IAS in a German student and a patient population using exploratory factor analysis. Methods A mixed student (N = 296) and a mixed patient (N = 130) sample completed the IAS. The data was submitted to principal components analyses (PCA) with subsequent oblique rotations. From identified factor structures, scales were derived and submitted to reliability analyses as well as to a preliminary validity analysis. Results The PCA revealed a four-factor solution in the student sample: (1) fear of illness and death; (2) treatment experience; (3) hypochondriacal beliefs; and (4) effect of symptoms. In the patient sample, the data was best explained by a two-factor solution: (1) health related anxiety and (2) effect of symptoms and treatment experience. All scales reached good to acceptable reliability coefficients. The scales derived from the student sample and those derived from the patient sample were able to distinguish between pain patients and a matched group of normal controls. Conclusion Our data suggests that the IAS is in student samples best represented by a four factor-solution and in patient samples by a two-factor-solution. PMID:17067384

Trophic factors from adipose tissue-derived multi-lineage progenitor cells promote cytodifferentiation of periodontal ligament cells

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

Sawada, Keigo; Takedachi, Masahide, E-mail: takedati@dent.osaka-u.ac.jp; Yamamoto, Satomi

Stem and progenitor cells are currently being investigated for their applicability in cell-based therapy for periodontal tissue regeneration. We recently demonstrated that the transplantation of adipose tissue-derived multi-lineage progenitor cells (ADMPCs) enhances periodontal tissue regeneration in beagle dogs. However, the molecular mechanisms by which transplanted ADMPCs induce periodontal tissue regeneration remain to be elucidated. In this study, trophic factors released by ADMPCs were examined for their paracrine effects on human periodontal ligament cell (HPDL) function. ADMPC conditioned medium (ADMPC-CM) up-regulated osteoblastic gene expression, alkaline phosphatase activity and calcified nodule formation in HPDLs, but did not significantly affect their proliferative response.more » ADMPCs secreted a number of growth factors, including insulin-like growth factor binding protein 6 (IGFBP6), hepatocyte growth factor and vascular endothelial growth factor. Among these, IGFBP6 was most highly expressed. Interestingly, the positive effects of ADMPC-CM on HPDL differentiation were significantly suppressed by transfecting ADMPCs with IGFBP6 siRNA. Our results suggest that ADMPCs transplanted into a defect in periodontal tissue release trophic factors that can stimulate the differentiation of HPDLs to mineralized tissue-forming cells, such as osteoblasts and cementoblasts. IGFBP6 may play crucial roles in ADMPC-induced periodontal regeneration. - Highlights: • ADMPC-derived humoral factors stimulate cytodifferentiation of HPDLs. • ADMPCs secret growth factors including IGFBP6, VEGF and HGF. • IGFBP6 is involved in the promotion effect of ADMPC-CM on HPDL cytodifferentiation.« less

Specific growth stimulation of cultured smooth muscle cells from spontaneously hypertensive rats by platelet-derived growth factor A-chain homodimer.

PubMed Central

Resink, T J; Scott-Burden, T; Hahn, A W; Rouge, M; Hosang, M; Powell, J S; Bühler, F R

1990-01-01

Cultured vascular smooth muscle cells (VSMC)1 from spontaneously hypertensive rats (SHR) possess specific cell surface receptors for both homodimeric forms of platelet-derived growth factor (PDGF-AA and PDGF-BB), in contrast to cells from normotensive Wistar Kyoto (WKY) animals, which express receptors only for the B-chain form of PDGF. Stimulation of quiescent VSMC from SHR with PDGF-AA resulted in activation of S6-kinase and induction of phosphoinositide catabolism, as well as cellular proliferation when cultures were maintained for prolonged periods with daily supplementation of the growth factor. WKY-derived VSMC showed no response to PDGF-AA, which was consistent with their lack of specific receptors for this homodimer. The responsiveness of quiescent cells from SHR and WKY to the B-chain homodimer was similar. The enhanced growth responsiveness of SHR-derived cells to fetal calf serum, as compared with cells from their normotensive counterparts, may be accounted for in part by their expression of receptors for the AA homodimer of PDGF. PMID:1965150

Matrix representations of SOn + 2 in an SOn × SO2 basis and some isoscalar factors for SOn + 2 ⊃ SOn × SO2

NASA Astrophysics Data System (ADS)

Pan, Feng; Cao, Yu-Fang

1992-02-01

Vector coherent state (VCS) theory is applied to the group chain SOn+2⊇SOn×SO2. Matrix elements of SOn+2 generators in the SOn+2⊇SOn×SO2 basis are derived. A new formula for the evaluation of some isoscalar factors for SOn+2⊇SOn×SO2 with branching multiplicity is derived in the VCS framework. As a simple example, a new expression of some isoscalar factors for SO5⊇SO3×SO2, which involves only 6j coefficients and K-normalization factors, are obtained by using this formula.

Origin of platelet-derived growth factor in megakaryocytes in guinea pigs.

PubMed Central

Chernoff, A; Levine, R F; Goodman, D S

1980-01-01

Growth factor activity, as determined by the stimulation of [3H]thymidine incorporation into the DNA of quiescent 3T3 cells in culture, was found in lysates of guinea pig platelets and megakaryocytes. Quantitative dilution studies demonstrated that, of the cells present in the guinea pig bone marrow, only the megakaryocyte possessed quantitatively significant growth factor activity. The amount of activity present in one megakaryocyte was equivalent to that present in 1,000-5,000 platelets, a value approximately comparable to the number of platelets shed from a single megakaryocyte. It is suggested that guinea pig platelet-derived growth factor has its origin in the megakaryocyte. PMID:7358851

Efficient generation of functional Schwann cells from adipose-derived stem cells in defined conditions

PubMed Central

Xie, Songtao; Lu, Fan; Han, Juntao; Tao, Ke; Wang, Hongtao; Simental, Alfred; Hu, Dahai

2017-01-01

ABSTRACT Schwann cells (SCs) are hitherto regarded as the most promising candidates for viable cell-based therapy to peripheral nervous system (PNS) injuries or degenerative diseases. However, the extreme drawbacks of transplanting autologous SCs for clinical applications still represent a significant bottleneck in neural regenerative medicine, mainly owing to the need of sacrificing a functional nerve to generate autologous SCs and the nature of slow expansion of the SCs. Thus, it is of great importance to establish an alternative cell system for the generation of sufficient SCs. Here, we demonstrated that adipose-derived stem cells (ADSCs) of rat robustly give rise to morphological, phenotypic and functional SCs using an optimized protocol. After undergoing a 3-week in vitro differentiation, almost all of treated ADSCs exhibited spindle shaped morphology similar to genuine SCs and expressed SC markers GFAP and S100. Most importantly, apart from acquisition of SC antigenic and biochemical features, the ADSC-derived SCs were functionally identical to native SCs as they possess a potential ability to form myelin, and secret nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF). The current study may provide an ideal strategy for harvesting sufficient SCs for cell-based treatment of various peripheral nerve injuries or disorders. PMID:28296571

Induced pluripotent stem cell-based therapy for age-related macular degeneration.

PubMed

Bracha, Peter; Moore, Nicholas A; Ciulla, Thomas A

2017-09-01

In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor.  Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells.  Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive.  Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression.

Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression.

PubMed

Wu, Lijun; Zhang, Xu; Zhang, Bin; Shi, Hui; Yuan, Xiao; Sun, Yaoxiang; Pan, Zhaoji; Qian, Hui; Xu, Wenrong

2016-09-01

Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.

12 CFR 217.34 - OTC derivative contracts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... net present value of the amount of unpaid premiums. Table 1 to § 217.34—Conversion Factor Matrix for... single OTC derivative contract is the greater of the mark-to-fair value of the OTC derivative contract or... with a negative mark-to-fair value, is calculated by multiplying the notional principal amount of the...

Monitoring desertification using the integrated CA GIS and RS with AHP-derived weights: a case study of Beijing and its neighboring areas in recent 20 years

NASA Astrophysics Data System (ADS)

Wang, Gongwen; Chen, Jianping; Li, Qing; Ding, Huoping

2007-06-01

This paper aims to monitor desertification evolution of different stages and assess its factors using remote sensing (RS) data and cellular automata (CA)-geographical information system (GIS) with an adaptive analytic hierarchy process (AHP) to derive weights of desertification factors. The study areas (114°E to 117°E and 39.5°to 42.2°N) are one of the important agro-pastoral transitional zone, located in Beijing and its neighboring areas, marginal desertified areas in North China. Desertification information including NDVI and desertification area were derived from the satellite images of 1987TM, 1996TM (with a resolution of 28.5), and 2006 CBERS-(with a resolution of 19.5 m) in study areas. The ancillary data in terms of meteorology, geology, 30m-DEM, hydrography can be statistical analyzed with GIS technology. A CA model based on the desertification factors with AHP-derived weights was built by AML program in ArcGIS workstation to assess the evolution of desertification in different stages (from 1987 to 1996, and from 1996 to 2006). The research results show that desertified areas was increased by 3.28% per year from 1987 to 1996, so was 0.51% per year from 1996 to 2006. Although the weights of desertification factors have some changes in different stages, the main factors including climate, NDVI, and terrain did not change except the values in study areas.

Parallel O(log n) algorithms for open- and closed-chain rigid multibody systems based on a new mass matrix factorization technique

NASA Technical Reports Server (NTRS)

Fijany, Amir

1993-01-01

In this paper, parallel O(log n) algorithms for computation of rigid multibody dynamics are developed. These parallel algorithms are derived by parallelization of new O(n) algorithms for the problem. The underlying feature of these O(n) algorithms is a drastically different strategy for decomposition of interbody force which leads to a new factorization of the mass matrix (M). Specifically, it is shown that a factorization of the inverse of the mass matrix in the form of the Schur Complement is derived as M(exp -1) = C - B(exp *)A(exp -1)B, wherein matrices C, A, and B are block tridiagonal matrices. The new O(n) algorithm is then derived as a recursive implementation of this factorization of M(exp -1). For the closed-chain systems, similar factorizations and O(n) algorithms for computation of Operational Space Mass Matrix lambda and its inverse lambda(exp -1) are also derived. It is shown that these O(n) algorithms are strictly parallel, that is, they are less efficient than other algorithms for serial computation of the problem. But, to our knowledge, they are the only known algorithms that can be parallelized and that lead to both time- and processor-optimal parallel algorithms for the problem, i.e., parallel O(log n) algorithms with O(n) processors. The developed parallel algorithms, in addition to their theoretical significance, are also practical from an implementation point of view due to their simple architectural requirements.

History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair.

PubMed

Walker, Melissa J; Xu, Xiao-Ming

2018-06-13

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, in combination with other factors and cell transplantations, for repairing the injured spinal cord. As studies of recent decades strongly suggest that combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.

Finite grid radius and thickness effects on retarding potential analyzer measured suprathermal electron density and temperature

NASA Technical Reports Server (NTRS)

Knudsen, William C.

1992-01-01

The effect of finite grid radius and thickness on the electron current measured by planar retarding potential analyzers (RPAs) is analyzed numerically. Depending on the plasma environment, the current is significantly reduced below that which is calculated using a theoretical equation derived for an idealized RPA having grids with infinite radius and vanishingly small thickness. A correction factor to the idealized theoretical equation is derived for the Pioneer Venus (PV) orbiter RPA (ORPA) for electron gasses consisting of one or more components obeying Maxwell statistics. The error in density and temperature of Maxwellian electron distributions previously derived from ORPA data using the theoretical expression for the idealized ORPA is evaluated by comparing the densities and temperatures derived from a sample of PV ORPA data using the theoretical expression with and without the correction factor.

Brain-Derived Neurotrophic Factor (BDNF) and Traumatic Brain Injury (Head and Spinal)

DTIC Science & Technology

2000-01-01

phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor- mediated survival and neuritogenesis of the neuroblastoma cell line ... SH - SY5Y , J. Neurochem. 73 (1999) 1409-1421. 15. Gottshalk, W.A., Jiang, H., Tartaglia, N., Feng, L., Figurov, A., Lu, B., Signaling mechanisms...NT-6), and neurotrophin-7 (NT-7) (4, 5, 24, 80). Neurotrophins are believed to promote their cell survival, growth, and differentiation effects

Serum levels of brain-derived neurotrophic factor (BNDF) in multiple sclerosis patients with Trichuris suis ova therapy.

PubMed

Rosche, Berit; Werner, Jonas; Benzel, Friderike Joëlle; Harms, Lutz; Danker-Hopfe, Heidi; Hellweg, Rainer

2013-01-01

We previously analysed clinical and immunological parameters under Trichuris suis ova (TSO) therapy in four patients with secondary progressive multiple sclerosis. The serum Brain-derived neurotrophic factor (BDNF) levels of these four patients were assessed before, during and after therapy with TSO and showed significant decrease of BDNF during TSO therapy (p < 0.05). © B. Rosche et al., published by EDP Sciences, 2013.

B-domain deleted recombinant factor VIII formulation and stability.

PubMed

Osterberg, T; Fatouros, A; Neidhardt, E; Warne, N; Mikaelsson, M

2001-04-01

B-domain deleted recombinant factor VIII (BDDrFVIII) is a deletion form of human coagulation factor VIII. A lyophilized formulation of highly purified BDDrFVIII has been developed that does not require the use of blood-derived products such as human serum albumin (HSA). By avoiding the use of blood-derived products, the BDDrFVIII formulation minimizes the risk of transmitting blood-borne pathogens that may be present in plasma-derived factor VIII or in other recombinant factor VIII products that contain HSA in their formulation. Upon reconstitution with saline (4 mL), the composition of the reconstituted product (62.5 to 250 IU/mL BDDrFVIII) is 18 mg/mL sodium chloride, 3.0 mg/mL sucrose, 1.5 mg/mL L-histidine, 0.25 mg/mL calcium chloride dihydrate, and 0.1 mg/mL polysorbate 80. The optimal combination of these excipients in the lyophilized BDDrFVIII formulation provides long-term stability, as measured by a variety of analytical methods. The formulation preserves factor VIII activity of lyophilized BDDrFVIII during storage for at least 24 months at 8 degrees C, and for up to 6 months at room temperature (25 degrees C). The reconstituted product retains its factor VIII potency for at least 100 hours at 25 degrees C, which would allow it to be continuously administered via an infusion pump, assuming the product is handled under aseptic conditions.

A metabolomic, geographic, and seasonal analysis of the contribution of pollen-derived adenosine to allergic sensitization.

PubMed

Mueller, Geoffrey A; Thompson, Peter M; DeRose, Eugene F; O'Connell, Thomas M; London, Robert E

2016-12-01

Studies on ragweed and birch pollen extracts suggested that the adenosine content is an important factor in allergic sensitization. However, exposure levels from other pollens and considerations of geographic and seasonal factors have not been evaluated. This study compared the metabolite profile of pollen species important for allergic disease, specifically measured the adenosine content, and evaluated exposure to pollen-derived adenosine. An NMR metabolomics approach was used to measure metabolite concentrations in twenty-six pollen extracts. Pollen count data was analyzed from five cities to model exposure. A principal component analysis of the various metabolites identified by NMR showed that pollen extracts could be differentiated primarily by sugar content: glucose, fructose, sucrose, and myo-inositol. In extracts of 10 mg of pollen/ml, the adenosine was highest for grasses (45 μM) followed by trees (23 μM) and weeds (19 μM). Pollen count data showed that tree pollen was typically 5-10 times the amount of other pollens. At the daily peaks of tree, grass, and weed season the pollen-derived adenosine exposure per day is likely to only be 1.1, 0.11, and 0.12 μg, respectively. Seasonal models of pollen exposure and respiration suggest that it would be a rare event limited to tree pollen season for concentrations of pollen-derived adenosine to approach physiological levels. Sugar content and other metabolites may be useful in classifying pollens. Unless other factors create localized exposures that are very different from these models, pollen-derived adenosine is unlikely to be a major factor in allergic sensitization.

CIRCULATING MICROPARTICLES IN PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES: CHARACTERIZATION AND ASSOCIATIONS

PubMed Central

Chaturvedi, Shruti; Cockrell, Erin; Espinola, Ricardo; Hsi, Linda; Fulton, Stacey; Khan, Mohammad; Li, Liang; Fonseca, Fabio; Kundu, Suman; McCrae, Keith R.

2014-01-01

The antiphospholipid syndrome is characterized by venous or arterial thrombosis and/or recurrent fetal loss in the presence of circulating antiphospholipid antibodies. These antibodies cause activation of endothelial and other cell types leading to the release of microparticles with procoagulant and pro-inflammatory properties. The aims of this study were to characterize the levels of endothelial cell, monocyte, platelet derived, and tissue factor-bearing microparticles in patients with antiphospholipid antibodies, to determine the association of circulating microparticles with anticardiolipin and anti-β2-glycoprotein antibodies, and to define the cellular origin of microparticles that express tissue factor. Microparticle content within citrated blood from 47 patients with antiphospholipid antibodies and 144 healthy controls was analyzed within 2 hours of venipuncture. Levels of Annexin-V, CD105 and CD144 (endothelial derived), CD41 (platelet derived) and tissue factor positive microparticles were significantly higher in patients than controls. Though levels of CD14 (monocyte-derived) microparticles in patient plasma were not significantly increased, increased levels of CD14 and tissue factor positive microparticles were observed in patients. Levels of microparticles that stained for CD105 and CD144 showed a positive correlation with IgG (R = 0.60, p=0.006) and IgM anti-beta2-glycoprotein I antibodies (R=0.58, p=0.006). The elevation of endothelial and platelet derived microparticles in patients with APS and their correlation with anti-β2-glycoprotein I antibodies suggests a chronic state of vascular cell activation in these individuals and an important role for β2-glycoprotein I in development of the pro-thrombotic state associated with antiphospholipid antibodies. PMID:25467081

Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada.

PubMed Central

1995-01-01

OBJECTIVE: To present current strategies for the treatment of hemophilia and von Willebrand's disease. OPTIONS: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered. VALUES: Minimizing morbidity and maximizing functional status and quality of life were given a high value. BENEFITS, HARMS AND COSTS: Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents. RECOMMENDATIONS: DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.VALIDATION: These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison. SPONSORS: These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. PMID:7600466

Mechanisms of regulation of cell-mediated immunity. III. The characterization of azobenzenearsonate-specific suppressor T-cell- derived-suppressor factors

PubMed Central

1979-01-01

Delayed type hypersensitivity to the hapten azobenzenearsonate (ABA) can be induced and suppressed by the administration of hapten-coupled syngeneic spleen cells by the appropriate route. Suppressor T cells stimulated by the intravenous administration of ABA-coupled spleen cells have been shown to produce a discrete subcellular factor(s) which is capable of suppressing delayed type hypersensitivity to azobenzenearsonate in the mouse. Such suppressor factors may be produced by the mechanical disruption of suppressor cells or by placing such suppressor cells in culture for 24 h. The suppressor factor(s) (SF) derived from ABA-specific suppressor cells exhibit biological specificity for the suppression of ABA delayed type hypersensitivity (DTH), but not trinitro-phenyl DTH, as well as the capacity to bind to ABA immunoadsorbents. Passage of suppressor factor(s) over reverse immunoadsorbents utilizing a rabbit anti-mouse F(ab')2 antiserum demonstrated that the antigen-specific T-cell derived SF does not bear conventional immunoglobulin markers. The suppressor factor(s) are not immunoglobulin molecules was further demonstrated by the inability of anti-ABA antibodies to suppress ABA DTH. Gel filtration of ABA suppressor factor(s) showed that the majority of the suppressive activity was present in a fraction with molecular weight ranging between 6.8 x 10(4) and 3.3 x 10(4) daltons. We also analyzed for the presence of determinants encoded by the H-2 major histocompatibility complex (MHC) and found that immunoadsorbents prepared utilizing antisera capable of interacting with gene products of the whole or selected gene regions of H-2 MHC, i.e., B10.D2 anti-B10.A and B10 anti- B10.A immunoadsorbents, retained the suppressive activity of ABA-SF. Elution of such columns with glycine HCl buffers (pH 2.8) permitted recovery of specific suppressive activity. Taken collectively such data supports the notion that suppressor T-cell-derived ABA suppressor factors have antigen-binding specificity as well as determinants controlled by the K end of the H-2 MHC. The distribution of strains capable of making SF has also been analyzed. The relationship of the antigen-binding specificity to VH gene products is discussed in this and the companion paper. PMID:312894

Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

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

El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument

2013-02-21

Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation inmore » ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.« less

Implementing human factors in clinical practice

PubMed Central

Timmons, Stephen; Baxendale, Bryn; Buttery, Andrew; Miles, Giulia; Roe, Bridget; Browes, Simon

2015-01-01

Objectives To understand whether aviation-derived human factors training is acceptable and useful to healthcare professionals. To understand whether and how healthcare professionals have been able to implement human factors approaches to patient safety in their own area of clinical practice. Methods Qualitative, longitudinal study using semi-structured interviews and focus groups, of a multiprofessional group of UK NHS staff (from the emergency department and operating theatres) who have received aviation-derived human factors training. Results The human factors training was evaluated positively, and thought to be both acceptable and relevant to practice. However, the staff found it harder to implement what they had learned in their own clinical areas, and this was principally attributed to features of the informal organisational cultures. Conclusions In order to successfully apply human factors approaches in hospital, careful consideration needs to be given to the local context and informal culture of clinical practice. PMID:24631959

The use of autologous blood-derived growth factors in bone regeneration

PubMed Central

Civinini, Roberto; Macera, Armando; Nistri, Lorenzo; Redl, Birgit; Innocenti, Massimo

2011-01-01

Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having platelet concentrations above baseline. When activated the platelets release growth factors that play an essential role in bone healing such as Platelet-derived Growth Factor, Transforming Growth Factor-β, Vascular Endothelial Growth Factor and others. Multiple basic science and in vivo animal studies agree that PRP has a role in the stimulation of the healing cascade in ligament, tendon, muscle cartilage and in bone regeneration in the last years PRP had a widespread diffusion in the treatment of soft tissue and bone healing. The purpose of this review is to describe the biological properties of platelets and its factors, the methods used for producing PRP, to provide a background on the underlying basic science and an overview of evidence based medicine on clinical application of PRP in bone healing. PMID:22461800

Exploring Factors Related to Young Children's Word-Meaning Derivations during Read-Alouds

ERIC Educational Resources Information Center

Christ, Tanya; Wang, X. Christine; Chiu, Ming Ming

2017-01-01

This study explores how child and text clues were related to 31 kindergarteners' word-meaning derivation outcomes for 372 words presented in books read aloud to children. Data were analyzed using a multilevel, cross-classification, ordered logit model. Children showed no word-meaning derivation 40% of the time, indicating a need for instruction.…

Differences in Preferential Sorting of Fine Particles in the Panama Basin Over the Past 25 kyr: Effects on 230Th-derived Focusing Factors

NASA Astrophysics Data System (ADS)

Loveley, M. R.; Marcantonio, F.; Lyle, M. W.; Wang, J. K.

2013-12-01

In this study, we attempt to understand how preferential sorting of fine particles during redistribution processes in the Panama Basin affects the 230Th constant-flux proxy. Fine particles likely contain greater amounts of 230Th, so that preferential sorting of fine particles may bias sediment mass accumulation rates (MARs). We examined sediments that span the past 25 kyr from two new sediment cores retrieved within about 56 km of each other in the northern part of the basin (MV1013-01-'4JC', 5° 44.699'N 85° 45.498' W, 1730 m depth; MV1014-01-'8JC', 6° 14.038'N 86° 2.613' W, 1993 m depth). Core 4JC, closer to the ridge top that bounds the basin (Cocos Ridge), has a thin sediment drape, while the deeper core 8JC, has a thicker sediment drape and lies further from the ridge top. 230Th-derived focusing factors from 4JC are similar and suggest winnowing with average values of about 0.5 and 0.6 during the Holocene and the last glacial, respectively. For 8JC, calculated average focusing factors are significantly different and suggest focusing with values of about 2 during the Holocene and 4 during the last glacial. Since the two sites are close to each other, one would expect similar rain rates and, therefore, similar 230Th-derived MARs within similar windows of time, i.e., the rain rate should not vary significantly at each site temporally. In addition, the radiocarbon-derived sand (>63μm) MARs should behave similarly since coarser particles are likely not transported by bottom currents. Sand MARs are, indeed, similar during the Holocene and the last glacial at each site. During the last glacial, however, sand MARs are about a factor of 3 higher than those during the Holocene. On the other hand, there is little variability in the 230Th-derived MARs both spatially and temporally. We interpret the discrepancies between the radiocarbon-derived sand and 230Th-derived MARs as being due to preferential sorting of fine particles during the redistribution of sediments by deep-sea currents. The 230Th-derived focusing factors are being overestimated at the deeper site and vice versa at the shallower site, and the degree of inaccuracy varies temporally. We discuss this temporal variability and its relationship to deep-sea current velocities.

Emission factors for hydraulically fractured gas wells derived using well- and battery-level reported data for Alberta, Canada.

PubMed

Tyner, David R; Johnson, Matthew R

2014-12-16

A comprehensive technical analysis of available industry-reported well activity and production data for Alberta in 2011 has been used to derive flaring, venting, and diesel combustion greenhouse gas and criteria air contaminant emission factors specifically linked to drilling, completion, and operation of hydraulically fractured natural gas wells. Analysis revealed that in-line ("green") completions were used at approximately 53% of wells completed in 2011, and in other cases the majority (99.5%) of flowback gases were flared rather than vented. Comparisons with limited analogous data available in the literature revealed that reported total flared and vented natural gas volumes attributable to tight gas well-completions were ∼ 6 times larger than Canadian Association of Petroleum Producers (CAPP) estimates for natural gas well-completion based on wells ca. 2000, but 62% less than an equivalent emission factor that can be derived from U.S. EPA data. Newly derived emission factors for diesel combustion during well drilling and completion are thought to be among the first such data available in the open literature, where drilling-related emissions for tight gas wells drilled in Alberta in 2011 were found to have increased by a factor of 2.8 relative to a typical well drilled in Canada in 2000 due to increased drilling lengths. From well-by-well analysis of production phase flared, vented, and fuel usage natural gas volumes reported at 3846 operating tight gas wells in 2011, operational emission factors were developed. Overall results highlight the importance of operational phase GHG emissions at upstream well sites (including on-site natural gas fuel use), and the critical levels of uncertainty in current estimates of liquid unloading emissions.

Oxalobacter formigenes–Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells

PubMed Central

Arvans, Donna; Jung, Yong-Chul; Antonopoulos, Dionysios; Koval, Jason; Granja, Ignacio; Bashir, Mohamed; Karrar, Eltayeb; Roy-Chowdhury, Jayanta; Musch, Mark; Asplin, John; Chang, Eugene

2017-01-01

Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, although Oxalobacter formigenes colonization is associated with reduced stone risk. O. formigenes interacts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion, via an unknown secretagogue. The difficulties in sustaining O. formigenes colonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects of O. formigenes culture conditioned medium (CM) on apical 14C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium, O. formigenes CM significantly stimulated oxalate uptake (>2.4-fold), whereas CM from Lactobacillus acidophilus did not. Treating the O. formigenes CM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that the O. formigenes–derived factors have molecular masses of 10–30 kDa. Treatment with the protein kinase A inhibitor H89 or the anion exchange inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid completely blocked the CM-induced oxalate transport. Knockdown of the oxalate transporter SLC26A6 also significantly restricted the induction of oxalate transport by CM. In a mouse model of primary hyperoxaluria type 1, rectal administration of O. formigenes CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude that O. formigenes–derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated with O. formigenes CM reflects the in vivo retention of biologic activity and the therapeutic potential of these factors. PMID:27738124

Understanding the dynamical structure of pulsating stars: The Baade-Wesselink projection factor of the δ Scuti stars AI Velorum and β Cassiopeiae

NASA Astrophysics Data System (ADS)

Guiglion, G.; Nardetto, N.; Mathias, P.; Domiciano de Souza, A.; Poretti, E.; Rainer, M.; Fokin, A.; Mourard, D.; Gieren, W.

2013-02-01

Aims: The Baade-Wesselink method of distance determination is based on the oscillations of pulsating stars. The key parameter of this method is the projection factor used to convert the radial velocity into the pulsation velocity. Our analysis was aimed at deriving for the first time the projection factor of δ Scuti stars, using high-resolution spectra of the high-amplitude pulsator AI Vel and of the fast rotator β Cas. Methods: The geometric component of the projection factor (i.e. p0) was calculated using a limb-darkening model of the intensity distribution for AI Vel, and a fast-rotator model for β Cas. Then, using SOPHIE/OHP data for β Cas and HARPS/ESO data for AI Vel, we compared the radial velocity curves of several spectral lines forming at different levels in the atmosphere and derived the velocity gradient associated to the spectral-line-forming regions in the atmosphere of the star. This velocity gradient was used to derive a dynamical projection factor p. Results: We find a flat velocity gradient for both stars and finally p = p0 = 1.44 for AI Vel and p = p0 = 1.41 for β Cas. By comparing Cepheids and δ Scuti stars, these results bring valuable insights into the dynamical structure of pulsating star atmospheres. They suggest that the period-projection factor relation derived for Cepheids is also applicable to δ Scuti stars pulsating in a dominant radial mode. This work uses observations made with the HARPS instrument at the 3.6 m telescope (La Silla, Chile) in the framework of the LP185.D-0056 and with the SOPHIE instrument at OHP (France).

Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.

PubMed

Kos, L; Aronzon, A; Takayama, H; Maina, F; Ponzetto, C; Merlino, G; Pavan, W

1999-02-01

The mechanisms governing development of neural crest-derived melanocytes, and how alterations in these pathways lead to hypopigmentation disorders, are not completely understood. Hepatocyte growth factor/scatter factor (HGF/SF) signaling through the tyrosine-kinase receptor, MET, is capable of promoting the proliferation, increasing the motility, and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro. In addition, transgenic mice that ubiquitously overexpress HGF/SF demonstrate hyperpigmentation in the skin and leptomenigenes and develop melanomas. To investigate whether HGF/ SF-MET signaling is involved in the development of neural crest-derived melanocytes, transgenic embryos, ubiquitously overexpressing HGF/SF, were analyzed. In HGF/SF transgenic embryos, the distribution of melanoblasts along the characteristic migratory pathway was not affected. However, additional ectopically localized melanoblasts were also observed in the dorsal root ganglia and neural tube, as early as 11.5 days post coitus (p.c.). We utilized an in vitro neural crest culture assay to further explore the role of HGF/SF-MET signaling in neural crest development. HGF/SF added to neural crest cultures increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and could replace mast-cell growth factor/Steel factor (MGF) in explant cultures. To examine whether HGF/SF-MET signaling is required for the proper development of melanocytes, embryos with a targeted Met null mutation (Met-/-) were analysed. In Met-/- embryos, melanoblast number and location were not overtly affected up to 14 days p.c. These results demonstrate that HGF/SF-MET signaling influences, but is not required for, the initial development of neural crest-derived melanocytes in vivo and in vitro.

Neurotrophically Induced Mesenchymal Progenitor Cells Derived from Induced Pluripotent Stem Cells Enhance Neuritogenesis via Neurotrophin and Cytokine Production

PubMed Central

Brick, Rachel M.; Sun, Aaron X.

2017-01-01

Abstract Adult tissue‐derived mesenchymal stem cells (MSCs) are known to produce a number of bioactive factors, including neurotrophic growth factors, capable of supporting and improving nerve regeneration. However, with a finite culture expansion capacity, MSCs are inherently limited in their lifespan and use. We examined here the potential utility of an alternative, mesenchymal‐like cell source, derived from induced pluripotent stem cells, termed induced mesenchymal progenitor cells (MiMPCs). We found that several genes were upregulated and proteins were produced in MiMPCs that matched those previously reported for MSCs. Like MSCs, the MiMPCs secreted various neurotrophic and neuroprotective factors, including brain‐derived neurotrophic factor (BDNF), interleukin‐6 (IL‐6), leukemia inhibitory factor (LIF), osteopontin, and osteonectin, and promoted neurite outgrowth in chick embryonic dorsal root ganglia (DRG) cultures compared with control cultures. Cotreatment with a pharmacological Trk‐receptor inhibitor did not result in significant decrease in MiMPC‐induced neurite outgrowth, which was however inhibited upon Jak/STAT3 blockade. These findings suggest that the MiMPC induction of DRG neurite outgrowth is unlikely to be solely dependent on BDNF, but instead Jak/STAT3 activation by IL‐6 and/or LIF is likely to be critical neurotrophic signaling pathways of the MiMPC secretome. Taken together, these findings suggest MiMPCs as a renewable, candidate source of therapeutic cells and a potential alternative to MSCs for peripheral nerve repair, in view of their ability to promote nerve growth by producing many of the same growth factors and cytokines as Schwann cells and signaling through critical neurotrophic pathways. stem cells translational Medicine 2018;7:45–58 PMID:29215199

East meets West: the influence of racial, ethnic and cultural risk factors on cardiac surgical risk model performance.

PubMed

Soo-Hoo, Sarah; Nemeth, Samantha; Baser, Onur; Argenziano, Michael; Kurlansky, Paul

2018-01-01

To explore the impact of racial and ethnic diversity on the performance of cardiac surgical risk models, the Chinese SinoSCORE was compared with the Society of Thoracic Surgeons (STS) risk model in a diverse American population. The SinoSCORE risk model was applied to 13 969 consecutive coronary artery bypass surgery patients from twelve American institutions. SinoSCORE risk factors were entered into a logistic regression to create a 'derived' SinoSCORE whose performance was compared with that of the STS risk model. Observed mortality was 1.51% (66% of that predicted by STS model). The SinoSCORE 'low-risk' group had a mortality of 0.15%±0.04%, while the medium-risk and high-risk groups had mortalities of 0.35%±0.06% and 2.13%±0.14%, respectively. The derived SinoSCORE model had a relatively good discrimination (area under of the curve (AUC)=0.785) compared with that of the STS risk score (AUC=0.811; P=0.18 comparing the two). However, specific factors that were significant in the original SinoSCORE but that lacked significance in our derived model included body mass index, preoperative atrial fibrillation and chronic obstructive pulmonary disease. SinoSCORE demonstrated limited discrimination when applied to an American population. The derived SinoSCORE had a discrimination comparable with that of the STS, suggesting underlying similarities of physiological substrate undergoing surgery. However, differential influence of various risk factors suggests that there may be varying degrees of importance and interactions between risk factors. Clinicians should exercise caution when applying risk models across varying populations due to potential differences that racial, ethnic and geographic factors may play in cardiac disease and surgical outcomes.

The pattern space factor and quality factor of cylindrical source antennas

NASA Astrophysics Data System (ADS)

Jarem, John M.

1982-09-01

For the first time the quality factor of cylindrical source antennas is derived by a plane wave expansion. The evanescent energy (and therefore the quality factor) as defined by a plane wave expansion is shown to be different from Collin and Rothschild's [IEEE Trans. Antennas Propagation AP-12, 23 (1964)] quality factor.

Misleading and reliable markers to differentiate between primate testis-derived multipotent stromal cells and spermatogonia in culture

PubMed Central

Eildermann, K.; Gromoll, J.; Behr, R.

2012-01-01

BACKGROUND Several studies have reported the generation of spermatogonia-derived pluripotent stem cells from human testes. The initial aim of the present study was the derivation of equivalent stem cells from an established and experimentally accessible non-human primate model, the common marmoset monkey (Callithrix jacchus). However, an essential prerequisite in the absence of transgenic reporters in primates and man is the availability of validated endogenous markers for the identification of specific cell types in vitro. METHODS AND RESULTS We cultured marmoset testicular cells in a similar way to that described for human testis-derived pluripotent cells and set out to characterize these cultures under different conditions and in differentiation assays applying established marker panels. Importantly, the cells emerged as testicular multipotent stromal cells (TMSCs) instead of (pluripotent) germ cell-derived cells. TMSCs expressed many markers such as GFR-α, GPR125, THY-1 (CD90), ITGA6, SSEA4 and TRA-1-81, which were considered as spermatogonia specific and were previously used for the enrichment or characterization of spermatogonia. Proliferation of TMSCs was highly dependent on basic fibroblast growth factor, a growth factor routinely present in germ cell culture media. As reliable markers for the distinction between spermatogonia and TMSCs, we established VASA, in combination with the spermatogonia-expressed factors, MAGEA4, PLZF and SALL4. CONCLUSIONS Marmoset monkey TMSCs and spermatogonia exhibit an overlap of markers, which may cause erroneous interpretations of experiments with testis-derived stem cells in vitro. We provide a marker panel for the unequivocal identification of spermatogonia providing a better basis for future studies on primate, including human, testis-derived stem cells. PMID:22442249

Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons

PubMed Central

Young, Allison; Petros, Timothy; Karayannis, Theofanis; McKenzie Chang, Melissa; Lavado, Alfonso; Iwano, Tomohiko; Nakajima, Miho; Taniguchi, Hiroki; Huang, Z. Josh; Heintz, Nathaniel; Oliver, Guillermo; Matsuzaki, Fumio; Machold, Robert P.

2015-01-01

Neurogliaform (RELN+) and bipolar (VIP+) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been elucidated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). Interestingly, Prox1 promotes the maturation of CGE-derived interneuron subtypes through intrinsic differentiation programs that operate in tandem with extrinsically driven neuronal activity-dependent pathways. Thus Prox1 represents the first identified transcription factor specifically required for the embryonic and postnatal acquisition of CGE-derived cortical interneuron properties. SIGNIFICANCE STATEMENT Despite the recognition that 30% of GABAergic cortical interneurons originate from the caudal ganglionic eminence (CGE), to date, a specific transcriptional program that selectively regulates the development of these populations has not yet been identified. Moreover, while CGE-derived interneurons display unique patterns of tangential and radial migration and preferentially populate the superficial layers of the cortex, identification of a molecular program that controls these events is lacking. Here, we demonstrate that the homeodomain transcription factor Prox1 is expressed in postmitotic CGE-derived cortical interneuron precursors and is maintained into adulthood. We found that Prox1 function is differentially required during both embryonic and postnatal stages of development to direct the migration, differentiation, circuit integration, and maintenance programs within distinct subtypes of CGE-derived interneurons. PMID:26377473

Isolation and expansion of human pluripotent stem cell-derived hepatic progenitor cells by growth factor defined serum-free culture conditions.

PubMed

Fukuda, Takayuki; Takayama, Kazuo; Hirata, Mitsuhi; Liu, Yu-Jung; Yanagihara, Kana; Suga, Mika; Mizuguchi, Hiroyuki; Furue, Miho K

2017-03-15

Limited growth potential, narrow ranges of sources, and difference in variability and functions from batch to batch of primary hepatocytes cause a problem for predicting drug-induced hepatotoxicity during drug development. Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells in vitro are expected as a tool for predicting drug-induced hepatotoxicity. Several studies have already reported efficient methods for differentiating hPSCs into hepatocyte-like cells, however its differentiation process is time-consuming, labor-intensive, cost-intensive, and unstable. In order to solve this problem, expansion culture for hPSC-derived hepatic progenitor cells, including hepatic stem cells and hepatoblasts which can self-renewal and differentiate into hepatocytes should be valuable as a source of hepatocytes. However, the mechanisms of the expansion of hPSC-derived hepatic progenitor cells are not yet fully understood. In this study, to isolate hPSC-derived hepatic progenitor cells, we tried to develop serum-free growth factor defined culture conditions using defined components. Our culture conditions were able to isolate and grow hPSC-derived hepatic progenitor cells which could differentiate into hepatocyte-like cells through hepatoblast-like cells. We have confirmed that the hepatocyte-like cells prepared by our methods were able to increase gene expression of cytochrome P450 enzymes upon encountering rifampicin, phenobarbital, or omeprazole. The isolation and expansion of hPSC-derived hepatic progenitor cells in defined culture conditions should have advantages in terms of detecting accurate effects of exogenous factors on hepatic lineage differentiation, understanding mechanisms underlying self-renewal ability of hepatic progenitor cells, and stably supplying functional hepatic cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Numerical investigation of fluid mud motion using a three-dimensional hydrodynamic and two-dimensional fluid mud coupling model

NASA Astrophysics Data System (ADS)

Yang, Xiaochen; Zhang, Qinghe; Hao, Linnan

2015-03-01

A water-fluid mud coupling model is developed based on the unstructured grid finite volume coastal ocean model (FVCOM) to investigate the fluid mud motion. The hydrodynamics and sediment transport of the overlying water column are solved using the original three-dimensional ocean model. A horizontal two-dimensional fluid mud model is integrated into the FVCOM model to simulate the underlying fluid mud flow. The fluid mud interacts with the water column through the sediment flux, current, and shear stress. The friction factor between the fluid mud and the bed, which is traditionally determined empirically, is derived with the assumption that the vertical distribution of shear stress below the yield surface of fluid mud is identical to that of uniform laminar flow of Newtonian fluid in the open channel. The model is validated by experimental data and reasonable agreement is found. Compared with numerical cases with fixed friction factors, the results simulated with the derived friction factor exhibit the best agreement with the experiment, which demonstrates the necessity of the derivation of the friction factor.

Roles of Cells from the Arterial Vessel Wall in Atherosclerosis.

PubMed

Wang, Di; Wang, Zhiyan; Zhang, Lili; Wang, Yi

2017-01-01

Atherosclerosis has been identified as a chronic inflammatory disease of the arterial vessel wall. Accumulating evidence indicates that different cells from the tunica intima, media, adventitia, and perivascular adipose tissue not only comprise the intact and normal arterial vessel wall but also participate all in the inflammatory response of atherosclerosis via multiple intricate pathways. For instance, endothelial dysfunction has historically been considered to be the initiator of the development of atherosclerosis. The migration and proliferation of smooth muscle cells also play a pivotal role in the progression of atherosclerosis. Additionally, the fibroblasts from the adventitia and adipocytes from perivascular adipose tissue have received considerable attention given their special functions that contribute to atherosclerosis. In addition, numerous types of cytokines produced by different cells from the arterial vessel wall, including endothelium-derived relaxing factors, endothelium-derived contracting factors, tumor necrosis factors, interleukin, adhesion molecules, interferon, and adventitium-derived relaxing factors, have been implicated in atherosclerosis. Herein, we summarize the possible roles of different cells from the entire arterial vessel wall in the pathogenesis of atherosclerosis.

Mitogenic and chondrogenic effects of fibroblast growth factor-2 in adipose-derived mesenchymal cells

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

Chiou, Michael; Xu Yue; Longaker, Michael T.

2006-05-05

Adipose-derived mesenchymal cells (AMCs) have demonstrated a great capacity for differentiating into bone, cartilage, and fat. Studies using bone marrow-derived mesenchymal cells (BMSCs) have shown that fibroblast growth factor (FGF)-2, a potent mitogenic factor, plays an important role in tissue engineering due to its effects in proliferation and differentiation for mesenchymal cells. The aim of this study was to investigate the function of FGF-2 in AMC chondrogenic differentiation and its possible contributions to cell-based therapeutics in skeletal tissue regeneration. Data demonstrated that FGF-2 significantly promoted the proliferation of AMCs and enhanced chondrogenesis in three-dimensional micromass culture. Moreover, priming AMCs withmore » treatment of FGF-2 at 10 ng/ml demonstrated that cells underwent chondrogenic phenotypic differentiation, possibly by inducing N-Cadherin, FGF-receptor 2, and transcription factor Sox9. Our results indicated that FGF-2 potentiates chondrogenesis in AMCs, similar to its functions in BMSCs, suggesting the versatile potential applications of FGF-2 in skeletal regeneration and cartilage repair.« less

Molecular mechanisms of maternal vascular dysfunction in preeclampsia.

PubMed

Goulopoulou, Styliani; Davidge, Sandra T

2015-02-01

In preeclampsia, as a heterogeneous syndrome, multiple pathways have been proposed for both the causal as well as the perpetuating factors leading to maternal vascular dysfunction. Postulated mechanisms include imbalance in the bioavailability and activity of endothelium-derived contracting and relaxing factors and oxidative stress. Studies have shown that placenta-derived factors [antiangiogenic factors, microparticles (MPs), cell-free nucleic acids] are released into the maternal circulation and act on the vascular wall to modify the secretory capacity of endothelial cells and alter the responsiveness of vascular smooth muscle cells to constricting and relaxing stimuli. These molecules signal their deleterious effects on the maternal vascular wall via pathways that provide the molecular basis for novel and effective therapeutic interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dengue Virus Infection of Mast Cells Triggers Endothelial Cell Activation ▿

PubMed Central

Brown, Michael G.; Hermann, Laura L.; Issekutz, Andrew C.; Marshall, Jean S.; Rowter, Derek; Al-Afif, Ayham; Anderson, Robert

2011-01-01

Vascular perturbation is a hallmark of severe forms of dengue disease. We show here that antibody-enhanced dengue virus infection of primary human cord blood-derived mast cells (CBMCs) and the human mast cell-like line HMC-1 results in the release of factor(s) which activate human endothelial cells, as evidenced by increased expression of the adhesion molecules ICAM-1 and VCAM-1. Endothelial cell activation was prevented by pretreatment of mast cell-derived supernatants with a tumor necrosis factor (TNF)-specific blocking antibody, thus identifying TNF as the endothelial cell-activating factor. Our findings suggest that mast cells may represent an important source of TNF, promoting vascular endothelial perturbation following antibody-enhanced dengue virus infection. PMID:21068256

Analytic Couple Modeling Introducing Device Design Factor, Fin Factor, Thermal Diffusivity Factor, and Inductance Factor

NASA Technical Reports Server (NTRS)

Mackey, Jon; Sehirlioglu, Alp; Dynys, Fred

2014-01-01

A set of convenient thermoelectric device solutions have been derived in order to capture a number of factors which are previously only resolved with numerical techniques. The concise conversion efficiency equations derived from governing equations provide intuitive and straight-forward design guidelines. These guidelines allow for better device design without requiring detailed numerical modeling. The analytical modeling accounts for factors such as i) variable temperature boundary conditions, ii) lateral heat transfer, iii) temperature variable material properties, and iv) transient operation. New dimensionless parameters, similar to the figure of merit, are introduced including the device design factor, fin factor, thermal diffusivity factor, and inductance factor. These new device factors allow for the straight-forward description of phenomenon generally only captured with numerical work otherwise. As an example a device design factor of 0.38, which accounts for thermal resistance of the hot and cold shoes, can be used to calculate a conversion efficiency of 2.28 while the ideal conversion efficiency based on figure of merit alone would be 6.15. Likewise an ideal couple with efficiency of 6.15 will be reduced to 5.33 when lateral heat is accounted for with a fin factor of 1.0.

Differential stimulation of neurotrophin release by the biocompatible nano-material (carbon nanotube) in primary cultured neurons.

PubMed

Kim, Yun Gi; Kim, Jong Wan; Pyeon, Hee Jang; Hyun, Jung Keun; Hwang, Ji-Young; Choi, Seong-Jun; Lee, Ja-Yeon; Deák, Ferenc; Kim, Hae-Won; Lee, Young Il

2014-01-01

In order to develop novel, effective therapies for central nervous system regeneration, it is essential to better understand the role of neurotrophic factors and to design, accordingly, better artificial scaffolds to support both neurite outgrowth and synapse formation. Both nerve growth factor and brain-derived neurotrophic factor are major factors in neural survival, development, synaptogenesis, and synaptic connectivity of primary cultured neurons. As a prime candidate coating material for such neural cultures, carbon nanotubes offer unique structural, mechanical, and electrical properties. In this study, carbon nanotubes coated glass-coverslips were used as the matrix of a primary neural culture system used to investigate the effects of carbon nanotubes on neurite outgrowth and nerve growth factor/brain-derived neurotrophic factor release and expression. For these purposes, we performed comparative analyses of primary cultured neurons on carbon nanotubes coated, non-coated, and Matrigel-coated coverslips. The morphological findings showed definite carbon nanotubes effects on the neurite outgrowths and synaptogenic figures in both cortical and hippocampal neurons when compared with the non-coated negative control. Although the carbon nanotubes did not change neurotrophin expression levels, it stimulated brain-derived neurotrophic factor release into the media from both types of neurons. Accordingly, we suggest a different mechanism of action between carbon nanotubes and Matrigel in relation to the specific neurotrophic factors. Since carbon nanotubes supply long-term extracellular molecular cues for the survival and neurite outgrowths of cultured neurons, the results from this study will contribute to an understanding of carbon nanotubes biological effects and provide new insight into their role in the secretion of neurotrophic factors.

Production of Human Monoclonal Rheumatoid Factor Secreting Hybridomas Derived from Rheumatoid Synovial Cells

DTIC Science & Technology

1989-01-01

lymphocytes obtained from patients with other We were then interested to see whether AD7 RF had types of arthritis who were seronegative were also...seropositive rheumatoid anhrius patients and from synowal cells in arthritis patients seroneganve for rheumatoidfactor. 1.0 Patients No. of hybridso 1gM RF...Production of human monoclonal rheumatoid factor secreting hybridomas derived from rheumatoid s’inovial cells 12. PEFTONAL AUTVOR(S) Robbins DL, Kenny

Platelet-Derived Growth Factor-BB Stimulates Fibronectin Gene Expression in Fibroblasts Isolated from Rat Thoracic Aorta

DTIC Science & Technology

1994-06-13

MARYLAND 20814-4799 TEACHING HOSPITALS WALTER REED ARMY MEDtCA L CENTER APPROVAL SHEET NAVAL HOSPITAL. BETHESDA MALCOLM GROW AIR FORCE MEDICAL ...CENTER WILFORD HALL "IR FORCE MEDICAL CENTER Title of Dissertation: "Platelet-derived growth factor-BB stimulates fibronectin gene expression in...fascinating world of basic medical science. His dedication and pursuit of excellence in all facets of his work are standards by which I will guide my own

An adipoinductive role of inflammation in adipose tissue engineering: key factors in the early development of engineered soft tissues.

PubMed

Lilja, Heidi E; Morrison, Wayne A; Han, Xiao-Lian; Palmer, Jason; Taylor, Caroline; Tee, Richard; Möller, Andreas; Thompson, Erik W; Abberton, Keren M

2013-05-15

Tissue engineering and cell implantation therapies are gaining popularity because of their potential to repair and regenerate tissues and organs. To investigate the role of inflammatory cytokines in new tissue development in engineered tissues, we have characterized the nature and timing of cell populations forming new adipose tissue in a mouse tissue engineering chamber (TEC) and characterized the gene and protein expression of cytokines in the newly developing tissues. EGFP-labeled bone marrow transplant mice and MacGreen mice were implanted with TEC for periods ranging from 0.5 days to 6 weeks. Tissues were collected at various time points and assessed for cytokine expression through ELISA and mRNA analysis or labeled for specific cell populations in the TEC. Macrophage-derived factors, such as monocyte chemotactic protein-1 (MCP-1), appear to induce adipogenesis by recruiting macrophages and bone marrow-derived precursor cells to the TEC at early time points, with a second wave of nonbone marrow-derived progenitors. Gene expression analysis suggests that TNFα, LCN-2, and Interleukin 1β are important in early stages of neo-adipogenesis. Increasing platelet-derived growth factor and vascular endothelial cell growth factor expression at early time points correlates with preadipocyte proliferation and induction of angiogenesis. This study provides new information about key elements that are involved in early development of new adipose tissue.

The Neuroprotective Mechanism of Low-Frequency rTMS on Nigral Dopaminergic Neurons of Parkinson's Disease Model Mice

PubMed Central

Dong, Qiaoyun; Wang, Yanyong; Gu, Ping; Shao, Rusheng; Zhao, Li; Liu, Xiqi; Wang, Zhanqiang; Wang, Mingwei

2015-01-01

Background. Parkinson's disease is a neurodegenerative disease in elder people, pathophysiologic basis of which is the severe deficiency of dopamine in the striatum. The purpose of the present study was to evaluate the neuroprotective effect of low-frequency rTMS on Parkinson's disease in model mice. Methods. The effects of low-frequency rTMS on the motor function, cortex excitability, neurochemistry, and neurohistopathology of MPTP-induced Parkinson's disease mice were investigated through behavioral detection, electrophysiologic technique, high performance liquid chromatography-electrochemical detection, immunohistochemical staining, and western blot. Results. Low-frequency rTMS could improve the motor coordination impairment of Parkinson's disease mice: the resting motor threshold significantly decreased in the Parkinson's disease mice; the degeneration of nigral dopaminergic neuron and the expression of tyrosine hydroxylase were significantly improved by low-frequency rTMS; moreover, the expressions of brain derived neurotrophic factor and glial cell line derived neurotrophic factor were also improved by low-frequency rTMS. Conclusions. Low-frequency rTMS had a neuroprotective effect on the nigral dopaminergic neuron which might be due to the improved expressions of brain derived neurotrophic factor and glial cell line-derived neurotrophic factor. The present study provided a theoretical basis for the application of low-frequency rTMS in the clinical treatment and recovery of Parkinson's disease. PMID:25883828

Adiabatic pressure dependence of the 2.7 and 1.9 micron water vapor bands

NASA Technical Reports Server (NTRS)

Mathai, C. V.; Walls, W. L.; Broersma, S.

1977-01-01

An acoustic excitation technique is used to determine the adiabatic pressure derivative of the spectral absorptance of the 2.7 and 1.9 micron water vapor bands, and the 3.5 micron HCl band. The dependence of this derivative on thermodynamic parameters such as temperature, concentration, and pressure is evaluated. A cross-flow water vapor system is used to measure spectral absorptance. Taking F as the ratio of nonrigid to rotor line strengths, it is found that an F factor correction is needed for the 2.7 micron band. The F factor for the 1.9 micron band is also determined. In the wings of each band a wavelength can be found where the concentration dependence is predominant. Farther out in the wings a local maximum occurs for the temperature derivative. It is suggested that the pressure derivative is significant in the core of the band.

A note on derivations of Murray–von Neumann algebras

PubMed Central

Kadison, Richard V.; Liu, Zhe

2014-01-01

A Murray–von Neumann algebra is the algebra of operators affiliated with a finite von Neumann algebra. In this article, we first present a brief introduction to the theory of derivations of operator algebras from both the physical and mathematical points of view. We then describe our recent work on derivations of Murray–von Neumann algebras. We show that the “extended derivations” of a Murray–von Neumann algebra, those that map the associated finite von Neumann algebra into itself, are inner. In particular, we prove that the only derivation that maps a Murray–von Neumann algebra associated with a factor of type II1 into that factor is 0. Those results are extensions of Singer’s seminal result answering a question of Kaplansky, as applied to von Neumann algebras: The algebra may be noncommutative and may even contain unbounded elements. PMID:24469831

40 CFR 86.609-98 - Calculation and reporting of test results.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., as appropriate, the final test results by or to the appropriate deterioration factor derived from the... configuration belongs, and then by multiplying by the appropriate reactivity adjustment factor, if applicable... deterioration factor as computed during the certification process is less than one, that deterioration factor is...

Factor Analysis of the Autism Spectrum Screening Questionnaire

ERIC Educational Resources Information Center

Posserud, Britt; Lundervold, Astri J.; Steijnen, Maaike C.; Verhoeven, Sophie; Stormark, Kjell Morten; Gillberg, Christopher

2008-01-01

The present study investigated the factor structure of parent and teacher Autism Spectrum Screening Questionnaire (ASSQ) in a population of 7-9 years old children. For validation purposes, factors derived were correlated with results on the Strengths and Difficulties Questionnaire (SDQ). A three-factor solution was identified on both parent and…

Singaporean Adolescents' Perceptions of Online Social Communication: An Exploratory Factor Analysis

ERIC Educational Resources Information Center

Zheng, Robert Z.; Cheok, Angeline; Khoo, Eng

2011-01-01

The current study investigated adolescents' perceptions in online social communication. Three factors were perceived by adolescents as critical to online social communication. These included self-identity, self-confidence, and self-social factors. Results showed significant differences between the factors derived from the current study and those…

Preferential Redistribution of Fine-Grained Particles in the Panama Basin and Potential Errors in 230Th-Derived Focusing Factors

NASA Astrophysics Data System (ADS)

Marcantonio, F.; Lyle, M. W.; Ibrahim, R.

2013-12-01

The 230Th constant-flux proxy technique, commonly used in paleoceanography to estimate sediment fluxes, is thought to differentiate lateral from vertical fluxes of sediment at sites that have undergone sediment redistribution. However, redistribution processes (focusing or winnowing) are expected to fractionate fine particles from those that are coarse. Since fine particles with greater surface area are known to contain greater concentrations of 230Th, one might expect that sediment redistribution would bias 230Th-derived sediment mass accumulation rates (MARs). We investigate this possibility in two regions of the Panama Basin where significant sediment focusing has been hypothesized to occur. We examine multicore sediments from paired sites at two locations, one close to the equator at the southern limit of the Panama Basin (Carnegie Ridge) where upwelling and primary productivity are high, and one at 6°N at the northern boundary of the Panama Basin (Cocos Ridge), where primary productivity is lower. The multicores, which are constrained by radiocarbon ages that span the latest Holocene at each paired site, represent regions that have undergone potential winnowing and focusing (thin vs thick sediment drapes identified using seismic reflection) at each Panama Basin location. Since the distance separating the paired sites at each location is no more than about 50 km, one would expect the 230Th-derived MARs to be similar, i.e., the rain rate should not be significantly different at each of the paired sites. The radiocarbon-derived sand fraction (>63-μm) MARs, which likely represent the vertical rain of particles not transported by bottom currents, are identical at each of the paired sites, with fluxes at the Carnegie Ridge about 3.5 times greater than those at the Cocos Ridge over the past several thousand years. Over the same time period, the 230Th-normalized MARs are relatively similar at both the Carnegie and Cocos sites, but are different by about 60% at each of the paired sites, with the higher MARs always at the potentially winnowed sites. The 'thick' Carnegie Ridge site has a 230Th-derived focusing factor of about 6. However, we believe that, given our observations of the radiocarbon-derived fluxes of sand, the high 230Th-derived focusing factor is likely an overestimate of the degree of focusing, and the average 230Th-derived MAR is likely an underestimate of the true MAR. Similarly, the biasing for the 'thin' Cocos site that has a 230Th-derived focusing factor of 0.2 (i.e., potential winnowing) is expected to be the opposite, namely, 230Th-derived fluxes are likely being overestimated there. The quantitative extent to which 230Th-derived focusing factors have been over- and under-estimated in the Panama Basin will be discussed. We hypothesize that size fractionation, as well as 230Th focusing errors, occur most frequently at lower current velocities where the fine and coarse fraction of the sediment components are more effectively sorted from each other.

The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone.

PubMed

Motamedi, Shima; Karimi, Isaac; Jafari, Fariba

2017-06-01

The brain-derived neurotrophic factor (BDNF) is involved in metabolic syndrome (MetS) and neurodegenerative diseases (NDD) like Alzheimer's disease, Huntington's disease, Parkinson's disease and depression. If one factor plays an essential role in the pathogenesis of two diseases, it can be concluded that there might be a common root in these two diseases, as well. This review was aimed to highlight the crucial roles of BDNF in the pathogenesis of MetS and NDD and to introduce sole prophylactic or therapeutic applications, BDNF gene therapy and BDFN administration, in controlling MetS and NDD.

Myeloma-derived macrophage inhibitory factor regulates bone marrow stromal cell-derived IL-6 via c-MYC.

PubMed

Piddock, Rachel E; Marlein, Christopher R; Abdul-Aziz, Amina; Shafat, Manar S; Auger, Martin J; Bowles, Kristian M; Rushworth, Stuart A

2018-05-16

Multiple myeloma (MM) remains an incurable malignancy despite the recent advancements in its treatment. The protective effects of the niche in which it develops has been well documented; however, little has been done to investigate the MM cell's ability to 're-program' cells within its environment to benefit disease progression. Here, we show that MM-derived macrophage migratory inhibitory factor (MIF) stimulates bone marrow stromal cells to produce the disease critical cytokines IL-6 and IL-8, prior to any cell-cell contact. Furthermore, we provide evidence that this IL-6/8 production is mediated by the transcription factor cMYC. Pharmacological inhibition of cMYC in vivo using JQ1 led to significantly decreased levels of serum IL-6-a highly positive prognostic marker in MM patients. Our presented findings show that MM-derived MIF causes BMSC secretion of IL-6 and IL-8 via BMSC cMYC. Furthermore, we show that the cMYC inhibitor JQ1 can reduce BMSC secreted IL-6 in vivo, irrespective of tumor burden. These data provide evidence for the clinical evaluation of both MIF and cMYC inhibitors in the treatment of MM.

Exploratory structural equation modeling of personality data.

PubMed

Booth, Tom; Hughes, David J

2014-06-01

The current article compares the use of exploratory structural equation modeling (ESEM) as an alternative to confirmatory factor analytic (CFA) models in personality research. We compare model fit, factor distinctiveness, and criterion associations of factors derived from ESEM and CFA models. In Sample 1 (n = 336) participants completed the NEO-FFI, the Trait Emotional Intelligence Questionnaire-Short Form, and the Creative Domains Questionnaire. In Sample 2 (n = 425) participants completed the Big Five Inventory and the depression and anxiety scales of the General Health Questionnaire. ESEM models provided better fit than CFA models, but ESEM solutions did not uniformly meet cutoff criteria for model fit. Factor scores derived from ESEM and CFA models correlated highly (.91 to .99), suggesting the additional factor loadings within the ESEM model add little in defining latent factor content. Lastly, criterion associations of each personality factor in CFA and ESEM models were near identical in both inventories. We provide an example of how ESEM and CFA might be used together in improving personality assessment. © The Author(s) 2014.

Connecting different TMD factorization formalisms in QCD

DOE PAGES

Collins, John; Rogers, Ted C.

2017-09-11

In the original Collins-Soper-Sterman (CSS) presentation of the results of transverse-momentum-dependent (TMD) factorization for the Drell-Yan process, results for perturbative coefficients can be obtained from calculations for collinear factorization. Here we show how to use these results, plus known results for the quark form factor, to obtain coefficients for TMD factorization in more recent formulations, e.g., that due to Collins, and apply them to known results at ordermore » $$\\alpha_s^2$$ and $$\\alpha_s^3$$. We also show that the ``non-perturbative'' functions as obtained from fits to data are equal in the two schemes. We compile the higher-order perturbative inputs needed for the updated CSS scheme by appealing to results obtained in a variety of different formalisms. In addition, we derive the connection between both versions of the CSS formalism and several formalisms based in soft-collinear effective theory (SCET). As a result, our work uses some important new results for factorization for the quark form factor, which we derive.« less

Connecting different TMD factorization formalisms in QCD

NASA Astrophysics Data System (ADS)

Collins, John; Rogers, Ted C.

2017-09-01

In the original Collins-Soper-Sterman (CSS) presentation of the results of transverse-momentum-dependent (TMD) factorization for the Drell-Yan process, results for perturbative coefficients can be obtained from calculations for collinear factorization. Here we show how to use these results, plus known results for the quark form factor, to obtain coefficients for TMD factorization in more recent formulations, e.g., that due to Collins, and apply them to known results at order αs2 and αs3. We also show that the "nonperturbative" functions as obtained from fits to data are equal in the two schemes. We compile the higher-order perturbative inputs needed for the updated CSS scheme by appealing to results obtained in a variety of different formalisms. In addition, we derive the connection between both versions of the CSS formalism and several formalisms based in soft-collinear effective theory (SCET). Our work uses some important new results for factorization for the quark form factor, which we derive.

Connecting different TMD factorization formalisms in QCD

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

Collins, John; Rogers, Ted C.

In the original Collins-Soper-Sterman (CSS) presentation of the results of transverse-momentum-dependent (TMD) factorization for the Drell-Yan process, results for perturbative coefficients can be obtained from calculations for collinear factorization. Here we show how to use these results, plus known results for the quark form factor, to obtain coefficients for TMD factorization in more recent formulations, e.g., that due to Collins, and apply them to known results at ordermore » $$\\alpha_s^2$$ and $$\\alpha_s^3$$. We also show that the ``non-perturbative'' functions as obtained from fits to data are equal in the two schemes. We compile the higher-order perturbative inputs needed for the updated CSS scheme by appealing to results obtained in a variety of different formalisms. In addition, we derive the connection between both versions of the CSS formalism and several formalisms based in soft-collinear effective theory (SCET). As a result, our work uses some important new results for factorization for the quark form factor, which we derive.« less

Growth factor and pro-inflammatory cytokine contents in platelet-rich plasma (PRP), plasma rich in growth factors (PRGF), advanced platelet-rich fibrin (A-PRF), and concentrated growth factors (CGF).

PubMed

Masuki, Hideo; Okudera, Toshimitsu; Watanebe, Taisuke; Suzuki, Masashi; Nishiyama, Kazuhiko; Okudera, Hajime; Nakata, Koh; Uematsu, Kohya; Su, Chen-Yao; Kawase, Tomoyuki

2016-12-01

The development of platelet-rich fibrin (PRF) drastically simplified the preparation procedure of platelet-concentrated biomaterials, such as platelet-rich plasma (PRP), and facilitated their clinical application. PRF's clinical effectiveness has often been demonstrated in pre-clinical and clinical studies; however, it is still controversial whether growth factors are significantly concentrated in PRF preparations to facilitate wound healing and tissue regeneration. To address this matter, we performed a comparative study of growth factor contents in PRP and its derivatives, such as advanced PRF (A-PRF) and concentrated growth factors (CGF). PRP and its derivatives were prepared from the same peripheral blood samples collected from healthy donors. A-PRF and CGF preparations were homogenized and centrifuged to produce extracts. Platelet and white blood cell counts in A-PRF and CGF preparations were determined by subtracting those counts in red blood cell fractions, supernatant acellular serum fractions, and A-PRF/CGF exudate fractions from those counts of whole blood samples. Concentrations of growth factors (TGF-β1, PDGF-BB, VEGF) and pro-inflammatory cytokines (IL-1β, IL-6) were determined using ELISA kits. Compared to PRP preparations, both A-PRF and CGF extracts contained compatible or higher levels of platelets and platelet-derived growth factors. In a cell proliferation assay, both A-PRF and CGF extracts significantly stimulated the proliferation of human periosteal cells without significant reduction at higher doses. These data clearly demonstrate that both A-PRF and CGF preparations contain significant amounts of growth factors capable of stimulating periosteal cell proliferation, suggesting that A-PRF and CGF preparations function not only as a scaffolding material but also as a reservoir to deliver certain growth factors at the site of application.

Endocytosed factor V is trafficked to CD42b+ proplatelet extensions during differentiation of human umbilical cord blood-derived megakaryocytes.

PubMed

Gertz, Jacqueline M; McLean, Kelley C; Bouchard, Beth A

2018-05-15

Plasma- and platelet-derived factor Va are essential for thrombin generation catalyzed by the prothrombinase complex; however, several observations demonstrate that the platelet-derived cofactor, which is formed following megakaryocyte endocytosis and modification of the plasma procofactor, factor V, is more hemostatically relevant. Factor V endocytosis, as a function of megakaryocyte differentiation and proplatelet formation, was assessed by flow cytometry and microscopy in CD34 + hematopoietic progenitor cells isolated from human umbilical cord blood and cultured for 12 days in the presence of cytokines to induce ex vivo differentiation into megakaryocytes. Expression of an early marker of megakaryocyte differentiation, CD41, endocytosis of factor V, and the percentage of CD41 + cells that endocytosed factor V increased from days 6 to 12 of differentiation. In contrast, statistically significant decreases in expression of the stem cell marker, CD34, and in the percentage of CD34 + cells that endocytosed factor V were observed. A statistically significant increase in the expression of CD42b, a late marker of megakaryocyte differentiation, was also observed over time, such that by Day 12, all CD42b + cells endocytosed factor V and expressed CD41. This endocytosed factor V was trafficked to proplatelet extensions and was localized in a punctate pattern in the cytoplasm consistent with its storage in α-granules. In conclusion, loss of CD34 and expression of CD42b define cells capable of factor V endocytosis and trafficking to proplatelet extensions during differentiation of megakaryocytes ex vivo from progenitor cells isolated from umbilical cord blood. © 2018 Wiley Periodicals, Inc.

Effects of Word and Morpheme Familiarity on Reading of Derived Words

ERIC Educational Resources Information Center

Carlisle, Joanne F.; Katz, Lauren A.

2006-01-01

The purpose of this study is to examine factors that influence students' reading of derived words. Recent research suggests that the lexical quality of a derived word depends on the familiarity of the word, its morphemic constituents (i.e., base word and affixes), and the frequency with which the base word appears in other words (i.e., members of…

The effects of platelet lysate patches on the activity of tendon-derived cells.

PubMed

Costa-Almeida, Raquel; Franco, Albina R; Pesqueira, Tamagno; Oliveira, Mariana B; Babo, Pedro S; Leonor, Isabel B; Mano, João F; Reis, Rui L; Gomes, Manuela E

2018-03-01

Platelet-derived biomaterials are widely explored as cost-effective sources of therapeutic factors, holding a strong potential for endogenous regenerative medicine. Particularly for tendon repair, treatment approaches that shift the injury environment are explored to accelerate tendon regeneration. Herein, genipin-crosslinked platelet lysate (PL) patches are proposed for the delivery of human-derived therapeutic factors in patch augmentation strategies aiming at tendon repair. Developed PL patches exhibited a controlled release profile of PL proteins, including bFGF and PDGF-BB. Additionally, PL patches exhibited an antibacterial effect by preventing the adhesion, proliferation and biofilm formation by S. aureus, a common pathogen in orthopaedic surgical site infections. Furthermore, these patches supported the activity of human tendon-derived cells (hTDCs). Cells were able to proliferate over time and an up-regulation of tenogenic genes (SCX, COL1A1 and TNC) was observed, suggesting that PL patches may modify the behavior of hTDCs. Accordingly, hTDCs deposited tendon-related extracellular matrix proteins, namely collagen type I and tenascin C. In summary, PL patches can act as a reservoir of biomolecules derived from PL and support the activity of native tendon cells, being proposed as bioinstructive patches for tendon regeneration. Platelet-derived biomaterials hold great interest for the delivery of therapeutic factors for applications in endogenous regenerative medicine. In the particular case of tendon repair, patch augmentation strategies aiming at shifting the injury environment are explored to improve tendon regeneration. In this study, PL patches were developed with remarkable features, including the controlled release of growth factors and antibacterial efficacy. Remarkably, PL patches supported the activity of native tendon cells by up-regulating tenogenic genes and enabling the deposition of ECM proteins. This patch holds great potential towards simultaneously reducing post-implantation surgical site infections and promoting tendon regeneration for prospective in vivo applications. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Role of bone marrow cells in the development of pancreatic fibrosis in a rat model of pancreatitis induced by a choline-deficient/ethionine-supplemented diet

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

Akita, Shingo; Kubota, Koji; Kobayashi, Akira, E-mail: kbys@shinshu-u.ac.jp

Highlights: Black-Right-Pointing-Pointer BMC-derived PSCs play a role in a rat CDE diet-induced pancreatitis model. Black-Right-Pointing-Pointer BMC-derived PSCs contribute mainly to the early stage of pancreatic fibrosis. Black-Right-Pointing-Pointer BMC-derived activated PSCs can produce PDGF and TGF {beta}1. -- Abstract: Bone marrow cell (BMC)-derived myofibroblast-like cells have been reported in various organs, including the pancreas. However, the contribution of these cells to pancreatic fibrosis has not been fully discussed. The present study examined the possible involvement of pancreatic stellate cells (PSCs) originating from BMCs in the development of pancreatic fibrosis in a clinically relevant rat model of acute pancreatitis induced by amore » choline-deficient/ethionine-supplemented (CDE) diet. BMCs from female transgenic mice ubiquitously expressing green fluorescent protein (GFP) were transplanted into lethally irradiated male rats. Once chimerism was established, acute pancreatitis was induced by a CDE diet. Chronological changes in the number of PSCs originating from the donor BMCs were examined using double immunofluorescence for GFP and markers for PSCs, such as desmin and alpha smooth muscle actin ({alpha}SMA), 1, 3 and 8 weeks after the initiation of CDE feeding. We also used immunohistochemical staining to evaluate whether the PSCs from the BMCs produce growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF) {beta}1. The percentage of BMC-derived activated PSCs increased significantly, peaking after 1 week of CDE treatment (accounting for 23.3 {+-} 0.9% of the total population of activated PSCs) and then decreasing. These cells produced both PDGF and TGF{beta}1 during the early stage of pancreatic fibrosis. Our results suggest that PSCs originating from BMCs contribute mainly to the early stage of pancreatic injury, at least in part, by producing growth factors in a rat CDE diet-induced pancreatitis model.« less

A Mixed-Methods Examination of Physical Activity and Sedentary Time in Overweight and Obese South Asian Men Living in the United Kingdom.

PubMed

Emadian, Amir; Thompson, Janice

2017-03-27

South Asian men living in the UK have higher rates of central obesity and Type 2 Diabetes Mellitus (T2DM) compared with their white British counterparts. Physical activity (PA) and sedentary time (ST) are important risk factors for the development of T2DM. The purpose of this study was to objectively measure PA, ST, and to explore the factors influencing these behaviours in this high-risk population. A mixed-methods cross-sectional research design was employed, including the quantification of PA and ST using the self-report International Physical Activity Questionnaire (IPAQ)-long form and accelerometry in overweight and obese UK South Asian men (n = 54), followed by semi-structured interviews in a purposive sub-sample to explore the factors influencing PA and ST (n = 31). Accelerometer-derived moderate-to-vigorous PA (MVPA) and ST were 298.9 ± 186.6 min/week and 551.4 ± 95.0 min/day, respectively. IPAQ-derived MVPA was significantly lower than accelerometer-derived MVPA (p < 0.001). IPAQ-derived ST was significantly higher than accelerometer-derived ST (p < 0.001). Lack of time and family commitments were identified as the main barriers to being more physically active, with group exercise identified as an important facilitator to being more active. A cultural norm of focusing on promoting education over sport participation during childhood was identified as an important factor influencing long-term PA behaviours. Work commitments and predominantly sedentary jobs were identified as the main barriers to reducing ST. Healthcare professionals and researchers need to consider the socio-cultural factors which affect PA engagement in overweight and obese South Asian men living in the UK, to ensure that advice and future interventions are tailored to address the needs of this population.

A Mixed-Methods Examination of Physical Activity and Sedentary Time in Overweight and Obese South Asian Men Living in the United Kingdom

PubMed Central

Emadian, Amir; Thompson, Janice L.

2017-01-01

South Asian men living in the UK have higher rates of central obesity and Type 2 Diabetes Mellitus (T2DM) compared with their white British counterparts. Physical activity (PA) and sedentary time (ST) are important risk factors for the development of T2DM. The purpose of this study was to objectively measure PA, ST, and to explore the factors influencing these behaviours in this high-risk population. A mixed-methods cross-sectional research design was employed, including the quantification of PA and ST using the self-report International Physical Activity Questionnaire (IPAQ)-long form and accelerometry in overweight and obese UK South Asian men (n = 54), followed by semi-structured interviews in a purposive sub-sample to explore the factors influencing PA and ST (n = 31). Accelerometer-derived moderate-to-vigorous PA (MVPA) and ST were 298.9 ± 186.6 min/week and 551.4 ± 95.0 min/day, respectively. IPAQ-derived MVPA was significantly lower than accelerometer-derived MVPA (p < 0.001). IPAQ-derived ST was significantly higher than accelerometer-derived ST (p < 0.001). Lack of time and family commitments were identified as the main barriers to being more physically active, with group exercise identified as an important facilitator to being more active. A cultural norm of focusing on promoting education over sport participation during childhood was identified as an important factor influencing long-term PA behaviours. Work commitments and predominantly sedentary jobs were identified as the main barriers to reducing ST. Healthcare professionals and researchers need to consider the socio-cultural factors which affect PA engagement in overweight and obese South Asian men living in the UK, to ensure that advice and future interventions are tailored to address the needs of this population. PMID:28346386

Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases.

PubMed

Son, Bo-Ra; Marquez-Curtis, Leah A; Kucia, Magda; Wysoczynski, Marcin; Turner, A Robert; Ratajczak, Janina; Ratajczak, Mariusz Z; Janowska-Wieczorek, Anna

2006-05-01

Human mesenchymal stem cells (MSCs) are increasingly being considered in cell-based therapeutic strategies for regeneration of various organs/tissues. However, the signals required for their homing and recruitment to injured sites are not yet fully understood. Because stromal-derived factor (SDF)-1 and hepatocyte growth factor (HGF) become up-regulated during tissue/organ damage, in this study we examined whether these factors chemoattract ex vivo-expanded MSCs derived from bone marrow (BM) and umbilical cord blood (CB). Specifically, we investigated the expression by MSCs of CXCR4 and c-met, the cognate receptors of SDF-1 and HGF, and their functionality after early and late passages of MSCs. We also determined whether MSCs express matrix metalloproteinases (MMPs), including membrane type 1 (MT1)-MMP, matrix-degrading enzymes that facilitate the trafficking of hematopoietic stem cells. We maintained expanded BM- or CB-derived MSCs for up to 15-18 passages with monitoring of the expression of 1) various tissue markers (cardiac and skeletal muscle, neural, liver, and endothelial cells), 2) functional CXCR4 and c-met, and 3) MMPs. We found that for up to 15-18 passages, both BM- and CB-derived MSCs 1) express mRNA for cardiac, muscle, neural, and liver markers, as well as the vascular endothelial (VE) marker VE-cadherin; 2) express CXCR4 and c-met receptors and are strongly attracted by SDF-1 and HGF gradients; 3) express MMP-2 and MT1-MMP transcripts and proteins; and 4) are chemo-invasive across the reconstituted basement membrane Matrigel. These in vitro results suggest that the SDF-1-CXCR4 and HGF-c-met axes, along with MMPs, may be involved in recruitment of expanded MSCs to damaged tissues.

Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia.

PubMed

Hori, Hikaru; Yoshimura, Reiji; Katsuki, Asuka; Atake, Kiyokazu; Igata, Ryohei; Konishi, Yuki; Beppu, Hiroki; Tominaga, Hirotaka

2017-03-06

Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites-homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)-, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.

Job compensable factors and factor weights derived from job analysis data.

PubMed

Chi, Chia-Fen; Chang, Tin-Chang; Hsia, Ping-Ling; Song, Jen-Chieh

2007-06-01

Government data on 1,039 job titles in Taiwan were analyzed to assess possible relationships between job attributes and compensation. For each job title, 79 specific variables in six major classes (required education and experience, aptitude, interest, work temperament, physical demands, task environment) were coded to derive the statistical predictors of wage for managers, professionals, technical, clerical, service, farm, craft, operatives, and other workers. Of the 79 variables, only 23 significantly related to pay rate were subjected to a factor and multiple regression analysis for predicting monthly wages. Given the heterogeneous nature of collected job titles, a 4-factor solution (occupational knowledge and skills, human relations skills, work schedule hardships, physical hardships) explaining 43.8% of the total variance but predicting only 23.7% of the monthly pay rate was derived. On the other hand, multiple regression with 9 job analysis items (required education, professional training, professional certificate, professional experience, coordinating, leadership and directing, demand on hearing, proportion of shift working indoors, outdoors and others, rotating shift) better predicted pay and explained 32.5% of the variance. A direct comparison of factors and subfactors of job evaluation plans indicated mental effort and responsibility (accountability) had not been measured with the current job analysis data. Cross-validation of job evaluation factors and ratings with the wage rates is required to calibrate both.

Prevalence of IgG antibodies to human parvovirus B19 in haemophilia children treated with recombinant factor (F)VIII only or with at least one plasma-derived FVIII or FIX concentrate: results from the French haemophilia cohort.

PubMed

Gaboulaud, Valérie; Parquet, Armelle; Tahiri, Cedric; Claeyssens, Ségolène; Potard, Valérie; Faradji, Albert; Peynet, Jocelyne; Costagliola, Dominique

2002-02-01

Human parvovirus B19 (B19) has been transmitted by some brands of virally attenuated plasma-derived factor VIII (FVIII) or IX (FIX) concentrates. To quantify the differences of human parvovirus B19 risk transmission between albumin-stabilized recombinant factor and plasma-derived factor, we studied the prevalence of IgG antibodies to B19 (anti-B19) in 193 haemophiliac children between 1 and 6-years of age who had previously been treated with albumin-stabilized recombinant FVIII only (n = 104), and in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates (n = 89). Association between the prevalence of anti-B19 and the treatment group was analysed using multivariate logistic regression. Age, severity and type of haemophilia, number of cumulative days of exposure to factor VIII or IX, previous history of red blood cells or plasma transfusion were considered as potential confounding variables. A higher prevalence of anti-B19 was found in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates than in children treated with albumin- stabilized recombinant FVIII only (OR: 22.3; CI: 7.9-62.8), independently of the other factors studied.

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

PubMed Central

Shiokawa, Mai; Fukuhara, Takasuke; Ono, Chikako; Yamamoto, Satomi; Okamoto, Toru; Watanabe, Noriyuki; Wakita, Takaji

2014-01-01

ABSTRACT Hepatitis C virus (HCV) is a major etiologic agent of chronic liver diseases. Although the HCV life cycle has been clarified by studying laboratory strains of HCV derived from the genotype 2a JFH-1 strain (cell culture-adapted HCV [HCVcc]), the mechanisms of particle formation have not been elucidated. Recently, we showed that exogenous expression of a liver-specific microRNA, miR-122, in nonhepatic cell lines facilitates efficient replication but not particle production of HCVcc, suggesting that liver-specific host factors are required for infectious particle formation. In this study, we screened human cancer cell lines for expression of the liver-specific α-fetoprotein by using a cDNA array database and identified liver-derived JHH-4 cells and stomach-derived FU97 cells, which express liver-specific host factors comparable to Huh7 cells. These cell lines permit not only replication of HCV RNA but also particle formation upon infection with HCVcc, suggesting that hepatic differentiation participates in the expression of liver-specific host factors required for HCV propagation. HCV inhibitors targeting host and viral factors exhibited different antiviral efficacies between Huh7 and FU97 cells. Furthermore, FU97 cells exhibited higher susceptibility for propagation of HCVcc derived from the JFH-2 strain than Huh7 cells. These results suggest that hepatic differentiation participates in the expression of liver-specific host factors required for complete propagation of HCV. IMPORTANCE Previous studies have shown that liver-specific host factors are required for efficient replication of HCV RNA and formation of infectious particles. In this study, we screened human cancer cell lines for expression of the liver-specific α-fetoprotein by using a cDNA array database and identified novel permissive cell lines for complete propagation of HCVcc without any artificial manipulation. In particular, gastric cancer-derived FU97 cells exhibited a much higher susceptibility to HCVcc/JFH-2 infection than observed in Huh7 cells, suggesting that FU97 cells would be useful for further investigation of the HCV life cycle, as well as the development of therapeutic agents for chronic hepatitis C. PMID:24599999

Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis.

PubMed

Hirata, Marina; Ishigami, Masatoshi; Matsushita, Yoshihiro; Ito, Takanori; Hattori, Hisashi; Hibi, Hideharu; Goto, Hidemi; Ueda, Minoru; Yamamoto, Akihito

2016-10-01

: Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl 4 )-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) resulted in fibrotic scar resolution. SHED-CM suppressed the gene expression of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED-CM induced tissue-repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED-CM suppressed the CCl 4 -induced apoptosis of primary cultured hepatocytes. SHED-CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF-depleted SHED-CM (dHGF-CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED-CM, but not dHGF-CM, inhibited CCl 4 -induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED-CM-mediated resolution of LF. Taken together, our findings suggest that SHED-CM provides multifaceted therapeutic benefits for the treatment of LF. This study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum-free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED-CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced differentiation of tissue-repairing macrophages expressing high levels of the profibrinolytic factor matrix metalloproteinase 13. Furthermore, hepatocyte growth factor played a central role in the SHED-CM-mediated resolution of LF. This is the first report demonstrating the multifaceted therapeutic benefits of secreted factors derived from SHEDs for LF. ©AlphaMed Press.

Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy.

PubMed

Saligan, L N; Lukkahatai, N; Holder, G; Walitt, B; Machado-Vieira, R

2016-12-01

Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men. Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors. FACT-F scores of 47 subjects decreased from baseline (43.95 ± 1.3) to mid-EBRT (38.36 ± 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (r s = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39). Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue.

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

Nisbet, A.F.; Woodman, R.F.M.

A database of soil-to-plant transfer factors for radiocesium and radiostrontium has been compiled for arable crops from published and unpublished sources. The database is more extensive than previous compilations of data published by the International Union of Radioecologists, containing new information for Scandinavia and Greece in particular. It also contains ancillary data on important soil characteristics. The database is sub-divided into 28 soil-crop combinations, covering four soil types and seven crop groups. Statistical analyses showed that transfer factors for radiocesium could not generally be predicted as a function of climatic region, type of experiment, age of contamination, or silt characteristics.more » However, significant relationships accounting for more than 30% of the variability in transfer factor were identified between transfer factors for radiostrontium and soil pH/organic matter status for a few soil-crop combinations. Best estimate transfer factors for radiocesium and radiostrontium were calculated for 28 soil-crop combinations, based on their geometric means: only the edible parts were considered. To predict the likely value of future individual transfer factors, 95% confidence intervals were also derived. A comparison of best estimate transfer factors derived in this study with recommended values published by the International Union of Radioecologists in 1989 and 1992 was made for comparable soil-crop groupings. While there were no significant differences between the best estimate values derived in this study and the 1992 data, radiological assessments that still use 1989 data may be unnecessarily cautious.« less

Signal Factors Secreted by 2D and Spheroid Mesenchymal Stem Cells and by Cocultures of Mesenchymal Stem Cells Derived Microvesicles and Retinal Photoreceptor Neurons

PubMed Central

Mao, Mao; Zhou, Liang

2017-01-01

We aim to identify levels of signal factors secreted by MSCs cultured in 2D monolayers (2D-MSCs), spheroids (spheroids MSCs), and cocultures of microvesicles (MVs) derived from 2D-MSCs or spheroid MSCs and retinal photoreceptor neurons. We seeded 2D-MSCs, spheroid MSCs, and cells derived from spheroids MSCs at equal numbers. MVs isolated from all 3 culture conditions were incubated with 661W cells. Levels of 51 signal factors in conditioned medium from those cultured conditions were quantified with bead-based assay. We found that IL-8, IL-6, and GROα were the top three most abundant signal factors. Moreover, compared to 2D-MSCs, levels of 11 cytokines and IL-2Rα were significantly increased in conditioned medium from spheroid MSCs. Finally, to test if enhanced expression of these factors reflects altered immunomodulating activities, we assessed the effect of 2D-MSC-MVs and 3D-MSC-MVs on CD14+ cell chemoattraction. Compared to 2D-MSC-MVs, 3D-MSC-MVs significantly decreased the chemotactic index of CD14+ cells. Our results suggest that spheroid culture conditions improve the ability of MSCs to selectively secrete signal factors. Moreover, 3D-MSC-MVs also possessed an enhanced capability to promote signal factors secretion compared to 2D-MSC-MVs and may possess enhanced immunomodulating activities and might be a better regenerative therapy for retinal degenerative diseases. PMID:28194184

Model reduction of dynamical systems by proper orthogonal decomposition: Error bounds and comparison of methods using snapshots from the solution and the time derivatives [Proper orthogonal decomposition model reduction of dynamical systems: error bounds and comparison of methods using snapshots from the solution and the time derivatives

DOE PAGES

Kostova-Vassilevska, Tanya; Oxberry, Geoffrey M.

2017-09-17

In this study, we consider two proper orthogonal decomposition (POD) methods for dimension reduction of dynamical systems. The first method (M1) uses only time snapshots of the solution, while the second method (M2) augments the snapshot set with time-derivative snapshots. The goal of the paper is to analyze and compare the approximation errors resulting from the two methods by using error bounds. We derive several new bounds of the error from POD model reduction by each of the two methods. The new error bounds involve a multiplicative factor depending on the time steps between the snapshots. For method M1 themore » factor depends on the second power of the time step, while for method 2 the dependence is on the fourth power of the time step, suggesting that method M2 can be more accurate for small between-snapshot intervals. However, three other factors also affect the size of the error bounds. These include (i) the norm of the second (for M1) and fourth derivatives (M2); (ii) the first neglected singular value and (iii) the spectral properties of the projection of the system’s Jacobian in the reduced space. Because of the interplay of these factors neither method is more accurate than the other in all cases. Finally, we present numerical examples demonstrating that when the number of collected snapshots is small and the first neglected singular value has a value of zero, method M2 results in a better approximation.« less

Connective Tissue Growth Factor Promotes Efficient Generation of Human Induced Pluripotent Stem Cell‐Derived Choroidal Endothelium

PubMed Central

Songstad, Allison E.; Worthington, Kristan S.; Chirco, Kathleen R.; Giacalone, Joseph C.; Whitmore, S. Scott; Anfinson, Kristin R.; Ochoa, Dalyz; Cranston, Cathryn M.; Riker, Megan J.; Neiman, Maurine; Stone, Edwin M.; Mullins, Robert F.

2017-01-01

Abstract Age‐related macular degeneration (AMD) is a leading cause of irreversible blindness in the Western world. Although, the majority of stem cell research to date has focused on production of retinal pigment epithelial (RPE) and photoreceptor cells for the purpose of evaluating disease pathophysiology and cell replacement, there is strong evidence that the choroidal endothelial cells (CECs) that form the choriocapillaris vessels are the first to be lost in this disease. As such, to accurately evaluate disease pathophysiology and develop an effective treatment, production of patient‐specific, stem cell‐derived CECs will be required. In this study, we report for the first time a stepwise differentiation protocol suitable for generating human iPSC‐derived CEC‐like cells. RNA‐seq analysis of the monkey CEC line, RF/6A, combined with two statistical screens allowed us to develop media comprised of various protein combinations. In both screens, connective tissue growth factor (CTGF) was identified as the key component required for driving CEC development. A second factor tumor necrosis factor (TNF)‐related weak inducer of apoptosis receptor was also found to promote iPSC to CEC differentiation by inducing endogenous CTGF secretion. CTGF‐driven iPSC‐derived CEC‐like cells formed capillary tube‐like vascular networks, and expressed the EC‐specific markers CD31, ICAM1, PLVAP, vWF, and the CEC‐restricted marker CA4. In combination with RPE and photoreceptor cells, patient‐specific iPSC derived CEC‐like cells will enable scientists to accurately evaluate AMD pathophysiology and develop effective cell replacement therapies. Stem Cells Translational Medicine 2017;6:1533–1546 PMID:28474838

Model reduction of dynamical systems by proper orthogonal decomposition: Error bounds and comparison of methods using snapshots from the solution and the time derivatives [Proper orthogonal decomposition model reduction of dynamical systems: error bounds and comparison of methods using snapshots from the solution and the time derivatives

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

Kostova-Vassilevska, Tanya; Oxberry, Geoffrey M.

In this study, we consider two proper orthogonal decomposition (POD) methods for dimension reduction of dynamical systems. The first method (M1) uses only time snapshots of the solution, while the second method (M2) augments the snapshot set with time-derivative snapshots. The goal of the paper is to analyze and compare the approximation errors resulting from the two methods by using error bounds. We derive several new bounds of the error from POD model reduction by each of the two methods. The new error bounds involve a multiplicative factor depending on the time steps between the snapshots. For method M1 themore » factor depends on the second power of the time step, while for method 2 the dependence is on the fourth power of the time step, suggesting that method M2 can be more accurate for small between-snapshot intervals. However, three other factors also affect the size of the error bounds. These include (i) the norm of the second (for M1) and fourth derivatives (M2); (ii) the first neglected singular value and (iii) the spectral properties of the projection of the system’s Jacobian in the reduced space. Because of the interplay of these factors neither method is more accurate than the other in all cases. Finally, we present numerical examples demonstrating that when the number of collected snapshots is small and the first neglected singular value has a value of zero, method M2 results in a better approximation.« less

Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: Possible role in mechanical stress-induced hyperpigmentation

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

Kurita, Masakazu, E-mail: masakazukurita@gmail.com; Okazaki, Mutsumi; Fujino, Takashi

2011-05-27

Highlights: {yields} Influence of cyclic stretch on melanogenetic paracrine cytokines was investigated. {yields} Keratinocyte-derived endothelin-1 was upregulated with cyclic stretch. {yields} Degree of upregulation increases dose-dependently. {yields} This upregulation possibly plays a role in the pathogenesis of pigmented disorders. -- Abstract: The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast-derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigatedmore » using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1{alpha}, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress.« less

Inhibition of TGF-β Signaling in SHED Enhances Endothelial Differentiation.

PubMed

Xu, J G; Gong, T; Wang, Y Y; Zou, T; Heng, B C; Yang, Y Q; Zhang, C F

2018-02-01

Low efficiency of deriving endothelial cells (ECs) from adult stem cells hampers their utilization in tissue engineering studies. The purpose of this study was to investigate whether suppression of transforming growth factor beta (TGF-β) signaling could enhance the differentiation efficiency of dental pulp-derived stem cells into ECs. We initially used vascular endothelial growth factor A (VEGF-A) to stimulate 2 dental pulp-derived stem cells (dental pulp stem cells and stem cells from human exfoliated deciduous teeth [SHED]) and compared their differentiation capacity into ECs. We further evaluated whether the vascular endothelial growth factor receptor I (VEGF-RI)-specific ligand placental growth factor-1 (PlGF-1) could mediate endothelial differentiation. Finally, we investigated whether the TGF-β signaling inhibitor SB-431542 could enhance the inductive effect of VEGF-A on endothelial differentiation, as well as the underlying mechanisms involved. ECs differentiated from dental pulp-derived stem cells exhibited the typical phenotypes of primary ECs, with SHED possessing a higher endothelial differentiation potential than dental pulp stem cells. VEGFR1-specific ligand-PLGF exerted a negligible effect on SHED-ECs differentiation. Compared with VEGF-A alone, the combination of VEGF-A and SB-431542 significantly enhanced the endothelial differentiation of SHED. The presence of SB-431542 inhibited the phosphorylation of Suppressor of Mothers Against Decapentaplegic 2/3 (SMAD2/3), allowing for VEGF-A-dependent phosphorylation and upregulation of VEGFR2. Our results indicate that the combination of VEGF-A and SB-431542 could enhance the differentiation of dental pulp-derived stem cells into endothelial cells, and this process is mediated through enhancement of VEGF-A-VEGFR2 signaling and concomitant inhibition of TGF-β-SMAD2/3 signaling.

An approximately factored incremental strategy for calculating consistent discrete aerodynamic sensitivity derivatives

NASA Technical Reports Server (NTRS)

Korivi, V. M.; Taylor, A. C., III; Newman, P. A.; Hou, G. J.-W.; Jones, H. E.

1992-01-01

An incremental strategy is presented for iteratively solving very large systems of linear equations, which are associated with aerodynamic sensitivity derivatives for advanced CFD codes. It is shown that the left-hand side matrix operator and the well-known factorization algorithm used to solve the nonlinear flow equations can also be used to efficiently solve the linear sensitivity equations. Two airfoil problems are considered as an example: subsonic low Reynolds number laminar flow and transonic high Reynolds number turbulent flow.

Regulatory Mechanisms Involved in the Expression of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor

DTIC Science & Technology

1996-03-01

neurotoxic dopamine analog that is taken up by nigral dopaminergic cells where it is metabolized to highly reactive oxygen free radicals that cause ...brain regions is elevated after other types of brain insults, including ischemia and hypoglycemia (see Lindvall et al. 1994 for review). Lindvall et a1...with kainic acid were also reported. These investigators also reported significant increases in BDNF mRNA levels in cultures of neonatal astrocytes

Platelet-derived-growth-factor-stimulated heterogeneous polyphosphoinositide metabolism and phosphate uptake in C3H fibroblasts.

PubMed Central

Holmsen, H; Male, R; Rongved, S; Langeland, N; Lillehaug, J

1989-01-01

Pig platelet-derived growth factor (PDGF) increased the rate of [32P]Pi uptake by murine fibroblasts, resulting in a 3-9-fold elevation of the specific radioactivity of ATP, PtdInsP, PtdInsP2, PtdIns and phosphatidic acid. The specific radioactivity was 10-60-fold higher in ATP than in the four phospholipids. These substances are therefore not in metabolic equilibrium, which complicates determination of inositol phospholipid turnover. PMID:2548480

Cytokine Response of Cultured Skeletal Muscle Cells Stimulated with Proinflammatory Factors Depends on Differentiation Stage

PubMed Central

Podbregar, Matej; Lainscak, Mitja; Prelovsek, Oja; Mars, Tomaz

2013-01-01

Myoblast proliferation and myotube formation are critical early events in skeletal muscle regeneration. The attending inflammation and cytokine signaling are involved in regulation of skeletal muscle cell proliferation and differentiation. Secretion of muscle-derived cytokines upon exposure to inflammatory factors may depend on the differentiation stage of regenerating muscle cells. Cultured human myoblasts and myotubes were exposed to 24-hour treatment with tumor necrosis factor (TNF)-α or lipopolysaccharide (LPS). Secretion of interleukin 6 (IL-6), a major muscle-derived cytokine, and interleukin 1 (IL-1), an important regulator of inflammatory response, was measured 24 hours after termination of TNF-α or LPS treatment. Myoblasts pretreated with TNF-α or LPS displayed robustly increased IL-6 secretion during the 24-hour period after removal of treatments, while IL-1 secretion remained unaltered. IL-6 secretion was also increased in myotubes, but the response was less pronounced compared with myoblasts. In contrast to myoblasts, IL-1 secretion was markedly stimulated in LPS-pretreated myotubes. We demonstrate that preceding exposure to inflammatory factors stimulates a prolonged upregulation of muscle-derived IL-6 and/or IL-1 in cultured skeletal muscle cells. Our findings also indicate that cytokine response to inflammatory factors in regenerating skeletal muscle partially depends on the differentiation stage of myogenic cells. PMID:23509435

Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases.

PubMed

Kumar, Hemant; Kim, In-Su; More, Sandeep Vasant; Kim, Byung-Wook; Choi, Dong-Kug

2014-01-01

Covering: 2000 to 2013. Oxidative stress is the central component of chronic diseases. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway is vital in the up-regulation of cytoprotective genes and enzymes in response to oxidative stress and treatment with certain dietary phytochemicals. Herein, we classify bioactive compounds derived from natural products that are Nrf2/ARE pathway activators and recapitulate the molecular mechanisms for inducing Nrf2 to provide favorable effects in experimental models of chronic diseases. Moreover, pharmacological inhibition of Nrf2 signalling has emerged as promising strategy against multi-drug resistance thereby improving the treatment efficacy. We have also enlisted natural product-derived inhibitors of Nrf2/ARE pathway.

Synthesis and In Vitro Cytotoxicity of the 4-(Halogenoanilino)-6-bromoquinazolines and Their 6-(4-Fluorophenyl) Substituted Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor Tyrosine Kinase

PubMed Central

Paumo, Hugues K.

2017-01-01

Series of the 2-unsubstituted and 2-(4-chlorophenyl)–substituted 4-anilino-6-bromoquinazolines and their 6-(4-fluorophenyl)–substituted derivatives were evaluated for in vitro cytotoxicity against MCF-7 and HeLa cells. The 2-unsubstituted 4-anilino-6-bromoquinazolines lacked activity, whereas most of their 2-(4-chlorophenyl) substituted derivatives were found to exhibit significant cytotoxicity and selectivity against HeLa cells. Replacement of bromine with 4-fluorophenyl group for the 2-unsubstituted 4-anilinoquinazolines resulted in superior activity against HeLa cells compared to Gefitinib. The presence of a 4-fluorophenyl group in the 2-(4-chlorophenyl) substituted derivatives led to increased cytotoxicity against HeLa cells, except for the 3-chloroanilino derivative. The most active compounds, namely, 3g, 3l, and 4l, were found to exhibit a moderate to significant inhibitory effect against epidermal growth factor receptor tyrosine kinase (EGFR-TK). The EGFR molecular docking model suggested that these compounds are nicely bound to the region of EGFR. PMID:29156606

The Evolution of Stress Intensity Factors and the Propagation of Cracks in Elastic Media

NASA Astrophysics Data System (ADS)

Friedman, Avner; Hu, Bei; Velazquez, Juan J. L.

When a crack Γs propagates in an elastic medium the stress intensity factors evolve with the tip x(s) of Γs. In this paper we derive formulae which describe the evolution of these stress intensity factors for a homogeneous isotropic elastic medium under plane strain conditions. Denoting by ψ=ψ(x,s) the stress potential (ψ is biharmonic and has zero traction along the crack Γs) and by κ(s) the curvature of the crack at the tip x(s), we prove that the stress intensity factors A1(s), A2(s), as functions of s, satisfy: where , are stress intensity factors of the tangential derivative of in the polar coordinate system at x(s) with θ=0 in the direction of the crack at x(s). The case of antiplane shearing is also briefly considered; in this case ψ is harmonic.

Psychometric analysis of the new ADHD DSM-V derived symptoms.

PubMed

Ghanizadeh, Ahmad

2012-03-20

Following the agreements on the reformulating and revising of ADHD diagnostic criteria, recently, the proposed revision for ADHD added 4 new symptoms to the hyperactivity and Impulsivity aspect in DSM-V. This study investigates the psychometric properties of the proposed ADHD diagnostic criteria. ADHD diagnosis was made according to DSM-IV. The parents completed the screening test of ADHD checklist of Child Symptom Inventory-4 and the 4 items describing the new proposed symptoms in DSM-V. The confirmatory factor analysis of the ADHD DSM-V derived items supports the loading of two factors including inattentiveness and hyperactivity/impulsivity. There is a sufficient reliability for the items. However, confirmatory factor analysis showed that the three-factor model is better fitted than the two-factor one. Moreover, the results of the exploratory analysis raised some concerns about the factor loading of the four new items. The current results support the two-factor model of the DSM-V ADHD diagnostic criteria including inattentiveness and hyperactivity/impulsivity. However, the four new items can be considered as a third factor.

Neurotrophin regulation of sodium and calcium channels in human neuroblastoma cells.

PubMed

Urbano, F J; Buño, W

2000-01-01

Neurotrophins, acting through tyrosine kinase family genes, are essential for neuronal differentiation. The expression of tyrosine kinase family genes is prognostic in neuroblastoma, and neurotrophins reduce proliferation and induce differentiation, indicating that neuroblastomas are regulated by neurotrophins. We tested the effects of nerve growth factor and brain-derived neurotrophic factor on Na(+) and Ca(2+) currents, using the whole-cell patch-clamp technique, in human neuroblastoma NB69 cells. Control cells exhibited a slow tetrodotoxin-resistant (IC(50)=98 nM) Na(+) current and a high-voltage-activated Ca(2+) current. Exposure to nerve growth factor (50 ng/ml) and/or brain-derived neurotrophic factor (5 ng/ml) produced the expression of a fast tetrodotoxin-sensitive (IC(50)=10 nM) Na(+) current after day 3, and suppressed the slow tetrodotoxin-resistant variety. The same type of high-voltage-activated Ca(2+) current was expressed in control and treated cells. The treatment increased the surface density of both Na(+) and Ca(2+) currents with time after plating, from 17 pA/pF at days 3-5 and 1-5 to 34 and 30 pA/pF after days 6-10, respectively. Therefore, both nerve growth factor and brain-derived neurotrophic factor, acting through different receptors of the tyrosine kinase family and also possibly the tumor necrosis factor receptor-II, were able to regulate differentiation and the expression of Na(+) and Ca(2+) channels, partially reproducing the modifications induced by diffusible astroglial factors. We show that neurotrophins induced differentiation to a neuronal phenotype and modified the expression of Na(+) and Ca(2+) currents, partially reproducing the effects of diffusible astroglial factors.

Coherence-limited solar power conversion: the fundamental thermodynamic bounds and the consequences for solar rectennas

NASA Astrophysics Data System (ADS)

Mashaal, Heylal; Gordon, Jeffrey M.

2014-10-01

Solar rectifying antennas constitute a distinct solar power conversion paradigm where sunlight's spatial coherence is a basic constraining factor. In this presentation, we derive the fundamental thermodynamic limit for coherence-limited blackbody (principally solar) power conversion. Our results represent a natural extension of the eponymous Landsberg limit, originally derived for converters that are not constrained by the radiation's coherence, and are irradiated at maximum concentration (i.e., with a view factor of unity to the solar disk). We proceed by first expanding Landsberg's results to arbitrary solar view factor (i.e., arbitrary concentration and/or angular confinement), and then demonstrate how the results are modified when the converter can only process coherent radiation. The results are independent of the specific power conversion mechanism, and hence are valid for diffraction-limited as well as quantum converters (and not just classical heat engines or in the geometric optics regime). The derived upper bounds bode favorably for the potential of rectifying antennas as potentially high-efficiency solar converters.

Observed parenting behaviors interact with a polymorphism of the brain-derived neurotrophic factor gene to predict the emergence of oppositional defiant and callous-unemotional behaviors at age 3 years.

PubMed

Willoughby, Michael T; Mills-Koonce, Roger; Propper, Cathi B; Waschbusch, Daniel A

2013-11-01

Using the Durham Child Health and Development Study, this study (N = 171) tested whether observed parenting behaviors in infancy (6 and 12 months) and toddlerhood/preschool (24 and 36 months) interacted with a child polymorphism of the brain-derived neurotrophic factor gene to predict oppositional defiant disorder (ODD) and callous-unemotional (CU) behaviors at age 3 years. Child genotype interacted with observed harsh and intrusive (but not sensitive) parenting to predict ODD and CU behaviors. Harsh-intrusive parenting was more strongly associated with ODD and CU for children with a methionine allele of the brain-derived neurotrophic factor gene. CU behaviors were uniquely predicted by harsh-intrusive parenting in infancy, whereas ODD behaviors were predicted by harsh-intrusive parenting in both infancy and toddlerhood/preschool. The results are discussed from the perspective of the contributions of caregiving behaviors as contributing to distinct aspects of early onset disruptive behavior.

Metastable Pluripotent States in NOD Mouse Derived ES Cells

PubMed Central

Hanna, Jacob; Markoulaki, Styliani; Mitalipova, Maisam; Cheng, Albert W.; Cassady, John P.; Staerk, Judith; Carey, Bryce W.; Lengner, Christopher J.; Foreman, Ruth; Love, Jennifer; Gao, Qing; Kim, Jongpil; Jaenisch, Rudolf

2009-01-01

Embryonic stem (ES) cells are isolated from the inner cell mass (ICM) of blastocysts, whereas epiblast stem cells (EpiSCs) are derived from the post-implantation epiblast and display a restricted developmental potential. Here we characterize pluripotent states in the non-obese diabetic (NOD) mouse strain, which prior to this study was considered “non-permissive” for ES cell derivation. We find that NOD stem cells can be stabilized by providing constitutive expression of Klf4 or c-Myc or small molecules that can replace these factors during in vitro reprogramming. The NOD ES and iPS cells appear “metastable”, as they acquire an alternative EpiSC-like identity after removal of the exogenous factors, while their reintroduction converts the cells back to ICM-like pluripotency. Our findings suggest that stem cells from different genetic backgrounds can assume distinct states of pluripotency in vitro, the stability of which is regulated by endogenous genetic determinants and can be modified by exogenous factors. PMID:19427283

Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

PubMed

Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; do Rosario Andre, Maria; Brazier-Mitouart, Helene; Waite, Janelle C; Chan, April S; Kalter, Julie; Ramos, Ilyssa; Wu, Qi; Williams, Caitlin; Wolchok, Jedd D; Chapman, Paul B; Peinado, Hector; Anandasabapathy, Niroshana; Ocean, Allyson J; Kaplan, Rosandra N; Greenfield, Jeffrey P; Bromberg, Jacqueline; Skokos, Dimitris; Lyden, David

2015-04-29

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.

The use of IFSAR data in GIS-based landslide susceptibility evaluation

NASA Astrophysics Data System (ADS)

Floris, M.; Squarzoni, C.; Hundseder, C.; Mason, M.; Genevois, R.

2010-05-01

GIS-based landslide susceptibility evaluation is based on the spatial relationships between landslides and their related factors. The analyses are highly conditioned by precision and accuracy of input factors, in particular landslides identification and characterization. Factors influencing landslide spatial hazard consist of geological, geomorphological, hydrogeological and tectonic features, geomechanical and geotechnical properties, land use and management, and DEM-derived factors (elevation, slope, aspect, curvature, superficial flow). The choice of influencing factors depends on: method of analysis, scale of inputs, aim of the outputs, availability and quality of the input data. Then, the choice can be made a priori, on the bases of an in-deep territorial knowledge and experts' judgements, or by performing statistical analyses, finalized to identify the significance of each of the influencing factor. Due to the large availability of terrain data, spatial models often include DEM-derived factors, but the resolution and accuracy of DEMs influence the final outputs. In this work the relationships between landslides occurred in the volcanic area of the Euganean Hills Regional Park (SE of Padua, Veneto region, Italy) and morphometric factors (slope, aspect and curvature) will be examined through a simple probability method. The use of complex and time consuming mathematical or statistical models is not always recommended, because often simple models can lead to more accurate results. Morphometric input factors are derived from DEMs created from vector elevation data of the regional cartography at 1:5.000 scale and with NEXTMap® data (http://www.intermap.com). NEXTMap® Digital Surface Model (DSM) and Digital Terrain Model (DTM) are generated using Intermap's IFSAR (Interferometric Synthetic Aperture Radar) technology mounted on an aircraft at a flight height of 8500 m above Mean Sea Level and under a side viewing angle of about 45°. The DSM represents the first reflective surface as illuminated by the radar. IFSAR sensors retrieve the mean height of the main scattering elements in a grid cell, known as the scattering phase centre height. The radar return from vegetation usually penetrates to some extend lower than the ‘first' tree canopy height. The DTM is derived from DSM applying a semi-automated process that classifies areas as obstructed (buildings and vegetation) and unobstructed , where the obstructed areas are processed to approximate bald earth. DSM and DTM data present a post spacing of 5 m and a vertical accuracy of 1 m (RMSE) or better in areas of unobstructed flat terrain. IFSAR elevation models are compared with photogrammetrically derived models (topographic map of Veneto Region) for the following aspects: Every elevation point of IFSAR models is derived through a direct measure of the terrain surface, while photogrammetric elevation models are usually compiled through digitalization and interpolation of contour lines. Frequent seam lines are evident in vector maps derived DEMs, compiled during many years, with different specifications and tools. IFSAR 5 m posted DEM's generate a much more detailed description of terrain features. Seamless and homogeneous IFSAR elevation models pave the way to accurate applications like landslides study and risk assessment. The results obtained using the two DEM sources will be compared. The contribution of IFSAR data to the GIS-based spatial analysis of the study area will be tested and discussed.

A DEIM Induced CUR Factorization

DTIC Science & Technology

2015-09-18

CUR approximate matrix factorization based on the Discrete Empirical Interpolation Method (DEIM). For a given matrix A, such a factorization provides a...CUR approximations based on leverage scores. 1 Introduction This work presents a new CUR matrix factorization based upon the Discrete Empirical...SUPPLEMENTARY NOTES 14. ABSTRACT We derive a CUR approximate matrix factorization based on the Discrete Empirical Interpolation Method (DEIM). For a given

Long non-coding RNA nuclear paraspeckle assembly transcript 1 inhibits the apoptosis of retina Müller cells after diabetic retinopathy through regulating miR-497/brain-derived neurotrophic factor axis.

PubMed

Li, Xiu-Juan

2018-05-01

The role of long non-coding RNA in diabetic retinopathy, a serious complication of diabetes mellitus, has attracted increasing attention in recent years. The purpose of this study was to explore whether long non-coding RNA nuclear paraspeckle assembly transcript 1 was involved in the context of diabetic retinopathy and its underlying mechanisms. Our results revealed that nuclear paraspeckle assembly transcript 1 was significantly downregulated in the retina of diabetes mellitus rats. Meanwhile, miR-497 was significantly increased in diabetes mellitus rats' retina and high glucose-treated Müller cells, but brain-derived neurotrophic factor was increased. We also found that high glucose-induced apoptosis of Müller cells was accompanied by the significant downregulation of nuclear paraspeckle assembly transcript 1 in vitro. Further study demonstrated that high glucose-promoted Müller cells apoptosis through downregulating nuclear paraspeckle assembly transcript 1 and downregulated nuclear paraspeckle assembly transcript 1 mediated this effect via negative regulating miR-497. Moreover, brain-derived neurotrophic factor was negatively regulated by miR-497 and associated with the apoptosis of Müller cells under high glucose. Our results suggested that under diabetic conditions, downregulated nuclear paraspeckle assembly transcript 1 decreased the expression of brain-derived neurotrophic factor through elevating miR-497, thereby promoting Müller cells apoptosis and aggravating diabetic retinopathy.

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

PubMed

Kutlu, Munir Gunes; Cole, Robert D; Connor, David A; Natwora, Brendan; Gould, Thomas J

2018-03-01

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Implementing human factors in clinical practice.

PubMed

Timmons, Stephen; Baxendale, Bryn; Buttery, Andrew; Miles, Giulia; Roe, Bridget; Browes, Simon

2015-05-01

To understand whether aviation-derived human factors training is acceptable and useful to healthcare professionals. To understand whether and how healthcare professionals have been able to implement human factors approaches to patient safety in their own area of clinical practice. Qualitative, longitudinal study using semi-structured interviews and focus groups, of a multiprofessional group of UK NHS staff (from the emergency department and operating theatres) who have received aviation-derived human factors training. The human factors training was evaluated positively, and thought to be both acceptable and relevant to practice. However, the staff found it harder to implement what they had learned in their own clinical areas, and this was principally attributed to features of the informal organisational cultures. In order to successfully apply human factors approaches in hospital, careful consideration needs to be given to the local context and informal culture of clinical practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-β1, IL-13 and oxidative stress.

PubMed

de Souza, Veruska Cintia Alexandrino; Pereira, Thiago Almeida; Teixeira, Valéria Wanderley; Carvalho, Helotonio; de Castro, Maria Carolina Accioly Brelaz; D'assunção, Carolline Guimarães; de Barros, Andréia Ferreira; Carvalho, Camila Lima; de Lorena, Virgínia Maria Barros; Costa, Vláudia Maria Assis; Teixeira, Álvaro Aguiar Coelho; Figueiredo, Regina Celia Bressan Queiroz; de Oliveira, Sheilla Andrade

2017-07-28

To evaluate the therapeutic effects of bone marrow-derived CD11b + CD14 + monocytes in a murine model of chronic liver damage. Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay. CD11b + CD14 + monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-β1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b + CD14 + monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin. Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.

Rat Bone Marrow-Derived Schwann-Like Cells Differentiated by the Optimal Inducers Combination on Microfluidic Chip and Their Functional Performance

PubMed Central

Lv, Decheng

2012-01-01

Numerous researches demonstrated the possibility of derivation of Schwann-like (SC-like) cells in vitro from bone marrow stromal cells (BMSCs). However, the concentration of the induce factors were different in those studies, especially for the critical factors forskolin (FSK) and β-heregulin (HRG). Here, we used a new and useful method to build an integrated microfluidic chip for rapid analyses of the optimal combination between the induce factors FSK and HRG. The microfluidic device was mainly composed of an upstream concentration gradient generator (CGG) and a downstream cell culture module. Rat BMSCs were cultured in the cell chambers for 11 days at the different concentrations of induce factors generated by CGG. The result of immunofluorescence staining on-chip showed that the group of 4.00 µM FSK and 250.00 ng/ml HRG presented an optimal effect to promote the derivation of SC-like cells. Moreover, the optimal SC-like cells obtained on-chip were further tested using DRG co-culture and ELISA to detect their functional performance. Our findings demonstrate that SC-like cells could be obtained with high efficiency and functional performance in the optimal inducers combination. PMID:22880114

Rat bone marrow-derived Schwann-like cells differentiated by the optimal inducers combination on microfluidic chip and their functional performance.

PubMed

Tian, Xiliang; Wang, Shouyu; Zhang, Zhen; Lv, Decheng

2012-01-01

Numerous researches demonstrated the possibility of derivation of Schwann-like (SC-like) cells in vitro from bone marrow stromal cells (BMSCs). However, the concentration of the induce factors were different in those studies, especially for the critical factors forskolin (FSK) and β-heregulin (HRG). Here, we used a new and useful method to build an integrated microfluidic chip for rapid analyses of the optimal combination between the induce factors FSK and HRG. The microfluidic device was mainly composed of an upstream concentration gradient generator (CGG) and a downstream cell culture module. Rat BMSCs were cultured in the cell chambers for 11 days at the different concentrations of induce factors generated by CGG. The result of immunofluorescence staining on-chip showed that the group of 4.00 µM FSK and 250.00 ng/ml HRG presented an optimal effect to promote the derivation of SC-like cells. Moreover, the optimal SC-like cells obtained on-chip were further tested using DRG co-culture and ELISA to detect their functional performance. Our findings demonstrate that SC-like cells could be obtained with high efficiency and functional performance in the optimal inducers combination.

Endothelial cell colony forming units derived from malignant breast diseases are resistant to tumor necrosis factor-α-induced apoptosis.

PubMed

Chou, Chen-Pin; Jiang, Shih Sheng; Pan, Huay-Ben; Yen, Yi-Chen; Tseng, Hui-Hwa; Hung, Yu-Ting; Wang, Ssu-Han; Chen, Yu-Lin; Chen, Ya-Wen

2016-11-24

Mobilisation of endothelial progenitor cells (EPCs) from the bone marrow is a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be elevated in certain malignant states. Using flow cytometry and a Hill-based colony forming unit (CFU) assay, the present study indicated that higher levels of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2) double-positive EPCs, as well as increased formation of endothelial cell colony-forming units (EC-CFUs) are associated with benign and malignant breast diseases, providing possible indicators for breast disease detection. Gene expression profiles revealed a genetic difference between CD34 + VEGFR2 + EPCs and EC-CFUs. Decreased expression of tumour necrosis factor receptor 2 (TNFR2) signalling-related genes and inhibition of tumour necrosis factor (TNF)-induced signalling were demonstrated in EC-CFUs derived from patients with malignant breast disease in comparison with those from healthy controls. Interestingly, our data provided the first evidence that EC-CFUs derived from patients with malignant breast disease were resistant to TNF-α-induced apoptosis, indicating a plausible target for future therapeutic interventions.

[Separation of [Rh-103m]-rhodocene derivatives from the parent [103Ru]ruthenocene derivatives and their organ distribution].

PubMed

Wenzel, M; Wu, Y F

1987-01-01

The radioactive decay of [103Ru]ruthenocene derivatives leads to 103mRh labelled rhodocinium derivatives, which can be separated by the extraction of a lipophilic solution of the ruthenocen derivate with water. The separation factor 103mRh/103Ru reaches values of 32:1 Rh3+ ions are not liberated and extracted. The organ distribution of the 103mRh labelled rhodocinium derivatives gained from ruthenocene and from N-isopropyl-ruthenocene amphetamine is different from the distribution of the parent ruthenocene compound. The liver and kidney uptake of the rhodocinium-amphetamine is much higher than the uptake with ruthenocene amphetamine.

In-vitro anticoagulant activity of fucoidan derivatives from brown seaweed Laminaria japonica

NASA Astrophysics Data System (ADS)

Wang, Jing; Zhang, Quanbin; Zhang, Zhongshan; Hou, Yun; Zhang, Hong

2011-05-01

Fucoidan, a group of sulfated heteropolysaccharides, was extracted from Laminaria japonica, an important economic alga species in China. The anticoagulant activity of fucoidan and its derivatives (including sulfated, phosphorylated, and aminated fucoidan) was examined using in-vitro anticoagulant systems. The correlation between chemical variations within the fucoidan group and anticoagulant activity was determined. The in-vitro anticoagulant properties of fucoidan and its derivatives were determined by measuring activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). The results indicate anticoagulant activity in all samples using APTT and TT assays; however, only the fucoidan derivatives affected the PT assay. Thus, the fucoidan derivatives were able to inhibit both intrinsic and extrinsic blood coagulants. Fucoidan (FPS) and its derivatives presented better anticoagulant activity than low molecular weight fucoidan (DFPS) and its derivatives, suggesting that molecular weight and proper conformation are contributing factors for anticoagulant activity of polysaccharides. Amino groups have a positive charge and can thus change the charge density of fucoidan. Accordingly, among the tested samples, aminated fucoidan (NF) was the most active reflecting the importance of charge density for anticoagulant activity. Available data obtained using in-vitro models suggest that the sulfate content, sulfate/total-sugar ratio, molecular weight, and the substituted group of fucoidan are important factors for anticoagulant activity but that the influence of sulfate, phosphate and amino groups on anticoagulant activity was different.

Conducting a battery of bioassays for gold nanoparticles to derive guideline value for the protection of aquatic ecosystems.

PubMed

Nam, Sun-Hwa; Shin, Yu-Jin; Lee, Woo-Mi; Kim, Shin Woong; Kwak, Jin Il; Yoon, Sung-Ji; An, Youn-Joo

2015-05-01

Gold nanoparticles (Au-NPs) are used in many applications, including the manufacture of products like cosmetics, paints, and electrochemical immunosensors, and in the detection, diagnosis, and treatment of tumors. However, there are no legal or recommended guidelines for protecting aquatic ecosystems from Au-NPs. In this study, we conducted a battery of bioassays and present toxicity values for two bacteria, one alga, one euglena, three cladoceran, and two fish species that were exposed to Au-NPs. Guideline values for protecting aquatic ecosystems from Au-NPs were derived using methods that are generally used to derive water-quality guidelines and are used in Australia, New Zealand, Canada, the European Community (EC), and the USA. Au-NPs had adverse effects on all test species, including growth inhibition of both bacteria, the alga, and the euglena; mortality and immobilization in the three cladocerans; and developmental malformations in the embryos and larvae of the two fish. Guideline values of 0.15 and 0.04 × 10(10) particles/mL were derived for Au-NPs using a species sensitivity distribution (SSD) and assessment factor. The guideline value derived for Au-NPs using an assessment factor was more stringent than that derived using SSD. This is the first study to derive guideline values for nanoparticles in water environments.

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium.

PubMed

Tunca, Zeliha; Ozerdem, Aysegul; Ceylan, Deniz; Yalçın, Yaprak; Can, Güneş; Resmi, Halil; Akan, Pınar; Ergör, Gül; Aydemir, Omer; Cengisiz, Cengiz; Kerim, Doyuran

2014-09-01

Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. Small sample size in different episodes and drug-free patients was the limitation of thestudy. Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of soluble factors derived from oral cancer cells on the production of interferon-γ from peripheral blood mononuclear cells following stimulation with OK-432.

PubMed

Ohe, Go; Sasai, Akiko; Uchida, Daisuke; Tamatani, Tetsuya; Nagai, Hirokazu; Miyamoto, Youji

2013-08-01

The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432.

Hotplate precipitation gauge calibrations and field measurements

NASA Astrophysics Data System (ADS)

Zelasko, Nicholas; Wettlaufer, Adam; Borkhuu, Bujidmaa; Burkhart, Matthew; Campbell, Leah S.; Steenburgh, W. James; Snider, Jefferson R.

2018-01-01

First introduced in 2003, approximately 70 Yankee Environmental Systems (YES) hotplate precipitation gauges have been purchased by researchers and operational meteorologists. A version of the YES hotplate is described in Rasmussen et al. (2011; R11). Presented here is testing of a newer version of the hotplate; this device is equipped with longwave and shortwave radiation sensors. Hotplate surface temperature, coefficients describing natural and forced convective sensible energy transfer, and radiative properties (longwave emissivity and shortwave reflectance) are reported for two of the new-version YES hotplates. These parameters are applied in a new algorithm and are used to derive liquid-equivalent accumulations (snowfall and rainfall), and these accumulations are compared to values derived by the internal algorithm used in the YES hotplates (hotplate-derived accumulations). In contrast with R11, the new algorithm accounts for radiative terms in a hotplate's energy budget, applies an energy conversion factor which does not differ from a theoretical energy conversion factor, and applies a surface area that is correct for the YES hotplate. Radiative effects are shown to be relatively unimportant for the precipitation events analyzed. In addition, this work documents a 10 % difference between the hotplate-derived and new-algorithm-derived accumulations. This difference seems consistent with R11's application of a hotplate surface area that deviates from the actual surface area of the YES hotplate and with R11's recommendation for an energy conversion factor that differs from that calculated using thermodynamic theory.

Linking FRRF Derived Photophysiology with Carbon-based Primary Productivity: Insights from Concepts of Cellular Energy Allocation

NASA Astrophysics Data System (ADS)

Schuback, N.; Schallenberg, C.; Duckham, C.; Flecken, M.; Maldonado, M. T.; Tortell, P. D.

2016-02-01

Active chlorophyll a fluorescence approaches, including fast repetition rate fluorometry (FRRF), have the potential to provide estimates of phytoplankton primary productivity at unprecedented spatial and temporal resolution. FRRF-derived productivity rates are based on estimates of charge separation in photosystem II (ETRRCII), which must be converted into ecologically relevant units of carbon fixation. Understanding sources of variability in the coupling of ETRRCII and carbon fixation provides important physiological insight into phytoplankton photosynthesis, and is critical for the application of FRRF as a primary productivity measurement tool. We present data from a series of experiments during which we simultaneously measured phytoplankton carbon fixation and ETRRCII in the iron-limited NE subarctic Pacific. Our results show significant variability of the derived conversion factor (Ve:C/nPSII), with highest values observed under conditions of excess excitation pressure at the level of photosystem II, caused by high light and/or low iron. Our results will be discussed in the context of metabolic plasticity, which evolved in phytoplankton to simultaneously maximize growth and provide photoprotection under fluctuating light and limiting nutrient availabilities. Because the derived conversion factor is associated with conditions of excess light, it correlates with the expression of non-photochemical quenching (NPQ) in the pigment antenna, also derived from FRRF measurements. Our results demonstrate a significant correlation between NPQ and the conversion factor Ve:C/nPSII, and the potential of this relationship to improve FRRF-based estimates of phytoplankton carbon fixation rates is discussed.

Inhibition of the Differentiation of Monocyte-Derived Dendritic Cells by Human Gingival Fibroblasts

PubMed Central

Séguier, Sylvie; Tartour, Eric; Guérin, Coralie; Couty, Ludovic; Lemitre, Mathilde; Lallement, Laetitia; Folliguet, Marysette; Naderi, Samah El; Terme, Magali; Badoual, Cécile; Lafont, Antoine; Coulomb, Bernard

2013-01-01

We investigated whether gingival fibroblasts (GFs) can modulate the differentiation and/or maturation of monocyte-derived dendritic cells (DCs) and analyzed soluble factors that may be involved in this immune modulation. Experiments were performed using human monocytes in co-culture with human GFs in Transwell® chambers or using monocyte cultures treated with conditioned media (CM) from GFs of four donors. The four CM and supernatants from cell culture were assayed by ELISA for cytokines involved in the differentiation of dendritic cells, such as IL-6, VEGF, TGFβ1, IL-13 and IL-10. The maturation of monocyte-derived DCs induced by LPS in presence of CM was also studied. Cell surface phenotype markers were analyzed by flow cytometry. In co-cultures, GFs inhibited the differentiation of monocyte-derived DCs and the strength of this blockade correlated with the GF/monocyte ratio. Conditioned media from GFs showed similar effects, suggesting the involvement of soluble factors produced by GFs. This inhibition was associated with a lower stimulatory activity in MLR of DCs generated with GFs or its CM. Neutralizing antibodies against IL-6 and VEGF significantly (P<0.05) inhibited the inhibitory effect of CM on the differentiation of monocytes-derived DCs and in a dose dependent manner. Our data suggest that IL-6 is the main factor responsible for the inhibition of DCs differentiation mediated by GFs but that VEGF is also involved and constitutes an additional mechanism. PMID:23936476

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

PubMed Central

Hocker, Harrison J.; Cho, Kwang-Jin; Chen, Chung-Ying K.; Rambahal, Nandini; Sagineedu, Sreenivasa Rao; Shaari, Khozirah; Stanslas, Johnson; Hancock, John F.; Gorfe, Alemayehu A.

2013-01-01

Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)—a bicyclic diterpenoid lactone isolated from Andrographis paniculata—and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP–GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP–GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras. PMID:23737504

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

Balasubramanian, Sivaprakasam; Eckert, Richard L., E-mail: reckert@umaryland.edu

We have proposed that it is important to examine the impact of chemopreventive agents on the function of normal human epidermal keratinocytes since these cells comprise the barrier that protects the body from a range of environmental insults. In this context, it is widely appreciated that cancer may be retarded by consumption or topical application of naturally occurring food-derived chemopreventive agents. Our studies show that (-)-epigallocatechin-3-gallate (EGCG), a green tea-derived polyphenol, acts to enhance the differentiation of normal human keratinocytes as evidenced by its ability to increase involucrin (hINV), transglutaminase type 1 (TG1) and caspase-14 gene expression. EGCG also stimulatesmore » keratinocyte morphological differentiation. These actions of EGCG are mediated via activation of a nPKC, Ras, MEKK1, MEK3, p38{delta}-ERK1/2 signaling cascade which leads to increased activator protein 1 (AP1) and CAATT enhancer binding protein (C/EBP) transcription factor expression, increased binding of these factors to DNA, and increased gene transcription. In contrast, apigenin, a dietary flavonoid derived from plants and vegetables, and curcumin, an agent derived from turmeric, inhibit differentiation by suppressing MAPK signal transduction and reducing API transcription factor level. Curcumin also acts to enhance apoptosis, although EGCG and apigenin do not stimulate apoptosis. In addition, all of these agents inhibit keratinocyte proliferation. These findings indicate that each of these diet-derived chemopreventive agents has a profound impact on normal human keratinocyte function and that they operate via distinct and sometimes opposing mechanisms. However, all are expected to act as chemopreventive agents.« less

Study of the quantitative, functional, cytogenetic, and immunoregulatory properties of bone marrow mesenchymal stem cells in patients with B-cell chronic lymphocytic leukemia.

PubMed

Pontikoglou, Charalampos; Kastrinaki, Maria-Christina; Klaus, Mirjam; Kalpadakis, Christina; Katonis, Pavlos; Alpantaki, Kalliopi; Pangalis, Gerassimos A; Papadaki, Helen A

2013-05-01

The bone marrow (BM) microenvironment has clearly been implicated in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL). However, the potential involvement of BM stromal progenitors, the mesenchymal stem cells (MSCs), in the pathophysiology of the disease has not been extensively investigated. We expanded in vitro BM-MSCs from B-CLL patients (n=11) and healthy individuals (n=16) and comparatively assessed their reserves, proliferative potential, differentiation capacity, and immunoregulatory effects on T- and B-cells. We also evaluated the anti-apoptotic effect of patient-derived MSCs on leukemic cells and studied their cytogenetic characteristics in comparison to BM hematopoietic cells. B-CLL-derived BM MSCs exhibit a similar phenotype, differentiation potential, and ability to suppress T-cell proliferative responses as compared with MSCs from normal controls. Furthermore, they do not carry the cytogenetic abnormalities of the leukemic clone, and they exert a similar anti-apoptotic effect on leukemic cells and healthy donor-derived B-cells, as their normal counterparts. On the other hand, MSCs from B-CLL patients significantly promote normal B-cell proliferation and IgG production, in contrast to healthy-donor-derived MSCs. Furthermore, they have impaired reserves, defective cellular growth due to increased apoptotic cell death and exhibit aberrant production of stromal cell-derived factor 1, B-cell activating factor, a proliferation inducing ligand, and transforming growth factor β1, cytokines that are crucial for the survival/nourishing of the leukemic cells. We conclude that ex vivo expanded B-CLL-derived MSCs harbor intrinsic qualitative and quantitative abnormalities that may be implicated in disease development and/or progression.

Combined platelet and plasma derivatives enhance proliferation of stem/progenitor cells maintaining their differentiation potential.

PubMed

Muraglia, Anita; Todeschi, Maria Rosa; Papait, Andrea; Poggi, Alessandro; Spanò, Raffaele; Strada, Paolo; Cancedda, Ranieri; Mastrogiacomo, Maddalena

2015-12-01

Platelet derivatives have been proposed as alternatives to animal sera given that for cell therapy applications, the use of fetal bovine/calf serum (FBS/FCS) is subjected to severe limitations for safety and ethical concerns. We developed a cell culture medium additive obtained by the combination of two blood-derived standardized components. A platelet lysate (PL) and a platelet-poor plasma (PPP) were produced in a lyophilized form. Each component was characterized for its growth factor content (platelet-derived growth factor-BB/vascular endothelial growth factor). PL and PPP were used as single components or in combination in different ratio at cumulative 5% final concentration in the culture medium. The single components were less effective than the component combination. In primary cell cultures (bone marrow stromal cells, adipose derived adult stem cells, osteoblasts, chondrocytes, umbilical cord-derived mesenchymal stromal cells, lymphocytes), the PL/PPP supplement promoted an increased cell proliferation in respect to the standard FCS culture in a dose-dependent manner, maintaining the cell functionality, clonogenicity, phenotype and differentiative properties throughout the culture. At a different component ratio, the supplement was also used to support proliferation of a cell line (U-937). The PL/PPP supplement is an efficient cell culture medium additive that can replace FCS to promote cell proliferation. It can outdo FCS, especially when adopted in primary cultures from tissue biopsies. Moreover, the dual component nature of the supplement allows the researcher to determine the more appropriate ratio of the two components for the nutritional and functional requirements of the cell type of interest. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Binding affinities of vascular endothelial growth factor (VEGF) for heparin-derived oligosaccharides

PubMed Central

Zhao, Wenjing; McCallum, Scott A.; Xiao, Zhongping; Zhang, Fuming; Linhardt, Robert J.

2011-01-01

Heparin and heparan sulphate (HS) exert their wide range of biological activities by interacting with extracellular protein ligands. Among these important protein ligands are various angiogenic growth factors and cytokines. HS-binding to vascular endothelial growth factor (VEGF) regulates multiple aspects of vascular development and function through its specific interaction with HS. Many studies have focused on HS-derived or HS-mimicking structures for the characterization of VEGF165 interaction with HS. Using a heparinase 1-prepared small library of heparin-derived oligosaccharides ranging from hexasaccharide to octadecasaccharide, we systematically investigated the heparin-specific structural features required for VEGF binding. We report the apparent affinities for the association between the heparin-derived oligosaccharides with both VEGF165 and VEGF55, a peptide construct encompassing exclusively the heparin-binding domain of VEGF165. An octasaccharide was the minimum size of oligosaccharide within the library to efficiently bind to both forms of VEGF and that a tetradecasaccharide displayed an effective binding affinity to VEGF165 comparable to unfractionated heparin. The range of relative apparent binding affinities among VEGF and the panel of heparin-derived oligosaccharides demonstrate that VEGF binding affinity likely depends on the specific structural features of these oligosaccharides including their degree of sulphation and sugar ring stereochemistry and conformation. Notably, the unique 3-O-sulpho group found within the specific antithrombin binding site of heparin is not required for VEGF165 binding. These findings afford new insight into the inherent kinetics and affinities for VEGF association with heparin and heparin-derived oligosaccharides with key residue specific modifications and may potentially benefit the future design of oligosaccharide-based anti-angiogenesis drugs. PMID:21658003

Erythroid Kruppel-like factor (EKLF) is recruited to the γ-globin gene promoter as a co-activator and is required for γ-globin gene induction by short-chain fatty acid derivatives

PubMed Central

Perrine, Susan P.; Mankidy, Rishikesh; Boosalis, Michael S.; Bieker, James J.; Faller, Douglas V.

2011-01-01

Objectives The erythroid Kruppel-like factor (EKLF) is an essential transcription factor for β-type globin gene switching, and specifically activates transcription of the adult β-globin gene promoter. We sought to determine if EKLF is also required for activation of the γ-globin gene by short-chain fatty acid (SCFA) derivatives, which are now entering clinical trials. Methods The functional and physical interaction of EKLF and co-regulatory molecules with the endogenous human globin gene promoters was studied in primary human erythroid progenitors and cell lines, using chromatin immunoprecipitation (ChIP) assays and genetic manipulation of the levels of EKLF and co-regulators. Results and conclusions Knockdown of EKLF prevents SCFA-induced expression of the γ-globin promoter in a stably expressed μLCRβprRlucAγprFluc cassette, and prevents induction of the endogenous γ-globin gene in primary human erythroid progenitors. EKLF is actively recruited to endogenous γ-globin gene promoters after exposure of primary human erythroid progenitors, and murine hematopoietic cell lines, to SCFA derivatives. The core ATPase BRG1 subunit of the human SWI/WNF complex, a ubiquitous multimeric complex that regulates gene expression by remodeling nucleosomal structure, is also required for γ-globin gene induction by SCFA derivatives. BRG1 is actively recruited to the endogenous γ-globin promoter of primary human erythroid progenitors by exposure to SCFA derivatives, and this recruitment is dependent upon the presence of EKLF. These findings demonstrate that EKLF, and the co-activator BRG1, previously demonstrated to be required for definitive or adult erythropoietic patterns of globin gene expression, are co-opted by SCFA derivatives to activate the fetal globin genes. PMID:19220418

Structure and Measurement of Acculturation/Enculturation for Asian Americans Using the ARSMA-II

ERIC Educational Resources Information Center

Lee, Richard M.; Yoon, Eunju; Liu-Tom, Hsin-Tine Tina

2006-01-01

The structure and measurement of acculturation/enculturation was investigated on 2 Asian American samples. Factor analyses revealed similar 2-factor structures for both acculturation and enculturation. The factor-analytic-derived measure yielded scores with adequate reliability and marginal construct validity. Acculturation/enculturation…

A three-step approach for the derivation and validation of high-performing predictive models using an operational dataset: congestive heart failure readmission case study.

PubMed

AbdelRahman, Samir E; Zhang, Mingyuan; Bray, Bruce E; Kawamoto, Kensaku

2014-05-27

The aim of this study was to propose an analytical approach to develop high-performing predictive models for congestive heart failure (CHF) readmission using an operational dataset with incomplete records and changing data over time. Our analytical approach involves three steps: pre-processing, systematic model development, and risk factor analysis. For pre-processing, variables that were absent in >50% of records were removed. Moreover, the dataset was divided into a validation dataset and derivation datasets which were separated into three temporal subsets based on changes to the data over time. For systematic model development, using the different temporal datasets and the remaining explanatory variables, the models were developed by combining the use of various (i) statistical analyses to explore the relationships between the validation and the derivation datasets; (ii) adjustment methods for handling missing values; (iii) classifiers; (iv) feature selection methods; and (iv) discretization methods. We then selected the best derivation dataset and the models with the highest predictive performance. For risk factor analysis, factors in the highest-performing predictive models were analyzed and ranked using (i) statistical analyses of the best derivation dataset, (ii) feature rankers, and (iii) a newly developed algorithm to categorize risk factors as being strong, regular, or weak. The analysis dataset consisted of 2,787 CHF hospitalizations at University of Utah Health Care from January 2003 to June 2013. In this study, we used the complete-case analysis and mean-based imputation adjustment methods; the wrapper subset feature selection method; and four ranking strategies based on information gain, gain ratio, symmetrical uncertainty, and wrapper subset feature evaluators. The best-performing models resulted from the use of a complete-case analysis derivation dataset combined with the Class-Attribute Contingency Coefficient discretization method and a voting classifier which averaged the results of multi-nominal logistic regression and voting feature intervals classifiers. Of 42 final model risk factors, discharge disposition, discretized age, and indicators of anemia were the most significant. This model achieved a c-statistic of 86.8%. The proposed three-step analytical approach enhanced predictive model performance for CHF readmissions. It could potentially be leveraged to improve predictive model performance in other areas of clinical medicine.

Modification and Factor Analysis of the Grief Experience Inventory in Non-Death Loss/Bereavement Situations.

ERIC Educational Resources Information Center

Zinner, Ellen S.; And Others

1991-01-01

Administered Grief Experience Inventory (GEI) to 102 mothers of brain-injured adolescents and young adults across 3 years postinjury. Factor analysis of data was computed and compared to factors derived from original GEI General Reference Group (n=135). Found strikingly similar factor structures between modified nondeath form and original GEI.…

Development of a model using the MATLAB System identification toolbox to estimate (222)Rn equilibrium factor from CR-39 based passive measurements.

PubMed

Abo-Elmagd, M; Sadek, A M

2014-12-01

Can and Bare method is a widely used passive method for measuring the equilibrium factor F through the determination of the track density ratio between bare (D) and filtered (Do) detectors. The dimensions of the used diffusion chamber are altering the deposition ratios of Po-isotopes on the chamber walls as well as the ratios of the existing alpha emitters in air. Then the measured filtered track density and therefore the resultant equilibrium factor is changed according to the diffusion chamber dimensions. For this reason, high uncertainty was expected in the measured F using different diffusion chambers. In the present work, F is derived as a function of both track density ratio (D/Do) and the dimensions of the used diffusion chambers (its volume to the total internal surface area; V/A). The accuracy of the derived formula was verified using the black-box modeling technique via the MATLAB System identification toolbox. The results show that the uncertainty of the calculated F by using the derived formula of F (D/Do, V/A) is only 5%. The obtained uncertainty ensures the quality of the derived function to calculate F using diffusion chambers with wide range of dimensions. Copyright © 2014 Elsevier Ltd. All rights reserved.

CDDO and Its Role in Chronic Diseases.

PubMed

Mathis, Bryan J; Cui, Taixing

2016-01-01

There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional Chinese medicine used in hepatitis therapy, was modified by chemical processes to form 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO). This modification increased anti-inflammatory activity significantly and additional functional groups on the CDDO backbone have shown promise in treating conditions ranging from kidney disease to obesity to diabetes. CDDO's therapeutic effect is due to its upregulation of the master antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) through conformational change of Nrf2-repressing, Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and multiple animal and human studies have verified subsequent activation of Nrf2-controlled antioxidant genes via upstream Antioxidant Response Element (ARE) regions. At the present time, positive results have been obtained in the laboratory and clinical trials with CDDO derivatives treating conditions such as lung injury, inflammation and chronic kidney disease. However, clinical trials for cancer and cardiovascular disease have not shown equally positive results and further exploration of CDDO and its derivatives is needed to put these shortcomings into context for the purpose of future therapeutic modalities.

Characterization of Shikonin Derivative Secretion in Lithospermum erythrorhizon Hairy Roots as a Model of Lipid-Soluble Metabolite Secretion from Plants

PubMed Central

Tatsumi, Kanade; Yano, Mariko; Kaminade, Kenta; Sugiyama, Akifumi; Sato, Mayuko; Toyooka, Kiminori; Aoyama, Takashi; Sato, Fumihiko; Yazaki, Kazufumi

2016-01-01

Shikonin derivatives are specialized lipophilic metabolites, secreted in abundant amounts from the root epidermal cells of Lithospermum erythrorhizon. Because they have anti-microbial activities, these compounds, which are derivatives of red naphthoquinone, are thought to serve as a chemical barrier for plant roots. The mechanism by which they are secreted from cells is, however, largely unknown. The shikonin production system in L. erythrorhizon is an excellent model for studying the mechanism by which lipophilic compounds are secreted from plant cells, because of the abundant amounts of these compounds produced by L. erythrorhizon, the 0 to 100% inducibility of their production, the light-specific inhibition of production, and the visibility of these products as red pigments. To date, many factors regulating shikonin biosynthesis have been identified, but no mechanism that regulates shikonin secretion without inhibiting biosynthesis has been detected. This study showed that inhibitors of membrane traffic strongly inhibit shikonin secretion without inhibiting shikonin production, suggesting that the secretion of shikonin derivatives into the apoplast utilizes pathways common to the ADP-ribosylation factor/guanine nucleotide exchange factor (ARF/GEF) system and actin filament polymerization, at least in part. These findings provide clues about the machinery involved in secreting lipid-soluble metabolites from cells. PMID:27507975

Characterization of Shikonin Derivative Secretion in Lithospermum erythrorhizon Hairy Roots as a Model of Lipid-Soluble Metabolite Secretion from Plants.

PubMed

Tatsumi, Kanade; Yano, Mariko; Kaminade, Kenta; Sugiyama, Akifumi; Sato, Mayuko; Toyooka, Kiminori; Aoyama, Takashi; Sato, Fumihiko; Yazaki, Kazufumi

2016-01-01

Shikonin derivatives are specialized lipophilic metabolites, secreted in abundant amounts from the root epidermal cells of Lithospermum erythrorhizon. Because they have anti-microbial activities, these compounds, which are derivatives of red naphthoquinone, are thought to serve as a chemical barrier for plant roots. The mechanism by which they are secreted from cells is, however, largely unknown. The shikonin production system in L. erythrorhizon is an excellent model for studying the mechanism by which lipophilic compounds are secreted from plant cells, because of the abundant amounts of these compounds produced by L. erythrorhizon, the 0 to 100% inducibility of their production, the light-specific inhibition of production, and the visibility of these products as red pigments. To date, many factors regulating shikonin biosynthesis have been identified, but no mechanism that regulates shikonin secretion without inhibiting biosynthesis has been detected. This study showed that inhibitors of membrane traffic strongly inhibit shikonin secretion without inhibiting shikonin production, suggesting that the secretion of shikonin derivatives into the apoplast utilizes pathways common to the ADP-ribosylation factor/guanine nucleotide exchange factor (ARF/GEF) system and actin filament polymerization, at least in part. These findings provide clues about the machinery involved in secreting lipid-soluble metabolites from cells.

Effect of cigarette smoke on monocyte procoagulant activity: Focus on platelet-derived brain-derived neurotrophic factor (BDNF).

PubMed

Amadio, Patrizia; Baldassarre, Damiano; Sandrini, Leonardo; Weksler, Babette B; Tremoli, Elena; Barbieri, Silvia S

2017-01-01

Cigarette smoke (CS) activates platelets, promotes vascular dysfunction, and enhances Tissue Factor (TF) expression in blood monocytes favoring pro-thrombotic states. Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophins involved in survival, growth, and maturation of neurons, is released by activated platelets (APLTs) and plays a role in the cardiovascular system. The effect of CS on circulating levels of BDNF is controversial and the function of circulating BDNF in atherothrombosis is not fully understood. Here, we have shown that human platelets, treated with an aqueous extract of CS (CSE), released BDNF in a dose-dependent manner. In addition, incubation of human monocytes with BDNF or with the supernatant of platelets activated with CSE increased TF activity by a Tropomyosin receptor kinase B (TrkB)-dependent mechanism. Finally, comparing serum and plasma samples of 12 male never smokers (NS) and 29 male active smokers (AS) we observed a significant increase in microparticle-associated TF activity (MP-TF) as well as BDNF in AS, while in serum, BDNF behaved oppositely. Taken together these findings suggest that platelet-derived BDNF is involved in the regulation of TF activity and that CS plays a role in this pathway by favoring a pro-atherothrombotic state.

Validity of CBCL-derived PTSD and dissociation scales: further evidence in a sample of neglected children and adolescents.

PubMed

Milot, Tristan; Plamondon, André; Ethier, Louise S; Lemelin, Jean-Pascal; St-Laurent, Diane; Rousseau, Michel

2013-05-01

There is growing evidence that child neglect is an important risk factor for posttraumatic stress disorder (PTSD) and dissociation. Considering that the Child Behavior Checklist (CBCL) is a widely used measure, the possibility of using validated CBCL-derived trauma symptoms scales could be particularly useful to better understand how trauma symptoms develop among neglected children and adolescents. This study examined the factor structure of three CBCL-derived measures of PTSD and dissociation (namely, PTSD scale, Dissociation scale, and PTSD/Dissociation scale) in a sample of 239 neglected children and adolescents aged 6 to 18 years using the latest version of CBCL (CBCL 6-18). Evidence of convergent validity of these scales was also examined for participants aged 12 and under using two well-validated measures of PTSD and Dissociation: the Trauma Symptoms Checklist for Young Children and the Child Dissociation Checklist. Findings suggest that CBCL-derived measures of trauma symptoms, especially PTSD and Dissociations scales, may be of heuristic value in the study of trauma symptomatology in neglected samples. Factor structure and evidence of convergent validity were supported for these two scales. Results also provide further support to the well-established assumption that PTSD and dissociation are two related but different constructs.

Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth.

PubMed

Nakayama, H; Iohara, K; Hayashi, Y; Okuwa, Y; Kurita, K; Nakashima, M

2017-07-01

We have previously demonstrated that dental pulp stem cells (DPSCs) isolated from mature teeth by granulocyte colony-stimulating factor (G-CSF)-induced mobilization method can enhance angiogenesis/vasculogenesis and improve pulp regeneration when compared with colony-derived DPSCs. However, the efficacy of this method in immature teeth with root-formative stage has never been investigated. Therefore, the aim of this study was to examine the stemness, biological characteristics, and regeneration potential in mobilized DPSCs compared with colony-derived DPSCs from immature teeth. Mobilized DPSCs isolated from immature teeth were compared to colony-derived DPSCs using methods including flow cytometry, migration assays, mRNA expression of angiogenic/neurotrophic factor, and induced differentiation assays. They were also compared in trophic effects of the secretome. Regeneration potential was further compared in an ectopic tooth transplantation model. Mobilized DPSCs had higher migration ability and expressed more angiogenic/neurotrophic factors than DPSCs. The mobilized DPSC secretome produced a higher stimulatory effect on migration, immunomodulation, anti-apoptosis, endothelial differentiation, and neurite extension. In addition, vascularization and pulp regeneration potential were higher in mobilized DPSCs than in DPSCs. G-CSF-induced mobilization method enhances regeneration potential of colony-derived DPSCs from immature teeth. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ultrastructure and growth factor content of equine platelet-rich fibrin gels.

PubMed

Textor, Jamie A; Murphy, Kaitlin C; Leach, J Kent; Tablin, Fern

2014-04-01

To compare fiber diameter, pore area, compressive stiffness, gelation properties, and selected growth factor content of platelet-rich fibrin gels (PRFGs) and conventional fibrin gels (FGs). PRFGs and conventional FGs prepared from the blood of 10 healthy horses. Autologous fibrinogen was used to form conventional FGs. The PRFGs were formed from autologous platelet-rich plasma of various platelet concentrations (100 × 10³ platelets/μL, 250 × 10³ platelets/μL, 500 × 10³ platelets/μL, and 1,000 × 10³ platelets/μL). All gels contained an identical fibrinogen concentration (20 mg/mL). Fiber diameter and pore area were evaluated with scanning electron microscopy. Maximum gelation rate was assessed with spectrophotometry, and gel stiffness was determined by measuring the compressive modulus. Gel weights were measured serially over 14 days as an index of contraction (volume loss). Platelet-derived growth factor-BB and transforming growth factor-β1 concentrations were quantified with ELISAs. Fiber diameters were significantly larger and mean pore areas were significantly smaller in PRFGs than in conventional FGs. Gel weight decreased significantly over time, differed significantly between PRFGs and conventional FGs, and was significantly correlated with platelet concentration. Platelet-derived growth factor-BB and transforming growth factor-β1 concentrations were highest in gels and releasates derived from 1,000 × 10³ platelets/μL. The inclusion of platelets in FGs altered the architecture and increased the growth factor content of the resulting scaffold. Platelets may represent a useful means of modifying these gels for applications in veterinary and human regenerative medicine.

Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders

PubMed Central

Autry, Anita E.

2012-01-01

Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development. PMID:22407616

Are emissions of black carbon from gasoline vehicles underestimated? Insights from near and on-road measurements.

PubMed

Liggio, John; Gordon, Mark; Smallwood, Gregory; Li, Shao-Meng; Stroud, Craig; Staebler, Ralf; Lu, Gang; Lee, Patrick; Taylor, Brett; Brook, Jeffrey R

2012-05-01

Measurements of black carbon (BC) with a high-sensitivity laser-induced incandescence (HS-LII) instrument and a single particle soot photometer (SP2) were conducted upwind, downwind, and while driving on a highway dominated by gasoline vehicles. The results are used with concurrent CO(2) measurements to derive fuel-based BC emission factors for real-world average fleet and heavy-duty diesel vehicles separately. The derived emission factors from both instruments are compared, and a low SP2 bias (relative to the HS-LII) is found to be caused by a BC mass mode diameter less than 75 nm, that is most prominent with the gasoline fleet but is not present in the heavy-duty diesel vehicle exhaust on the highway. Results from both the LII and the SP2 demonstrate that the BC emission factors from gasoline vehicles are at least a factor of 2 higher than previous North American measurements, and a factor of 9 higher than currently used emission inventories in Canada, derived with the MOBILE 6.2C model. Conversely, the measured BC emission factor for heavy-duty diesel vehicles is in reasonable agreement with previous measurements. The results suggest that greater attention must be paid to black carbon from gasoline engines to obtain a full understanding of the impact of black carbon on air quality and climate and to devise appropriate mitigation strategies. © 2012 American Chemical Society

Calculating LOAEL/NOAEL uncertainty factors for wildlife species in ecological risk assessments

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

Suedel, B.C.; Clifford, P.A.; Ludwig, D.F.

1995-12-31

Terrestrial ecological risk assessments frequently require derivation of NOAELs or toxicity reference values (TRVS) against which to compare exposure estimates. However, much of the available information from the literature is LOAELS, not NOAELS. Lacking specific guidance, arbitrary factors of ten are sometimes employed for extrapolating NOAELs from LOAELs. In this study, the scientific literature was searched to obtain chronic and subchronic studies reporting NOAEL and LOAEL data for wildlife and laboratory species. Results to date indicate a mean conversion factor of 4.0 ({+-} 2.61 S.D.), with a minimum of 1. 6 and a maximum of 10 for 106 studies acrossmore » several classes of compounds (I.e., metals, pesticides, volatiles, etc.). These data suggest that an arbitrary factor of 10 conversion factor is unnecessarily restrictive for extrapolating NOAELs from LOAELs and that a factor of 4--5 would be more realistic for deriving toxicity reference values for wildlife species. Applying less arbitrary and more realistic conversion factors in ecological risk assessments will allow for a more accurate estimate of NOAEL values for assessing risk to wildlife populations.« less

A cyclic peptide derived from alpha-fetoprotein inhibits the proliferative effects of the epidermal growth factor and estradiol in MCF7 cells.

PubMed

Torres, Cristian; Antileo, Elmer; Epuñán, Maráa José; Pino, Ana María; Valladares, Luis Emilio; Sierralta, Walter Daniel

2008-06-01

A cyclic peptide derived from the active domain of alpha-fetoprotein (AFP) significantly inhibited the proliferation of MCF7 cells stimulated with the epidermal growth factor (EGF) or estradiol (E2). The action of these three agents on cell growth was independent of the presence of calf serum in the culture medium. Our results demonstrated that the cyclic peptide interfered markedly with the regulation of MAPK by activated c-erbB2. The cyclic peptide showed no effect on the E2-stimulated release of matrix metalloproteinases 2 and 9 nor on the shedding of heparin-binding EGF into the culture medium. We propose that the AFP-derived cyclic peptide represents a valuable novel antiproliferative agent for treating breast cancer.

A DFT study on surface-enhanced Raman spectroscopy of aromatic dithiol derivatives adsorbed on gold nanojunctions

NASA Astrophysics Data System (ADS)

You, Tingting; Lang, Xiufeng; Huang, Anping; Yin, Penggang

2018-01-01

A computational study on aromatic dithiol derivatives (HS-Ar-X-Ar-SH, X = O, S, Se, NH, CH2, Ndbnd N, CHdbnd CH, Ctbnd C) interacting with gold cluster(s) was presented to investigate the chemical enhancement mechanism related to surface-enhanced Raman spectroscopy (SERS) for molecular junctions. Density functional theory (DFT) were performed on derivatives molecules as well as their single-end-linked (SEL) or double-end-linked (DEL) complexes for geometric, spectra, electronic and excitation properties, leading to discussions on dominant factor during SERS process. The resulted enhancement factors of SEL and DEL complexes exhibited specific dependency on linking atom or functional group between two phenyls, which was in accordance with the variation of polarizabilities and molecule-cluster transition energy.

Platelet-Rich Plasma Derived Growth Factors Contribute to Stem Cell Differentiation in Musculoskeletal Regeneration.

PubMed

Qian, Yun; Han, Qixin; Chen, Wei; Song, Jialin; Zhao, Xiaotian; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

2017-01-01

Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of PRP derived GFs with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.

Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence

PubMed Central

Shanmugam, Muthu K.; Dai, Xiaoyun; Kumar, Alan Prem; Tan, Benny KH; Sethi, Gautam; Bishayee, Anupam

2014-01-01

Oleanolic acid (OA, 3β-hydroxyolean-12-en-28-oic acid) is a ubiquitous pentacyclic multifunctional triterpenoid, widely found in several dietary and medicinal plants. Natural and synthetic OA derivatives can modulate multiple signaling pathways including nuclear factor-κB, AKT, signal transducer and activator of transcription 3, mammalian target of rapamycin, caspases, intercellular adhesion molecule 1, vascular endothelial growth factor, and poly (ADP-ribose) polymerase in a variety of tumor cells. Importantly, synthetic derivative of OA, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), and its C-28 methyl ester (CDDO-Me) and C28 imidazole (CDDO-Im) have demonstrated potent antiangiogenic and antitumor activities in rodent cancer models. These agents are presently under evaluation in phase I studies in cancer patients. This review summarizes the diverse molecular targets of OA and its derivatives and also provides clear evidence on their promising potential in preclinical and clinical situations. PMID:24486850

Study on reduction and back extraction of Pu(IV) by urea derivatives in nitric acid conditions

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

Ye, G.A.; Xiao, S.T.; Yan, T.H.

2013-07-01

The reduction kinetics of Pu(IV) by hydroxyl-semicarbazide (HSC), hydroxyurea (HU) and di-hydroxyurea (DHU) in nitric acid solutions were investigated separately with adequate kinetic equations. In addition, counter-current cascade experiments were conducted for Pu split from U in nitric acid media using three kinds of reductant, respectively. The results show that urea derivatives as a kind of novel salt-free reductant can reduce Pu(IV) to Pu(III) rapidly in the nitric acid solutions. The stripping experimental results showed that Pu(IV) in the organic phase can be stripped rapidly to the aqueous phase by the urea derivatives, and the separation factors of plutonium /uraniummore » can reach more than 10{sup 4}. This indicates that urea derivatives is a kind of promising salt-free agent for uranium/plutonium separation. In addition, the complexing effect of HSC with Np(IV) was revealed, and Np(IV) can be back-extracted by HSC with a separation factor of about 20.« less

Factors, fiction and endothelium-derived hyperpolarizing factor.

PubMed

Sandow, Shaun L

2004-09-01

1. The principal mediators of vascular tone are neural, endothelial and physical stimuli that result in the initiation of dilator and constrictor responses to facilitate the control of blood pressure. Two primary vasodilatory stimuli produced by the endothelium are nitric oxide (NO) and prostaglandins. An additional endothelium-dependent vasodilatory mechanism is characterized as the hyperpolarization-mediated relaxation that remains after the inhibition of the synthesis of NO and prostaglandins. This mechanism is due to the action of a so-called endothelium-derived hyperpolarizing factor (EDHF) and is dependent on either the release of diffusible factor(s) and/or to a direct contact-mediated mechanism. 2. Most evidence supports the concept that 'EDHF' activity is dependent on contact-mediated mechanisms. This involves the transfer of an endothelium-derived electrical current, as an endothelium-derived hyperpolarization (EDH), through direct heterocellular coupling of endothelial cells and smooth muscle cells via myoendothelial gap junctions (MEGJ). However, there is a lack of consensus with regard to the nature and mechanism of action of EDHF/EDH (EDH(F)), which has been shown to vary within and between vascular beds, as well as among species, strains, sex and during development, ageing and disease. 3. In addition to actual heterogeneity in EDH(F), further heterogeneity has resulted from the less-than-optimal design, analysis and interpretation of data in some key papers in the EDHF literature; with such views being perpetuated in the subsequent literature. 4. The focus of the present brief review is to examine what factors are proposed as EDH(F) and highlight the correlative structural and functional studies from our laboratory that demonstrate an integral role for MEGJ in the conduction of EDH, which account for the heterogeneity in EDH(F), while incorporating the reported diffusible mechanisms in the regulation of this activity. Furthermore, in addition to the reported heterogeneity in the nature and mechanism of action of EDH(F), the contribution of experimental design and technique to this heterogeneity will be examined.

Platelet-Rich Blood Derivatives for Stem Cell-Based Tissue Engineering and Regeneration

PubMed Central

Kaushik, Gaurav; Leijten, Jeroen; Khademhosseini, Ali

2016-01-01

Platelet rich blood derivatives have been widely used in different fields of medicine and stem cell based tissue engineering. They represent natural cocktails of autologous growth factor, which could provide an alternative for recombinant protein based approaches. Platelet rich blood derivatives, such as platelet rich plasma, have consistently shown to potentiate stem cell proliferation, migration, and differentiation. Here, we review the spectrum of platelet rich blood derivatives, discuss their current applications in tissue engineering and regenerative medicine, reflect on their effect on stem cells, and highlight current translational challenges. PMID:27047733

Regulation of GluR2 promoter activity by neurotrophic factors via a neuron-restrictive silencer element.

PubMed

Brené, S; Messer, C; Okado, H; Hartley, M; Heinemann, S F; Nestler, E J

2000-05-01

The AMPA glutamate receptor subunit GluR2, which plays a critical role in regulation of AMPA channel function, shows altered levels of expression in vivo after several chronic perturbations. To evaluate the possibility that transcriptional mechanisms are involved, we studied a 1254-nucleotide fragment of the 5'-promoter region of the mouse GluR2 gene in neural-derived cell lines. We focused on regulation of GluR2 promoter activity by two neurotrophic factors, which are known to be altered in vivo in some of the same systems that show GluR2 regulation. Glial-cell line derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) both induced GluR2 promoter activity. This was associated with increased expression of endogenous GluR2 immunoreactivity in the cells as measured by Western blotting. The effect of GDNF and BDNF appeared to be mediated via a NRSE (neuron-restrictive silencer element) present within the GluR2 promoter. The response to these neurotrophic factors was lost upon mutating or deleting this site, but not several other putative response elements present within the promoter. Moreover, overexpression of REST (restrictive element silencer transcription factor; also referred to as NRSF or neuron restrictive silencer factor), which is known to act on NRSEs in other genes to repress gene expression, blocked the ability of GDNF to induce GluR2 promoter activity. However, GDNF did not alter endogenous levels of REST in the cells. Together, these findings suggest that GluR2 expression can be regulated by neurotrophic factors via an apparently novel mechanism involving the NRSE present within the GluR2 gene promoter.

The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1

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

Schindelhauer, D.; Schuffenhauer, S.; Meitinger, T.

1995-08-10

The gene coding for glial cell line derived neurotrophic factor (GDNF) has biological properties that may have potential as a treatment for Parkinson`s and motoneuron diseases. Using the NIGMS Mapping Panel 2, we have localized the GDNF gene to human chromosome 5p12-p13.1. Large NruI and NotI fragments on chromosome 5 will facilitate the construction of a long-range map of the region. 26 refs., 1 fig., 1 tab.

A new criterion for predicting rolling-element fatigue lives of through-hardened steels

NASA Technical Reports Server (NTRS)

Chevalier, J. L.; Zaretsky, E. V.; Parker, R. J.

1972-01-01

A carbide factor was derived based upon a statistical analysis which related rolling-element fatigue life to the total number of residual carbide particles per unit area, median residual carbide size, and percent residual carbide area. An equation was experimentally determined which predicts material hardness as a function of temperature. The limiting temperatures of all of the materials studied were dependent on initial room temperature hardness and tempering temperature. An equation was derived combining the effects of material hardness, carbide factor, and bearing temperature to predict rolling-element bearing life.

Method for computing a roughness factor for veneer surfaces

Treesearch

Chung-Yun Hse

1972-01-01

Equations for determining the roughness factor (ratio of true surface to apparent area) of rotary-cut veneer were derived from an assumed tracheid model. With data measured on southern pine veneers, the equations indicated that the roughness factor of latewood was near unity, whereas that of earlywood was about 2.

14 CFR 1214.813 - Computation of sharing and pricing parameters.

Code of Federal Regulations, 2012 CFR

2012-01-01

... paragraph of this section shall be applied as indicated. The procedure for computing Shuttle load factor, charge factor, and flight price for Spacelab payloads replaces the procedure contained in the Shuttle policy. (2) Shuttle charge factors as derived herein apply to the standard mission destination of 160 nmi...

14 CFR 1214.813 - Computation of sharing and pricing parameters.

Code of Federal Regulations, 2013 CFR

2013-01-01

... paragraph of this section shall be applied as indicated. The procedure for computing Shuttle load factor, charge factor, and flight price for Spacelab payloads replaces the procedure contained in the Shuttle policy. (2) Shuttle charge factors as derived herein apply to the standard mission destination of 160 nmi...

14 CFR § 1214.813 - Computation of sharing and pricing parameters.

Code of Federal Regulations, 2014 CFR

2014-01-01

... paragraph of this section shall be applied as indicated. The procedure for computing Shuttle load factor, charge factor, and flight price for Spacelab payloads replaces the procedure contained in the Shuttle policy. (2) Shuttle charge factors as derived herein apply to the standard mission destination of 160 nmi...

14 CFR 1214.813 - Computation of sharing and pricing parameters.

Code of Federal Regulations, 2011 CFR

2011-01-01

... paragraph of this section shall be applied as indicated. The procedure for computing Shuttle load factor, charge factor, and flight price for Spacelab payloads replaces the procedure contained in the Shuttle policy. (2) Shuttle charge factors as derived herein apply to the standard mission destination of 160 nmi...

Professional Identity, Career Commitment, and Career Entrenchment of Midlevel Student Affairs Professionals

ERIC Educational Resources Information Center

Wilson, Maureen E.; Liddell, Debora L.; Hirschy, Amy S.; Pasquesi, Kira

2016-01-01

The purposes of this study were to identify factors of midlevel student affairs administrators' professional identity and to examine the association of those factors to career commitment, career entrenchment, and demographic characteristics. Principal axis factor analysis derived 3 dimensions of professional identity: career contentment, community…

Glial cell line-derived neurotrophic factor and endothelial cells promote self-renewal of rabbit germ cells with spermatogonial stem cell properties.

PubMed

Kubota, Hiroshi; Wu, Xin; Goodyear, Shaun M; Avarbock, Mary R; Brinster, Ralph L

2011-08-01

Previous studies suggest that exogenous factors crucial for spermatogonial stem cell (SSC) self-renewal are conserved among several mammalian species. Since glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are critical for rodent SSC self-renewal, we hypothesized that they might promote self-renewal of nonrodent SSCs. Therefore, we cultured testicular germ cells from prepubertal rabbits in the presence of GDNF and FGF2 and found they proliferated indefinitely as cellular clumps that displayed characteristics previously identified for rodent SSCs. The rabbit germ cells could not be maintained on mouse embryonic fibroblast (STO) feeders that support rodent SSC self-renewal in vitro but were rather supported on mouse yolk sac-derived endothelial cell (C166) feeder layers. Proliferation of rabbit germ cells was dependent on GDNF. Of critical importance was that clump-forming rabbit germ cells colonized seminiferous tubules of immunodeficient mice, proliferated for at least 6 mo, while retaining an SSC phenotype in the testes of recipient mice, indicating that they were rabbit SSCs. This study demonstrates that GDNF is a mitogenic factor promoting self-renewal that is conserved between rodent and rabbit SSCs; with an evolutionary separation of ∼ 60 million years. These findings provide a foundation to study the mechanisms governing SSC self-renewal in nonrodent species.

First Insights into Human Fingertip Regeneration by Echo-Doppler Imaging and Wound Microenvironment Assessment.

PubMed

Jafari, Paris; Muller, Camillo; Grognuz, Anthony; Applegate, Lee Ann; Raffoul, Wassim; di Summa, Pietro G; Durand, Sébastien

2017-05-13

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome.

First Insights into Human Fingertip Regeneration by Echo-Doppler Imaging and Wound Microenvironment Assessment

PubMed Central

Jafari, Paris; Muller, Camillo; Grognuz, Anthony; Applegate, Lee Ann; Raffoul, Wassim; di Summa, Pietro G.; Durand, Sébastien

2017-01-01

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome. PMID:28505080

Induction of endothelial cell proliferation by angiogenic factors released by activated monocytes

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

Pakala, Rajbabu; Watanabe, Takuya; Benedict, Claude R

2002-06-01

Introduction: Cell-cell interaction is an essential component of atherosclerotic plaque development. Activated monocytes appear to play a central role in the development of atherosclerosis, not only through foam cell formation but also via the production of various growth factors that induce proliferation of different cell types that are involved in the plaque development. Using serum free co-culture method, we determined the effect of monocytes on endothelial cell proliferation. Methods: Endothelial cell proliferation is determined by the amount of [{sup 3}H]thymidine incorporated in to the DNA. Basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) levels inmore » the conditioned medium were determined by ELISA. Results: Conditioned medium from unactivated monocytes partially inhibited endothelial cell proliferation, whereas conditioned medium from activated monocytes promoted endothelial cell proliferation. The mitogenic effect of conditioned medium derived from activated monocytes is due to the presence of b-FGF, VEGF and IL-8. Neutralizing antibodies against b-FGF, VEGF and IL-8 partially reversed the mitogenic effect of conditioned medium derived from activated monocytes. When b-FGF, VEGF and IL-8 were immunoprecipitated from conditioned medium derived from activated monocytes, it is less mitogenic to endothelial cells. Conclusion: Activated monocytes may play an important role in the development of atherosclerotic plaque by producing endothelial cell growth factors.« less

Resistivity Correction Factor for the Four-Probe Method: Experiment II

NASA Astrophysics Data System (ADS)

Yamashita, Masato; Yamaguchi, Shoji; Nishii, Toshifumi; Kurihara, Hiroshi; Enjoji, Hideo

1989-05-01

Experimental verification of the theoretically derived resistivity correction factor F is presented. Factor F can be applied to a system consisting of a disk sample and a four-probe array. Measurements are made on isotropic graphite disks and crystalline ITO films. Factor F can correct the apparent variations of the data and lead to reasonable resistivities and sheet resistances. Here factor F is compared to other correction factors; i.e. FASTM and FJIS.

EVALUATING SOIL EROSION PARAMETER ESTIMATES FROM DIFFERENT DATA SOURCES

EPA Science Inventory

Topographic factors and soil loss estimates that were derived from thee data sources (STATSGO, 30-m DEM, and 3-arc second DEM) were compared. Slope magnitudes derived from the three data sources were consistently different. Slopes from the DEMs tended to provide a flattened sur...

Inhibitory Effects of the Four Main Theaflavin Derivatives Found in Black Tea on Ovarian Cancer Cells.

PubMed

Gao, Ying; Rankin, Gary O; Tu, Youying; Chen, Yi Charlie

2016-02-01

Some polyphenols induce apoptosis and inhibit angiogenesis. Consumption of black tea, rich in polyphenols, has been found to reduce ovarian cancer risk. Theaflavin (TF1), theaflavin-3-gallate (TF2a), theaflavin-3'-gallate (TF2b) and theaflavin-3, 3'-digallate (TF3) are four main theaflavin derivatives found in black tea. Cell proliferation assay, Hoechst 33342 staining assay, Caspase-Glo Assay, western blot, human umbilical vein endothelial cell tube formation assay and vascular endothelial growth factor (VEGF) enzyme-linked immunosorbent assay were performed. All four theaflavin derivatives reduced viability of ovarian cancer cells at lower concentrations than with normal ovarian cells. TF1 mainly mediated apoptosis via the intrinsic pathway, while the others via the intrinsic and extrinsic pathways. TF1 inhibited tube formation via reducing VEGF secretion in a hypoxia-inducible factor 1α-independent manner, while the others in a HIF1α-dependent way. All four theaflavin derivatives inhibited ovarian cancer cells. Some of the effects and mechanisms of TF1 are different from those of the other three theaflavin derivatives. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

NMDA receptor mediates proliferation and CREB phosphorylation in postnatal Müller glia-derived retinal progenitors

PubMed Central

Ramírez, Mónica

2009-01-01

Purpose Postnatal retinal Müller glia are considered to be retinal progenitors as they retain the ability to dedifferentiate, proliferate, and differentiate to new retinal glia and neurons after injury. The proliferation and differentiation processes are coordinated by several extrinsic factors and neurotransmitters, including glutamate. Thus, the appropriate numbers and proportions of the different cell types are generated to form a functional retina during development and during injury repair. Here we analyze the changes in the proliferation of postnatal Müller glia-derived progenitors after activation of the N-methyl-D-aspartate (NMDA) glutamate receptors. Methods Müller glia-derived progenitor cell cultures were characterized by immunocytochemistry with antibodies against the NR1 subunit of the NMDA receptor and the progenitor cell marker nestin. The effect of glutamate receptor agonists and antagonists on cell proliferation was analyzed by BrdU incorporation or Ki67 immunostaining, cell counting, and by immunolabeling of phosphorylated cAMP response element binding protein (P-CREB) transcription factor. The effect of NMDA receptor activation was analyzed in vivo by P-CREB immunohistochemistry in retinal sections of Long-Evans NMDA injected rats. Results We show that NMDA receptor activation significantly increases the proliferation rate of Müller-glia derived progenitor cells and that this increase can be blocked by NMDA receptor antagonists. Furthermore, we show that CREB phosphorylation is induced in NMDA-treated Müller-glia derived progenitor cells in culture and that specific pharmacological inhibition of CREB phosphorylation results in a decreased number of proliferating cells. We confirmed the relevance of these observations by the analysis of retinal sections after NMDA injection in vivo where immunoreactivity to phosphorylated CREB is also increased after treatment. Conclusions In the present study we show that NMDA receptor activation induces postnatal Müller glia-derived retinal cell progenitor proliferation and transcription factor CREB phosphorylation both in culture and in vivo. The identification of the molecular determinants of mature retinal progenitors such as transcription factor CREB and NMDA receptor-induced players should facilitate the control of growth and manipulation of progenitor cell cultures and the possible identification of the molecular mechanisms involved in progenitor self-renewal. PMID:19365572

Role of nitric oxide in progression and regression of atherosclerosis.

PubMed Central

Cooke, J P

1996-01-01

Endothelium-derived nitric oxide is a potent endogenous vasodilator that is derived from the metabolism of L-arginine. This endothelial factor inhibits circulating blood elements from interacting with the vessel wall. Platelet adherence and aggregation as well as monocyte adherence and infiltration are opposed by this paracrine substance. By virtue of these characteristics, endothelium-derived nitric oxide inhibits atherogenesis in animal models and may even induce regression. Images Figure 1. PMID:8686299

l-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

PubMed Central

Furuya, Shigeki; Tabata, Toshihide; Mitoma, Junya; Yamada, Keiko; Yamasaki, Miwako; Makino, Asami; Yamamoto, Toshifumi; Watanabe, Masahiko; Kano, Masanobu; Hirabayashi, Yoshio

2000-01-01

Glial cells support the survival and development of central neurons through the supply of trophic factors. Here we demonstrate that l-serine (l-Ser) and glycine (Gly) also are glia-derived trophic factors. These amino acids are released by astroglial cells and promote the survival, dendritogenesis, and electrophysiological development of cultured cerebellar Purkinje neurons. Although l-Ser and Gly are generally classified as nonessential amino acids, 3-phosphoglycerate dehydrogenase (3PGDH), a key enzyme for their biosynthesis, is not expressed in Purkinje neurons. By contrast, the Bergman glia, a native astroglia in the cerebellar cortex, highly expresses 3PGDH. These data suggest that l-Ser and Gly mediate the trophic actions of glial cells on Purkinje neurons. PMID:11016963

Effects of naringin, a flavanone glycoside in grapefruits and citrus fruits, on the nigrostriatal dopaminergic projection in the adult brain

PubMed Central

Jung, Un Ju; Kim, Sang Ryong

2014-01-01

Recently, we have demonstrated the ability of naringin, a well-known flavanone glycoside of grapefruits and citrus fruits, to prevent neurodegeneration in a neurotoxin model of Parkinson's disease. Intraperitoneal injection of naringin protected the nigrostriatal dopaminergic projection by increasing glial cell line-derived neurotrophic factor expression and decreasing the level of tumor necrosis factor-alpha in dopaminergic neurons and microglia, respectively. These results suggest that naringin can impart to the adult dopaminergic neurons the ability to produce glial cell line-derived neurotrophic factor against Parkinson's disease with anti-inflammatory effects. Based on these results, we would like to describe an important perspective on its possibility as a therapeutic agent for Parkinson's disease. PMID:25317167

Platelet-derived growth factor A mRNA in platelets is associated with the degree of hepatic fibrosis in chronic hepatitis C.

PubMed

Tanikawa, Aline Aki; Grotto, Rejane Maria Tommasini; Silva, Giovanni Faria; Ferrasi, Adriana Camargo; Sarnighausen, Valéria Cristina Rodrigues; Pardini, Maria Inês de Moura Campos

2017-01-01

Transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor (PDGF) are the main cytokines related to hepatic fibrogenesis. RNA isolated from the platelets and hepatic tissue of 43 HCV carriers was used for quantitative polymerase chain reaction to determine TGFB1, PDGFA, and PDGFB RNA expression. The mRNA expression of PDGFA in platelets was significantly lower in the group with advanced fibrosis than in the group with early-stage fibrosis. TGFB1 was more frequently expressed in platelets than in hepatic tissue, which was different from PDGFB. A pathway mediated by overexpression of TGFB1 via PDGFA in megakaryocytes could be involved in the development of fibrosis.

Development of an ex vivo cellular model of rheumatoid arthritis: critical role of CD14-positive monocyte/macrophages in the development of pannus tissue.

PubMed

Nozaki, Toshiko; Takahashi, Kyoko; Ishii, Osamu; Endo, Sachio; Hioki, Kyoji; Mori, Toshihito; Kikukawa, Tadahiro; Boumpas, Dimitrios T; Ozaki, Shoichi; Yamada, Hidehiro

2007-09-01

To establish an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue (ST). Inflammatory cells that infiltrated pannus tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST-derived inflammatory cells. Single-cell suspensions of ST-derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. ST-derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop pannus. CD14 and CD2 cells were depleted by negative selection. Culture of ST-derived inflammatory cells from 92 of 111 patients with RA resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks. Ex vivo tissue contained fibroblasts, macrophages, T cells, and tartrate-resistant acid phosphatase-positive multinucleated cells. On calcium phosphate-coated slides, ST-derived inflammatory cell cultures showed numerous resorption pits. ST-derived inflammatory cell cultures continuously produced matrix metalloproteinase 9 and proinflammatory cytokines associated with osteoclastogenesis, such as tumor necrosis factor alpha, interleukin-8, and macrophage colony-stimulating factor. More importantly, transferring ST-derived inflammatory cells into the joints of immunodeficient mice resulted in the development of pannus tissue and erosive joint lesions. Both in vitro development and in vivo development of pannus tissue by ST-derived inflammatory cells were inhibited by depleting CD14-positive, but not CD2-positive, cells from ST-derived inflammatory cells. These findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of pannus. This may prove informative in the screening of potential antirheumatic drugs.

Quantification of platelets and platelet derived growth factors from platelet-rich-plasma (PRP) prepared at different centrifugal force (g) and time.

PubMed

Arora, Satyam; Doda, Veena; Kotwal, Urvershi; Dogra, Mitu

2016-02-01

Platelet derived biomaterials represent a key source of cytokines and growth factors extensively used for tissue regeneration; wound healing and tissue repair. Our study was to quantify platelets and growth factors released by PRP when prepared at different centrifugal force (g) and time. Our study was approved by the institutional ethical committee. One hundred millilitres of whole blood (WB) was collected in bag with CPDA as the anticoagulant(AC); (14 mL for 100 mL WB ratio). Nine aliquots of 10 mL each were made from the bag and set of three aliquots were made a group. PRP was prepared at varying centrifugal force (group A: -110 g, group B: -208 g & group C: -440 g) & time (1: -5 min, 2: -10 min & 3: -20 min). Contents of each PRP prepared were analysed. Commercial sandwich ELISA kits were used to quantify the concentrations of CD62P (Diaclone SAS; France), Platelet derived growth factors-AB (Qayee-Bio; China), transforming growth factor-β1 (DRG; Germany) and vascular endothelial growth factor (Boster Immuno Leader; USA) released in each PRP prepared. Eight volunteers were enrolled in the study (24-30 years). The baseline blood counts of all the volunteers were comparable (p ≥ 0.05). Mean ± SD of platelet yield of all nine groups ranged from 17.2 ± 4.2% to 78.7 ± 5.7%. Each PRP was activated with calcified thromboplastin to quantify the growth factors released by them. Significantly higher (p < 0.05) transforming growth factor-β1 and vascular endothelial growth factor were released compared to the baseline. Our study highlights the variation in both force (g) and time results in changes at cellular level and growth factor concentrations. Copyright © 2016 Elsevier Ltd. All rights reserved.

The poor man's Geographic Information System: plot expansion factors

Treesearch

Paul C. Van Deusen

2007-01-01

Plot expansion factors can serve as a crude Geographic Information System for users of Forest Inventory and Analysis (FIA) data. Each FIA plot has an associated expansion factor that is often interpreted as the number of forested acres that the plot represents. The derivation of expansion factors is discussed and it is shown that the mapped plot design requires a...

Resistivity Correction Factor for the Four-Probe Method: Experiment III

NASA Astrophysics Data System (ADS)

Yamashita, Masato; Nishii, Toshifumi; Kurihara, Hiroshi; Enjoji, Hideo; Iwata, Atsushi

1990-04-01

Experimental verification of the theoretically derived resistivity correction factor F is presented. Factor F is applied to a system consisting of a rectangular parallelepiped sample and a square four-probe array. Resistivity and sheet resistance measurements are made on isotropic graphites and crystalline ITO films. Factor F corrects experimental data and leads to reasonable resistivity and sheet resistance.

The Construct Validity of Scores on the Ways of Coping Questionnaire: Confirmatory Analysis of Alternative Factor Structures.

ERIC Educational Resources Information Center

Edwards, Jeffrey R.; O'Neill, Regina M.

1998-01-01

Confirmatory factor analysis was used to evaluate alternative factor structures, based on previous exploratory factor analyses and coping dimensions derived from the theory of R. Lazarus, for the Ways of Coping Questionnaire (S. Folkman and R. Lazarus, 1988). Results from responses of 654 college graduates provide little support for the factor…

Indirect estimation of emission factors for phosphate surface mining using air dispersion modeling.

PubMed

Tartakovsky, Dmitry; Stern, Eli; Broday, David M

2016-06-15

To date, phosphate surface mining suffers from lack of reliable emission factors. Due to complete absence of data to derive emissions factors, we developed a methodology for estimating them indirectly by studying a range of possible emission factors for surface phosphate mining operations and comparing AERMOD calculated concentrations to concentrations measured around the mine. We applied this approach for the Khneifiss phosphate mine, Syria, and the Al-Hassa and Al-Abyad phosphate mines, Jordan. The work accounts for numerous model unknowns and parameter uncertainties by applying prudent assumptions concerning the parameter values. Our results suggest that the net mining operations (bulldozing, grading and dragline) contribute rather little to ambient TSP concentrations in comparison to phosphate processing and transport. Based on our results, the common practice of deriving the emission rates for phosphate mining operations from the US EPA emission factors for surface coal mining or from the default emission factor of the EEA seems to be reasonable. Yet, since multiple factors affect dispersion from surface phosphate mines, a range of emission factors, rather than only a single value, was found to satisfy the model performance. Copyright © 2016 Elsevier B.V. All rights reserved.

Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor-1.

PubMed

Mooney, R A; Freund, G G; Way, B A; Bordwell, K L

1992-11-25

Tyrosine phosphorylation is a mechanism of signal transduction shared by many growth factor receptors and oncogene products. Phosphotyrosine phosphatases (PTPases) potentially modulate or counter-regulate these signaling pathways. To test this hypothesis, the transmembrane PTPase CD45 (leukocyte common antigen) was expressed in the murine cell line C127. Hormone-dependent autophosphorylation of the platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1) receptors was markedly reduced in cells expressing the transmembrane PTPase. Tyrosine phosphorylation of other PDGF-dependent phosphoproteins (160, 140, and 55 kDa) and IGF-1-dependent phosphoproteins (145 kDa) was similarly decreased. Interestingly, the pattern of growth factor-independent tyrosine phosphorylations was comparable in cells expressing the PTPase and control cells. This suggests a selectivity or accessibility of the PTPase limited to a subset of cellular phosphotyrosyl proteins. The maximum mitogenic response to PDGF and IGF-1 in cells expressing the PTPase was decreased by 67 and 71%, respectively. These results demonstrate that a transmembrane PTPase can both affect the tyrosine phosphorylation state of growth factor receptors and modulate proximal and distal cellular responses to the growth factors.

Assessing plant senescence reflectance index-retrieved vegetation phenology and its spatiotemporal response to climate change in the Inner Mongolian Grassland.

PubMed

Ren, Shilong; Chen, Xiaoqiu; An, Shuai

2017-04-01

Plant phenology is a key link for controlling interactions between climate change and biogeochemical cycles. Satellite-derived normalized difference vegetation index (NDVI) has been extensively used to detect plant phenology at regional scales. Here, we introduced a new vegetation index, plant senescence reflectance index (PSRI), and determined PSRI-derived start (SOS) and end (EOS) dates of the growing season using Moderate Resolution Imaging Spectroradiometer data from 2000 to 2011 in the Inner Mongolian Grassland. Then, we validated the reliability of PSRI-derived SOS and EOS dates using NDVI-derived SOS and EOS dates. Moreover, we conducted temporal and spatial correlation analyses between PSRI-derived SOS/EOS date and climatic factors and revealed spatiotemporal patterns of PSRI-derived SOS and EOS dates across the entire research region at pixel scales. Results show that PSRI has similar performance with NDVI in extracting SOS and EOS dates in the Inner Mongolian Grassland. Precipitation regime is the key climate driver of interannual variation of grassland phenology, while temperature and precipitation regimes are the crucial controlling factors of spatial differentiation of grassland phenology. Thus, PSRI-derived vegetation phenology can effectively reflect land surface vegetation dynamics and its response to climate change. Moreover, a significant linear trend of PSRI-derived SOS and EOS dates was detected only at small portions of pixels, which is consistent with that of greenup and brownoff dates of herbaceous plant species in the Inner Mongolian Grassland. Overall, PSRI is a useful and robust metric in addition to NDVI for monitoring land surface grassland phenology.

Assessing plant senescence reflectance index-retrieved vegetation phenology and its spatiotemporal response to climate change in the Inner Mongolian Grassland

NASA Astrophysics Data System (ADS)

Ren, Shilong; Chen, Xiaoqiu; An, Shuai

2017-04-01

Plant phenology is a key link for controlling interactions between climate change and biogeochemical cycles. Satellite-derived normalized difference vegetation index (NDVI) has been extensively used to detect plant phenology at regional scales. Here, we introduced a new vegetation index, plant senescence reflectance index (PSRI), and determined PSRI-derived start (SOS) and end (EOS) dates of the growing season using Moderate Resolution Imaging Spectroradiometer data from 2000 to 2011 in the Inner Mongolian Grassland. Then, we validated the reliability of PSRI-derived SOS and EOS dates using NDVI-derived SOS and EOS dates. Moreover, we conducted temporal and spatial correlation analyses between PSRI-derived SOS/EOS date and climatic factors and revealed spatiotemporal patterns of PSRI-derived SOS and EOS dates across the entire research region at pixel scales. Results show that PSRI has similar performance with NDVI in extracting SOS and EOS dates in the Inner Mongolian Grassland. Precipitation regime is the key climate driver of interannual variation of grassland phenology, while temperature and precipitation regimes are the crucial controlling factors of spatial differentiation of grassland phenology. Thus, PSRI-derived vegetation phenology can effectively reflect land surface vegetation dynamics and its response to climate change. Moreover, a significant linear trend of PSRI-derived SOS and EOS dates was detected only at small portions of pixels, which is consistent with that of greenup and brownoff dates of herbaceous plant species in the Inner Mongolian Grassland. Overall, PSRI is a useful and robust metric in addition to NDVI for monitoring land surface grassland phenology.

Source apportionment of organic compounds in Berlin using positive matrix factorization - assessing the impact of biogenic aerosol and biomass burning on urban particulate matter.

PubMed

Wagener, Sandra; Langner, Marcel; Hansen, Ute; Moriske, Heinz-Jörn; Endlicher, Wilfried R

2012-10-01

Source apportionment of 13 organic compounds, elemental carbon and organic carbon of ambient PM(10) and PM(1) was performed with positive matrix factorization (PMF). Samples were collected at three sites characterized by different vegetation influences in Berlin, Germany in 2010. The aim was to determine organic, mainly biogenic sources and their impact on urban aerosol collected in a densely populated region. A 6-factor solution provided the best data fit for both PM-fractions, allowing the sources isoprene- and α-pinene-derived secondary organic aerosol (SOA), bio primary, primarily attributable to fungal spores, bio/urban primary including plant fragments in PM(10) and cooking and traffic emissions in PM(1), biomass burning and combustion fossil to be identified. With mean concentrations up to 2.6 μg Cm(-3), biomass burning dominated the organic fraction in cooler months. Concentrations for α-pinene-derived SOA exceeded isoprene-derived concentrations. Estimated secondary organic carbon contributions to total organic carbon (OC) were between 7% and 42% in PM(10) and between 11% and 60% in PM(1), which is slightly lower than observed for US- or Asian cities. Primary biogenic emissions reached up to 33% of OC in the PM(10)-fraction in the late summer and autumn months. Temperature-dependence was found for both SOA-factors, correlations with ozone and mix depth only for the α-pinene-derived SOA-factor. Latter indicated input of α-pinene from the borders, highlighting differences in the origin of the precursors of both factors. Most factors were regionally distributed. High regional distribution was found to be associated with stronger influence of ambient parameters and higher concentrations at the background station. A significant contribution of biogenic emissions and biomass burning to urban organic aerosol could be stated. This indicates a considerable impact on PM concentrations also in cities in a densely populated area, and should draw the attention concerning health aspects not only to cardio-vascular diseases but also to allergy issues. Copyright © 2012 Elsevier B.V. All rights reserved.

Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

PubMed

Kumar, B V S Suneel; Lakshmi, Narasu; Kumar, M Ravi; Rambabu, Gundla; Manjashetty, Thimmappa H; Arunasree, Kalle M; Sriram, Dharmarajan; Ramkumar, Kavya; Neamati, Nouri; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Several fibroblast growth factors are expressed during pre-attachment bovine conceptus development and regulate interferon-tau expression from trophectoderm.

PubMed

Cooke, Flavia N T; Pennington, Kathleen A; Yang, Qien; Ealy, Alan D

2009-02-01

The trophectoderm-derived factor interferon tau (IFNT) maintains the uterus in a pregnancy-receptive state in cattle and sheep. Fibroblast growth factors (FGFs) are implicated in regulating IFNT expression and potentially other critical events associated with early conceptus development in cattle. The overall objectives of this work were to identify the various FGFs and FGF receptors (FGFRs) expressed in elongating pre-attachment bovine conceptuses and determine if these FGFs regulate conceptus development and/or mediate IFNT production. In vitro-derived bovine blastocysts and in vivo-derived elongated conceptuses collected at day 17 of pregnancy express at least four FGFR subtypes (R1c, R2b, R3c, R4). In addition, transcripts for FGF1, 2, and 10 but not FGF7 are present in elongated bovine conceptuses. The expression pattern of FGF10 most closely resembled that of IFNT, with both transcripts remaining low in day 8 and day 11 conceptuses and increasing substantially in day 14 and day 17 conceptuses. Supplementation with recombinant FGF1, 2 or 10 increased IFNT mRNA levels in bovine trophectoderm cells and bovine blastocysts and increased IFNT protein concentrations in trophectoderm-conditioned medium. Blastocyst development was not affected by any of the FGFs. In summary, at least four FGFRs reside in pre- and peri-attachment bovine conceptuses. Moreover, conceptuses express at least three candidate FGFs during elongation, the time of peak IFNT expression. These findings provide new insight for how conceptus-derived factors such as FGF1, 2, and 10 may control IFNT expression during early pregnancy in cattle.

Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells

PubMed Central

Kozhevnikova, Mariya; König, Niclas; Zhou, Chunfang; Leao, Richardson; Knöpfel, Thomas; Pankratova, Stanislava; Trolle, Carl; Berezin, Vladimir; Bock, Elisabeth; Aldskogius, Håkan

2013-01-01

Stem cell transplantation holds great hope for the replacement of damaged cells in the nervous system. However, poor long-term survival after transplantation and insufficiently robust differentiation of stem cells into specialized cell types in vivo remain major obstacles for clinical application. Here, we report the development of a novel technological approach for the local delivery of exogenous trophic factor mimetics to transplanted cells using specifically designed silica nanoporous particles. We demonstrated that delivering Cintrofin and Gliafin, established peptide mimetics of the ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, respectively, with these particles enabled not only robust functional differentiation of motor neurons from transplanted embryonic stem cells but also their long-term survival in vivo. We propose that the delivery of growth factors by mesoporous nanoparticles is a potentially versatile and widely applicable strategy for efficient differentiation and functional integration of stem cell derivatives upon transplantation. PMID:24089415

The development of human mast cells. An historical reappraisal

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

Ribatti, Domenico, E-mail: domenico.ribatti@uniba.it

2016-03-15

The understanding of mast cell (MC) differentiation is derived mainly from in vitro studies of different stages of stem and progenitor cells. The hematopoietic lineage development of human MCs is unique compared to other myeloid-derived cells. Human MCs originate from CD34{sup +}/CD117{sup +}/CD13{sup +}multipotent hematopoietic progenitors, which undergo transendothelial recruitment into peripheral tissues, where they complete differentiation. Stem cell factor (SCF) is a major chemotactic factor for MCs and their progenitors. SCF also elicits cell-cell and cell-substratum adhesion, facilitates the proliferation, and sustains the survival, differentiation, and maturation, of MCs. Because MC maturation is influenced by local microenvironmental factors, differentmore » MC phenotypes can develop in different tissues and organs. - Highlights: • Human mast cells originate from CD34/CD117/CD13 positive multipotent hematopoietic progenitors. • Stem cell factor is a major chemotactic factor for mast cells and their progenitors. • Different mast cell phenotypes can develop in different tissues and organs.« less

Basic Aspects of Tumor Cell Fatty Acid-Regulated Signaling and Transcription Factors

PubMed Central

Comba, Andrea; Lin, Yi-Hui; Eynard, Aldo Renato; Valentich, Mirta Ana; Fernandez-Zapico, Martin Ernesto; Pasqualini, Marìa Eugenia

2012-01-01

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids (PUFAs) of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P-450 (CYP-450), seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator–activated receptors (PPARs) or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C [PKC]) and other transcription factors (nuclear factor kappa B [NFκB] and sterol regulatory element binding protein [SREBP]). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer, and provide insight into the development of new therapeutic strategies for a better management of whole-body lipid metabolism. PMID:22048864

Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors.

PubMed

Comba, Andrea; Lin, Yi-Hui; Eynard, Aldo Renato; Valentich, Mirta Ana; Fernandez-Zapico, Martín Ernesto; Pasqualini, Marìa Eugenia

2011-12-01

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases, cyclooxygenases, and cytochrome P-450, seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator-activated receptors or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C) and other transcription factors (nuclear factor kappa B and sterol regulatory element binding protein). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer and provide insight into the development of new therapeutic strategies for a better management of whole body lipid metabolism.

Update of Neurotrophic Factors in Neurobiology of Addiction and Future Directions

PubMed Central

Koskela, Maryna; Bäck, Susanne; Võikar, Vootele; Richie, Christopher T.; Domanskyi, Andrii; Harvey, Brandon K.; Airavaara, Mikko

2016-01-01

Drug addiction is a chronic brain disease and drugs of abuse cause long lasting neuroadaptations. Addiction is characterized by the loss of control over drug use despite harmful consequences, and high rates of relapse even after long periods of abstinence. Neurotrophic factors (NTFs) are well known for their actions on neuronal survival in the peripheral nervous system. Moreover, NTFs have been shown to be involved in synaptic plasticity in the brain. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are two of the most studied NTFs and both of them have been reported to increase craving when administered into the mesocorticolimbic dopaminergic system after drug self-administration. Here we review recent data on BDNF and GDNF functions in addiction-related behavior and discuss them in relation to previous findings. Finally, we give an insight into how new technologies could aid in further elucidating the role of these factors in drug addiction. PMID:27189755

BODY SIZE-SPECIFIC EFFECTIVE DOSE CONVERSION COEFFICIENTS FOR CT SCANS.

PubMed

Romanyukha, Anna; Folio, Les; Lamart, Stephanie; Simon, Steven L; Lee, Choonsik

2016-12-01

Effective dose from computed tomography (CT) examinations is usually estimated using the scanner-provided dose-length product and using conversion factors, also known as k-factors, which correspond to scan regions and differ by age according to five categories: 0, 1, 5, 10 y and adult. However, patients often deviate from the standard body size on which the conversion factor is based. In this study, a method for deriving body size-specific k-factors is presented, which can be determined from a simple regression curve based on patient diameter at the centre of the scan range. Using the International Commission on Radiological Protection reference paediatric and adult computational phantoms paired with Monte Carlo simulation of CT X-ray beams, the authors derived a regression-based k-factor model for the following CT scan types: head-neck, head, neck, chest, abdomen, pelvis, abdomen-pelvis (AP) and chest-abdomen-pelvis (CAP). The resulting regression functions were applied to a total of 105 paediatric and 279 adult CT scans randomly sampled from patients who underwent chest, AP and CAP scans at the National Institutes of Health Clinical Center. The authors have calculated and compared the effective doses derived from the conventional age-specific k-factors with the values computed using their body size-specific k-factor. They found that by using the age-specific k-factor, paediatric patients tend to have underestimates (up to 3-fold) of effective dose, while underweight and overweight adult patients tend to have underestimates (up to 2.6-fold) and overestimates (up to 4.6-fold) of effective dose, respectively, compared with the effective dose determined from their body size-dependent factors. The authors present these size-specific k-factors as an alternative to the existing age-specific factors. The body size-specific k-factor will assess effective dose more precisely and on a more individual level than the conventional age-specific k-factors and, hence, improve awareness of the true exposure, which is important for the clinical community to understand. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Restoring and Enhancing Productivity of Degraded Tephra-Derived Soils

Treesearch

Chuck Bulmer; Jim Archuleta; Mike Curran

2007-01-01

Soil restoration (sometimes termed enhancement) is an important strategy for sustaining the productivity of managed forest landscapes. Tephra-derived soils have unique physical and chemical characteristics that affect their response to disturbance and restoration. A variety of factors reduce forest productivity on degraded soils. Site-specific information on soil...

Metabolically-Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates (External Review Draft)

EPA Science Inventory

EPA has released a draft report entitled, Metabolically-Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates, for independent external peer review and public comment. NCEA published the Exposure Factors Handbook in 1997. This comprehens...

Efficient Molecular Organic Light-Emitting Diodes Based on Silole Derivatives

DTIC Science & Technology

2003-01-01

TPD) and tris-(8-hydroxyquinoline) aluminum ( Alq3 ), commonly used in MOLEDs, have hole and electron mobilities that differ by a factor of ~1000 (~10...and subsequent device degradation. In addition to the widely used electron transporter Alq3 , [8] derivatives of nathrolines, [7] oxadiazoles, [9

Knowledge of Some Derivational Processes in Two Samples of Bilingual Children

ERIC Educational Resources Information Center

Marckworth, M. Lois

1978-01-01

A report on a study concerning the bilingual child in a monolingual community. It investigates the acquisition of a set of English derivational morphemes by bilingual children and the effect of external factors, such as school, exposure time, age and home, in the children's language experience. (AMH)

Adipose-derived stem cells and periodontal tissue engineering.

PubMed

Tobita, Morikuni; Mizuno, Hiroshi

2013-01-01

Innovative developments in the multidisciplinary field of tissue engineering have yielded various implementation strategies and the possibility of functional tissue regeneration. Technologic advances in the combination of stem cells, biomaterials, and growth factors have created unique opportunities to fabricate tissues in vivo and in vitro. The therapeutic potential of human multipotent mesenchymal stem cells (MSCs), which are harvested from bone marrow and adipose tissue, has generated increasing interest in a wide variety of biomedical disciplines. These cells can differentiate into a variety of tissue types, including bone, cartilage, fat, and nerve tissue. Adipose-derived stem cells have some advantages compared with other sources of stem cells, most notably that a large number of cells can be easily and quickly isolated from adipose tissue. In current clinical therapy for periodontal tissue regeneration, several methods have been developed and applied either alone or in combination, such as enamel matrix proteins, guided tissue regeneration, autologous/allogeneic/xenogeneic bone grafts, and growth factors. However, there are various limitations and shortcomings for periodontal tissue regeneration using current methods. Recently, periodontal tissue regeneration using MSCs has been examined in some animal models. This method has potential in the regeneration of functional periodontal tissues because the various secreted growth factors from MSCs might not only promote the regeneration of periodontal tissue but also encourage neovascularization of the damaged tissues. Adipose-derived stem cells are especially effective for neovascularization compared with other MSC sources. In this review, the possibility and potential of adipose-derived stem cells for regenerative medicine are introduced. Of particular interest, periodontal tissue regeneration with adipose-derived stem cells is discussed.

Stimulation of Skin and Wound Fibroblast Migration by Mesenchymal Stem Cells Derived from Normal Donors and Chronic Wound Patients

PubMed Central

Rodriguez-Menocal, Luis; Salgado, Marcela; Ford, Dwayne

2012-01-01

Chronic wounds continue to be a major cause of morbidity for patients and an economic burden on the health care system. Novel therapeutic approaches to improved wound healing will need, however, to address cellular changes induced by a number of systemic comorbidities seen in chronic wound patients, such as diabetes, chronic renal failure, and arterial or venous insufficiency. These effects likely include impaired inflammatory cell migration, reduced growth factor production, and poor tissue remodeling. The multifunctional properties of bone marrow-derived mesenchymal stem cells (MSCs), including their ability to differentiate into various cell types and capacity to secrete factors important in accelerating healing of cutaneous wounds, have made MSCs a promising agent for tissue repair and regeneration. In this study we have used an in vitro scratch assay procedure incorporating labeled MSCs and fibroblasts derived from normal donors and chronic wound patients in order to characterize the induction of mobilization when these cells are mixed. A modified Boyden chamber assay was also used to examine the effect of soluble factors on fibroblast migration. These studies suggest that MSCs play a role in skin wound closure by affecting dermal fibroblast migration in a dose-dependent manner. Deficiencies were noted, however, in chronic wound patient fibroblasts and MSCs as compared with those derived from normal donors. These findings provide a foundation to develop therapies targeted specifically to the use of bone marrow-derived MSCs in wound healing and may provide insight into why some wounds do not heal. PMID:23197781

Stage specific requirement of platelet-derived growth factor receptor-α in embryonic development.

PubMed

Qian, Chen; Wong, Carol Wing Yan; Wu, Zhongluan; He, Qiuming; Xia, Huimin; Tam, Paul Kwong Hang; Wong, Kenneth Kak Yuen; Lui, Vincent Chi Hang

2017-01-01

Platelet-derived growth factor receptor alpha (PDGFRα) is a cell-surface receptor tyrosine kinase for platelet-derived growth factors. Correct timing and level of Pdgfra expression is crucial for embryo development, and deletion of Pdgfra caused developmental defects of multiple endoderm and mesoderm derived structures, resulting in a complex phenotypes including orofacial cleft, spina bifida, rib deformities, and omphalocele in mice. However, it is not clear if deletion of Pdgfra at different embryonic stages differentially affects these structures. To address the temporal requirement of Pdgfra in embryonic development. We have deleted the Pdgfra in Pdgfra-expressing tissues at different embryonic stages in mice, examined and quantified the developmental anomalies. Current study showed that (i) conditional deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele, and (ii) the day of Pdgfra deletion influenced the combinations, incidence and severities of these anomalies. Deletion of Pdgfra caused apoptosis of Pdgfra-expressing tissues, and developmental defects of their derivatives. Orofacial cleft, spina bifida and omphalocele are among the commonest skeletal and abdominal wall defects of newborns, but their genetic etiologies are largely unknown. The remarkable resemblance of our conditional Pdgfra knockout embryos to theses human congenital anomalies, suggesting that dysregulated PDGFRA expression could cause these anomalies in human. Future work should aim at defining (a) the regulatory elements for the expression of the human PDGFRA during embryonic development, and (b) if mutations / sequence variations of these regulatory elements cause these anomalies.

Stimulation of skin and wound fibroblast migration by mesenchymal stem cells derived from normal donors and chronic wound patients.

PubMed

Rodriguez-Menocal, Luis; Salgado, Marcela; Ford, Dwayne; Van Badiavas, Evangelos

2012-03-01

Chronic wounds continue to be a major cause of morbidity for patients and an economic burden on the health care system. Novel therapeutic approaches to improved wound healing will need, however, to address cellular changes induced by a number of systemic comorbidities seen in chronic wound patients, such as diabetes, chronic renal failure, and arterial or venous insufficiency. These effects likely include impaired inflammatory cell migration, reduced growth factor production, and poor tissue remodeling. The multifunctional properties of bone marrow-derived mesenchymal stem cells (MSCs), including their ability to differentiate into various cell types and capacity to secrete factors important in accelerating healing of cutaneous wounds, have made MSCs a promising agent for tissue repair and regeneration. In this study we have used an in vitro scratch assay procedure incorporating labeled MSCs and fibroblasts derived from normal donors and chronic wound patients in order to characterize the induction of mobilization when these cells are mixed. A modified Boyden chamber assay was also used to examine the effect of soluble factors on fibroblast migration. These studies suggest that MSCs play a role in skin wound closure by affecting dermal fibroblast migration in a dose-dependent manner. Deficiencies were noted, however, in chronic wound patient fibroblasts and MSCs as compared with those derived from normal donors. These findings provide a foundation to develop therapies targeted specifically to the use of bone marrow-derived MSCs in wound healing and may provide insight into why some wounds do not heal.

Stromal cell derived factor-1alpha protects stem cell derived insulin-producing cells from glucotoxicity under high glucose conditions in-vitro and ameliorates drug induced diabetes in rats

PubMed Central

2013-01-01

Background Diabetes mellitus is affecting more than 300 million people worldwide. Current treatment strategies cannot prevent secondary complications. Stem cells due to their regenerative power have long been the attractive target for the cell-based therapies. Mesenchymal stem cells (MSCs) possess the ability to differentiate into several cell types and to escape immune recognition in vitro. MSCs can be differentiated into insulin-producing cells (IPCs) and could be an exciting therapy for diabetes but problems like poor engraftment and survivability need to be confronted. It was hypothesized that stromal cell derived factor- 1alpha (SDF-1alpha) will enhance therapeutic potential of stem cell derived IPCs by increasing their survival and proliferation rate. Methods Novel culture conditions were developed to differentiate bone marrow derived mesenchymal stem cells (BMSCs) into IPCs by using endocrine differentiation inducers and growth factors via a three stage protocol. In order to enhance their therapeutic potential, we preconditioned IPCs with SDF-1alpha. Results Our results showed that SDF-1alpha increases survival and proliferation of IPCs and protects them from glucotoxicity under high glucose conditions in vitro. SDF-1alpha also enhances the glucose responsive insulin secretion in IPCs in vitro. SDF-1alpha preconditioning reverses hyperglycemia and increase serum insulin in drug induced diabetic rats. Conclusions The differentiation of BMSCs into IPCs and enhancement of their therapeutic potential by SDF-1alpha preconditioning may contribute to cell based therapies for diabetes. PMID:23648189

Gasoline Composition in 2008

EPA Science Inventory

Gasoline composition in the U.S is determined by factors related to crude oil source, refinery capacity, geography and regulatory factors. Major regulation derived from the Clean Air Act and its amendments determines the benzene and former oxygenate requirements for reformulated...

Alcohol Enhances HIV Infection of Cord Blood Monocyte-Derived Macrophages

PubMed Central

Mastrogiannis, Dimitrios S.; Wang, Xu; Dai, Min; Li, Jieliang; Wang, Yizhong; Zhou, Yu; Sakarcan, Selin; Peña, Juliet Crystal; Ho, Wenzhe

2014-01-01

Alcohol consumption or alcohol abuse is common among pregnant HIV+ women and has been identified as a potential behavioral risk factor for the transmission of HIV. In this study, we examined the impact of alcohol on HIV infection of cord blood monocyte-derived macrophages (CBMDM). We demonstrated that alcohol treatment of CBMDM significantly enhanced HIV infection of CBMDM. Investigation of the mechanisms of alcohol action on HIV demonstrated that alcohol inhibited the expression of several HIV restriction factors, including anti-HIV microRNAs, APOBEC3G and APOBEC3H. Additionally, alcohol also suppressed the expression of IFN regulatory factor 7 (IRF-7) and retinoic acid-inducible gene I (RIG-I), an intracellular sensor of viral infection. The suppression of these IFN regulatory factors was associated with reduced expression of type I IFN. These experimental findings suggest that maternal alcohol consumption may facilitate HIV infection, promoting vertical transmission of HIV. PMID:25053361

Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

PubMed Central

Mariga, Abigail; Mitre, Mariela; Chao, Moses V.

2017-01-01

Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease. PMID:27015693

Characteristic investigation of Golay9 multiple mirror telescope with a spherical primary mirror

NASA Astrophysics Data System (ADS)

Wu, Feng; Wu, Quanying; Zhu, Xifang; Xiang, Ruxi; Qian, Lin

2017-10-01

The sparse aperture provides a novel solution to the manufacturing difficulties of modern super large telescopes. Golay configurations are optimal in the sparse aperture family. Characteristics of the Golay9 multiple mirror telescope having a spherical primary mirror are investigated. The arrangement of the nine sub-mirrors is discussed after the planar Golay9 configuration is analyzed. The characteristics of the entrance pupil are derived by analyzing the sub-aperture shapes with different relative apertures and sub-mirror sizes. Formulas about the fill factor and the overlay factor are deduced. Their maximal values are presented based on the derived tangency condition. Formulas for the point spread function (PSF) and the modulation transfer function (MTF) of the Golay9 MMT are also deduced. Two Golay9 MMT have been developed by Zemax simulation. Their PSF, MTF, fill factors, and overlay factors prove that our theoretical results are consistent with the practical simulation ones.

Method for removing atomic-model bias in macromolecular crystallography

DOEpatents

Terwilliger, Thomas C [Santa Fe, NM

2006-08-01

Structure factor bias in an electron density map for an unknown crystallographic structure is minimized by using information in a first electron density map to elicit expected structure factor information. Observed structure factor amplitudes are combined with a starting set of crystallographic phases to form a first set of structure factors. A first electron density map is then derived and features of the first electron density map are identified to obtain expected distributions of electron density. Crystallographic phase probability distributions are established for possible crystallographic phases of reflection k, and the process is repeated as k is indexed through all of the plurality of reflections. An updated electron density map is derived from the crystallographic phase probability distributions for each one of the reflections. The entire process is then iterated to obtain a final set of crystallographic phases with minimum bias from known electron density maps.

Host Range Factor 1 from Lymantria dispar Nucleopolyhedrovirus (NPV) Is an Essential Viral Factor Required for Productive Infection of NPVs in IPLB-Ld652Y Cells Derived from L. dispar

PubMed Central

Ishikawa, Hiroki; Ikeda, Motoko; Felipe Alves, Cristiano A.; Thiem, Suzanne M.; Kobayashi, Michihiro

2004-01-01

Host range factor 1 (HRF-1) of Lymantria dispar multinucleocapsid nucleopolyhedrovirus promotes Autographa californica MNPV replication in nonpermissive Ld652Y cells derived from L. dispar. Here we demonstrate that restricted Hyphantria cunea NPV replication in Ld652Y cells was not due to apoptosis but was likely due to global protein synthesis arrest that could be restored by HRF-1. Our data also showed that HRF-1 promoted the production of progeny virions for two other baculoviruses, Bombyx mori NPV and Spodoptera exigua MNPV, whose replication in Ld652Y cells is limited to replication of viral DNA without successful production of infectious progeny virions. Thus, HRF-1 is an essential viral factor required for productive infection of NPVs in Ld652Y cells. PMID:15507661

Host range factor 1 from Lymantria dispar Nucleopolyhedrovirus (NPV) is an essential viral factor required for productive infection of NPVs in IPLB-Ld652Y cells derived from L. dispar.

PubMed

Ishikawa, Hiroki; Ikeda, Motoko; Alves, Cristiano A Felipe; Thiem, Suzanne M; Kobayashi, Michihiro

2004-11-01

Host range factor 1 (HRF-1) of Lymantria dispar multinucleocapsid nucleopolyhedrovirus promotes Autographa californica MNPV replication in nonpermissive Ld652Y cells derived from L. dispar. Here we demonstrate that restricted Hyphantria cunea NPV replication in Ld652Y cells was not due to apoptosis but was likely due to global protein synthesis arrest that could be restored by HRF-1. Our data also showed that HRF-1 promoted the production of progeny virions for two other baculoviruses, Bombyx mori NPV and Spodoptera exigua MNPV, whose replication in Ld652Y cells is limited to replication of viral DNA without successful production of infectious progeny virions. Thus, HRF-1 is an essential viral factor required for productive infection of NPVs in Ld652Y cells.

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

PubMed Central

Numakawa, Tadahiro; Odaka, Haruki; Adachi, Naoki

2017-01-01

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs. PMID:29099059

Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes.

PubMed

Mizuno, Tetsuya; Kuno, Reiko; Nitta, Atsumi; Nabeshima, Toshitaka; Zhang, Guiqin; Kawanokuchi, Jun; Wang, Jinyan; Jin, Shijie; Takeuchi, Hideyuki; Suzumura, Akio

2005-12-20

We examined the neuroprotective role of nicergoline in neuron-microglia or neuron-astrocytes co-cultures. Nicergoline, an ergoline derivative, significantly suppressed the neuronal cell death induced by co-culture with activated microglia or astrocytes stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To elucidate the mechanism by which nicergoline exerts a neuroprotective effect, we examined the production of inflammatory mediators and neurotrophic factors in activated microglia and astrocytes following nicergoline treatment. In microglia stimulated with LPS and IFN-gamma, nicergoline suppressed the production of superoxide anions, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in a dose-dependent manner. In astrocytes, nicergoline also suppressed the production of proinflammatory cytokines and enhanced brain-derived neurotrophic factor (BDNF). Thus, nicergoline-mediated neuroprotection resulted primarily from the inhibition of inflammatory mediators and the upregulation of neurotrophic factors by glial cells.

An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells.

PubMed

Shin, Jae-Yeon; Kong, Sun-Young; Yoon, Hye Jin; Ann, Jihyae; Lee, Jeewoo; Kim, Hyun-Jung

2015-07-01

P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2'-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.

Nonlocal modeling and buckling features of cracked nanobeams with von Karman nonlinearity

NASA Astrophysics Data System (ADS)

Akbarzadeh Khorshidi, Majid; Shaat, Mohamed; Abdelkefi, Abdessattar; Shariati, Mahmoud

2017-01-01

Buckling and postbuckling behaviors of cracked nanobeams made of single-crystalline nanomaterials are investigated. The nonlocal elasticity theory is used to model the nonlocal interatomic effects on the beam's performance accounting for the beam's axial stretching via von Karman nonlinear theory. The crack is then represented as torsional spring where the crack severity factor is derived accounting for the nonlocal features of the beam. By converting the beam into an equivalent infinite long plate with an edge crack subjected to a tensile stress at the far field, the crack energy release rate, intensity factor, and severity factor are derived according to the nonlocal elasticity theory. An analytical solution for the buckling and the postbuckling responses of cracked nonlocal nanobeams accounting for the beam axial stretching according to von Karman nonlinear theory of kinematics is derived. The impacts of the nonlocal parameter on the critical buckling loads and the static nonlinear postbuckling responses of cracked nonlocal nanobeams are studied. The results indicate that the buckling and postbuckling behaviors of cracked nanobeams are strongly affected by the crack location, crack depth, nonlocal parameter, and length-to-thickness ratio.

Role of endothelium-derived relaxing factors in adrenomedullin-induced vasodilation in the rat kidney.

PubMed

Wangensteen, Rosemary; Quesada, Andrés; Sainz, Juan; Duarte, Juan; Vargas, Félix; Osuna, Antonio

2002-05-24

The present study aimed to evaluate the contributions of endothelium-derived hyperpolarizing factor (EDHF), the nitric oxide (NO)-cGMP pathway, and prostaglandins to adrenomedullin-induced vasodilation in isolated rat kidney. Inhibition of the NO-cGMP pathway with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo-[4,3a]quinoxalin-1-one (ODQ) reduced the maximal vasodilator response to adrenomedullin by approximately 50%. Pretreatment of the vessels with the potassium channel inhibitor, tetraethylammonium or increased extracellular K(+), also decreased the maximal response to adrenomedullin by approximately 50%. The simultaneous administration of blockers of both endothelium-derived relaxing factors had a combined effect that almost suppressed adrenomedullin-induced vasodilation. The administration of indomethacin did not modify the renal response to adrenomedullin. Our results suggest that the vasodilator response to adrenomedullin in the isolated perfused kidney of rats is mediated by EDHF and NO to a similar extent. Our data also provide evidence that prostaglandins play no role in the vasodilator response to adrenomedullin in the renal vasculature.

The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin

PubMed Central

Choi, Wonseon; Wolber, Rainer; Gerwat, Wolfram; Mann, Tobias; Batzer, Jan; Smuda, Christoph; Liu, Hongfang; Kolbe, Ludger; Hearing, Vincent J.

2010-01-01

Interactions between melanocytes and neighboring cells in the skin are important in regulating skin color in humans. We recently demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. In this study, we tested the hypothesis that dermal fibroblasts regulate the constitutive skin color of individuals ranging from very light to very dark. We used microarray analysis to compare gene expression patterns in fibroblasts derived from lighter skin types compared to darker skin types, with a focus on secreted proteins. We identified a number of genes that differ dramatically in expression and, among the expressed proteins, neuregulin-1, which is secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting that it is one of the major factors determining human skin color. PMID:20736300

Platelet lysate from whole blood-derived pooled platelet concentrates and apheresis-derived platelet concentrates for the isolation and expansion of human bone marrow mesenchymal stromal cells: production process, content and identification of active components

PubMed Central

Fekete, Natalie; Gadelorge, Mélanie; Fürst, Daniel; Maurer, Caroline; Dausend, Julia; Fleury-Cappellesso, Sandrine; Mailänder, Volker; Lotfi, Ramin; Ignatius, Anita; Sensebé, Luc; Bourin, Philippe; Schrezenmeier, Hubert; Rojewski, Markus Thomas

2012-01-01

Background aims The clinical use of human mesenchymal stromal cells (MSC) requires ex vivo expansion in media containing supplements such as fetal bovine serum or, alternatively, human platelet lysate (PL). Methods Platelet concentrates were frozen, quarantine stored, thawed and sterile filtered to obtain PL. PL content and its effect on fibroblast-colony-forming unit (CFU-F) formation, MSC proliferation and large-scale expansion were studied. Results PL contained high levels of basic fibroblast growth factor (bFGF), soluble CD40L (sCD40L), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-derived growth factor AA (PDGF-AA), platelet-derived growth factor AB/BB (PDGF-AB/BB), chemokine (C-C) ligand 5 (CCL5; RANTES) transforming growth factor-β1 (TGF-β1) and chemokine (C-X-C) ligand 1/2/3 (GRO), with low batch-to-batch variability, and most were stable for up to 14 days. Inhibition of PDGF-BB and bFGF decreased MSC proliferation by about 20% and 50%, respectively. The strongest inhibition (about 75%) was observed with a combination of anti-bFGF + anti-PDGF-BB and anti-bFGF + anti-TGF-β1 + anti-PDGF-BB. Interestingly, various combinations of recombinant PDGF-BB, bFGF and TGF-β1 were not sufficient to promote cell proliferation. PL from whole blood-derived pooled platelet concentrates and apheresis platelet concentrates did not differ significantly in their growth-promoting activity on MSC. Conclusions PL enhances MSC proliferation and can be regarded as a safe tool for MSC expansion for clinical purposes. \\in particular, PDGF-BB and bFGF are essential components for the growth-promoting effect of PL, but are not sufficient for MSC proliferation. PMID:22296115

Determination and confirmation of nicotinic acid and its analogues and derivates in pear and apple blossoms using high-performance liquid chromatography-diode array-electrospray ionization mass spectrometry.

PubMed

Paternoster, Thomas; Vrhovsek, Urska; Pertot, Ilaria; Duffy, Brion; Gessler, Cesare; Mattivi, Fulvio

2009-11-11

Erwinia amylovora causes fire blight, a serious disease of apple and pear. The bacterial pathogen colonizes the flower stigma and hypanthium, where it multiplies and then invades through natural openings (nectarthodes). E. amylovora requires nicotinic acid as growth factor, and competition for nicotinic acid is being explored as a novel biocontrol strategy. The ability of E. amylovora to substitute nicotinic acid with analogues or derivates as growth factors has not been investigated yet. Furthermore, the presence and/or variable concentration of nicotinic acid and its analogues/derivates in the hypanthium could be associated with the different susceptibilities to fire blight of hosts and nonhosts and with the differential sensitivity to the disease among apple and pear varieties. Currently, no methods to specifically quantify nicotinic acid and nicotinic acid analogues/derivates in the hypanthium of apple and pear blossoms are available. This study demonstrates that E. amylovora can grow using nicotinamide and 6-hydroxynicotinic acid as alternative growth factors to nicotinic acid, but not using 2-hydroxynicotinic acid. A novel HPLC/ES-MS method was developed for the detection and quantification of nicotinic acid and its analogues/derivates directly in the hypanthium of apple and pear blossoms. Analyses established the presence of nicotinic acid and nicotinamide, whereas no detectable amounts of 6-hydroxynicotinic acid and 2-hydroxynicotinic acid were observed. Mean nicotinic acid content in the pear hypanthium was found to be approximately 2 orders of magnitude higher than in the apple hypanthium, which may contribute to the differential susceptibility of these two host species to fire blight. Contents of nicotinamide were in contrast similar. Nicotinic acid can therefore be considered a relevant factor in the pathogen establishment in pear blossoms, whereas nicotinamide could cover a primary role in apple blossoms.

A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth.

PubMed

Bardelli, A; Longati, P; Williams, T A; Benvenuti, S; Comoglio, P M

1999-10-08

Interaction of the hepatocyte growth factor (HGF) with its receptor, the Met tyrosine kinase, results in invasive growth, a genetic program essential to embryonic development and implicated in tumor metastasis. Met-mediated invasive growth requires autophosphorylation of the receptor on tyrosines located in the kinase activation loop (Tyr(1234)-Tyr(1235)) and in the carboxyl-terminal tail (Tyr(1349)-Tyr(1356)). We report that peptides derived from the Met receptor tail, but not from the activation loop, bind the receptor and inhibit the kinase activity in vitro. Cell delivery of the tail receptor peptide impairs HGF-dependent Met phosphorylation and downstream signaling. In normal and transformed epithelial cells, the tail receptor peptide inhibits HGF-mediated invasive growth, as measured by cell migration, invasiveness, and branched morphogenesis. The Met tail peptide inhibits the closely related Ron receptor but does not significantly affect the epidermal growth factor, platelet-derived growth factor, or vascular endothelial growth factor receptor activities. These experiments show that carboxyl-terminal sequences impair the catalytic properties of the Met receptor, thus suggesting that in the resting state the nonphosphorylated tail acts as an intramolecular modulator. Furthermore, they provide a strategy to selectively target the MET proto-oncogene by using small, cell-permeable, peptide derivatives.

Are genetic variants in the platelet-derived growth factor [beta] gene associated with chronic pancreatitis?

PubMed

Muddana, Venkata; Park, James; Lamb, Janette; Yadav, Dhiraj; Papachristou, Georgios I; Hawes, Robert H; Brand, Randall; Slivka, Adam; Whitcomb, David C

2010-11-01

Platelet-derived growth factor [beta] (PDGF-[beta]) is a major signal in proliferation and matrix synthesis through activated pancreatic stellate cells, leading to fibrosis of the pancreas. Recurrent acute pancreatitis (RAP) seems to predispose to chronic pancreatitis (CP) in some patients but not others. We tested the hypothesis that 2 known PDGF-[beta] polymorphisms are associated with progression from RAP to CP. We also tested the hypothesis that PDGF-[beta] polymorphisms in combination with environmental risk factors such as alcohol and smoking are associated with CP. Three hundred eighty-two patients with CP (n = 176) and RAP (n = 206) and 251 controls were evaluated. Platelet-derived growth factor [beta] polymorphisms +286 A/G (rs#1800818) seen in 5'-UTR and +1135 A/C (rs#1800817) in first intron were genotyped using single-nucleotide polymorphism polymerase chain reaction approach and confirmed by DNA sequencing. The genotypic frequencies for PDGF-[beta] polymorphisms in positions +286 and +1135 were found to be similar in controls and patients with RAP and CP. There was no difference in genotypic frequencies among RAP, CP, and controls in subjects in the alcohol and smoking subgroups. Known variations in the PDGF-[beta] gene do not have a significant effect on promoting or preventing fibrogenesis in pancreatitis. Further evaluation of this important pathway is warranted.

Photodynamic treatment of epithelial tissue derived from patients with endometrial cancer: a contribution to the role of laminin and epidermal growth factor receptor in photodynamic therapy

NASA Astrophysics Data System (ADS)

Ziolkowski, Piotr P.; Symonowicz, Krzysztof; Osiecka, Beata J.; Rabczynski, Jerzy; Gerber, Jerzy

1999-07-01

Photodynamic therapy (PDT) was used to treat endometrial G1 cancer tissue derived from patients who had undergone a total hysterectomy and bilateral salpingo-oophorectomy. After surgical treatment the cancerous tissue was kept in a medium containing Dulbecco solution, fetal calf serum, and antibiotics. The tissue was then exposed to hematoporphyrin derivative (0.1 mg/l) and 24 h later exposed to light (total light dose--18 J/sq cm). Necrosis depth was evaluated 24 h later using a light microscope. In order to assess the possible role of the basal membrane component laminin, as well as epidermal growth factor receptor susceptibility to PDT, immunohistochemical studies were carried out. Additionally, nucleolar organizer regions evaluation was performed. Our experiment confirmed that PDT results in the necrosis in the treated endometrial cancer, while not affecting the laminin in the cancerous tissue. In contrast, PDT strongly affects the epidermal growth factor receptor and nucleolar organizer regions in cancer cells. We suggest that laminin may contribute to the prevention of cancer dissemination in the cases where PDT has to be repeated, and that after PDT the cells become less susceptible to a mitogen, like, e.g., epidermal growth factor.

Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish.

PubMed

Cacialli, Pietro; Palladino, Antonio; Lucini, Carla

2018-06-01

Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.

Large-scale expansion of Wharton's jelly-derived mesenchymal stem cells on gelatin microbeads, with retention of self-renewal and multipotency characteristics and the capacity for enhancing skin wound healing.

PubMed

Zhao, Guifang; Liu, Feilin; Lan, Shaowei; Li, Pengdong; Wang, Li; Kou, Junna; Qi, Xiaojuan; Fan, Ruirui; Hao, Deshun; Wu, Chunling; Bai, Tingting; Li, Yulin; Liu, Jin Yu

2015-03-19

Successful stem cell therapy relies on large-scale generation of stem cells and their maintenance in a proliferative multipotent state. This study aimed to establish a three-dimension culture system for large-scale generation of hWJ-MSC and investigated the self-renewal activity, genomic stability and multi-lineage differentiation potential of such hWJ-MSC in enhancing skin wound healing. hWJ-MSC were seeded on gelatin microbeads and cultured in spinning bottles (3D). Cell proliferation, karyotype analysis, surface marker expression, multipotent differentiation (adipogenic, chondrogenic, and osteogenic potentials), and expression of core transcription factors (OCT4, SOX2, NANOG, and C-MYC), as well as their efficacy in accelerating skin wound healing, were investigated and compared with those of hWJ-MSC derived from plate cultres (2D), using in vivo and in vitro experiments. hWJ-MSC attached to and proliferated on gelatin microbeads in 3D cultures reaching a maximum of 1.1-1.30×10(7) cells on 0.5 g of microbeads by days 8-14; in contrast, hWJ-MSC derived from 2D cultures reached a maximum of 6.5 -11.5×10(5) cells per well in a 24-well plate by days 6-10. hWJ-MSC derived by 3D culture incorporated significantly more EdU (P<0.05) and had a significantly higher proliferation index (P<0.05) than those derived from 2D culture. Immunofluorescence staining, real-time PCR, flow cytometry analysis, and multipotency assays showed that hWJ-MSC derived from 3D culture retained MSC surface markers and multipotency potential similar to 2D culture-derived cells. 3D culture-derived hWJ-MSC also retained the expression of core transcription factors at levels comparable to their 2D culture counterparts. Direct injection of hWJ-MSC derived from 3D or 2D cultures into animals exhibited similar efficacy in enhancing skin wound healing. Thus, hWJ-MSC can be expanded markedly in gelatin microbeads, while retaining MSC surface marker expression, multipotent differential potential, and expression of core transcription factors. These cells also efficiently enhanced skin wound healing in vivo, in a manner comparable to that of hWJ-MSC obtained from 2D culture.

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis.

PubMed

Tichet, Mélanie; Prod'Homme, Virginie; Fenouille, Nina; Ambrosetti, Damien; Mallavialle, Aude; Cerezo, Michael; Ohanna, Mickaël; Audebert, Stéphane; Rocchi, Stéphane; Giacchero, Damien; Boukari, Fériel; Allegra, Maryline; Chambard, Jean-Claude; Lacour, Jean-Philippe; Michiels, Jean-François; Borg, Jean-Paul; Deckert, Marcel; Tartare-Deckert, Sophie

2015-04-30

Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.

Brain-derived neurotrophic factor secreted by the cerebral endothelium: A new actor of brain function?

PubMed

Marie, Christine; Pedard, Martin; Quirié, Aurore; Tessier, Anne; Garnier, Philippe; Totoson, Perle; Demougeot, Céline

2018-06-01

Low cerebral levels of brain-derived neurotrophic factor (BDNF), which plays a critical role in many brain functions, have been implicated in neurodegenerative, neurological and psychiatric diseases. Thus, increasing BDNF levels in the brain is considered an attractive possibility for the prevention/treatment of various brain diseases. To date, BDNF-based therapies have largely focused on neurons. However, given the cross-talk between endothelial cells and neurons and recent evidence that BDNF expressed by the cerebral endothelium largely accounts for BDNF levels present in the brain, it is likely that BDNF-based therapies would be most effective if they also targeted the cerebral endothelium. In this review, we summarize the available knowledge about the biology and actions of BDNF derived from endothelial cells of the cerebral microvasculature and we emphasize the remaining gaps and shortcomings.

Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon

PubMed Central

Verhoef, Talitha I; Redekop, William K; Daly, Ann K; van Schie, Rianne M F; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse

2014-01-01

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose–response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials. PMID:23919835

Derived Basic Ability Factors: A Factor Analysis Replication Study.

ERIC Educational Resources Information Center

Lee, Mickey, M.; Lee, Lynda Newby

The purpose of this study was to replicate the study conducted by Potter, Sagraves, and McDonald to determine whether their recommended analysis could separate criterion variables into similar factors that were stable from year to year and from school to school. The replication samples consisted of all students attending Louisiana State University…

Stability of Q-Factors across Two Data Collection Methods.

ERIC Educational Resources Information Center

Daniel, Larry G.

The purpose of the present study was to determine how two different data collection techniques would affect the Q-factors derived from several factor analytic procedures. Faculty members (N=146) from seven middle schools responded to 61 items taken from an instrument designed to measure aspects of an idealized middle school culture; the instrument…

INCREASED PRODUCTION OF NERVE GROWTH FACTOR, NEUROTROPHIN-3, AND NEUROTROPHIN-4 IN A PENICILLIUM CHRYSOGENUM -INDUCED ALLERGIC ASTHMA MODEL IN MICE

EPA Science Inventory

Increased levels of neurotrophins (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], neurotrophin [NT]-3, and/or NT-4) have been associated with asthmatics and in animal models of allergic asthma. In our mouse model for fungal allergic asthma, repeated pulmona...

Nrf2 Deficiency in Dendritic Cells Enhances the Adjuvant Effect of Ambient Ultrafine Particles on Allergic Sensitization

EPA Science Inventory

Airborne particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM-associated chemicals is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II...

Recruitment and retention: factors that affect pericyte migration

PubMed Central

Aguilera, Kristina Y.

2013-01-01

Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyros-ine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might infuence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed. PMID:23912898

Analytic variance estimates of Swank and Fano factors

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

Gutierrez, Benjamin; Badano, Aldo; Samuelson, Frank, E-mail: frank.samuelson@fda.hhs.gov

Purpose: Variance estimates for detector energy resolution metrics can be used as stopping criteria in Monte Carlo simulations for the purpose of ensuring a small uncertainty of those metrics and for the design of variance reduction techniques. Methods: The authors derive an estimate for the variance of two energy resolution metrics, the Swank factor and the Fano factor, in terms of statistical moments that can be accumulated without significant computational overhead. The authors examine the accuracy of these two estimators and demonstrate how the estimates of the coefficient of variation of the Swank and Fano factors behave with data frommore » a Monte Carlo simulation of an indirect x-ray imaging detector. Results: The authors' analyses suggest that the accuracy of their variance estimators is appropriate for estimating the actual variances of the Swank and Fano factors for a variety of distributions of detector outputs. Conclusions: The variance estimators derived in this work provide a computationally convenient way to estimate the error or coefficient of variation of the Swank and Fano factors during Monte Carlo simulations of radiation imaging systems.« less

United Formula for the Friction Factor in the Turbulent Region of Pipe Flow.

PubMed

Li, Shuolin; Huai, Wenxin

2016-01-01

Friction factor is an important element in both flow simulations and river engineering. In hydraulics, studies on the friction factor in turbulent regions have been based on the concept of three flow regimes, namely, the fully smooth regime, the fully rough regime, and the transitional regime, since the establishment of the Nikuradze's chart. However, this study further demonstrates that combining the friction factor with Reynolds number yields a united formula that can scale the entire turbulent region. This formula is derived by investigating the correlation between friction in turbulent pipe flow and its influencing factors, i.e., Reynolds number and relative roughness. In the present study, the formulae of Blasius and Stricklerare modified to rearrange the implicit model of Tao. In addition, we derive a united explicit formula that can compute the friction factor in the entire turbulent regimes based on the asymptotic behavior of the improved Tao's model. Compared with the reported formulae of Nikuradze, the present formula exhibits higher computational accuracy for the original pipe experiment data of Nikuradze.

Factor validity and norms for the aberrant behavior checklist in a community sample of children with mental retardation.

PubMed

Marshburn, E C; Aman, M G

1992-09-01

The Aberrant Behavior Checklist (ABC) is a 58-item rating scale that was developed primarily to measure the effects of pharmacological intervention in individuals living in residential facilities. This study investigated the use of the ABC in a sample of community children with mental retardation. Teacher ratings on the ABC were collected on 666 students attending special classes. The data were factor analyzed and compared with other studies using the ABC. In addition, subscales were analyzed as a function of age, sex, and classroom placement, and preliminary norms were derived. A four-factor solution of the ABC was obtained. Congruence between the four derived factors and corresponding factors from the original ABC was high (congruence coefficients ranged between .87 and .96). Classroom placement and age had significant effects on subscale scores, whereas sex failed to affect ratings. The current results are sufficiently close to the original factor solution that the original scoring method can be used with community samples, although further studies are needed to look at this in more detail.

Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation.

PubMed

O'Keeffe, Gerard W; Gutierrez, Humberto; Howard, Laura; Laurie, Christopher W; Osorio, Catarina; Gavaldà, Núria; Wyatt, Sean L; Davies, Alun M

2016-02-15

Nerve growth factor (NGF) is the prototypical target-derived neurotrophic factor required for sympathetic neuron survival and for the growth and ramification of sympathetic axons within most but not all sympathetic targets. This implies the operation of additional target-derived factors for regulating terminal sympathetic axon growth and branching. Here report that growth differentiation factor 5 (GDF5), a widely expressed member of the transforming growth factor beta (TGFβ) superfamily required for limb development, promoted axon growth from mouse superior cervical ganglion (SCG) neurons independently of NGF and enhanced axon growth in combination with NGF. GDF5 had no effect on neuronal survival and influenced axon growth during a narrow window of postnatal development when sympathetic axons are ramifying extensively in their targets in vivo. SCG neurons expressed all receptors capable of participating in GDF5 signaling at this stage of development. Using compartment cultures, we demonstrated that GDF5 exerted its growth promoting effect by acting directly on axons and by initiating retrograde canonical Smad signalling to the nucleus. GDF5 is synthesized in sympathetic targets, and examination of several anatomically circumscribed tissues in Gdf5 null mice revealed regional deficits in sympathetic innervation. There was a marked, highly significant reduction in the sympathetic innervation density of the iris, a smaller though significant reduction in the trachea, but no reduction in the submandibular salivary gland. There was no reduction in the number of neurons in the SCG. These findings show that GDF5 is a novel target-derived factor that promotes sympathetic axon growth and branching and makes a distinctive regional contribution to the establishment of sympathetic innervation, but unlike NGF, plays no role in regulating sympathetic neuron survival.

Student learning of upper-level thermal and statistical physics: The derivation and use of the Boltzmann factor

NASA Astrophysics Data System (ADS)

Thompson, John

2015-04-01

As the Physical Review Focused Collection demonstrates, recent frontiers in physics education research include systematic investigations at the upper division. As part of a collaborative project, we have examined student understanding of several topics in upper-division thermal and statistical physics. A fruitful context for research is the Boltzmann factor in statistical mechanics: the standard derivation involves several physically justified mathematical steps as well as the invocation of a Taylor series expansion. We have investigated student understanding of the physical significance of the Boltzmann factor as well as its utility in various circumstances, and identified various lines of student reasoning related to the use of the Boltzmann factor. Results from written data as well as teaching interviews suggest that many students do not use the Boltzmann factor when answering questions related to probability in applicable physical situations, even after lecture instruction. We designed an inquiry-based tutorial activity to guide students through a derivation of the Boltzmann factor and to encourage deep connections between the physical quantities involved and the mathematics. Observations of students working through the tutorial suggest that many students at this level can recognize and interpret Taylor series expansions, but they often lack fluency in creating and using Taylor series appropriately, despite previous exposure in both calculus and physics courses. Our findings also suggest that tutorial participation not only increases the prevalence of relevant invocation of the Boltzmann factor, but also helps students gain an appreciation of the physical implications and meaning of the mathematical formalism behind the formula. Supported in part by NSF Grants DUE-0817282, DUE-0837214, and DUE-1323426.

Comparison of direct measures of adiposity with indirect measures for assessing cardiometabolic risk factors in preadolescent girls.

PubMed

Hetherington-Rauth, Megan; Bea, Jennifer W; Lee, Vinson R; Blew, Robert M; Funk, Janet; Lohman, Timothy G; Going, Scott B

2017-02-23

Childhood overweight and obesity remains high, contributing to cardiometabolic risk factors at younger ages. It is unclear which measures of adiposity serve as the best proxies for identifying children at metabolic risk. This study assessed whether DXA-derived direct measures of adiposity are more strongly related to cardiometabolic risk factors in children than indirect measures. Anthropometric and DXA measures of adiposity and a comprehensive assessment of cardiometabolic risk factors were obtained in 288, 9-12 year old girls, most being of Hispanic ethnicity. Multiple regression models for each metabolic parameter were run against each adiposity measure while controlling for maturation and ethnicity. In addition, regression models including both indirect and direct measures were developed to assess whether using direct measures of adiposity could provide a better prediction of the cardiometabolic risk factors beyond that of using indirect measures alone. Measures of adiposity were significantly correlated with cardiometabolic risk factors (p < 0.05) except fasting glucose. After adjusting for maturation and ethnicity, indirect measures of adiposity accounted for 29-34% in HOMA-IR, 10-13% in TG, 14-17% in HDL-C, and 5-8% in LDL-C while direct measures accounted for 29-34% in HOMA-IR, 10-12% in TG, 13-16% in HDL-C, and 5-6% in LDL-C. The addition of direct measures of adiposity to indirect measures added significantly to the variance explained for HOMA-IR (p = 0.04). Anthropometric measures may perform as well as the more precise direct DXA-derived measures of adiposity for assessing most CVD risk factors in preadolescent girls. The use of DXA-derived adiposity measures together with indirect measures may be advantageous for predicting insulin resistance risk. NCT02654262 . Retrospectively registered 11 January 2016.

Wound-healing potential of human umbilical cord blood-derived mesenchymal stromal cells in vitro--a pilot study.

PubMed

You, Hi-Jin; Namgoong, Sik; Han, Seung-Kyu; Jeong, Seong-Ho; Dhong, Eun-Sang; Kim, Woo-Kyung

2015-11-01

Our previous studies demonstrated that human bone marrow-derived mesenchymal stromal cells have great potential for wound healing. However, it is difficult to clinically utilize cultured stem cells. Recently, human umbilical cord blood-derived mesenchymal stromal cells (hUCB-MSCs) have been commercialized for cartilage repair as a first cell therapy product that uses allogeneic stem cells. Should hUCB-MSCs have a superior effect on wound healing as compared with fibroblasts, which are the main cell source in current cell therapy products for wound healing, they may possibly replace fibroblasts. The purpose of this in vitro study was to compare the wound-healing activity of hUCB-MSCs with that of fibroblasts. This study was particularly designed to compare the effect of hUCB-MSCs on diabetic wound healing with those of allogeneic and autologous fibroblasts. Healthy (n = 5) and diabetic (n = 5) fibroblasts were used as the representatives of allogeneic and autologous fibroblasts for diabetic patients in the control group. Human UCB-MSCs (n = 5) were used in the experimental group. Cell proliferation, collagen synthesis and growth factor (basic fibroblast growth factor, vascular endothelial growth factor and transforming growth factor-β) production were compared among the three cell groups. Human UCB-MSCs produced significantly higher amounts of vascular endothelial growth factor and basic fibroblast growth factor when compared with both fibroblast groups. Human UCB-MSCs were superior to diabetic fibroblasts but not to healthy fibroblasts in collagen synthesis. There were no significant differences in cell proliferation and transforming growth factor-β production. Human UCB-MSCs may have greater capacity for diabetic wound healing than allogeneic or autologous fibroblasts, especially in angiogenesis. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Modelling of Piezothermoelastic Beam with Fractional Order Derivative

NASA Astrophysics Data System (ADS)

Kumar, Rajneesh; Sharma, Poonam

2016-04-01

This paper deals with the study of transverse vibrations in piezothermoelastic beam resonators with fractional order derivative. The fractional order theory of thermoelasticity developed by Sherief et al. [1] has been used to study the problem. The expressions for frequency shift and damping factor are derived for a thermo micro-electromechanical (MEM) and thermo nano-electromechanical (NEM) beam resonators clamped on one side and free on another. The effect of fractional order derivative on the derived expressions is observed analytically and shown graphically in the case of Lead Zirconate Titanate (PZT)-5A material. For α = 1, our results agree with those that are obtained by Grover and Sharma [20] and other particular cases of interest are also discussed.

Improved cellular thermotolerance in cloned Holstein cattle derived with cytoplasts from a thermotolerant breed.

PubMed

Lee, Jai-Wei; Li, Hung; Wu, Hung-Yi; Liu, Shyh-Shyan; Shen, Perng-Chin

2016-03-01

The objective of this study was to compare the thermotolerance of ear fibroblasts derived from various SCNT cattle. Specimens were produced from cloned embryos that had been reconstructed using donor cells (d) from the same Holstein cow (Hd) and the ooplasm (o) from Holstein cattle (Ho) or Taiwan yellow cattle (Yo). Polymorphism in the D-loop region of mitochondrial DNA in ear fibroblasts derived from SCNT cattle reconstructed with the Y ooplasm and H donor cells (SCNT-Yo-Hd) indicates that the cytoplasm originated from Bos indicus. The rates of apoptosis in heat-shocked ear fibroblasts derived from SCNT-Yo-Hd cattle (1.9%) and purebred Y cattle (1.5%) were significantly (P < 0.05) lower than those of cells derived from SCNT cattle reconstructed with the H ooplasm (SCNT-Ho-Hd: 3.4%), donor cells (4.0%), and purebred Holstein (4.1%) cattle. At the protein level, the relative abundances of apoptosis-inducing factor, B cell lymphoma 2-associated X protein, endonuclease G, cytochrome c, cysteinyl aspartate-specific proteinases 3, 8 and 9 in ear fibroblasts derived from SCNT-Yo-Hd cattle were significantly (P < 0.05) lower than those of cells derived from SCNT-Ho-Hd cattle after heat shock. In contrast, the relative abundances of heat shock proteins 27, 70 and B cell lymphoma 2 in ear fibroblasts derived from SCNT-Yo-Hd cattle were higher (P < 0.05) than those of fibroblasts derived from SCNT-Ho-Hd cattle. Moreover, heat-shocked ear fibroblasts derived from SCNT-Yo-Hd cattle have a significantly (P < 0.05) lower percentage of apoptosis-inducing factor-positive nuclei than do heat-shocked ear fibroblasts derived from SCNT-Ho-Hd cattle (11.1% vs. 18.5%). Taken together, these results report that ear fibroblasts derived from SCNT cattle reconstructed using the Y ooplasm are more thermotolerant than ear fibroblasts derived from SCNT cattle reconstructed using the H ooplasm. This is an indication that the cytoplasm may be a major determinant of thermal sensitivity in bovine ear fibroblasts. Copyright © 2016 Elsevier Inc. All rights reserved.

Spatial derivatives of flow quantities behind curved shocks of all strengths

NASA Technical Reports Server (NTRS)

Darden, C. M.

1984-01-01

Explicit formulas in terms of shock curvature are developed for spatial derivatives of flow quantities behind a curved shock for two-dimensional inviscid steady flow. Factors which yield the equations indeterminate as the shock strength approaches 0 have been cancelled analytically so that formulas are valid for shocks of any strength. An application for the method is shown in the solution of shock coalescence when nonaxisymmetric effects are felt through derivatives in the circumferential direction. The solution of this problem requires flow derivatives behind the shock in both the axial and radial direction.

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway.

PubMed

Wang, Bohan; Ning, Hongxiu; Reed-Maldonado, Amanda B; Zhou, Jun; Ruan, Yajun; Zhou, Tie; Wang, Hsun Shuan; Oh, Byung Seok; Banie, Lia; Lin, Guiting; Lue, Tom F

2017-02-16

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157-an inhibitor of PERK-effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy.

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway

PubMed Central

Wang, Bohan; Ning, Hongxiu; Reed-Maldonado, Amanda B.; Zhou, Jun; Ruan, Yajun; Zhou, Tie; Wang, Hsun Shuan; Oh, Byung Seok; Banie, Lia; Lin, Guiting; Lue, Tom F.

2017-01-01

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157—an inhibitor of PERK—effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy. PMID:28212323

Chick derived induced pluripotent stem cells by the poly-cistronic transposon with enhanced transcriptional activity.

PubMed

Katayama, Masafumi; Hirayama, Takashi; Tani, Tetsuya; Nishimori, Katsuhiko; Onuma, Manabu; Fukuda, Tomokazu

2018-02-01

Induced pluripotent stem (iPS) cell technology lead terminally differentiated cells into the pluripotent stem cells through the expression of defined reprogramming factors. Although, iPS cells have been established in a number of mammalian species, including mouse, human, and monkey, studies on iPS cells in avian species are still very limited. To establish chick iPS cells, six factors were used within the poly-cistronic reprogramming vector (PB-R6F), containing M3O (MyoD derived transactivation domain fused with Oct3/4), Sox2, Klf4, c-Myc, Lin28, and Nanog. The PB-R6F derived iPS cells were alkaline-phosphatase and SSEA-1 positive, which are markers of pluripotency. Elevated levels of endogenous Oct3/4 and Nanog genes were detected in the established iPS cells, suggesting the activation of the FGF signaling pathway is critical for the pluripotent status. Histological analysis of teratoma revealed that the established chick iPS cells have differentiation ability into three-germ-layer derived tissues. This is the first report of establishment of avian derived iPS cells with a single poly-cistronic transposon based expression system. The establishment of avian derived iPS cells could contribute to the genetic conservation and modification of avian species. © 2017 Wiley Periodicals, Inc.

Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells.

PubMed

Masamune, Atsushi; Yoshida, Naoki; Hamada, Shin; Takikawa, Tetsuya; Nabeshima, Tatsuhide; Shimosegawa, Tooru

2018-01-01

Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor β1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment. Copyright © 2017 Elsevier Inc. All rights reserved.

IGF-1 and BDNF promote chick bulbospinal neurite outgrowth in vitro.

PubMed

Salie, Rishard; Steeves, John D

2005-11-01

Injured neurons in the CNS do not experience significant functional regeneration and so spinal cord insult often results in permanently compromised locomotor ability. The capability of a severed axon to re-grow is thought to depend on numerous factors, one of which is the decreased availability of neurotrophic factors. Application of trophic factors to axotomized neurons has been shown to enhance survival and neurite outgrowth. Although brainstem-spinal connections play a pivotal role in motor dysfunction after spinal cord injury, relatively little is known about the trophic sensitivity of these populations. This study explores the response of bulbospinal populations to various trophic factors. Several growth factors were initially examined for potential trophic effects on the projection neurons of the brainstem. Brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) significantly enhance mean process length in both the vestibulospinal neurons and spinal projection neurons from the raphe nuclei. Nerve growth factor (NGF), neurotrophin-4 (NT-4) and glial derived neurotrophic factor (GDNF) did not effect process outgrowth in vestibulospinal neurons. At the developmental stages used in this study, it was determined that receptors for BDNF and IGF-1 were present both on bulbospinal neurons and on surrounding cells with a non-neuronal morphology.

SOCS3 Deficiency in Myeloid Cells Promotes Tumor Development: Involvement of STAT3 Activation and Myeloid-Derived Suppressor Cells

PubMed Central

Yu, Hao; Liu, Yudong; McFarland, Braden C.; Deshane, Jessy S.; Hurst, Douglas R.; Ponnazhagan, Selvarangan; Benveniste, Etty N.; Qin, Hongwei

2015-01-01

Suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor, which has a striking ability to promote tumor survival while suppressing antitumor immunity. We report for the first time that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminished CD8+ T-cell infiltration in tumors. The importance of MDSCs in promoting tumor growth is documented by reduced tumor growth upon depletion of MDSCs. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1+CD11b+Ly6G+ MDSC phenotype. Importantly, we identify granulocyte colony-stimulating factor (G-CSF) as a critical factor secreted by the tumor microenvironment that promotes development of MDSCs via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1+CD11b+ MDSCs and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, via inhibition of STAT3 activation. PMID:25649351

Deriving adaptive operating rules of hydropower reservoirs using time-varying parameters generated by the EnKF

NASA Astrophysics Data System (ADS)

Feng, Maoyuan; Liu, Pan; Guo, Shenglian; Shi, Liangsheng; Deng, Chao; Ming, Bo

2017-08-01

Operating rules have been used widely to decide reservoir operations because of their capacity for coping with uncertain inflow. However, stationary operating rules lack adaptability; thus, under changing environmental conditions, they cause inefficient reservoir operation. This paper derives adaptive operating rules based on time-varying parameters generated using the ensemble Kalman filter (EnKF). A deterministic optimization model is established to obtain optimal water releases, which are further taken as observations of the reservoir simulation model. The EnKF is formulated to update the operating rules sequentially, providing a series of time-varying parameters. To identify the index that dominates the variations of the operating rules, three hydrologic factors are selected: the reservoir inflow, ratio of future inflow to current available water, and available water. Finally, adaptive operating rules are derived by fitting the time-varying parameters with the identified dominant hydrologic factor. China's Three Gorges Reservoir was selected as a case study. Results show that (1) the EnKF has the capability of capturing the variations of the operating rules, (2) reservoir inflow is the factor that dominates the variations of the operating rules, and (3) the derived adaptive operating rules are effective in improving hydropower benefits compared with stationary operating rules. The insightful findings of this study could be used to help adapt reservoir operations to mitigate the effects of changing environmental conditions.

Generation and characterization of human iPSC line generated from mesenchymal stem cells derived from adipose tissue.

PubMed

Zapata-Linares, Natalia; Rodriguez, Saray; Mazo, Manuel; Abizanda, Gloria; Andreu, Enrique J; Barajas, Miguel; Prosper, Felipe; Rodriguez-Madoz, Juan R

2016-01-01

In this work, mesenchymal stem cells derived from adipose tissue (ADSCs) were used for the generation of the human-induced pluripotent stem cell line G15.AO. Cell reprogramming was performed using retroviral vectors containing the Yamanaka factors, and the generated G15.AO hiPSC line showed normal karyotype, silencing of the exogenous reprogramming factors, induction of the typical pluripotency-associated markers, alkaline phosphatase enzymatic activity, and in vivo and in vitro differentiation ability to the three germ layers. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.