Decreased Serum Hepatocyte Growth Factor (HGF in Individuals with Bipolar Disorder Normalizes after Zinc and Anti-oxidant Therapy

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A.J. Russo

2010-01-01

Full Text Available Aim To assess serum HGF concentration in individuals with bipolar disorder and investigate the efficacy of zinc therapy on these levels. Subjects and Methods Serum from 35 individuals diagnosed with bipolar disorder and 19 age and gender similar controls were tested for HGF concentration using ELISAs, and copper and zinc plasma levels using inductively-coupled plasma-mass spectrometry. Results HGF serum levels of individuals with bipolar disorder were significantly lower than age and gender similar controls ( P = 0.0021. HGF serum concentration was significantly lower in Bipolar patients pre-therapy ( P = 0.0009 and HGF levels normalized post-therapy. Zinc levels in these same individuals also normalized ( P = 0.0046 and patient's perceived severity of Bipolar symptoms significantly decreased after therapy ( P = 0.0003. We also found a significant direct correlation between Zinc and HGF serum concentration in the bipolar patients ( P = 0.04. Discussion These results suggest an association between low HGF levels and bipolar disorder and also demonstrate that zinc therapy may be associated with the normalization of HGF levels and decrease in severity of disease.

In Vivo Real-Time Imaging of Exogenous HGF-Triggered Cell Migration in Rat Intact Soleus Muscles

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Ishido, Minenori; Kasuga, Norikatsu

2012-01-01

The transplantation of myogenic cells is a potentially effective therapy for muscular dystrophy. However, this therapy has achieved little success because the diffusion of transplanted myogenic cells is limited. Hepatocyte growth factor (HGF) is one of the primary triggers to induce myogenic cell migration in vitro. However, to our knowledge, whether exogenous HGF can trigger the migration of myogenic cells (i.e. satellite cells) in intact skeletal muscles in vivo has not been reported. We previously reported a novel in vivo real-time imaging method in rat skeletal muscles. Therefore, the present study examined the relationship between exogenous HGF treatment and cell migration in rat intact soleus muscles using this imaging method. As a result, it was indicated that the cell migration velocity was enhanced in response to increasing exogenous HGF concentration in skeletal muscles. Furthermore, the expression of MyoD was induced in satellite cells in response to HGF treatment. We first demonstrated in vivo real-time imaging of cell migration triggered by exogenous HGF in intact soleus muscles. The experimental method used in the present study will be a useful tool to understand further the regulatory mechanism of HGF-induced satellite cell migration in skeletal muscles in vivo

Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF)

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Serrano, Isabel; Diez-Marques, Maria L.; Rodriguez-Puyol, Manuel [Department of Physiology, University of Alcala, Alcala de Henares, Madrid (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Instituto Reina Sofia de Investigacion Nefrologica (Spain); Herrero-Fresneda, Inmaculada [Nephrology Unit, IDIBELL, Hospital de Bellvitge, Barcelona (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Garcia del Moral, Raimundo [Department of Pathology, University of Granada (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Dedhar, Shoukat [Department of Integrative Oncology, BC Cancer Research Center, Vancouver, BC (Canada); Ruiz-Torres, Maria P., E-mail: mpiedad.ruiz@uah.es [Department of Physiology, University of Alcala, Alcala de Henares, Madrid (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Instituto Reina Sofia de Investigacion Nefrologica (Spain); Rodriguez-Puyol, Diego [Nephrology Unit, Hospital Universitario Principe de Asturias, Alcala de Henares, Madrid (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Instituto Reina Sofia de Investigacion Nefrologica (Spain)

2012-11-15

Integrin-linked kinase (ILK) is an intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The present work analyzes the role of ILK in wound healing in adult animals using a conditional knock-out of the ILK gene generated with the tamoxifen-inducible Cre-lox system (CRE-LOX mice). Results show that ILK deficiency leads to retarded wound closure in skin. Intracellular mechanisms involved in this process were analyzed in cultured mouse embryonic fibroblast (MEF) isolated from CRE-LOX mice and revealed that wounding promotes rapid activation of phosphatidylinositol 3-kinase (PI3K) and ILK. Knockdown of ILK resulted in a retarded wound closure due to a decrease in cellular proliferation and loss of HGF protein expression during the healing process, in vitro and in vivo. Alterations in cell proliferation and wound closure in ILK-deficient MEF or mice could be rescued by exogenous administration of human HGF. These data demonstrate, for the first time, that the activation of PI3K and ILK after skin wounding are critical for HGF-dependent tissue repair and wound healing. -- Highlights: Black-Right-Pointing-Pointer ILK deletion results in decreased HGF expression and delayed scratch wound repair. Black-Right-Pointing-Pointer PI3K/ILK/AKT pathway signals through HGF to regulate wound healing. Black-Right-Pointing-Pointer An ILK-dependent increase in HGF expression is responsible for wound healing in vivo. Black-Right-Pointing-Pointer ILK-KO mice are used to confirm the requirement for ILK function in wound healing. Black-Right-Pointing-Pointer Human HGF treatment restores delayed wound closure in vitro and in vivo.

HGF/SF increases number of skin melanocytes but does not alter quality or quantity of follicular melanogenesis.

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Agnieszka Wolnicka-Glubisz

Full Text Available Melanins are an important factor determining the vulnerability of mammalian skin to UV radiation and thus to UV-induced skin cancers. Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF have extra-follicular dermal melanocytes, notably in the papillary upper dermis, and are susceptible to UV-induced melanoma. Pigmented HGF/SF neonatal mice are more susceptible than albino HGF/SF animals to UVA -induced melanoma, indicating an involvement of melanin in melanoma formation. This raises the question of the effect of transgenic HGF/SF on melanization. We developed a methodology to accurately quantitate both the production of melanin and the efficiency of melanogenesis in normal, and HGF/SF transgenic mice in vivo. Skin and hair shafts of 5 day old and adult (3 week old C57BL/6-HGF/SF and corresponding C57BL/6 wild type mice were investigated by electron paramagnetic resonance spectroscopy (EPR to quantitate melanin, by transmission electron microscopy (TEM for the presence of melanosomes, and by standard histology and by Western blotting and zymography to determine the expression and activity of melanogenesis-related proteins. Eumelanin but no phaeomelanin was detected in transgenic C57BL/6-HGF and C57BL/6 wild type mice. Transgenic HGF/SF overexpression did not change the type of melanin produced in the skin or hair, did not affect the terminal content of melanin production in standard samples of hair and did not influence hair cycle/morphogenesis-related changes in skin thickness. No melanocytes were found in the epidermis and no melanosomes were found in epidermal keratinocytes. HGF/SF transgenic mice thus lack the epidermal melanin UV-protection found in constitutively dark human skin. We conclude that melanocytes in the HGF/SF transgenic mouse, particularly in the papillary dermis, are vulnerable to UVA which interacts with eumelanin but not phaeomelanin to induce melanoma.

Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

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Husmann, Knut, E-mail: khusmann@research.balgrist.ch [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Ducommun, Pascal [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich (Switzerland); Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland)

2015-09-04

The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS and 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.

The Hepatocyte Growth Factor (HGF/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

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Marjorie Boissinot

2014-08-01

Full Text Available Met is the receptor of hepatocyte growth factor (HGF, a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML, and myeloproliferative neoplasms (MPNs. The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs.

The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

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Boissinot, Marjorie [Translational Neuro-Oncology Group, Leeds Institute of Cancer and Pathology, University of Leeds, Level 5 Wellcome Trust Brenner Building, St James’s Hospital, Leeds LS9 7TF (United Kingdom); Vilaine, Mathias [Institute of Research on Cancer and Aging (IRCAN), CNRS-Inserm-UNS UMR 7284, U 1081, Centre A. Lacassagne, 33 Avenue Valombrose, Nice 06189 (France); Hermouet, Sylvie, E-mail: sylvie.hermouet@univ-nantes.fr [Centre Hospitalier Universitaire (CHU), Place Alexis Ricordeau, Nantes 44093 (France); Inserm UMR892, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 8 quai Moncousu, Nantes cedex 44007 (France)

2014-08-12

Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs)

Regulation of HGF and SDF-1 expression by oral fibroblasts--implications for invasion of oral cancer.

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Daly, Aisling J; McIlreavey, Leanne; Irwin, Chris R

2008-07-01

Invasion and metastasis of oral squamous cell carcinoma (OSCC) is dependent on signals received from stromal fibroblasts present in the surrounding connective tissue. The aim of this study was to investigate the regulation of expression of two important signaling molecules--HGF and SDF-1--by both stromal fibroblasts and their 'activated' form, myofibroblasts, and to determine the role of these two factors in stimulating OSCC cell invasion in vitro. Fibroblasts and myofibroblasts produced similar levels of HGF and SDF-1. IL-1alpha and OSCC cell conditioned medium both stimulated HGF and SDF-1 expression, while TGF-beta(1) inhibited production of each factor. Myofibroblast-derived conditioned medium stimulated OSCC cell invasion through matrigel. Blocking antibodies to both HGF and SDF-1 reduced the level of invasion. In fibroblast-free organotypic raft cultures, addition of HGF and SDF-1 stimulated OSCC cell invasion into the underlying collagen gel, although the pattern of invasion differed from that induced by fibroblasts. Fibroblast-derived HGF and SDF-1 appear to play central roles in the reciprocal interactions between OSCC cells and underlying stromal fibroblasts leading to the local invasion of oral cancer.

Oral fibroblasts produce more HGF and KGF than skin fibroblasts in response to co-culture with keratinocytes

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Grøn, Birgitte; Stoltze, Kaj; Andersson, Anders

2002-01-01

The production of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) in subepithelial fibroblasts from buccal mucosa, periodontal ligament, and skin was determined after co-culture with keratinocytes. The purpose was to detect differences between the fibroblast subpopulations...... days by ELISA. When cultured on polystyrene, the constitutive level of KGF and HGF in periodontal fibroblasts was higher than the level in buccal and skin fibroblasts. In the presence of keratinocytes, all three types of fibroblasts in general increased their HGF and KGF production 2-3 times. When...... cells were maintained in collagen, the level of HGF and KGF was decreased mainly in skin cultures. However, in oral fibroblasts, induction after stimulation was at a similar level in collagen compared to on polystyrene. Skin fibroblasts maintained in collagen produced almost no HGF whether...

Decreased Hepatocyte Growth Factor (HGF) and Gamma Aminobutyric Acid (GABA) in Individuals with Obsessive-Compulsive Disorder (OCD).

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Russo, Anthony J; Pietsch, Stefanie C

2013-01-01

There is support for the role of gamma aminobutyric acid (GABA) in the etiology of mood disorders. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF and GABA as well as symptom severity in individuals with obsessive-compulsive disorder (OCD). Plasma from 15 individuals with OCD (9 males, 6 females;, mean age 38.7 years) and 17 neurotypical controls (10 males, 7 females; mean age 35.2 years) was assessed for HGF, GABA, urokinase plasminogen activator (uPA), and urokinase plasminogen activator receptor (uPAR) concentration using enzyme-linked immunosorbest assays ELISAs. Symptom severity was assessed in these OCD individuals and compared with HGF and GABA concentrations. In this preliminary study, individuals with OCD had significantly decreased HGF levels, decreased plasma levels of GABA and decreased uPA. We found that both uPA and uPAR levels correlate with HGF. Both low uPA and low uPAR levels correlate with high symptom severity in individuals with OCD. Low GABA levels in OCD individuals also correlate with high symptom severity. These results demonstrate a preliminary association between HGF, GABA, uPA levels, and OCD and suggest that plasma GABA and uPA levels are related to symptom severity in individuals with OCD.

Role of Sphingosine Kinase 1 and S1P Transporter Spns2 in HGF-mediated Lamellipodia Formation in Lung Endothelium.

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Fu, Panfeng; Ebenezer, David L; Berdyshev, Evgeny V; Bronova, Irina A; Shaaya, Mark; Harijith, Anantha; Natarajan, Viswanathan

2016-12-30

Hepatocyte growth factor (HGF) signaling via c-Met is known to promote endothelial cell motility and angiogenesis. We have previously reported that HGF stimulates lamellipodia formation and motility of human lung microvascular endothelial cells (HLMVECs) via PI3K/Akt signal transduction and reactive oxygen species generation. Here, we report a role for HGF-induced intracellular sphingosine-1-phosphate (S1P) generation catalyzed by sphingosine kinase 1 (SphK1), S1P transporter, spinster homolog 2 (Spns2), and S1P receptor, S1P 1 , in lamellipodia formation and perhaps motility of HLMVECs. HGF stimulated SphK1 phosphorylation and enhanced intracellular S1P levels in HLMVECs, which was blocked by inhibition of SphK1. HGF enhanced co-localization of SphK1/p-SphK1 with actin/cortactin in lamellipodia and down-regulation or inhibition of SphK1 attenuated HGF-induced lamellipodia formation in HLMVECs. In addition, down-regulation of Spns2 also suppressed HGF-induced lamellipodia formation, suggesting a key role for inside-out S1P signaling. The HGF-mediated phosphorylation of SphK1 and its localization in lamellipodia was dependent on c-Met and ERK1/2 signaling, but not the PI3K/Akt pathway; however, blocking PI3K/Akt signaling attenuated HGF-mediated phosphorylation of Spns2. Down-regulation of S1P 1 , but not S1P 2 or S1P 3 , with specific siRNA attenuated HGF-induced lamellipodia formation. Further, HGF enhanced association of Spns2 with S1P 1 that was blocked by inhibiting SphK1 activity with PF-543. Moreover, HGF-induced migration of HLMVECs was attenuated by down-regulation of Spns2 . Taken together, these results suggest that HGF/c-Met-mediated lamellipodia formation, and perhaps motility is dependent on intracellular generation of S1P via activation and localization of SphK1 to cell periphery and Spns2-mediated extracellular transportation of S1P and its inside-out signaling via S1P 1 . © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines.

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Walderik W Zomerman

Full Text Available Recent clinical trials investigating receptor tyrosine kinase (RTK inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET and epidermal growth factor receptor family (ErbB1-4 inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1-4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA's resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma.

Activated HGF-c-Met Axis in Head and Neck Cancer

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Levi Arnold

2017-12-01

Full Text Available Head and neck squamous cell carcinoma (HNSCC is a highly morbid disease. Recent developments including Food and Drug Administration (FDA approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met and its ligand hepatocyte growth factor (HGF are overexpressed in head and neck squamous cell carcinoma (HNSCC; and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ, cellular Src kinase (c-Src, phosphotidylinsitol-3-OH kinase (PI3K alpha serine/threonine-protein kinase (Akt, mitogen activate protein kinase (MAPK, and wingless-related integration site (Wnt pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR and vascular endothelial growth factor receptor (VEGFR and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes.

Effects of HGF gene polymorphisms and protein expression on transhepatic arterial chemotherapeutic embolism efficacy and prognosis in patients with primary liver cancer

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Chen HY

2017-02-01

Full Text Available Hai-Yong Chen,1,2 Yao-Min Chen,3 Jian Wu,1,2 Fu-Chun Yang,1,2 Zhen Lv,1,2 Yi-Gang Qian,1,2 Shu-Sen Zheng1,2 1Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 3Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Objective: To investigate the correlations of two hepatocyte growth factor (HGF gene polymorphisms (rs5745652 and rs2074725 and their protein expression levels with the efficacy of transhepatic arterial chemotherapeutic embolism (TACE and prognosis in patients with primary liver cancer (PLC. Methods: From March 2011 to June 2012, 109 PLC patients (the case group who chose TACE as primary treatment and 80 healthy people (the control group who had undergone physical examination in The First Affiliated Hospital, Zhejiang University were selected during the same period. Gene polymorphisms of HGF rs5745652 and HGF rs2074725 were detected. Serum HGF level, treating efficacy, survival quality, and 3-year survival rate for PLC patients who received TACE were observed. Results: There were significant differences in genotype and allele frequencies of HGF rs5745652 and HGF rs2074725, between the case and control groups (all P<0.05. Compared with CT+TT genotype of HGF rs5745652, patients carrying CC genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate (all P<0.05. In rs2074725, patients carrying CA+AA genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate compared with patients carrying rs2074725 CC genotype (all P<0.05. Gene polymorphisms of HGF rs5745652 and HGF rs2074725, tumor size, and Barcelona Clinic Liver Cancer stage were independent prognostic factors for PLC (P<0.05. Conclusion: Our

Interaction of integrin β4 with S1P receptors in S1P- and HGF-induced endothelial barrier enhancement.

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Ni, Xiuqin; Epshtein, Yulia; Chen, Weiguo; Zhou, Tingting; Xie, Lishi; Garcia, Joe G N; Jacobson, Jeffrey R

2014-06-01

We previously reported sphingosine 1-phosphate (S1P) and hepatocyte growth factor (HGF) augment endothelial cell (EC) barrier function and attenuate murine acute lung inury (ALI). While the mechanisms underlying these effects are not fully understood, S1P and HGF both transactivate the S1P receptor, S1PR1 and integrin β4 (ITGB4) at membrane caveolin-enriched microdomains (CEMs). In the current study, we investigated the roles of S1PR2 and S1PR3 in S1P/HGF-mediated EC signaling and their associations with ITGB4. Our studies confirmed ITGB4 and S1PR2/3 are recruited to CEMs in human lung EC in response to either S1P (1 µM, 5 min) or HGF (25 ng/ml, 5 min). Co-immunoprecipitation experiments identified an S1P/HGF-mediated interaction of ITGB4 with both S1PR2 and S1PR3. We then employed an in situ proximity ligation assay (PLA) to confirm a direct ITGB4-S1PR3 association induced by S1P/HGF although a direct association was not detectable between S1PR2 and ITGB4. S1PR1 knockdown (siRNA), however, abrogated S1P/HGF-induced ITGB4-S1PR2 associations while there was no effect on ITGB4-S1PR3 associations. Moreover, PLA confirmed a direct association between S1PR1 and S1PR2 induced by S1P and HGF. Finally, silencing of S1PR2 significantly attenuated S1P/HGF-induced EC barrier enhancement as measured by transendothelial resistance while silencing of S1PR3 significantly augmented S1P/HGF-induced barrier enhancement. These results confirm an important role for S1PR2 and S1PR3 in S1P/HGF-mediated EC barrier responses that are associated with their complex formation with ITGB4. Our findings elucidate novel mechanisms of EC barrier regulation that may ultimately lead to new therapeutic targets for disorders characterized by increased vascular permeability including ALI. © 2013 Wiley Periodicals, Inc.

Matriptase is required for the active form of hepatocyte growth factor induced Met, focal adhesion kinase and protein kinase B activation on neural stem/progenitor cell motility.

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Fang, Jung-Da; Lee, Sheau-Ling

2014-07-01

Hepatocyte growth factor (HGF) is a chemoattractant and inducer for neural stem/progenitor (NS/P) cell migration. Although the type II transmembrane serine protease, matriptase (MTP) is an activator of the latent HGF, MTP is indispensable on NS/P cell motility induced by the active form of HGF. This suggests that MTP's action on NS/P cell motility involves mechanisms other than proteolytic activation of HGF. In the present study, we investigate the role of MTP in HGF-stimulated signaling events. Using specific inhibitors of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) or focal adhesion kinase (FAK), we demonstrated that in NS/P cells HGF-activated c-Met induces PI3k-Akt signaling which then leads to FAK activation. This signaling pathway ultimately induces MMP2 expression and NS/P cell motility. Knocking down of MTP in NS/P cells with specific siRNA impaired HGF-stimulation of c-Met, Akt and FAK activation, blocked HGF-induced production of MMP2 and inhibited HGF-stimulated NS/P cell motility. MTP-knockdown NS/P cells cultured in the presence of recombinant protein of MTP protease domain or transfected with the full-length wild-type but not the protease-defected MTP restored HGF-responsive events in NS/P cells. In addition to functioning as HGF activator, our data revealed novel function of MTP on HGF-stimulated c-Met signaling activation. Copyright © 2014. Published by Elsevier B.V.

Multiple regulatory mechanisms of hepatocyte growth factor expression in malignant cells with a short poly(dA) sequence in the HGF gene promoter.

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Sakai, Kazuko; Takeda, Masayuki; Okamoto, Isamu; Nakagawa, Kazuhiko; Nishio, Kazuto

2015-01-01

Hepatocyte growth factor (HGF) expression is a poor prognostic factor in various types of cancer. Expression levels of HGF have been reported to be regulated by shorter poly(dA) sequences in the promoter region. In the present study, the poly(dA) mononucleotide tract in various types of human cancer cell lines was examined and compared with the HGF expression levels in those cells. Short deoxyadenosine repeat sequences were detected in five of the 55 cell lines used in the present study. The H69, IM95, CCK-81, Sui73 and H28 cells exhibited a truncated poly(dA) sequence in which the number of poly(dA) repeats was reduced by ≥5 bp. Two of the cell lines exhibited high HGF expression, determined by reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The CCK-81, Sui73 and H28 cells with shorter poly(dA) sequences exhibited low HGF expression. The cause of the suppression of HGF expression in the CCK-81, Sui73 and H28 cells was clarified by two approaches, suppression by methylation and single nucleotide polymorphisms in the HGF gene. Exposure to 5-Aza-dC, an inhibitor of DNA methyltransferase 1, induced an increased expression of HGF in the CCK-81 cells, but not in the other cells. Single-nucleotide polymorphism (SNP) rs72525097 in intron 1 was detected in the Sui73 and H28 cells. Taken together, it was found that the defect of poly(dA) in the HGF promoter was present in various types of cancer, including lung, stomach, colorectal, pancreas and mesothelioma. The present study proposes the negative regulation mechanisms by methylation and SNP in intron 1 of HGF for HGF expression in cancer cells with short poly(dA).

Gram-scale production of plasmid pUDK-HGF with current good manufacturing practices for gene therapy of critical limb ischemia.

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Hu, ChunSheng; Cheng, XiaoChen; Lu, YuXin; Wu, ZuZe; Zhang, QingLin

2016-11-16

The demand of a plasmid encoding human hepatocyte growth factor gene (pUDK-HGF) in large quantities at high purity and concentration has increased for gene therapy of critical limb ischemia (CLI) in clinical trials. In this article, we produced pUDK-HGF in compliance with current good manufacturing practices at gram scale. The process included a 50-L batch fermentation, continuous alkaline lysis, and integrated three-step chromatography on Sepharose 6 Fast Flow, PlasmidSelect Xtra, and Source 15Q. The production process has been scaled up to yield 4.24 ± 0.41 g of pharmaceutical pUDK-HGF from 1.0 kg bacterial cell paste and the overall yield reached range from 58.37 to 66.70%. The final pUDK-HGF product exhibited high purity with supercoiled percentage of > 95.8% and undetectable residual RNA, contaminated protein, and bacterial endotoxin. The phase I clinical study indicates that intramuscular injection of pUDK-HGF is safe, well tolerated, and may provide symptomatic relief to CLI patients. These results show that our manufacturing process of pUDK-HGF is efficient in producing pharmaceutical-grade plasmid DNA and is safe for clinical applications.

Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure.

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Chiang, Chih-Hung; Wu, Wai-Wah; Li, Hsin-Yang; Chien, Yueh; Sun, Cho-Chin; Peng, Chi-Hsien; Lin, Alex Tong-Long; Huang, Chi-Shuan; Lai, Ying-Hsiu; Chiou, Shih-Hwa; Hung, Shuen-Iu; Chang, Yuh-Lih; Lan, Yuan-Tzu; Liu, Dean-Mo; Chien, Chian-Shiu; Huo, Teh-Ia; Lee, Shou-Dong; Wang, Chien-Ying

2015-01-01

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

HGF and BFGF Secretion by Human Adipose-Derived Stem Cells Improves Ovarian Function During Natural Aging via Activation of the SIRT1/FOXO1 Signaling Pathway.

Science.gov (United States)

Ding, Chenyue; Zou, Qinyan; Wang, Fuxin; Wu, Huihua; Wang, Wei; Li, Hong; Huang, Boxian

2018-01-01

Human adipose-derived stem cells (hADSCs) are a potential therapeutic option for clinical applications because of their ability to produce cytokines and their capacity for trilineage differentiation. To date, few researchers have investigated the effects of hADSCs on natural ovarian aging (NOA). An NOA mouse model and human ovarian granule cells (hGCs) collected from individuals with NOA were prepared to assess the therapeutic effects and illuminate the mechanism of hADSCs in curing NOA. Enzyme-linked immunosorbent assay was used to detect the serum levels of sex hormones and antioxidative enzymes. The proliferation rate and marker expression level of hGCs were measured by flow cytometry (FACS). Cytokines were measured by a protein antibody array methodology. Western blot assays were used to determine the protein expression levels of SIRT1 and FOXO1. Our results showed that hADSCs displayed therapeutic activity against ovarian function in an NOA mouse model, increasing the proliferation rate and marker expression level of hGCs. Furthermore, the yields of hADSC-secreted HGF and bFGF were higher than those of other growth factors. FACS showed that combination treatment with the growth factors HGF and bFGF more strongly promoted proliferation and inhibited apoptosis in hGCs than HGF or bFGF treatment alone. FACS and ELISA revealed that the combination treatment with both growth factors inhibited oxidative stress more forcefully than treatments with only one of these growth factors. In addition, protein assays demonstrated that combination treatment with both growth factors suppressed oxidative stress by up-regulating the expression of SIRT1 and FOXO1. These findings demonstrate for the first time the molecular cascade and related cell biology events involved in the mechanism by which HGF and bFGF derived from hADSCs improved ovarian function during natural aging via reduction of oxidative stress by activating the SIRT1/FOXO1 signaling pathway. © 2018 The Author

Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks

DEFF Research Database (Denmark)

Hammond, Dean E; Hyde, Russell; Kratchmarova, Irina

2010-01-01

549 lung adenocarcinoma cells with EGF or HGF. In total, we obtained quantitative information for 274 proteins, which respond to either or both stimuli by >1.5 fold changes in enrichment, following immuno-precipitation with antiphosphotyrosine antibodies. The data reveal a high degree of overlap...

Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and β4 integrin function in MDA-MB-231 breast cancer cells

International Nuclear Information System (INIS)

Lee, W.-J.; Chen, W.-K.; Wang, C.-J.; Lin, W.-L.; Tseng, T.-H.

2008-01-01

Hepatocyte growth factor (HGF) and its receptor, Met, known to control invasive growth program have recently been shown to play crucial roles in the survival of breast cancer patients. The diet-derived flavonoids have been reported to possess anti-invasion properties; however, knowledge on the pharmacological and molecular mechanisms in suppressing HGF/Met-mediated tumor invasion and metastasis is poorly understood. In our preliminary study, we use HGF as an invasive inducer to investigate the effect of flavonoids including apigenin, naringenin, genistein and kaempferol on HGF-dependent invasive growth of MDA-MB-231 human breast cancer cells. Results show that apigenin presents the most potent anti-migration and anti-invasion properties by Boyden chamber assay. Furthermore, apigenin represses the HGF-induced cell motility and scattering and inhibits the HGF-promoted cell migration and invasion in a dose-dependent manner. The effect of apigenin on HGF-induced signaling activation involving invasive growth was evaluated by immunoblotting analysis, it shows that apigenin blocks the HGF-induced Akt phosphorylation but not Met, ERK, and JNK phosphorylation. In addition to MDA-MB-231 cells, apigenin exhibits inhibitory effect on HGF-induced Akt phosphorylation in hepatoma SK-Hep1 cells and lung carcinoma A549 cells. By indirect immunofluorescence microscopy assay, apigenin inhibits the HGF-induced clustering of β4 integrin at actin-rich adhesive site and lamellipodia through PI3K-dependent manner. Treatment of apigenin inhibited HGF-stimulated integrin β4 function including cell-matrix adhesion and cell-endothelial cells adhesion in MDA-MB-231 cells. By Akt-siRNA transfection analysis, it confirmed that apigenin inhibited HGF-promoted invasive growth involving blocking PI3K/Akt pathway. Finally, we evaluated the effect of apigenin on HGF-promoted metastasis by lung colonization of tumor cells in nude mice and organ metastasis of tumor cells in chick embryo. By

ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation.

Science.gov (United States)

Koubek, Emily J; Santy, Lorraine C

2018-05-04

Hepatocyte growth factor (HGF) is a potent signaling factor that acts on epithelial cells, causing them to dissociate and scatter. This migration is coordinated by a number of small GTPases, such as ARF6 and Rac1. Active ARF6 is required for HGF-stimulated migration and intracellular levels of ARF6-GTP and Rac1-GTP increase following HGF treatment. During migration, cross talk between ARF6 and Rac1 occurs through formation of a multi-protein complex containing the ARF-GEF cytohesin-2, the scaffolding protein GRASP/Tamalin, and the Rac1-GEF Dock180. Previously, the role of ARF6 in this process was unclear. We have now found that ARF6 and ARF1 regulate trafficking of GRASP and Dock180 to the plasma membrane following HGF treatment. Trafficking of GRASP and Dock180 is impaired by blocking ARF6-mediated recycling pathways and is required for HGF-stimulated Rac1 activation. Finally, HGF treatment stimulates association of GRASP and Dock180. Inhibition of ARF6 trafficking pathways traps GRASP and Dock180 as a complex in the cell.

Up-regulation of DRP-3 long isoform during the induction of neural progenitor cells by glutamate treatment in the ex vivo rat retina

Energy Technology Data Exchange (ETDEWEB)

Tokuda, Kazuhiro, E-mail: r502um@yamaguchi-u.ac.jp [Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi (Japan); Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi (Japan); Kuramitsu, Yasuhiro; Byron, Baron; Kitagawa, Takao [Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi (Japan); Tokuda, Nobuko [Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Ube (Japan); Kobayashi, Daiki; Nagayama, Megumi; Araki, Norie [Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Sonoda, Koh-Hei [Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi (Japan); Nakamura, Kazuyuki [Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi (Japan)

2015-08-07

Glutamate has been shown to induce neural progenitor cells in the adult vertebrate retina. However, protein dynamics during progenitor cell induction by glutamate are not fully understood. To identify specific proteins involved in the process, we employed two-dimensional electrophoresis-based proteomics on glutamate untreated and treated retinal ex vivo sections. Rat retinal tissues were incubated with 1 mM glutamate for 1 h, followed by incubation in glutamate-free media for a total of 24 h. Consistent with prior reports, it was found that mitotic cells appeared in the outer nuclear layer without any histological damage. Immunohistological evaluations and immunoblotting confirmed the emergence of neuronal progenitor cells in the mature retina treated with glutamate. Proteomic analysis revealed the up-regulation of dihydropyrimidinase-related protein 3 (DRP-3), DRP-2 and stress-induced-phosphoprotein 1 (STIP1) during neural progenitor cell induction by glutamate. Moreover, mRNA expression of DRP-3, especially, its long isoform, robustly increased in the treated retina compared to that in the untreated retina. These results may indicate that glutamate induces neural progenitor cells in the mature rat retina by up-regulating the proteins which mediate cell mitosis and neurite growth. - Highlights: • Glutamate induced neuronal progenitor cells in the mature rat retina. • Proteomic analysis revealed the up-regulation of DRP-3, DRP-2 and STIP1. • mRNA expression of DRP-3, especially, its long isoform, robustly increased.

The value of gated myocardial perfusion imaging for the evaluation of early treatment effectiveness of ischemic heart disease using Ad-HGF myocardial injection

International Nuclear Information System (INIS)

Feng Jianlin; Cheng Xu; Li Jianhua; Xu Zhaoqiang; Li Dianfu; Yuan Biao; Zhang Yourong; Cao Kejiang; Huang Jun

2008-01-01

Objective: Hepatocyte growth factor (HGF) has multipotent actions mediated by c- Mesenchymal epithelial transition factor (Met) receptor. Preclinical studies in animal models of myocardial ischemia demonstrated that treatment with HGF could benefit myocardial perfusion, cardiac remodeling, angiogenesis and myocardial function. This study used gated 99 Tc m -methoxyisobutylisonitrile (MIBI) myocardial perfusion imaging (G-MPI) to assess the early treatment effectiveness of adenovirus HGF (Ad-HGF) directly administered in ischemic heart disease (IHD) patients. Methods: Eighteen patients with IHD were divided into 3 groups receiving low dose [5 x 10 8 plaque forming unit (PFU)/site], medium (1.5 x 10 9 PFU/site) and high dose (5 x l0 9 PFU/site) of Ad-HGF. And the Ad-HGF was injected at 10 sites in each patient. Rest G-MPI was performed before and after treatment for myocardial perfusion and left ventricular function measurement. Stata 7.0 was used to analyse the data. Results: (1) After Ad-HGF, myocardial perfusion was improved in 3/6, 5/6 and 6/6 patients in low, medium and high dosage groups. The dosage of AD-HGF was closely correlated with the improvement of myocardial perfusion (χ 2 =4.34, P<0.05). (2) Left ventricular ejection fraction (LVEF) was significantly increased [(50.1 ± 6.4)% vs (58.7 ± 5.6)%, t=6.1, P<0.01], end-diastolic volume [EDV, (137.7 ± 33.2) ml vs (123.7 ± 32.7) ml] and end-systolic volume [ESV, (70.2 ± 22.4) ml vs (51.9 ± 14.9) ml] were significantly reduced. (3) The LVEFs were increased in all groups, and the LVEF improvement in the high dosage group [(8.6 ± 5.9)%] was significantly greater than the other two groups [(4.3 ± l.2)%, (6.8 ± 5.7)%]. The difference of post-treatment improvement on LVEF between the low and medium dosage groups was not significant. The dosage of Ad-HGF was closely correlated with the improvement of LVEF (r=0.67, P< 0.01). Conclusion: G-MPI is a reliable method for evaluating the early effectiveness of

Hepatocyte growth factor enhances death receptor-induced apoptosis by up-regulating DR5

International Nuclear Information System (INIS)

Li, Yang; Fan, Xing; Goodwin, C Rory; Laterra, John; Xia, Shuli

2008-01-01

Hepatocyte growth factor (HGF) and its receptor c-MET are commonly expressed in malignant gliomas and embryonic neuroectodermal tumors including medulloblastoma and appear to play an important role in the growth and dissemination of these malignancies. Dependent on cell context and the involvement of specific downstream effectors, both pro- and anti-apoptotic effects of HGF have been reported. Human medulloblastoma cells were treated with HGF for 24–72 hours followed by death receptor ligand TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) for 24 hours. Cell death was measured by MTT and Annexin-V/PI flow cytometric analysis. Changes in expression levels of targets of interest were measured by Northern blot analysis, quantitative reverse transcription-PCR, Western blot analysis as well as immunoprecipitation. In this study, we show that HGF promotes medulloblastoma cell death induced by TRAIL. TRAIL alone triggered apoptosis in DAOY cells and death was enhanced by pre-treating the cells with HGF for 24–72 h prior to the addition of TRAIL. HGF (100 ng/ml) enhanced TRAIL (10 ng/ml) induced cell death by 36% (P < 0.001). No cell death was associated with HGF alone. Treating cells with PHA-665752, a specific c-Met receptor tyrosine kinase inhibitor, significantly abrogated the enhancement of TRAIL-induced cell death by HGF, indicating that its death promoting effect requires activation of its canonical receptor tyrosine kinase. Cell death induced by TRAIL+HGF was predominately apoptotic involving both extrinsic and intrinsic pathways as evidenced by the increased activation of caspase-3, 8, 9. Promotion of apoptosis by HGF occurred via the increased expression of the death receptor DR5 and enhanced formation of death-inducing signal complexes (DISC). Taken together, these and previous findings indicate that HGF:c-Met pathway either promotes or inhibits medulloblastoma cell death via pathway and context specific mechanisms

Umbilical Cord-derived Mesenchymal Stem Cells Instruct Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF.

Science.gov (United States)

Deng, Yinan; Zhang, Yingcai; Ye, Linsen; Zhang, Tong; Cheng, Jintao; Chen, Guihua; Zhang, Qi; Yang, Yang

2016-12-05

Human UC-MSCs are regarded as an attractive alternative to BM-MSCs for clinical applications due to their easy preparation, higher proliferation and lower immunogenicity. However, the mechanisms underlying immune suppression by UC-MSCs are still unclear. We studied the mechanism of inhibition by UC-MSCs during the differentiation of monocytes into DCs and focused on the specific source and the role of the involved cytokines. We found that UC-MSCs suppressed monocyte differentiation into DCs and instructed monocytes towards other cell types, with clear decreases in the expression of co-stimulatory molecules, in the secretion of inflammatory factors and in allostimulatory capacity. IL6, HGF and IL10 might be involved in this process because they were detected at higher levels in a coculture system. UC-MSCs produce IL-6 and HGF, and neutralization of IL-6 and HGF reversed the suppressive effect of UC-MSCs. IL10 was not produced by UC-MSCs but was exclusively produced by monocytes after exposure to UC-MSCs, IL-6 or HGF. In summary, we found that the UC-MSC-mediated inhibitory effect was dependent on IL6 and HGF secreted by UC-MSCs and that this effect induced monocyte-derived cells to produce IL10, which might indirectly strengthen the suppressive effect of UC-MSCs.

Myocardial perfusion imaging, coronary angiography and histological examination in experimental treatment of Ad-HGF for myocardial infarction

International Nuclear Information System (INIS)

Li Jianhua; Feng Jianlin; Cheng Xu; Li Dianfu; Zhang Youfu

2007-01-01

Objective: Gene therapy has drawn a great attention. A swine model of adenovirus hepatocyte growth factor(Ad-HGF) treated myocardial infarction(MI) was utilized, with the effect being assessed by rest myocardial perfusion imaging, coronary angiography and histological examination. Methods: Three groups of MI swine treated with Ad-HGF at low dose [n=5, Ad-HGF 10 8 plague forming unit (PFU)/ site], medium dose(n=5, 4 x 10 8 PFU/site), and high dose (n=5, 5 x 10 9 PFU/site), a control group treated with normal saline(NS, n=5) and a blank control group (n=5) underwent rest myocardial perfusion imaging and coronary angiography before and after treatment. The imaging results were analyzed along with histological findings in each group. Results: The state of myocardial perfusion and Rentrop scores remained unchanged in the blank control and NS groups after treatment. Whereas there was a significant improvement in the two variables in all three groups treated with Ad-HGF. The scores of left circumflex coronary artery (LCX) before and after treated were 7.8 ± 1.3 and 16.4 ± 1.1 (low-dose), 8.2 ± 1.6 and 17.6 ± 0.9 (medium-dose), 8.4 ± 1.5 and 19.0 ± 0.7 (high-dose), respectively. No significant differences were noted among the 3 groups. The number of vessels of NS group was markedly less than that of other groups. Conclusion: Myocardial perfusion imaging seems to be more accurate than coronary angiography and histological examination in evaluating the effects of Ad-HGF on myocardial infarction. (authors)

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model.

Science.gov (United States)

Gómez-Mauricio, Guadalupe; Moscoso, Isabel; Martín-Cancho, María-Fernanda; Crisóstomo, Verónica; Prat-Vidal, Cristina; Báez-Díaz, Claudia; Sánchez-Margallo, Francisco M; Bernad, Antonio

2016-07-16

Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model. Pig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry. Intramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium. The simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.

Umbilical Cord-derived Mesenchymal Stem Cells Instruct Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF

Science.gov (United States)

Deng, Yinan; Zhang, Yingcai; Ye, Linsen; Zhang, Tong; Cheng, Jintao; Chen, Guihua; Zhang, Qi; Yang, Yang

2016-01-01

Human UC-MSCs are regarded as an attractive alternative to BM-MSCs for clinical applications due to their easy preparation, higher proliferation and lower immunogenicity. However, the mechanisms underlying immune suppression by UC-MSCs are still unclear. We studied the mechanism of inhibition by UC-MSCs during the differentiation of monocytes into DCs and focused on the specific source and the role of the involved cytokines. We found that UC-MSCs suppressed monocyte differentiation into DCs and instructed monocytes towards other cell types, with clear decreases in the expression of co-stimulatory molecules, in the secretion of inflammatory factors and in allostimulatory capacity. IL6, HGF and IL10 might be involved in this process because they were detected at higher levels in a coculture system. UC-MSCs produce IL-6 and HGF, and neutralization of IL-6 and HGF reversed the suppressive effect of UC-MSCs. IL10 was not produced by UC-MSCs but was exclusively produced by monocytes after exposure to UC-MSCs, IL-6 or HGF. In summary, we found that the UC-MSC-mediated inhibitory effect was dependent on IL6 and HGF secreted by UC-MSCs and that this effect induced monocyte-derived cells to produce IL10, which might indirectly strengthen the suppressive effect of UC-MSCs. PMID:27917866

A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2.

Directory of Open Access Journals (Sweden)

Daniela Annibali

Full Text Available The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miR-103--restrain ID2 expression by directly targeting the coding sequence and 3' untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.

The HGF Receptor c-Met Is Overexpressed in Esophageal Adenocarcinoma

Directory of Open Access Journals (Sweden)

Luis J. Herrera

2005-01-01

Full Text Available The hepatocyte growth factor (HGF receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE, and normal esophagus (NE using immunohistochemistry (IHC and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100% EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2-overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted.

Microfluidic wound-healing assay to assess the regenerative effect of HGF on wounded alveolar epithelium.

Science.gov (United States)

Felder, Marcel; Sallin, Pauline; Barbe, Laurent; Haenni, Beat; Gazdhar, Amiq; Geiser, Thomas; Guenat, Olivier

2012-02-07

We present a microfluidic epithelial wound-healing assay that allows characterization of the effect of hepatocyte growth factor (HGF) on the regeneration of alveolar epithelium using a flow-focusing technique to create a regular wound in the epithelial monolayer. The phenotype of the epithelial cell was characterized using immunostaining for tight junction (TJ) proteins and transmission electron micrographs (TEMs) of cells cultured in the microfluidic system, a technique that is reported here for the first time. We demonstrate that alveolar epithelial cells cultured in a microfluidic environment preserve their phenotype before and after wounding. In addition, we report a wound-healing benefit induced by addition of HGF to the cell culture medium (19.2 vs. 13.5 μm h(-1) healing rate).

SNP analyses of growth factor genes EGF, TGFβ-1, and HGF reveal haplotypic association of EGF with autism

International Nuclear Information System (INIS)

Toyoda, Takao; Nakamura, Kazuhiko; Yamada, Kazuo; Thanseem, Ismail; Anitha, Ayyappan; Suda, Shiro; Tsujii, Masatsugu; Iwayama, Yoshimi; Hattori, Eiji; Toyota, Tomoko; Miyachi, Taishi; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Kawai, Masayoshi; Sekine, Yoshimoto; Tsuchiya, Kenji; Sugihara, Gen-ichi; Ouchi, Yasuomi; Sugiyama, Toshiro; Takei, Nori; Yoshikawa, Takeo; Mori, Norio

2007-01-01

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-β (TGFβ) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGFβ1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGFβ1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism

Clinical significance of estimation of changes in serum SF, VEGF and HGF levels and after transfusion of red blood cells in patients with chronic nephritis

International Nuclear Information System (INIS)

Mu Peidong; He Haoming

2011-01-01

Objective: To observe the changes of serum SF, VEGF and HGF levels and after transfusion of red blood cells (RBC) in patients with chronic nephritis. Methods: Serum SF (with RIA) and serum VEGF, HGF (with ELISA) levels were measured in 30 patients with chronic nephritis both before and after a course of transfusion of RBC and 35 controls. Results: Before transfusion the serum SF levels in the patients were significantly lower than those in controls (P 0.05). Conclusion: Determination of serum SF, VEGF and HGF levels were clinically useful for the progress, prognosis and judgement of chronic nephritis. (authors)

Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer

Directory of Open Access Journals (Sweden)

Demin Jiao

2016-01-01

Full Text Available The epithelial-mesenchymal transition (EMT and angiogenesis have emerged as two pivotal events in cancer progression. Curcumin has been extensively studied in preclinical models and clinical trials of cancer prevention due to its favorable toxicity profile. However, the possible involvement of curcumin in the EMT and angiogenesis in lung cancer remains unclear. This study found that curcumin inhibited hepatocyte growth factor (HGF-induced migration and EMT-related morphological changes in A549 and PC-9 cells. Moreover, pretreatment with curcumin blocked HGF-induced c-Met phosphorylation and downstream activation of Akt, mTOR, and S6. These effects mimicked that of c-Met inhibitor SU11274 or PI3 kinase inhibitor LY294002 or mTOR inhibitor rapamycin treatment. c-Met gene overexpression analysis further demonstrated that curcumin suppressed lung cancer cell EMT by inhibiting c-Met/Akt/mTOR signaling pathways. In human umbilical vein endothelial cells (HUVECs, we found that curcumin also significantly inhibited PI3K/Akt/mTOR signaling and induced apoptosis and reduced migration and tube formation of HGF-treated HUVEC. Finally, in the experimental mouse model, we showed that curcumin inhibited HGF-stimulated tumor growth and induced an increase in E-cadherin expression and a decrease in vimentin, CD34, and vascular endothelial growth factor (VEGF expression. Collectively, these findings indicated that curcumin could inhibit HGF-promoted EMT and angiogenesis by targeting c-Met and blocking PI3K/Akt/mTOR pathways.

SNP analyses of growth factor genes EGF, TGF{beta}-1, and HGF reveal haplotypic association of EGF with autism

Energy Technology Data Exchange (ETDEWEB)

Toyoda, Takao; Thanseem, Ismail; Kawai, Masayoshi; Sekine, Yoshimoto [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Nakamura, Kazuhiko; Anitha, Ayyappan; Suda, Shiro [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Yamada, Kazuo [Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama (Japan); Tsujii, Masatsugu [Faculty of Sociology, Chukyo University, Toyota, Aichi (Japan); [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan); Iwayama, Yoshimi; Hattori, Eiji; Toyota, Tomoko; Yoshikawa, Takeo [Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama (Japan); Miyachi, Taishi; Tsuchiya, Kenji; Sugihara, Gen-ichi; Matsuzaki, Hideo [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan); Iwata, Yasuhide; Suzuki, Katsuaki [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Mori, Norio [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of Medicine, Osaka University (Japan); Ouchi, Yasuomi [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan); [The Positron Medical Center, Hamamatsu Medical Center, Hamamatsu (Japan); Sugiyama, Toshiro [Aichi Children' s Health and Medical Center, Obu, Aichi (Japan); Takei, Nori [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan)

2007-09-07

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-{beta} (TGF{beta}) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGF{beta}1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGF{beta}1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.

The TAM-family receptor Mer mediates production of HGF through the RhoA-dependent pathway in response to apoptotic cells.

Science.gov (United States)

Park, Hyun-Jung; Baen, Ji-Yeon; Lee, Ye-Ji; Choi, Youn-Hee; Kang, Jihee Lee

2012-08-01

The TAM receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. We investigated the roles of the TAM receptors in mediating the induction of hepatocyte growth factor (HGF) during the interaction of macrophages with apoptotic cells. Mer-specific neutralizing antibody, small interfering RNA (siRNA), and a recombinant Mer protein (Mer/Fc) inhibited HGF mRNA and protein expression, as well as activation of RhoA, Akt, and specific mitogen-activated protein (MAP) kinases in response to apoptotic cells. Inhibition of Axl or Tyro3 with specific antibodies, siRNA, or Fc-fusion proteins did not prevent apoptotic cell-induced HGF mRNA and protein expression and did not inhibit activation of the postreceptor signaling molecules RhoA and certain MAP kinases, including extracellular signal-regulated protein kinase and c-Jun NH(2)-terminal kinase. However, Axl- and Tyro3-specific blockers did inhibit the activation of Akt and p38 MAP kinase in response to apoptotic cells. In addition, none of the TAM receptors mediated the effects of apoptotic cells on transforming growth factor-β or epidermal growth factor mRNA expression. However, they were involved in the induction of vascular endothelial growth factor mRNA expression. Our data provide evidence that when macrophages interact with apoptotic cells, only Mer of the TAM-family receptors is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway.

The (PrS/HGF-pDNA) multilayer films for gene-eluting stent coating: Gene-protecting, anticoagulation, antibacterial properties, and in vivo antirestenosis evaluation.

Science.gov (United States)

Chang, Hao; Ren, Ke-feng; Zhang, He; Wang, Jin-lei; Wang, Bai-liang; Ji, Jian

2015-02-01

Vascular gene-eluting stents (GES) is a promising strategy for treatment of cardiovascular disease. Very recently, we have proved that the (protamine sulfate/plasmid DNA encoding hepatocyte growth factor) (PrS/HGF-pDNA) multilayer can serve as a powerful tool for enhancing competitiveness of endothelial cell over smooth muscle cell, which opens perspectives for the regulation of intercellular competitiveness in the field of interventional therapy. However, before the gene multilayer films could be used in vascular stents for real clinical application, the preservation of gene bioactivity during the industrial sterilization and the hemocompatibility of film should be taken into account. Actually, both are long been ignored issues in the field of gene coating for GES. In this study, we demonstrate that the (PrS/HGF-pDNA) multilayer film exhibits the good gene-protecting abilities, which is confirmed by using the industrial sterilizations (gamma irradiation and ethylene oxide) and a routine storage condition (dry state at 4°C for 30 days). Furthermore, hemocompatible measurements (such as platelet adhesion and whole blood coagulation) and antibacterial assays (bacteria adhesion and growth inhibition) indicate the good anticoagulation and antibacterial properties of the (PrS/HGF-pDNA) multilayer film. The in vivo preliminary data of angiography and histological analysis suggest that the (PrS/HGF-pDNA) multilayer coated stent can reduce the in-stent restenosis. This work reveals that the (PrS/HGF-pDNA) multilayer film could be a promising candidate as coating for GES, which is of great potential in future clinic application. © 2014 Wiley Periodicals, Inc.

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.

Science.gov (United States)

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.

Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines

NARCIS (Netherlands)

Zomerman, Waldrik W; Plasschaert, Sabine L. A.; Diks, Sander H.; Lourens, Harm-Jan; Meeuwsen-de Boer, Tiny; Hoving, Eelco W.; den Dunnen, Wilfred F. A.; de Bont, Eveline S. J. M.

2015-01-01

Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte

Increased Epidermal Growth Factor Receptor (EGFR Associated with Hepatocyte Growth Factor (HGF and Symptom Severity in Children with Autism Spectrum Disorders (ASDs

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Anthony J. Russo

2014-01-01

Full Text Available Background One in 88 children in the US is thought to have one of the autism spectrum disorders (ASDs. ASDs are characterized by social impairments and communication problems. Growth factors and their receptors may play a role in the etiology of ASDs. Research has shown that epidermal growth factor receptor (EGFR activation is associated with nerve cell development and repair. This study was designed to measure plasma levels of EGFR in autistic children and correlate these levels with its ligand, epidermal growth factor, other related putative biomarkers such as hepatocyte growth factor (HGF, the ligand for MET (MNNG HOS transforming gene receptor, as well as the symptom severity of 19 different behavioral symptoms. Subjects and Methods Plasma EGFR concentration was measured in 33 autistic children and 34 age- and gender-similar neurotypical controls, using an enzyme-linked immunosorbent assay. Plasma EGFR levels were compared to putative biomarkers known to be associated with EGFR and MET and severity levels of 19 autism-related symptoms. Results We found plasma EGFR levels significantly higher in autistic children, when compared to neurotypical controls. EGFR levels correlated with HGF and high-mobility group protein B1 (HMGB1 levels, but not other tested putative biomarkers, and EGFR levels correlated significantly with severity of expressive language, conversational language, focus/attention, hyperactivity, eye contact, and sound sensitivity deficiencies. Conclusions These results suggest a relationship between increased plasma EGFR levels and designated symptom severity in autistic children. A strong correlation between plasma EGFR and HGF and HMGB1 suggests that increased EGFR levels may be associated with the HGF/Met signaling pathway, as well as inflammation.

Expression and migratory analysis of 5 human uveal melanoma cell lines for CXCL12, CXCL8, CXCL1, and HGF

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Di Cesare Sebastian

2007-01-01

Full Text Available Abstract Background The aim of this study was to characterize the presence and roles of CXCL12, CXCL8, CXCL1, and HGF in five human uveal melanoma cell lines, using different methods, in order to ascertain their significance in this disease. Methods Five human uveal melanoma cell lines (92.1, SP6.5, MKT-BR, OCM-1, and UW-1 of known proliferative, invasive, and metastatic potential were used in this experiment. A migration assay was used in order to assess the responsiveness of each cell line towards the four chosen chemotactic factors. Immunohistochemistry was then performed for all five cell lines (cytospins using antibodies directed toward CXCL1, CXCL8 and their receptors CXCR2 and CXCR1 respectively. Quantitative real-time PCR was then performed on all five cell lines in order to establish the presence of these four chemotactic factors. Results All five human uveal melanoma cell lines migrated towards the four chosen chemotactic factors at a level greater than that of the negative control. Chemokines CXCL1 and CXCL8 resulted in the greatest number of migrating cells in all five of our cell lines. Immunohistochemistry confirmed the expression of CXCL1, CXCL8, and their receptors CXCR2 and CXCR1 in all five of the cell lines. Quantitative real-time PCR results established expression of CXCL8, CXCL1, and HGF in all 5 cell lines tested. CXCL1 and CXCL8 are highly expressed in SP6.5 and UW-1. None of the five cell lines expressed any detectable levels of CXCL12. Conclusion The migratory ability of the 5 human uveal melanoma cell lines was positively influenced by the four chemotactic factors tested, namely CXCL12, CXCL8, CXCL1, and HGF. Self-expression of chemotactic factors CXCL8, CXCL1, and HGF may indicate an autocrine system, which perhaps contributes to the cells' metastatic ability in vivo.

Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway.

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Leung, E; Xue, A; Wang, Y; Rougerie, P; Sharma, V P; Eddy, R; Cox, D; Condeelis, J

2017-05-11

During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates. We found that tumor cells and macrophages, when plated together on the micro-patterned substrates, do not demonstrate sustained directional migration in only one direction (sustained directionality) but show random bi-directional walking. Sustained directionality of tumor cells as seen in vivo was established in vitro when beads coated with human umbilical vein endothelial cells were placed at one end of the micro-patterned 'ECM fibers' within the assay. We demonstrated that these endothelial cells supply the hepatocyte growth factor (HGF) required for the chemotactic gradient responsible for sustained directionality. Using this in vitro reconstituted streaming system, we found that directional streaming is dependent on, and most effectively blocked, by inhibiting the HGF/C-Met signaling pathway between endothelial cells and tumor cells. Key observations made with the in vitro reconstituted system implicating C-Met signaling were confirmed in vivo in mammary tumors using the in vivo invasion assay and intravital multiphoton imaging of tumor cell streaming. These results establish HGF/C-Met as a central organizing signal in blood vessel-directed tumor cell migration in vivo and highlight a promising role for C-Met inhibitors in blocking tumor cell streaming and metastasis in vivo, and for use in human trials.

IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: Regulation by SOCS3

International Nuclear Information System (INIS)

Sun Rui; Jaruga, Barbara; Kulkarni, Shailin; Sun Haoyu; Gao Bin

2005-01-01

The precise role of IL-6 in liver regeneration and hepatocyte proliferation is controversial and the role of SOCS3 in liver regeneration remains unknown. Here we show that in vitro treatment with IL-6 inhibited primary mouse hepatocyte proliferation. IL-6 induced p21 cip1 protein expression in primary mouse hepatocytes. Disruption of the p21 cip1 gene abolished the inhibitory effect of IL-6 on cell proliferation. Co-culture with nonparenchymal liver cells diminished IL-6 inhibition of hepatocyte proliferation, which was likely due to IL-6 stimulation of nonparenchymal cells to produce HGF. Finally, IL-6 induced higher levels of p21 cip1 protein expression and a slightly stronger inhibition of cell proliferation in SOCS3 +/- mouse hepatocytes compared to wild-type hepatocytes, while liver regeneration was enhanced and prolonged in SOCS3 +/- mice. Our findings suggest that IL-6 directly inhibits hepatocyte proliferation via a p21 cip1 -dependent mechanism and indirectly enhances hepatocyte proliferation via stimulating nonparenchymal cells to produce HGF. SOCS3 negatively regulates liver regeneration

Microfluidic wound-healing assay to assess the regenerative effect of HGF on wounded alveolar epithelium.

OpenAIRE

Felder Marcel; Sallin Pauline; Barbe Laurent; Haenni Beat; Gazdhar Amiq; Geiser Thomas; Guenat Olivier

2012-01-01

We present a microfluidic epithelial wound healing assay that allows characterization of the effect of hepatocyte growth factor (HGF) on the regeneration of alveolar epithelium using a flow focusing technique to create a regular wound in the epithelial monolayer. The phenotype of the epithelial cell was characterized using immunostaining for tight junction (TJ) proteins and transmission electron micrographs (TEMs) of cells cultured in the microfluidic system a technique that is reported here ...

Extremely Low-Frequency Electromagnetic Fields Promote In Vitro Neuronal Differentiation and Neurite Outgrowth of Embryonic Neural Stem Cells via Up-Regulating TRPC1

Science.gov (United States)

Ma, Qinlong; Chen, Chunhai; Deng, Ping; Zhu, Gang; Lin, Min; Zhang, Lei; Xu, Shangcheng; He, Mindi; Lu, Yonghui; Duan, Weixia; Pi, Huifeng; Cao, Zhengwang; Pei, Liping; Li, Min; Liu, Chuan; Zhang, Yanwen; Zhong, Min; Zhou, Zhou; Yu, Zhengping

2016-01-01

Exposure to extremely low-frequency electromagnetic fields (ELF-EMFs) can enhance hippocampal neurogenesis in adult mice. However, little is focused on the effects of ELF-EMFs on embryonic neurogenesis. Here, we studied the potential effects of ELF-EMFs on embryonic neural stem cells (eNSCs). We exposed eNSCs to ELF-EMF (50 Hz, 1 mT) for 1, 2, and 3 days with 4 hours per day. We found that eNSC proliferation and maintenance were significantly enhanced after ELF-EMF exposure in proliferation medium. ELF-EMF exposure increased the ratio of differentiated neurons and promoted the neurite outgrowth of eNSC-derived neurons without influencing astrocyes differentiation and the cell apoptosis. In addition, the expression of the proneural genes, NeuroD and Ngn1, which are crucial for neuronal differentiation and neurite outgrowth, was increased after ELF-EMF exposure. Moreover, the expression of transient receptor potential canonical 1 (TRPC1) was significantly up-regulated accompanied by increased the peak amplitude of intracellular calcium level induced by ELF-EMF. Furthermore, silencing TRPC1 expression eliminated the up-regulation of the proneural genes and the promotion of neuronal differentiation and neurite outgrowth induced by ELF-EMF. These results suggest that ELF-EMF exposure promotes the neuronal differentiation and neurite outgrowth of eNSCs via up-regulation the expression of TRPC1 and proneural genes (NeuroD and Ngn1). These findings also provide new insights in understanding the effects of ELF-EMF exposure on embryonic brain development. PMID:26950212

Short-term mastication after weaning upregulates GABAergic signalling and reduces dendritic spine in thalamus.

Science.gov (United States)

Ogawa, Mana; Nagai, Toshitada; Saito, Yoshikazu; Miyaguchi, Hitonari; Kumakura, Kei; Abe, Keiko; Asakura, Tomiko

2018-04-06

Mastication enhances brain function and mental health, but little is known about the molecular mechanisms underlying the effects of mastication on neural development in early childhood. Therefore, we analysed the gene expression in juvenile neural circuits in rats fed with a soft or chow diet immediately after weaning. We observed that the gene expression patterns in the thalamus varied depending on the diet. Furthermore, gene ontology analysis revealed that two terms were significantly enhanced: chemical synaptic transmission and positive regulation of dendritic spine morphogenesis. With respect to chemical synaptic transmission, glutamate decarboxylase and GABA receptors were upregulated in the chow diet group. The related genes, including vesicular GABA transporter, were also upregulated, suggesting that mastication activates GABAergic signalling. With respect to dendritic spine morphogenesis, Ingenuity Pathway Analysis predicted fewer extension of neurites and neurons and fewer number of branches in the chow diet group. The numbers of spines in the ventral posterolateral and posteromedial regions were significantly decreased. These results suggest that mastication in the early developing period upregulates GABAergic signalling genes, with a decrease of spines in the thalamus. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Hepatocyte growth factor in renal failure: promise and reality.

Science.gov (United States)

Vargas, G A; Hoeflich, A; Jehle, P M

2000-04-01

Can science discover some secrets of Greek mythology? In the case of Prometheus, we can now suppose that his amazing hepatic regeneration was caused by a peptide growth factor called hepatocyte growth factor (HGF). Increasing evidence indicates that HGF acts as a multifunctional cytokine on different cell types. This review addresses the molecular mechanisms that are responsible for the pleiotropic effects of HGF. HGF binds with high affinity to its specific tyrosine kinase receptor c-met, thereby stimulating not only cell proliferation and differentiation, but also cell migration and tumorigenesis. The three fundamental principles of medicine-prevention, diagnosis, and therapy-may be benefited by the rational use of HGF. In renal tubular cells, HGF induces mitogenic and morphogenetic responses. In animal models of toxic or ischemic acute renal failure, HGF acts in a renotropic and nephroprotective manner. HGF expression is rapidly up-regulated in the remnant kidney of nephrectomized rats, inducing compensatory growth. In a mouse model of chronic renal disease, HGF inhibits the progression of tubulointerstitial fibrosis and kidney dysfunction. Increased HGF mRNA transcripts were detected in mesenchymal and tubular epithelial cells of rejecting kidney. In transplanted patients, elevated HGF levels may indicate renal rejection. When HGF is considered as a therapeutic agent in human medicine, for example, to stimulate kidney regeneration after acute injury, strategies need to be developed to stimulate cell regeneration and differentiation without an induction of tumorigenesis.

Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist.

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Simonneau, Claire; Bérénice Leclercq; Mougel, Alexandra; Adriaenssens, Eric; Paquet, Charlotte; Raibaut, Laurent; Ollivier, Nathalie; Drobecq, Hervé; Marcoux, Julien; Cianférani, Sarah; Tulasne, David; de Jonge, Hugo; Melnyk, Oleg; Vicogne, Jérôme

2015-03-01

The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a "head to tail" dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists.

Hepatocyte Growth Factor Gene-Modified Mesenchymal Stem Cells Augment Sinonasal Wound Healing.

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Li, Jing; Zheng, Chun-Quan; Li, Yong; Yang, Chen; Lin, Hai; Duan, Hong-Gang

2015-08-01

This study was designed to investigate the effects of hepatocyte growth factor (HGF) transgenic mesenchymal stem cells (HGF-MSCs) on wound healing in the sinonasal mucosa and nasal epithelial cells (NECs). We also sought to determine whether HGF-MSCs and MSCs can migrate into the injured mucosa and differentiate into ciliated cells. Human HGF-overexpressing umbilical cord MSCs (hHGF-UCMSCs) were established, and upregulation of hHGF expression was confirmed by real-time PCR (RT-PCR) and enzyme-linked immunosorbant assay (ELISA). To investigate the paracrine effect of human MSCs (hMSCs) on nasal epithelial repair, hMSC- and HGF-MSC-conditioned media (CM) were used in NEC proliferation assays and in an in vitro scratch-wound repair model. The in vivo sinonasal wound-healing model was established, and all enrolled rabbits were randomly assigned to four groups: the GFP-MSC group, the HGF-MSC group, the Ad-HGF group, and the surgery control group. The average decreased diameter was recorded, and the medial wall of the maxillary sinus was removed for histological analysis and scanning electron microscopy. Collagen deposition in the wound tissue was detected via Masson trichrome (M&T) staining. The distribution of MSCs and HGF-MSCs was observed by immunofluorescence. MSCs improved nasal wound healing both in vivo and in vitro. HGF overexpression in MSCs augmented the curative effects. Reduced collagen deposition and transforming growth factor beta1 (TGF-β1) expression were detected in the HGF-MSC group compared with the MSC-, Ad-HGF-, and phosphate-buffered saline-treated groups based on M&T staining and ELISA. The enhanced therapeutic effects of HGF-MSCs were accompanied by decreased level of the fibrogenic cytokine TGF-β1. In addition, both HGF-MSCs and MSCs can migrate to the injured mucosa and epithelial layer.

Neural stem cells enhance nerve regeneration after sciatic nerve injury in rats.

Science.gov (United States)

Xu, Lin; Zhou, Shuai; Feng, Guo-Ying; Zhang, Lu-Ping; Zhao, Dong-Mei; Sun, Yi; Liu, Qian; Huang, Fei

2012-10-01

With the development of tissue engineering and the shortage of autologous nerve grafts in nerve reconstruction, cell transplantation in a conduit is an alternative strategy to improve nerve regeneration. The present study evaluated the effects and mechanism of brain-derived neural stem cells (NSCs) on sciatic nerve injury in rats. At the transection of the sciatic nerve, a 10-mm gap between the nerve stumps was bridged with a silicon conduit filled with 5 × 10(5) NSCs. In control experiments, the conduit was filled with nerve growth factor (NGF) or normal saline (NS). The functional and morphological properties of regenerated nerves were investigated, and expression of hepatocyte growth factor (HGF) and NGF was measured. One week later, there was no connection through the conduit. Four or eight weeks later, fibrous connections were evident between the proximal and distal segments. Motor function was revealed by measurement of the sciatic functional index (SFI) and sciatic nerve conduction velocity (NCV). Functional recovery in the NSC and NGF groups was significantly more advanced than that in the NS group. NSCs showed significant improvement in axon myelination of the regenerated nerves. Expression of NGF and HGF in the injured sciatic nerve was significantly lower in the NS group than in the NSCs and NGF groups. These results and other advantages of NSCs, such as ease of harvest and relative abundance, suggest that NSCs could be used clinically to enhance peripheral nerve repair.

Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways

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Weibo Chen

2014-01-01

Full Text Available Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.

Upregulation of Syndecan-1 in the bone marrow microenvironment in multiple myeloma is associated with angiogenesis

DEFF Research Database (Denmark)

Andersen, Niels F; Kristensen, Ida B; Preiss, Birgitte S

2014-01-01

: In this study, we examined the association between bone marrow angiogenesis estimated as micro-vessel density (MVD) and gene expression of SDC1, HGF, VEGF and IL6 in whole bone marrow biopsies from healthy volunteers (n = 10), patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 35...... plasma cell percentage and SDC1 gene expression was detected in patients with MM (P angiogenesis and gene...... expression of HGF, VEGF and IL6 was seen. CONCLUSION: Our study indicates that SDC1 expressed by the bone marrow microenvironment is involved in angiogenesis in MM....

Upregulated expression of Nogo-A and NgR in an experimental model of focal microgyria regulates the migration, proliferation and self-renewal of subventricular zone neural progenitors

Energy Technology Data Exchange (ETDEWEB)

Yu, Sixun; Shu, Haifeng; Yang, Tao; Huang, Haidong [Department of Neurosurgery, General Hospital of the People' s Liberation Army Chengdu Military Region, Chengdu, Sichuan, 610083 (China); Li, Song [Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037 (China); Zhao, Ziyi [Central Laboratory, Teaching Hospital of Chengdu University of Traditional Chinese Medicine, 610075 (China); Kuang, Yongqin, E-mail: kuangyongqin@163.com [Department of Neurosurgery, General Hospital of the People' s Liberation Army Chengdu Military Region, Chengdu, Sichuan, 610083 (China)

2016-04-29

Nogo-A and its receptor (NgR) were first described as myelin-associated inhibitors of neuronal regeneration in response to injury. In recent years, knowledge about the important role of the Nogo-A protein in several neuronal pathologies has grown considerably. Here, we employed a neonatal cortex freeze-lesion (NFL) model in neonatal rats and measured the expression of Nogo-A and NgR in the resulting cerebrocortical microdysgenesis 5–75 days after freezing injury. We observed marked upregulation of Nogo-A and NgR in protein levels. Furthermore, the migration of neural precursor cells (NPCs) derived from the subventricular zone (SVZ) toward the sits of injury was perturbed by treatment of NgR antagonist peptide NEP1-40. In vitro analysis showed that the knockdown of NgR by lentivirus-delivered siRNA promoted in axonal regeneration and SVZ-derived neural stem cell/progenitor cell (SVZ-NPCs) adhesion and migration, findings which were similar to the effects of NEP1-40. Taken together, our results indicate an important role for NgR in regulating the physiological processes of SVZ-NPCs. The observation of upregulated Nogo-A/NgR in lesion sites in the NFL model suggest that the effects of the perturbed Nogo-A are a key feature during the development and/or the progression of cortical malformation. - Highlights: • NFL model is an accurate experimental reproduction of focal microgyria of FCD. • The increase of the Nogo-A Levels occurs in response to freeze-induced focal lesioning. • Nogo-A/NgR may play a critical role for in the pathologic progression of FCD. • Nogo-A is associated with the migration, proliferation and self-renewal of SVZ-NPCs.

VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

International Nuclear Information System (INIS)

Sun, Jinqiao; Sha, Bin; Zhou, Wenhao; Yang, Yi

2010-01-01

This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

Science.gov (United States)

2016-10-01

signaling inhibition in AR-positive CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, our work...positive CRPC models , as detailed in the initial proposal, we found that combined MET inhibition and enzalutamide (AR antagonist) treatment was more...wide analyses, we will be able to better test the study hypothesis with increased patient accrual. Figure: Waterfall plots showing association

LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells

International Nuclear Information System (INIS)

Harrison, Susan MW; Knifley, Teresa; Chen, Min; O’Connor, Kathleen L

2013-01-01

Various pathways impinge on the actin-myosin pathway to facilitate cell migration and invasion including members of the Rho family of small GTPases and MAPK. However, the signaling components that are considered important for these processes vary substantially within the literature with certain pathways being favored. These distinctions in signaling pathways utilized are often attributed to differences in cell type or physiological conditions; however, these attributes have not been systematically assessed. To address this question, we analyzed the migration and invasion of MDA-MB-231 breast carcinoma cell line in response to various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF) and determined the involvement of select signaling pathways that impact myosin light chain phosphorylation. LPA, a potent stimulator of the Rho-ROCK pathway, surprisingly did not require the Rho-ROCK pathway to stimulate migration but instead utilized Rac and MAPK. In contrast, LPA-stimulated invasion required Rho, Rac, and MAPK. Of these three major pathways, EGF-stimulated MDA-MB-231 migration and invasion required Rho; however, Rac was essential only for invasion and MAPK was dispensable for migration. HGF signaling, interestingly, utilized the same pathways for migration and invasion, requiring Rho but not Rac signaling. Notably, the dependency of HGF-stimulated migration and invasion as well as EGF-stimulated invasion on MAPK was subject to the inhibitors used. As expected, myosin light chain kinase (MLCK), a convergence point for MAPK and Rho family GTPase signaling, was required for all six conditions. These observations suggest that, while multiple signaling pathways contribute to cancer cell motility, not all pathways operate under all conditions. Thus, our study highlights the plasticity of cancer cells to adapt to multiple migratory cues

Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.

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Mónica Díaz-Coránguez

Full Text Available Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.

Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.

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Díaz-Coránguez, Mónica; Segovia, José; López-Ornelas, Adolfo; Puerta-Guardo, Henry; Ludert, Juan; Chávez, Bibiana; Meraz-Cruz, Noemi; González-Mariscal, Lorenza

2013-01-01

Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB) was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs) cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM) from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.

Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

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Davis Rodney

2006-07-01

laminin-binding integrins, nor can they be linked to expression of the known HGF receptor Met, as neither LNCaP nor clonally-derived C4-2 sub-line contain any detectable Met protein. Even in the absence of Met, small GTPases are activated, linking HGF stimulation to membrane protrusion and integrin activation. Membrane-localized nucelolin levels increase during cancer progression, as modeled by both the PC3 and LNCaP prostate cancer progression cell lines. Conclusion We propose that cell surface localized nucleolin protein may function in these cells as a novel HGF receptor. Membrane localized nucleolin binds heparin-bound growth factors (including HGF and appears upregulated during prostate cancer progression. Antibodies against nucleolin are able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. HGF-nucleolin interactions could be partially responsible for the complexity of HGF responses and met expression reported in the literature.

Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

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Tate, Amanda; Isotani, Shuji; Bradley, Michael J; Sikes, Robert A; Davis, Rodney; Chung, Leland WK; Edlund, Magnus

2006-01-01

expression of the known HGF receptor Met, as neither LNCaP nor clonally-derived C4-2 sub-line contain any detectable Met protein. Even in the absence of Met, small GTPases are activated, linking HGF stimulation to membrane protrusion and integrin activation. Membrane-localized nucelolin levels increase during cancer progression, as modeled by both the PC3 and LNCaP prostate cancer progression cell lines. We propose that cell surface localized nucleolin protein may function in these cells as a novel HGF receptor. Membrane localized nucleolin binds heparin-bound growth factors (including HGF) and appears upregulated during prostate cancer progression. Antibodies against nucleolin are able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. HGF-nucleolin interactions could be partially responsible for the complexity of HGF responses and met expression reported in the literature

Up-regulation of neural indicators of empathic concern in an offender population.

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Arbuckle, Nathan L; Shane, Matthew S

2017-08-01

Empathic concern has traditionally been conceived of as a spontaneous reaction to others experiencing pain or distress. As such, the potential role of more deliberate control over empathic responses has frequently been overlooked. The present fMRI study evaluated the role of such deliberate control in empathic concern by examining the extent to which a sample of offenders recruited through probation/parole could voluntarily modulate their neural activity to another person in pain. Offenders were asked to either passively view pictures of other people in painful or non-painful situations, or to actively modulate their level of concern for the person in pain. During passive viewing of painful versus non-painful pictures, offenders showed minimal neural activity in regions previously linked to empathy for pain (e.g., dorsal anterior cingulate cortex and bilateral insula). However, when instructed to try to increase their concern for the person in pain, offenders demonstrated significant increases within these regions. These findings are consistent with recent theories of empathy as motivational in nature, and suggest that limitations in empathic concern may include a motivational component.

Low concentrations of methylmercury inhibit neural progenitor cell proliferation associated with up-regulation of glycogen synthase kinase 3β and subsequent degradation of cyclin E in rats

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Fujimura, Masatake, E-mail: fujimura@nimd.go.jp [Department of Basic Medical Science, National Institute for Minamata Disease, Kumamoto (Japan); Usuki, Fusako [Department of Clinical Medicine, National Institute for Minamata Disease, Kumamoto (Japan)

2015-10-01

Methylmercury (MeHg) is an environmental neurotoxicant. The developing nervous system is susceptible to low concentrations of MeHg; however, the effect of MeHg on neural progenitor cell (NPC) proliferation, a key stage of neurogenesis during development, remains to be clarified. In this study, we investigated the effect of low concentrations of MeHg on NPCs by using a primary culture system developed using the embryonic rat cerebral cortex. NPC proliferation was suppressed 48 h after exposure to 10 nM MeHg, but cell death was not observed. Western blot analyses for cyclins A, B, D1, and E demonstrated that MeHg down-regulated cyclin E, a promoter of the G1/S cell cycle transition. Cyclin E has been shown to be degraded following the phosphorylation by glycogen synthase kinase 3β (GSK-3β). The time course study showed that GSK-3β was up-regulated 3 h after exposure to 10 nM MeHg, and cyclin E degradation 48 h after MeHg exposure. We further demonstrated that GSK-3β inhibitors, lithium and SB-415286, suppressed MeHg-induced inhibition of NPC proliferation by preventing cyclin E degradation. These results suggest that the inhibition of NPC proliferation induced by low concentration of MeHg was associated with up-regulation of GSK-3β at the early stage and subsequent degeneration of cyclin E. - Highlights: • NPC proliferation was suppressed by 10 nM MeHg, but cell death was not observed. • MeHg induced down-regulation of cyclin E, a promoter of cell cycle progression. • GSK-3β was up-regulated by 10 nM MeHg, leading to cyclin E degradation. • GSK-3β inhibitors suppressed MeHg-induced degradation of cyclin E.

Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma.

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Guofeng Yu

Full Text Available As the main source of extracellular matrix proteins in tumor stroma, hepatic stellate cells (HSCs have a great impact on biological behaviors of hepatocellular carcinoma (HCC. In the present study, we have investigated a mechanism whereby HSCs modulate the chemoresistance of hepatoma cells. We used human HSC line lx-2 and chemotherapeutic agent cisplatin to investigate their effects on human HCC cell line Hep3B. The results showed that cisplatin resistance in Hep3B cells was enhanced with LX-2 CM (cultured medium exposure in vitro as well as co-injection with LX-2 cells in null mice. Meanwhile, in presence of LX-2 CM, Hep3B cells underwent epithelial to mesenchymal transition (EMT and upregulation of cancer stem cell (CSC -like properties. Besides, LX-2 cells synthesized and secreted hepatic growth factor (HGF into the CM. HGF receptor tyrosine kinase mesenchymal-epithelial transition factor (Met was activated in Hep3B cells after LX-2 CM exposure. The HGF level of LX-2 CM could be effectively reduced by using HGF neutralizing antibody. Furthermore, depletion of HGF in LX-2 CM abolished its effects on activation of Met as well as promotion of the EMT, CSC-like features and cisplatin resistance in Hep3B cells. Collectively, secreting HGF into tumor milieu, HSCs may decrease hepatoma cells sensitization to chemotherapeutic agents by promoting EMT and CSC-like features via HGF/Met signaling.

Distinct steps of neural induction revealed by Asterix, Obelix and TrkC, genes induced by different signals from the organizer.

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Sonia Pinho

2011-04-01

Full Text Available The amniote organizer (Hensen's node can induce a complete nervous system when grafted into a peripheral region of a host embryo. Although BMP inhibition has been implicated in neural induction, non-neural cells cannot respond to BMP antagonists unless previously exposed to a node graft for at least 5 hours before BMP inhibitors. To define signals and responses during the first 5 hours of node signals, a differential screen was conducted. Here we describe three early response genes: two of them, Asterix and Obelix, encode previously undescribed proteins of unknown function but Obelix appears to be a nuclear RNA-binding protein. The third is TrkC, a neurotrophin receptor. All three genes are induced by a node graft within 4-5 hours but they differ in the extent to which they are inducible by FGF: FGF is both necessary and sufficient to induce Asterix, sufficient but not necessary to induce Obelix and neither sufficient nor necessary for induction of TrkC. These genes are also not induced by retinoic acid, Noggin, Chordin, Dkk1, Cerberus, HGF/SF, Somatostatin or ionomycin-mediated Calcium entry. Comparison of the expression and regulation of these genes with other early neural markers reveals three distinct "epochs", or temporal waves, of gene expression accompanying neural induction by a grafted organizer, which are mirrored by specific stages of normal neural plate development. The results are consistent with neural induction being a cascade of responses elicited by different signals, culminating in the formation of a patterned nervous system.

Disentangling the Complexity of HGF Signaling by Combining Qualitative and Quantitative Modeling.

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Lorenza A D'Alessandro

2015-04-01

Full Text Available Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF stimulated phosphoinositide-3-kinase (PI3K and mitogen activated protein kinase (MAPK signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.

The neural correlates of cognitive reappraisal during emotional autobiographical memory recall.

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Holland, Alisha C; Kensinger, Elizabeth A

2013-01-01

We used fMRI to investigate the neural processes engaged as individuals down- and up-regulated the emotions associated with negative autobiographical memories (AMs) using cognitive reappraisal strategies. Our analyses examined neural activity during three separate phases, as participants (a) viewed a reappraisal instruction (i.e., Decrease, Increase, Maintain), (b) searched for an AM referenced by a self-generated cue, and (c) elaborated upon the details of the AM being held in mind. Decreasing emotional intensity primarily engaged activity in regions previously implicated in cognitive control (e.g., dorsal and ventral lateral pFC), emotion generation and processing (e.g., amygdala, insula), and visual imagery (e.g., precuneus) as participants searched for and retrieved events. In contrast, increasing emotional intensity engaged similar regions during the instruction phase (i.e., before a memory cue was presented) and again as individuals later elaborated upon the details of the events they had recalled. These findings confirm that reappraisal can modulate neural activity during the recall of personally relevant events, although the time course of this modulation appears to depend on whether individuals are attempting to down- or up-regulate their emotions.

Replicable Expansion and Differentiation of Neural Precursors from Adult Canine Skin

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Thomas Duncan

2017-08-01

Full Text Available Repopulation of brain circuits by neural precursors is a potential therapeutic strategy for neurodegenerative disorders; however, choice of cell is critical. Previously, we introduced a two-step culture system that generates a high yield of neural precursors from small samples of adult canine skin. Here, we probe their gene and protein expression profiles in comparison with dermal fibroblasts and brain-derived neural stem cells and characterize their neuronal potential. To date, we have produced >50 skin-derived neural precursor (SKN lines. SKNs can be cultured in a highly replicable fashion and uniformly express a panel of identifying markers. Upon differentiation, they self-upregulate neural specification genes, generating neurons with basic electrophysiological functionality. This unique population of neural precursors, derived from mature skin, overcomes many of the practical issues that have limited clinical translation of alternative cell types. Easily accessible, neuronally committed, and patient specific, SKNs may have potential for the treatment of brain disorders.

Genetic deletion of Rnd3 in neural stem cells promotes proliferation via upregulation of Notch signaling.

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Dong, Huimin; Lin, Xi; Li, Yuntao; Hu, Ronghua; Xu, Yang; Guo, Xiaojie; La, Qiong; Wang, Shun; Fang, Congcong; Guo, Junli; Li, Qi; Mao, Shanping; Liu, Baohui

2017-10-31

Rnd3, a Rho GTPase, is involved in the inhibition of actin cytoskeleton dynamics through the Rho kinase-dependent signaling pathway. We previously demonstrated that mice with genetic deletion of Rnd3 developed a markedly larger brain compared with wild-type mice. Here, we demonstrate that Rnd3 knockout mice developed an enlarged subventricular zone, and we identify a novel role for Rnd3 as an inhibitor of Notch signaling in neural stem cells. Rnd3 deficiency, both in vivo and in vitro , resulted in increased levels of Notch intracellular domain protein. This led to enhanced Notch signaling and promotion of aberrant neural stem cell growth, thereby resulting in a larger subventricular zone and a markedly larger brain. Inhibition of Notch activity abrogated this aberrant neural stem cell growth.

Role of cMET in the Development and Progression of Colorectal Cancer

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Ilaria Bossi

2013-09-01

Full Text Available Mesenchymal-epithelial transition (MET is a member of a distinct subfamily of heterodimeric receptor tyrosine kinase receptors that specifically binds the hepatocyte growth factor (HGF. Binding to HGF leads to receptor dimerization/multimerization and phosphorylation, resulting in its catalytic activation. MET activation drives the malignant progression of several tumor types, including colorectal cancer (CRC, by promoting signaling cascades that mainly result in alterations of cell motility, survival, and proliferation. MET is aberrantly activated in many human cancers through various mechanisms, including point mutations, gene amplification, transcriptional up-regulation, or ligand autocrine loops. MET promotes cell scattering, invasion, and protection from apoptosis, thereby acting as an adjuvant pro-metastatic gene for many tumor types. In CRC, MET expression confers more aggressiveness and worse clinical prognosis. With all of this rationale, inhibitors that target the HGF/MET axis with different types of response have been developed. HGF and MET are new promising targets to understand the pathogenesis of CRC and for the development of new, targeted therapies.

Sublethal irradiation promotes invasiveness of neuroblastoma cells

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Schweigerer, Lothar; Rave-Fraenk, Margret; Schmidberger, Heinz; Hecht, Monica

2005-01-01

Neuroblastoma is the most frequent extracranial solid tumour of childhood. Despite multiple clinical efforts, clinical outcome has remained poor. Neuroblastoma is considered to be radiosensitive, but some clinical studies including the German trial NB90 failed to show a clinical benefit of radiation therapy. The mechanisms underlying this apparent discrepancy are still unclear. We have therefore investigated the effects of radiation on neuroblastoma cell behaviour in vitro. We show that sublethal doses of irradiation up-regulated the expression of the hepatocyte growth factor (HGF) and its receptor c-Met in some neuroblastoma cell lines. The increase in HGF/c-Met expression was correlated with enhanced invasiveness and activation of proteases degrading the extracellular matrix. Thus, irradiation at sublethal doses may promote the metastatic dissemination of neuroblastoma cells through activating the HGF/c-Met pathway and triggering matrix degradation

Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma.

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Papa, Eleanna; Weller, Michael; Weiss, Tobias; Ventura, Elisa; Burghardt, Isabel; Szabó, Emese

2017-12-13

Multiple target inhibition has gained considerable interest in combating drug resistance in glioblastoma, however, understanding the molecular mechanisms of crosstalk between signaling pathways and predicting responses of cancer cells to targeted interventions has remained challenging. Despite the significant role attributed to transforming growth factor (TGF)-β family and hepatocyte growth factor (HGF)/c-MET signaling in glioblastoma pathogenesis, their functional interactions have not been well characterized. Using genetic and pharmacological approaches to stimulate or antagonize the TGF-β pathway in human glioma-initiating cells (GIC), we observed that TGF-β exerts an inhibitory effect on c-MET phosphorylation. Inhibition of either mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway attenuated this effect. A comparison of c-MET-driven and c-MET independent GIC models revealed that TGF-β inhibits stemness in GIC at least in part via its negative regulation of c-MET activity, suggesting that stem cell (SC) maintenance may be controlled by the balance between these two oncogenic pathways. Importantly, immunohistochemical analyses of human glioblastoma and ex vivo single-cell gene expression profiling of TGF-β and HGF confirm the negative interaction between both pathways. These novel insights into the crosstalk of two major pathogenic pathways in glioblastoma may explain some of the disappointing results when targeting either pathway alone in human glioblastoma patients and inform on potential future designs on targeted pharmacological or genetic intervention.

Hepatocyte growth factor/c-MET axis-mediated tropism of cord blood-derived unrestricted somatic stem cells for neuronal injury.

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Trapp, Thorsten; Kögler, Gesine; El-Khattouti, Abdelouahid; Sorg, Rüdiger V; Besselmann, Michael; Föcking, Melanie; Bührle, Christian P; Trompeter, Ingo; Fischer, Johannes C; Wernet, Peter

2008-11-21

An under-agarose chemotaxis assay was used to investigate whether unrestricted somatic stem cells (USSC) that were recently characterized in human cord blood are attracted by neuronal injury in vitro. USSC migrated toward extracts of post-ischemic brain tissue of mice in which stroke had been induced. Moreover, apoptotic neurons secrete factors that strongly attracted USSC, whereas necrotic and healthy neurons did not. Investigating the expression of growth factors and chemokines in lesioned brain tissue and neurons and of their respective receptors in USSC revealed expression of hepatocyte growth factor (HGF) in post-ischemic brain and in apoptotic but not in necrotic neurons and of the HGF receptor c-MET in USSC. Neuronal lesion-triggered migration was observed in vitro and in vivo only when c-MET was expressed at a high level in USSC. Neutralization of the bioactivity of HGF with an antibody inhibited migration of USSC toward neuronal injury. This, together with the finding that human recombinant HGF attracts USSC, document that HGF signaling is necessary for the tropism of USSC for neuronal injury. Our data demonstrate that USSC have the capacity to migrate toward apoptotic neurons and injured brain. Together with their neural differentiation potential, this suggests a neuroregenerative potential of USSC. Moreover, we provide evidence for a hitherto unrecognized pivotal role of the HGF/c-MET axis in guiding stem cells toward brain injury, which may partly account for the capability of HGF to improve function in the diseased central nervous system.

Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell

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Chiou, S.-H.; Chen, S.-J.; Peng, C-H.; Chang, Y.-L.; Ku, H.-H.; Hsu, W.-M.; Ho, Larry L.-T.; Lee, C.-H.

2006-01-01

Fluoxetine is a widely used antidepressant compound which inhibits the reuptake of serotonin in the central nervous system. Recent studies have shown that fluoxetine can promote neurogenesis and improve the survival rate of neurons. However, whether fluoxetine modulates the proliferation or neuroprotection effects of neural stem cells (NSCs) needs to be elucidated. In this study, we demonstrated that 20 μM fluoxetine can increase the cell proliferation of NSCs derived from the hippocampus of adult rats by MTT test. The up-regulated expression of Bcl-2, Bcl-xL and the cellular FLICE-inhibitory protein (c-FLIP) in fluoxetine-treated NSCs was detected by real-time RT-PCR. Our results further showed that fluoxetine protects the lipopolysaccharide-induced apoptosis in NSCs, in part, by activating the expression of c-FLIP. Moreover, c-FLIP induction by fluoxetine requires the activation of the c-FLIP promoter region spanning nucleotides -414 to -133, including CREB and SP1 sites. This effect appeared to involve the phosphatidylinositol-3-kinase-dependent pathway. Furthermore, fluoxetine treatment significantly inhibited the induction of proinflammatory factor IL-1β, IL-6, and TNF-α in the culture medium of LPS-treated NSCs (p < 0.01). The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that fluoxentine increased the functional production of serotonin in NSCs. Together, these data demonstrate the specific activation of c-FLIP by fluoxetine and indicate the novel role of fluoxetine for neuroprotection in the treatment of depression

Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum.

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Ono, Yoshihiro J; Hayashi, Masami; Tanabe, Akiko; Hayashi, Atsushi; Kanemura, Masanori; Terai, Yoshito; Ohmichi, Masahide

2015-06-01

The pathogenesis of endometriosis, a chronic painful gynecological disease characterized by the presence of endometrial tissue located outside of the uterus and often adhering to the peritoneum, is known to be estrogen dependent. However, the precise pathophysiology of endometriosis remains elusive. Recent studies indicate that the epithelial-to-mesenchymal transition (EMT) of human endometrial cells is important for the progression of endometriosis, and another previous study has implicated hepatocyte growth factor (HGF) in endometriosis progression. The aim of the present study was to examine the role of estradiol in the regulation of HGF production and progression of peritoneal endometriosis, focusing on the interactions between the peritoneum and endometriotic cells. Consequently, estradiol was found to promote the proliferation, invasion, and migration of immortalized human endometrial epithelial cells (hEECs) via HGF upregulation, and the estradiol-induced direct binding of estrogen receptor-α to the HGF promoter was confirmed on a chromatin immunoprecipitation (ChIP) assay. Estradiol also induced the EMT in hEECs by promoting HGF production. Furthermore, human mesothelial cells underwent the mesothelial-to-mesenchymal transition (MMT) during culture with estradiol-stimulated hEEC conditioned medium. Importantly, estradiol itself did not induce the MMT, and the estradiol-stimulated hEEC-conditioned medium in the presence of HGF antibodies reversed the MMT process. These results, which were obtained using immortalized hEECs, indicate that estradiol-induced HGF production may play a crucial role in the peritoneal implantation of human endometriotic cells by exerting proliferative and invasive effects via the EMT in hEECs and promoting the MMT in mesothelial cells. Copyright © 2015 the American Physiological Society.

Neural stem cell proliferation and differentiation in the conductive PEDOT-HA/Cs/Gel scaffold for neural tissue engineering.

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Wang, Shuping; Guan, Shui; Xu, Jianqiang; Li, Wenfang; Ge, Dan; Sun, Changkai; Liu, Tianqing; Ma, Xuehu

2017-09-26

Engineering scaffolds with excellent electro-activity is increasingly important in tissue engineering and regenerative medicine. Herein, conductive poly(3,4-ethylenedioxythiophene) doped with hyaluronic acid (PEDOT-HA) nanoparticles were firstly synthesized via chemical oxidant polymerization. A three-dimensional (3D) PEDOT-HA/Cs/Gel scaffold was then developed by introducing PEDOT-HA nanoparticles into a chitosan/gelatin (Cs/Gel) matrix. HA, as a bridge, not only was used as a dopant, but also combined PEDOT into the Cs/Gel via chemical crosslinking. The PEDOT-HA/Cs/Gel scaffold was used as a conductive substrate for neural stem cell (NSC) culture in vitro. The results demonstrated that the PEDOT-HA/Cs/Gel scaffold had excellent biocompatibility for NSC proliferation and differentiation. 3D confocal fluorescence images showed cells attached on the channel surface of Cs/Gel and PEDOT-HA/Cs/Gel scaffolds with a normal neuronal morphology. Compared to the Cs/Gel scaffold, the PEDOT-HA/Cs/Gel scaffold not only promoted NSC proliferation with up-regulated expression of Ki67, but also enhanced NSC differentiation into neurons and astrocytes with up-regulated expression of β tubulin-III and GFAP, respectively. It is expected that this electro-active and bio-active PEDOT-HA/Cs/Gel scaffold will be used as a conductive platform to regulate NSC behavior for neural tissue engineering.

Activation of c-MET induces a stem-like phenotype in human prostate cancer.

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Geert J L H van Leenders

Full Text Available Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model or represent an inducible population emerging upon appropriate stimulation of differentiated cells. Hepatocyte Growth Factor (HGF receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145 prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'. We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its ligands Jagged-1 and Delta-like 4. Small molecules SU11274 and PHA665752 targeting c-MET activity were both able to block the molecular and biologic effects of HGF. Knock-down of c-MET by shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.

Function of FEZF1 during early neural differentiation of human embryonic stem cells.

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Liu, Xin; Su, Pei; Lu, Lisha; Feng, Zicen; Wang, Hongtao; Zhou, Jiaxi

2018-01-01

The understanding of the mechanism underlying human neural development has been hampered due to lack of a cellular system and complicated ethical issues. Human embryonic stem cells (hESCs) provide an invaluable model for dissecting human development because of unlimited self-renewal and the capacity to differentiate into nearly all cell types in the human body. In this study, using a chemical defined neural induction protocol and molecular profiling, we identified Fez family zinc finger 1 (FEZF1) as a potential regulator of early human neural development. FEZF1 is rapidly up-regulated during neural differentiation in hESCs and expressed before PAX6, a well-established marker of early human neural induction. We generated FEZF1-knockout H1 hESC lines using CRISPR-CAS9 technology and found that depletion of FEZF1 abrogates neural differentiation of hESCs. Moreover, loss of FEZF1 impairs the pluripotency exit of hESCs during neural specification, which partially explains the neural induction defect caused by FEZF1 deletion. However, enforced expression of FEZF1 itself fails to drive neural differentiation in hESCs, suggesting that FEZF1 is necessary but not sufficient for neural differentiation from hESCs. Taken together, our findings identify one of the earliest regulators expressed upon neural induction and provide insight into early neural development in human.

Upregulation of cognitive control networks in older adults’ speech comprehension

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Julia eErb

2013-12-01

Full Text Available Speech comprehension abilities decline with age and with age-related hearing loss, but it is unclear how this decline expresses in terms of central neural mechanisms. The current study examined neural speech processing in a group of older adults (aged 56–77, n=16, with varying degrees of sensorineural hearing loss, and compared them to a cohort of young adults (aged 22–31, n=30, self-reported normal hearing. In an fMRI experiment, listeners heard and repeated back degraded sentences (4-band vocoding, which preserves the temporal envelope of the acoustic signal, while substantially degrading spectral information. Behaviourally, older adults adapted to degraded speech at the same rate as young listeners, although their overall comprehension of degraded speech was lower. Neurally, both older and young adults relied on the left anterior insula for degraded more than clear speech perception. However, anterior insula engagement in older adults was dependent on hearing acuity. Young adults additionally employed the anterior cingulate cortex (ACC. Interestingly, this age group × degradation interaction was driven by a reduced dynamic range in older adults, who displayed elevated levels of ACC activity in both conditions, consistent with a persistent upregulation in cognitive control irrespective of task difficulty. For correct speech comprehension, older adults recruited the middle frontal gyrus in addition to a core speech comprehension network on which young adults relied, suggestive of a compensatory mechanism. Taken together, the results indicate that older adults increasingly recruit cognitive control networks, even under optimal listening conditions, at the expense of these systems’ dynamic range.

HGF-transgenic MSCs can improve the effects of tissue self-repair in a rabbit model of traumatic osteonecrosis of the femoral head.

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Qian Wen

Full Text Available BACKGROUND: Osteonecrosis of the femoral head (ONFH is generally characterized as an irreversible disease and tends to cause permanent disability. Therefore, understanding the pathogenesis and molecular mechanisms of ONFH and developing effective therapeutic methods is critical for slowing the progress of the disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study, an experimental rabbit model of early stage traumatic ONFH was established, validated, and used for an evaluation of therapy. Computed tomography (CT and magnetic resonance (MR imaging confirmed that this model represents clinical Association Research Circulation Osseous (ARCO phase I or II ONFH, which was also confirmed by the presence of significant tissue damage in osseous tissue and vasculature. Pathological examination detected obvious self-repair of bone tissue up to 2 weeks after trauma, as indicated by revascularization (marked by CD105 and expression of collagen type I (Col I, osteocalcin, and proliferating cell nuclear antigen. Transplantation of hepatocyte growth factor (HGF-transgenic mesenchymal stem cells (MSCs 1 week after trauma promoted recovery from ONFH, as evidenced by a reversed pattern of Col I expression compared with animals receiving no therapeutic treatment, as well as increased expression of vascular endothelial growth factor. CONCLUSIONS/SIGNIFICANCE: These results indicate that the transplantation of HGF-transgenic MSCs is a promising method for the treatment for ONFH and suggest that appropriate interference therapy during the tissue self-repair stage contributes to the positive outcomes. This study also provides a model for the further study of the ONFH etiology and therapeutic interventions.

Expression levels of novel cytokine IL-32 in periodontitis and its role in the suppression of IL-8 production by human gingival fibroblasts stimulated with Porphyromonas gingivalis

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Kazuhisa Ouhara

2012-03-01

Full Text Available Background:IL-32 was recently found to be elevated in the tissue of rheumatoid arthritis and inflammatory bowel disease. Periodontitis is a chronic inflammatory disease caused by polymicrobial infections that result in soft tissue destruction and alveolar bone loss. Although IL-32 is also thought to be associated with periodontal disease, its expression and possible role in periodontal tissue remain unclear. Therefore, this study investigated the expression patterns of IL-32 in healthy and periodontally diseased gingival tissue. The expression of IL-32 in cultured human gingival fibroblasts (HGF as well as effects of autocrine IL-32 on IL-8 production from HGF were also examined.Methods:Periodontal tissue was collected from both healthy volunteers and periodontitis patients, and immunofluorescent staining was performed in order to determine the production of IL-32. Using real-time PCR and ELISA, mRNA expression and protein production of IL-32 in HGF, stimulated by Porphyromonas gingivalis (Pg, were also investigated.Results:Contrary to our expectation, the production of IL-32 in the periodontitis patients was significantly lower than in the healthy volunteers. According to immunofluorescent microscopy, positive staining for IL-32 was detected in prickle and basal cell layers in the epithelium as well as fibroblastic cells in connective tissue. Addition of fixed Pg in vitro was found to suppress the otherwise constitutive expression of IL-32 mRNA and protein in HGF. However, recombinant IL-32 in vitro inhibited the expression of IL-8 mRNA by HGF stimulated with Pg. Interestingly, anti-IL-32 neutralizing antibody upregulated the IL-8 mRNA expression in non-stimulated HGF, indicating that constitutive expression of IL-32 in HGF suppressed IL-8 mRNA expression in the absence of bacterial stimulation.Conclusion:These results indicate that IL-32 is constitutively produced by HGF which can be suppressed by Pg and may play a role in the downregulation

N-Cadherin Upregulation Promotes the Neurogenic Differentiation of Menstrual Blood-Derived Endometrial Stem Cells.

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Liu, Yanli; Yang, Fen; Liang, Shengying; Liu, Qing; Fu, Sulei; Wang, Zhenyu; Yang, Ciqing; Lin, Juntang

2018-01-01

Peripheral nerve injuries are typically caused by either trauma or medical disorders, and recently, stem cell-based therapies have provided a promising treatment approach. Menstrual blood-derived endometrial stem cells (MenSCs) are considered an ideal therapeutic option for peripheral nerve repair due to a noninvasive collection procedure and their high proliferation rate and immunological tolerance. Here, we successfully isolated MenSCs and examined their biological characteristics including their morphology, multipotency, and immunophenotype. Subsequent in vitro studies demonstrated that MenSCs express high levels of neurotrophic factors, such as NT3, NT4, BDNF, and NGF, and are capable of transdifferentiating into glial-like cells under conventional induction conditions. Moreover, upregulation of N-cadherin (N-cad) mRNA and protein expression was observed after neurogenic differentiation. In vivo studies clearly showed that N-cad knockdown via in utero electroporation perturbed the migration and maturation of mouse neural precursor cells (NPCs). Finally, a further transfection assay also confirmed that N-cad upregulation in MenSCs results in the expression of S100. Collectively, our results confirmed the paracrine effect of MenSCs on neuroprotection as well as their potential for transdifferentiation into glial-like cells and demonstrated that N-cad upregulation promotes the neurogenic differentiation of MenSCs, thereby providing support for transgenic MenSC-based therapy for peripheral nerve injury.

Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis.

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Yerlikaya, Gülen; Balendran, Sukirthini; Pröstling, Katharina; Reischer, Theresa; Birner, Peter; Wenzl, Rene; Kuessel, Lorenz; Streubel, Berthold; Husslein, Heinrich

2016-09-01

Endometriosis is a benign gynaecological disease, affecting women during their reproductive years. Angiogenesis represents a crucial step in the pathogenesis of endometriosis, because endometriotic lesions require neovascularization. In this study several angiogenesis-related genes have been studied in the context of endometriosis. Some of the analyzed angiogenic factors as well as their interactions were studied the first time regarding a possible association with endometriosis. This case-control study consisted of 205 biopsies of 114 patients comprising 61 endometriosis patients and 53 control patients. Among them in 29 cases paired samples were obtained. VEGFA, VEGFR2, HIF1A, HGF, NRP1, PDGFB, FGF18, TNFα, TGFB2, EPHB4, EPO and ANG mRNA expression was analyzed by qRT-PCR in ectopic tissue samples, in eutopic endometrium of women with and without endometriosis, and in unaffected peritoneum of women with and without endometriosis. VEGFR2, HIF1A, HGF, PDGFB, NRP1 and EPHB4 are overexpressed in ectopic lesions compared to eutopic tissues. VEGFR2, HGF, PDGFB, NRP1, and EPHB4 showed highest mRNA levels in peritoneal implants, in contrast HIF1A showed the highest expression in ovarian endometriomas. Correlation analyses of angiogenic factors in ectopic lesions revealed the strongest associations between VEGFR2, PDGFB, and EPHB4. We further showed a significant upregulation of VEGFR2, HIF1A and EPHB4 in eutopic endometrium of women with endometriosis compared to that of controls and a trend towards upregulation of HGF. Additionally, a significant downregulation for HIF1A, HGF and EPHB4 was observed in unaffected peritoneal tissues of women with endometriosis compared to controls. We identified new genes (EPHB4 and NRP1) that may contribute to angiogenesis in endometriosis beside known factors (VEGFA, VEGFR2, HIF1A, HGF, and PDGFB). Correlation studies revealed the putative importance of EBHB4 in association with endometriosis. Our analyses support preliminary reports

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.

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Cao, Zhongwei; Ye, Tinghong; Sun, Yue; Ji, Gaili; Shido, Koji; Chen, Yutian; Luo, Lin; Na, Feifei; Li, Xiaoyan; Huang, Zhen; Ko, Jane L; Mittal, Vivek; Qiao, Lina; Chen, Chong; Martinez, Fernando J; Rafii, Shahin; Ding, Bi-Sen

2017-08-30

The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs ( Hgf iΔEC/iΔEC ) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in Hgf iΔEC/iΔEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.

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Soong, Joanne; Chen, Yulin; Shustef, Elina M; Scott, Glynis A

2012-04-01

Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.

miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice

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Fang Gao

2017-04-01

Full Text Available Summary: Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl, was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs into intermediate neural progenitors (INPs in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment. : In this article, Han and colleagues show that miR-342-5p acts as a downstream effector of Notch signaling in the mouse CNS. Notch signal inhibits miR-342-5p expression by regulating its host gene Evl. And with attenuated Notch signal in NSCs, miR-342-5p is upregulated to promote NSCs transition into INPs, and to inhibit astrocyte commitment by targeting GFAP. Keywords: neural stem cells, intermediate neural progenitors, Notch, RBP-J, neuron, glia, miR-342-5p

The neural basis of learning to spell again: An fMRI study of spelling training in acquired dysgraphia.

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Jeremy Purcell

2015-05-01

1 For all participants we identified brain areas associated with a normalized response for the TRAINING words at the post-training time point. 2 For all participants we identified an up-regulation of the TRAINING response (i.e., the TRAINING neural response was initially low and then increased post-training; whereas in only one participant did we also observe a down-regulation of the training response (i.e., the TRAINING neural response was initially high, but then decreased post-training. 3 Although the areas associated with the normalized TRAINING response were different in each individual, they all include areas typically associated with the spelling system (Purcell et al. 2011, including the right homologues of typically left hemisphere spelling regions. Across the participants, the following areas of normalization were observed: bilateral superior temporal gyrus, inferior frontal gyrus, and the bilateral inferior temporal/fusiform gyrus. Discussion: We found that the predominant BOLD response to training involved an up-regulation of the neural response to spelling the TRAINING items. In addition, we found individual differences in the neurotopography of the normalization response patterns although all were with within brain areas that form a part of the spelling network(Purcell et al. 2011. This work provides evidence regarding one aspect of the multiplicity of neural responses associated with recovery of spelling in individuals with acquired dysgraphia.

The effect of strategies, goals and stimulus material on the neural mechanisms of emotion regulation: A meta-analysis of fMRI studies.

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Morawetz, Carmen; Bode, Stefan; Derntl, Birgit; Heekeren, Hauke R

2017-01-01

Emotion regulation comprises all extrinsic and intrinsic control processes whereby people monitor, evaluate and modify the occurrence, intensity and duration of emotional reactions. Here we sought to quantitatively summarize the existing neuroimaging literature to investigate a) whether different emotion regulation strategies are based on different or the same neural networks; b) which brain regions in particular support the up- and down-regulation of emotions, respectively; and c) to which degree the neural networks realising emotion regulation depend on the stimulus material used to elicit emotions. The left ventrolateral prefrontal cortex (VLPFC), the anterior insula and the supplementary motor area were consistently activated independent of the regulation strategy. VLPFC and posterior cingulate cortex were the main regions consistently found to be recruited during the up-regulation as well as the down-regulation of emotion. The down-regulation compared to the up-regulation of emotions was associated with more right-lateralized activity while up-regulating emotions more strongly modulated activity in the ventral striatum. Finally, the process of emotion regulation appeared to be unaffected by stimulus material. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex.

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George, Sophie A; Rodriguez-Santiago, Mariana; Riley, John; Rodriguez, Elizabeth; Liberzon, Israel

2015-01-01

Post-traumatic stress disorder (PTSD) is a chronic, debilitating disorder. Only two pharmacological agents are approved for PTSD treatment, and they often do not address the full range of symptoms nor are they equally effective in all cases. Animal models of PTSD are critical for understanding the neurobiology involved and for identification of novel therapeutic targets. Using the rodent PTSD model, single prolonged stress (SPS), we have implicated aberrant excitatory neural transmission and glucocorticoid receptor (GR) upregulation in the medial prefrontal cortex (mPFC) and hippocampus (HPC) in fear memory abnormalities associated with PTSD. The objective of this study is to examine the potential protective effect of antiepileptic phenytoin (PHE) administration on SPS-induced extinction retention deficits and GR expression. Forty-eight SPS-treated male Sprague Dawley rats or controls were administered PHE (40, 20 mg/kg, vehicle) for 7 days following SPS stressors; then, fear conditioning, extinction, and extinction retention were tested. Fear conditioning and extinction were unaffected by SPS or PHE, but SPS impaired extinction retention, and both doses of PHE rescued this impairment. Similarly, SPS increased GR expression in the mPFC and dorsal HPC, and PHE prevented SPS-induced GR upregulation in the mPFC. These data demonstrate that PHE administration can prevent the development of extinction retention deficits and upregulation of GR. PHE exerts inhibitory effects on voltage-gated sodium channels and decreases excitatory neural transmission via glutamate antagonism. If glutamate hyperactivity in the days following SPS contributes to SPS-induced deficits, then these data may suggest that the glutamatergic system constitutes a target for secondary prevention.

A regulating element essential for PDGFRA transcription is recognized by neural tube defect-associated PRX homeobox transcription factors

NARCIS (Netherlands)

Joosten, Paul H. L. J.; Toepoel, Mascha; van Oosterhout, Dirk; Afink, Gijs B.; van Zoelen, Everardus J. J.

2002-01-01

We have previously shown that deregulated expression of the platelet-derived growth factor alpha-receptor (PDGFRA) can be associated with neural tube defects (NTDs) in both men and mice. In the present study, we have investigated the transcription factors that control the up-regulation of PDGFRA

Three-dimensional neural differentiation of embryonic stem cells with ACM induction in microfibrous matrices in bioreactors.

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Liu, Ning; Ouyang, Anli; Li, Yan; Yang, Shang-Tian

2013-01-01

The clinical use of pluripotent stem cell (PSC)-derived neural cells requires an efficient differentiation process for mass production in a bioreactor. Toward this goal, neural differentiation of murine embryonic stem cells (ESCs) in three-dimensional (3D) polyethylene terephthalate microfibrous matrices was investigated in this study. To streamline the process and provide a platform for process integration, the neural differentiation of ESCs was induced with astrocyte-conditioned medium without the formation of embryoid bodies, starting from undifferentiated ESC aggregates expanded in a suspension bioreactor. The 3D neural differentiation was able to generate a complex neural network in the matrices. When compared to 2D differentiation, 3D differentiation in microfibrous matrices resulted in a higher percentage of nestin-positive cells (68% vs. 54%) and upregulated gene expressions of nestin, Nurr1, and tyrosine hydroxylase. High purity of neural differentiation in 3D microfibrous matrix was also demonstrated in a spinner bioreactor with 74% nestin + cells. This study demonstrated the feasibility of a scalable process based on 3D differentiation in microfibrous matrices for the production of ESC-derived neural cells. © 2013 American Institute of Chemical Engineers.

Peri-Implant Crestal Bone Loss: A Putative Mechanism

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Yuko Ujiie

2012-01-01

Full Text Available Purpose. The immunological mechanisms of peri-implant crestal bone loss have, hitherto, not been elucidated. We hypothesized that bacterial products from the microgap cause upregulation of cytokines in otherwise healthy peri-implant cells, which results in osteoclast formation and, ultimately, in bone resorption. Materials and Methods. We used RT-PCR and ELISA to assay mediators of osteoclastogenesis in rat and human macrophages (r-and hMO; bone marrow derived stromal cells (r-and hBMCs; and human gingival fibroblasts (hGF—with or without stimulation by LPS. TRAP positive multinucleate cells were assessed for their resorptive ability. Results. We show that IL-1α, IL-1β, and IL-6 were expressed by all examined cell types, and TNF-α was upregulated in hGF. Secretion of IL-1α and IL-1β proteins was stimulated in hMO by LPS, and IL-6 protein secretion was highly stimulated in hBMCs and hGF. Both LPS and RANKL stimulated macrophages to form osteoclast-like TRAP positive cells, which resorbed calcium phosphate substrates. Conclusion. Taken together, the results of our study support the hypothesis that bacterial endotoxins upregulate enhanced mediators of osteoclastogenesis in resident cells found in the healthy peri-implant compartment and that the local synergistic action of cytokines secreted by such cells results in the genesis of resorptively active osteoclasts.

Capacity of Human Dental Follicle Cells to Differentiate into Neural Cells In Vitro

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Shingo Kanao

2017-01-01

Full Text Available The dental follicle is an ectomesenchymal tissue surrounding the developing tooth germ. Human dental follicle cells (hDFCs have the capacity to commit to differentiation into multiple cell types. Here we investigated the capacity of hDFCs to differentiate into neural cells and the efficiency of a two-step strategy involving floating neurosphere-like bodies for neural differentiation. Undifferentiated hDFCs showed a spindle-like morphology and were positive for neural markers such as nestin, β-III-tubulin, and S100β. The cellular morphology of several cells was neuronal-like including branched dendrite-like processes and neurites. Next, hDFCs were used for neurosphere formation in serum-free medium containing basic fibroblast growth factor, epidermal growth factor, and B27 supplement. The number of cells with neuronal-like morphology and that were strongly positive for neural markers increased with sphere formation. Gene expression of neural markers also increased in hDFCs with sphere formation. Next, gene expression of neural markers was examined in hDFCs during neuronal differentiation after sphere formation. Expression of Musashi-1 and Musashi-2, MAP2, GFAP, MBP, and SOX10 was upregulated in hDFCs undergoing neuronal differentiation via neurospheres, whereas expression of nestin and β-III-tubulin was downregulated. In conclusion, hDFCs may be another optimal source of neural/glial cells for cell-based therapies to treat neurological diseases.

Roles of bHLH genes in neural stem cell differentiation

International Nuclear Information System (INIS)

Kageyama, Ryoichiro; Ohtsuka, Toshiyuki; Hatakeyama, Jun; Ohsawa, Ryosuke

2005-01-01

Neural stem cells change their characteristics over time during development: they initially proliferate only and then give rise to neurons first and glial cells later. In the absence of the repressor-type basic helix-loop-helix (bHLH) genes Hes1, Hes3 and Hes5, neural stem cells do not proliferate sufficiently but prematurely differentiate into neurons and become depleted without making the later born cell types such as astrocytes and ependymal cells. Thus, Hes genes are essential for maintenance of neural stem cells to make cells not only in correct numbers but also in full diversity. Hes genes antagonize the activator-type bHLH genes, which include Mash1, Math and Neurogenin. The activator-type bHLH genes promote the neuronal fate determination and induce expression of Notch ligands such as Delta. These ligands activate Notch signaling and upregulate Hes1 and Hes5 expression in neighboring cells, thereby maintaining these cells undifferentiated. Thus, the activator-type and repressor-type bHLH genes regulate each other, allowing only subsets of cells to undergo differentiation while keeping others to stay neural stem cells. This regulation is essential for generation of complex brain structures of appropriate size, shape and cell arrangement

Differentiation of neurons from neural precursors generated in floating spheres from embryonic stem cells

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Forrester Jeff

2009-09-01

Full Text Available Abstract Background Neural differentiation of embryonic stem (ES cells is usually achieved by induction of ectoderm in embryoid bodies followed by the enrichment of neuronal progenitors using a variety of factors. Obtaining reproducible percentages of neural cells is difficult and the methods are time consuming. Results Neural progenitors were produced from murine ES cells by a combination of nonadherent conditions and serum starvation. Conversion to neural progenitors was accompanied by downregulation of Oct4 and NANOG and increased expression of nestin. ES cells containing a GFP gene under the control of the Sox1 regulatory regions became fluorescent upon differentiation to neural progenitors, and ES cells with a tau-GFP fusion protein became fluorescent upon further differentiation to neurons. Neurons produced from these cells upregulated mature neuronal markers, or differentiated to glial and oligodendrocyte fates. The neurons gave rise to action potentials that could be recorded after application of fixed currents. Conclusion Neural progenitors were produced from murine ES cells by a novel method that induced neuroectoderm cells by a combination of nonadherent conditions and serum starvation, in contrast to the embryoid body method in which neuroectoderm cells must be selected after formation of all three germ layers.

A Bivalent Securinine Compound SN3-L6 Induces Neuronal Differentiation via Translational Upregulation of Neurogenic Transcription Factors

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Yumei Liao

2018-04-01

Full Text Available Developing therapeutic approaches that target neuronal differentiation will be greatly beneficial for the regeneration of neurons and synaptic networks in neurological diseases. Protein synthesis (mRNA translation has recently been shown to regulate neurogenesis of neural stem/progenitor cells (NSPCs. However, it has remained unknown whether engineering translational machinery is a valid approach for manipulating neuronal differentiation. The present study identifies that a bivalent securinine compound SN3-L6, previously designed and synthesized by our group, induces potent neuronal differentiation through a novel translation-dependent mechanism. An isobaric tag for relative and absolute quantitation (iTRAQ-based proteomic analysis in Neuro-2a progenitor cells revealed that SN3-L6 upregulated a group of neurogenic transcription regulators, and also upregulated proteins involved in RNA processing, translation, and protein metabolism. Notably, puromycylation and metabolic labeling of newly synthesized proteins demonstrated that SN3-L6 induced rapid and robust activation of general mRNA translation. Importantly, mRNAs of the proneural transcription factors Foxp1, Foxp4, Hsf1, and Erf were among the targets that were translationally upregulated by SN3-L6. Either inhibition of translation or knockdown of these transcription factors blocked SN3-L6 activity. We finally confirmed that protein synthesis of a same set of transcription factors was upregulated in primary cortical NPCs. These findings together identify a new compound for translational activation and neuronal differentiation, and provide compelling evidence that reprogramming transcriptional regulation network at translational levels is a promising strategy for engineering NSPCs.

Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD.

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Yuanquan Song

2009-12-01

Full Text Available In humans, mutations in electron transfer flavoprotein (ETF or electron transfer flavoprotein dehydrogenase (ETFDH lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.

Binding of Cdc42 to phospholipase D1 is important in neurite outgrowth of neural stem cells

International Nuclear Information System (INIS)

Yoon, Mee-Sup; Cho, Chan Ho; Lee, Ki Sung; Han, Joong-Soo

2006-01-01

We previously demonstrated that phospholipase D (PLD) expression and PLD activity are upregulated during neuronal differentiation. In the present study, employing neural stem cells from the brain cortex of E14 rat embryos, we investigated the role of Rho family GTPases in PLD activation and in neurite outgrowth of neural stem cells during differentiation. As neuronal differentiation progressed, the expression levels of Cdc42 and RhoA increased. Furthermore, Cdc42 and PLD1 were mainly localized in neurite, whereas RhoA was localized in cytosol. Co-immunoprecipitation revealed that Cdc42 was bound to PLD1 during differentiation, whereas RhoA was associated with PLD1 during both proliferation and differentiation. These results indicate that the association between Cdc42 and PLD1 is related to neuronal differentiation. To examine the effect of Cdc42 on PLD activation and neurite outgrowth, we transfected dominant negative Cdc42 (Cdc42N17) and constitutively active Cdc42 (Cdc42V12) into neural stem cells, respectively. Overexpression of Cdc42N17 decreased both PLD activity and neurite outgrowth, whereas co-transfection with Cdc42N17 and PLD1 restored them. On the other hand, Cdc42V12 increased both PLD activity and neurite outgrowth, suggesting that active state of Cdc42 is important in upregulation of PLD activity which is responsible for the increase of neurite outgrowth

Effects and mechanisms of melatonin on neural differentiation of induced pluripotent stem cells.

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Shu, Tao; Wu, Tao; Pang, Mao; Liu, Chang; Wang, Xuan; Wang, Juan; Liu, Bin; Rong, Limin

2016-06-03

Melatonin, a lipophilic molecule mainly synthesized in the pineal gland, has properties of antioxidation, anti-inflammation, and antiapoptosis to improve neuroprotective functions. Here, we investigate effects and mechanisms of melatonin on neural differentiation of induced pluripotent stem cells (iPSCs). iPSCs were induced into neural stem cells (NSCs), then further differentiated into neurons in medium with or without melatonin, melatonin receptor antagonist (Luzindole) or Phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002). Melatonin significantly promoted the number of neurospheres and cell viability. In addition, Melatonin markedly up-regulated gene and protein expression of Nestin and MAP2. However, Luzindole or LY294002 attenuated these increase. The expression of pAKT/AKT were increased by Melatonin, while Luzindole or LY294002 declined these melatonin-induced increase. These results suggest that melatonin significantly increased neural differentiation of iPSCs via activating PI3K/AKT signaling pathway through melatonin receptor. Copyright © 2016 Elsevier Inc. All rights reserved.

Ceramide-induced TCR up-regulation

DEFF Research Database (Denmark)

Menné, C; Lauritsen, Jens Peter Holst; Dietrich, J

2000-01-01

to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase......The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein...... kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected...

Wnt/Yes-Associated Protein Interactions During Neural Tissue Patterning of Human Induced Pluripotent Stem Cells.

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Bejoy, Julie; Song, Liqing; Zhou, Yi; Li, Yan

2018-04-01

Human induced pluripotent stem cells (hiPSCs) have special ability to self-assemble into neural spheroids or mini-brain-like structures. During the self-assembly process, Wnt signaling plays an important role in regional patterning and establishing positional identity of hiPSC-derived neural progenitors. Recently, the role of Wnt signaling in regulating Yes-associated protein (YAP) expression (nuclear or cytoplasmic), the pivotal regulator during organ growth and tissue generation, has attracted increasing interests. However, the interactions between Wnt and YAP expression for neural lineage commitment of hiPSCs remain poorly explored. The objective of this study is to investigate the effects of Wnt signaling and YAP expression on the cellular population in three-dimensional (3D) neural spheroids derived from hiPSCs. In this study, Wnt signaling was activated using CHIR99021 for 3D neural spheroids derived from human iPSK3 cells through embryoid body formation. Our results indicate that Wnt activation induces nuclear localization of YAP and upregulates the expression of HOXB4, the marker for hindbrain/spinal cord. By contrast, the cells exhibit more rostral forebrain neural identity (expression of TBR1) without Wnt activation. Cytochalasin D was then used to induce cytoplasmic YAP and the results showed the decreased HOXB4 expression. In addition, the incorporation of microparticles in the neural spheroids was investigated for the perturbation of neural patterning. This study may indicate the bidirectional interactions of Wnt signaling and YAP expression during neural tissue patterning, which have the significance in neurological disease modeling, drug screening, and neural tissue regeneration.

Chromatin remodeling agent trichostatin A: a key-factor in the hepatic differentiation of human mesenchymal stem cells derived of adult bone marrow

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Vinken Mathieu

2007-04-01

Full Text Available Abstract Background The capability of human mesenchymal stem cells (hMSC derived of adult bone marrow to undergo in vitro hepatic differentiation was investigated. Results Exposure of hMSC to a cocktail of hepatogenic factors [(fibroblast growth factor-4 (FGF-4, hepatocyte growth factor (HGF, insulin-transferrin-sodium-selenite (ITS and dexamethasone] failed to induce hepatic differentiation. Sequential exposure to these factors (FGF-4, followed by HGF, followed by HGF+ITS+dexamethasone, however, resembling the order of secretion during liver embryogenesis, induced both glycogen-storage and cytokeratin (CK18 expression. Additional exposure of the cells to trichostatin A (TSA considerably improved endodermal differentiation, as evidenced by acquisition of an epithelial morphology, chronological expression of hepatic proteins, including hepatocyte-nuclear factor (HNF-3β, alpha-fetoprotein (AFP, CK18, albumin (ALB, HNF1α, multidrug resistance-associated protein (MRP2 and CCAAT-enhancer binding protein (C/EBPα, and functional maturation, i.e. upregulated ALB secretion, urea production and inducible cytochrome P450 (CYP-dependent activity. Conclusion hMSC are able to undergo mesenchymal-to-epithelial transition. TSA is hereby essential to promote differentiation of hMSC towards functional hepatocyte-like cells.

NFIX Regulates Neural Progenitor Cell Differentiation During Hippocampal Morphogenesis

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Heng, Yee Hsieh Evelyn; McLeay, Robert C.; Harvey, Tracey J.; Smith, Aaron G.; Barry, Guy; Cato, Kathleen; Plachez, Céline; Little, Erica; Mason, Sharon; Dixon, Chantelle; Gronostajski, Richard M.; Bailey, Timothy L.; Richards, Linda J.; Piper, Michael

2014-01-01

Neural progenitor cells have the ability to give rise to neurons and glia in the embryonic, postnatal and adult brain. During development, the program regulating whether these cells divide and self-renew or exit the cell cycle and differentiate is tightly controlled, and imbalances to the normal trajectory of this process can lead to severe functional consequences. However, our understanding of the molecular regulation of these fundamental events remains limited. Moreover, processes underpinning development of the postnatal neurogenic niches within the cortex remain poorly defined. Here, we demonstrate that Nuclear factor one X (NFIX) is expressed by neural progenitor cells within the embryonic hippocampus, and that progenitor cell differentiation is delayed within Nfix−/− mice. Moreover, we reveal that the morphology of the dentate gyrus in postnatal Nfix−/− mice is abnormal, with fewer subgranular zone neural progenitor cells being generated in the absence of this transcription factor. Mechanistically, we demonstrate that the progenitor cell maintenance factor Sry-related HMG box 9 (SOX9) is upregulated in the hippocampus of Nfix−/− mice and demonstrate that NFIX can repress Sox9 promoter-driven transcription. Collectively, our findings demonstrate that NFIX plays a central role in hippocampal morphogenesis, regulating the formation of neuronal and glial populations within this structure. PMID:23042739

Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: From mouse brain to neural differentiation of patient derived iPSC

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Zeynab Nayernia

2017-10-01

Full Text Available There is emerging evidence for the involvement of reactive oxygen species (ROS in the regulation of stem cells and cellular differentiation. Absence of the ROS-generating NADPH oxidase NOX2 in chronic granulomatous disease (CGD patients, predominantly manifests as immune deficiency, but has also been associated with decreased cognition. Here, we investigate the role of NOX enzymes in neuronal homeostasis in adult mouse brain and in neural cells derived from human induced pluripotent stem cells (iPSC. High levels of NOX2 were found in mouse adult neurogenic regions. In NOX2-deficient mice, neurogenic regions showed diminished redox modifications, as well as decrease in neuroprecursor numbers and in expression of genes involved in neural differentiation including NES, BDNF and OTX2. iPSC from healthy subjects and patients with CGD were used to study the role of NOX2 in human in vitro neuronal development. Expression of NOX2 was low in undifferentiated iPSC, upregulated upon neural induction, and disappeared during neuronal differentiation. In human neurospheres, NOX2 protein and ROS generation were polarized within the inner cell layer of rosette structures. NOX2 deficiency in CGD-iPSCs resulted in an abnormal neural induction in vitro, as revealed by a reduced expression of neuroprogenitor markers (NES, BDNF, OTX2, NRSF/REST, and a decreased generation of mature neurons. Vector-mediated NOX2 expression in NOX2-deficient iPSCs rescued neurogenesis. Taken together, our study provides novel evidence for a regulatory role of NOX2 during early stages of neurogenesis in mouse and human.

DNA topoisomerase IIβ stimulates neurite outgrowth in neural differentiated human mesenchymal stem cells through regulation of Rho-GTPases (RhoA/Rock2 pathway) and Nurr1 expression.

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Zaim, Merve; Isik, Sevim

2018-04-25

DNA topoisomerase IIβ (topo IIβ) is known to regulate neural differentiation by inducing the neuronal genes responsible for critical neural differentiation events such as neurite outgrowth and axon guidance. However, the pathways of axon growth controlled by topo IIβ have not been clarified yet. Microarray results of our previous study have shown that topo IIβ silencing in neural differentiated primary human mesenchymal stem cells (hMSCs) significantly alters the expression pattern of genes involved in neural polarity, axonal growth, and guidance, including Rho-GTPases. This study aims to further analyze the regulatory role of topo IIβ on the process of axon growth via regulation of Rho-GTPases. For this purpose, topo IIβ was silenced in neurally differentiated hMSCs. Cells lost their morphology because of topo IIβ deficiency, becoming enlarged and flattened. Additionally, a reduction in both neural differentiation efficiency and neurite length, upregulation in RhoA and Rock2, downregulation in Cdc42 gene expression were detected. On the other hand, cells were transfected with topo IIβ gene to elucidate the possible neuroprotective effect of topo IIβ overexpression on neural-induced hMSCs. Topo IIβ overexpression prompted all the cells to exhibit neural cell morphology as characterized by longer neurites. RhoA and Rock2 expressions were downregulated, whereas Cdc42 expression was upregulated. Nurr1 expression level correlated with topo IIβ in both topo IIβ-overexpressed and -silenced cells. Furthermore, differential translocation of Rho-GTPases was detected by immunostaining in response to topo IIβ. Our results suggest that topo IIβ deficiency could give rise to neurodegeneration through dysregulation of Rho-GTPases. However, further in-vivo research is needed to demonstrate if re-regulation of Rho GTPases by topo IIβ overexpression could be a neuroprotective treatment in the case of neurodegenerative diseases.

Transcriptional profiling of adult neural stem-like cells from the human brain.

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Cecilie Jonsgar Sandberg

Full Text Available There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60. Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate. We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6, foetal human neural stem cells (n = 1 and human brain tissues (n = 12. The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular

NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation

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Chen, Zhi-Dong; Xu, Liang; Tang, Kan-Kai; Gong, Fang-Xiao; Liu, Jing-Quan; Ni, Yin; Jiang, Ling-Zhi; Hong, Jun; Han, Fang; Li, Qian; Yang, Xiang-Hong; Sun, Ren-Hua; Mo, Shi-Jing

2016-01-01

Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKβ phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKβ phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. - Highlights: • EGFR activation significantly decreases hypoxia-induced PC12 cells injury. • EGFR activation abrogates the transcriptional repression of cyclin D1 induced by hypoxia in a NF

NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation

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Chen, Zhi-Dong [Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang (China); Xu, Liang [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China); Tang, Kan-Kai [Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang (China); Gong, Fang-Xiao; Liu, Jing-Quan; Ni, Yin; Jiang, Ling-Zhi; Hong, Jun; Han, Fang; Li, Qian; Yang, Xiang-Hong [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China); Sun, Ren-Hua, E-mail: jqin168@hotmail.com [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China); Mo, Shi-Jing, E-mail: msj860307@163.com [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China)

2016-09-10

Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKβ phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKβ phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. - Highlights: • EGFR activation significantly decreases hypoxia-induced PC12 cells injury. • EGFR activation abrogates the transcriptional repression of cyclin D1 induced by hypoxia in a NF

Evaluation of therapeutic effectiveness of neural transplantation using PET imaging technique

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Inaji, Motoki

2004-01-01

Neural transplantation is expected as an eradicative treatment of intractable central neural disease. In addition to behavioral observations, the recent development of the in vivo imaging technique also enabled to assess functions of neural graft in living subjects. Then we performed the PET scans using the unilateral 6-OHDA-lesioned rats in order to assess the pre- and post-synaptic functions in the striatum after transplantation of fetal dopaminergic neurons. As a result of PET scan, the images of [11C]PE2I, tracer of dopamine transporter, showed increased accumulation in the region which corresponded to the transplanted site after the graft. Because dopamine transporter exists on the cytoplasma membrane of axonal terminal, the accumulation of [11C]PE2I was regarded as a market of survival and maturation of transplanted cells. Also the images of [11C]raclopride, tracer of dopamine D2 receptor, revealed that up-regulation of D2 receptors normalized 4 weeks after transplantation. [11C]Raclopride was considered a marker of change of secondary dopaminergic environment. We believed that assessments with PET bring us much information, and it will increasingly contribute to a development of the regenerative medicine. (author)

Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis.

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Milstone, Zachary J; Lawson, Grace; Trivedi, Chinmay M

2017-12-01

Craniofacial anomalies involve defective pharyngeal arch development and neural crest function. Copy number variation at 1p35, containing histone deacetylase 1 (Hdac1), or 6q21-22, containing Hdac2, are implicated in patients with craniofacial defects, suggesting an important role in guiding neural crest development. However, the roles of Hdac1 and Hdac2 within neural crest cells remain unknown. The neural crest and its derivatives express both Hdac1 and Hdac2 during early murine development. Ablation of Hdac1 and Hdac2 within murine neural crest progenitor cells cause severe hemorrhage, atrophic pharyngeal arches, defective head morphogenesis, and complete embryonic lethality. Embryos lacking Hdac1 and Hdac2 in the neural crest exhibit decreased proliferation and increased apoptosis in both the neural tube and the first pharyngeal arch. Mechanistically, loss of Hdac1 and Hdac2 upregulates cyclin-dependent kinase inhibitors Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, Cdkn2c, and Tp53 within the first pharyngeal arch. Our results show that Hdac1 and Hdac2 function redundantly within the neural crest to regulate proliferation and the development of the pharyngeal arches by means of repression of cyclin-dependent kinase inhibitors. Developmental Dynamics 246:1015-1026, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

[Intramuscular injection of lentivirus-mediated EPAS1 gene improves hind limb ischemia and its mechanism in a rat model of peripheral artery vascular disease].

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Wang, Zhihong; Gu, Hongbin; Yang, Fan; Xie, Huajie; Sheng, Lei; Li, Mingfei

2017-11-01

Objective To investigate the effect of over-expressed endothelial Per-Arnt-Sim domain protein 1 (EPAS1) on peripheral arterial disease (PAD) in a rat model. Methods PAD rat model was established by external iliac artery ligation followed by lentivirus-mediated EPAS1 gene injection into rat right adductor magnus. The models were evaluated by quantitative analysis of gait disturbance. The changes of blood flow in the posterior extremity of the rats were detected using laser Doppler. The expressions of EPAS1, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) mRNAs were tested by real-time quantitative PCR. The expression of α-smooth muscle actin (αSMA) was detected by immunohistochemical staining. Results Compared with lenti-EGFP group, rat hind limb function and circulation got recovered obviously 7 days after lenti-EPAS1 injection. The mRNA expressions of EPAS1, HGF, bFGF, and VEGF were up-regulated in the lenti-EPAS1-treated sites.The expression of αSMA showed an obvious increase in the lenti-EPAS1-treated muscles. Conclusion Over-expressed lenti-EPAS1 can promote angiogenesis via the up-regulation of EPAS1-related angiogenic factors in the muscles of the affected hind limb and reduce gait disturbance.

Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.

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Shibata, Shumei; Miwa, Toru; Wu, Hsiao-Huei; Levitt, Pat; Ohyama, Takahiro

2016-08-03

The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media. During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis. The relation of this developmental process to stria vascularis function is currently unknown. In characterizing the molecular differentiation of developing peripheral auditory structures, we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium. Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte-derived intermediate cells in the stria vascularis. Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling. In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages. These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies. We found the roles of hepatocyte growth factor (HGF) signaling in stria vascularis development for the first time and that lack of HGF signaling in the inner ear leads to profound hearing loss in the mouse. Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97. Our findings reveal an additional example of context-dependent c-MET signaling diversity, required here for proper cellular invasion developmentally that is essential for specific aspects of auditory-related organogenesis. Copyright © 2016 the authors 0270-6474/16/368200-10$15.00/0.

Hepatocyte Growth Factor–c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing

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Shibata, Shumei; Miwa, Toru; Wu, Hsiao-Huei; Levitt, Pat

2016-01-01

The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media. During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis. The relation of this developmental process to stria vascularis function is currently unknown. In characterizing the molecular differentiation of developing peripheral auditory structures, we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium. Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte-derived intermediate cells in the stria vascularis. Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling. In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages. These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies. SIGNIFICANCE STATEMENT We found the roles of hepatocyte growth factor (HGF) signaling in stria vascularis development for the first time and that lack of HGF signaling in the inner ear leads to profound hearing loss in the mouse. Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97. Our findings reveal an additional example of context-dependent c-MET signaling diversity, required here for proper cellular invasion developmentally that is essential for specific aspects of auditory-related organogenesis. PMID:27488639

Maternal Diabetes Alters Expression of MicroRNAs that Regulate Genes Critical for Neural Tube Development

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Seshadri Ramya

2017-07-01

Full Text Available Maternal diabetes is known to cause neural tube defects (NTDs in embryos and neuropsychological deficits in infants. Several metabolic pathways and a plethora of genes have been identified to be deregulated in developing brain of embryos by maternal diabetes, although the exact mechanism remains unknown. Recently, miRNAs have been shown to regulate genes involved in brain development and maturation. Therefore, we hypothesized that maternal diabetes alters the expression of miRNAs that regulate genes involved in biological pathways critical for neural tube development and closure during embryogenesis. To address this, high throughput miRNA expression profiling in neural stem cells (NSCs isolated from the forebrain of embryos from normal or streptozotocin-induced diabetic pregnancy was carried out. It is known that maternal diabetes results in fetal hypoglycemia/hyperglycemia or hypoxia. Hence, NSCs from embryos of control pregnant mice were exposed to low or high glucose or hypoxia in vitro. miRNA pathway analysis revealed distinct deregulation of several biological pathways, including axon guidance pathway, which are critical for brain development in NSCs exposed to different treatments. Among the differentially expressed miRNAs, the miRNA-30 family members which are predicted to target genes involved in brain development was upregulated in NSCs from embryos of diabetic pregnancy when compared to control. miRNA-30b was found to be upregulated while its target gene Sirtuin 1 (Sirt1, as revealed by luciferase assay, was down regulated in NSCs from embryos of diabetic pregnancy. Further, overexpression of miRNA-30b in NSCs, resulted in decreased expression of Sirt1 protein, and altered the neuron/glia ratio. On the other hand, siRNA mediated knockdown of Sirt1 in NSCs promoted astrogenesis, indicating that miRNA-30b alters lineage specification via Sirt1. Overall, these results suggest that maternal diabetes alters the genes involved in neural tube

ADAM13 Induces Cranial Neural Crest by Cleaving Class B Ephrins and Regulating Wnt Signaling

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Wei, Shuo; Xu, Guofeng; Bridges, Lance C.; Williams, Phoebe; White, Judith M.; DeSimone, Douglas W.

2010-01-01

SUMMARY The cranial neural crest (CNC) are multipotent embryonic cells that contribute to craniofacial structures and other cells and tissues of the vertebrate head. During embryogenesis, CNC is induced at the neural plate boundary through the interplay of several major signaling pathways. Here we report that the metalloproteinase activity of ADAM13 is required for early induction of CNC in Xenopus. In both cultured cells and X. tropicalis embryos, membrane-bound Ephrins (Efns) B1 and B2 were identified as substrates for ADAM13. ADAM13 upregulates canonical Wnt signaling and early expression of the transcription factor snail2, whereas EfnB1 inhibits the canonical Wnt pathway and snail2 expression. We propose that by cleaving class B Efns, ADAM13 promotes canonical Wnt signaling and early CNC induction. PMID:20708595

Presenilins are required for maintenance of neural stem cells in the developing brain

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Kim Woo-Young

2008-01-01

Full Text Available Abstract The early embryonic lethality of mutant mice bearing germ-line deletions of both presenilin genes precluded the study of their functions in neural development. We therefore employed the Cre-loxP technology to generate presenilin conditional double knockout (PS cDKO mice, in which expression of both presenilins is inactivated in neural progenitor cells (NPC or neural stem cells and their derivative neurons and glia beginning at embryonic day 11 (E11. In PS cDKO mice, dividing NPCs labeled by BrdU are decreased in number beginning at E13.5. By E15.5, fewer than 20% of NPCs remain in PS cDKO mice. The depletion of NPCs is accompanied by severe morphological defects and hemorrhages in the PS cDKO embryonic brain. Interkinetic nuclear migration of NPCs is also disrupted in PS cDKO embryos, as evidenced by displacement of S-phase and M-phase nuclei in the ventricular zone of the telencephalon. Furthermore, the depletion of neural progenitor cells in PS cDKO embryos is due to NPCs exiting cell cycle and differentiating into neurons rather than reentering cell cycle between E13.5 and E14.5 following PS inactivation in most NPCs. The length of cell cycle, however, is unchanged in PS cDKO embryos. Expression of Notch target genes, Hes1 and Hes5, is significantly decreased in PS cDKO brains, whereas Dll1 expression is up-regulated, indicating that Notch signaling is effectively blocked by PS inactivation. These findings demonstrate that presenilins are essential for neural progenitor cells to re-enter cell cycle and thus ensure proper expansion of neural progenitor pool during embryonic neural development.

Cognitive emotion regulation in children: Reappraisal of emotional faces modulates neural source activity in a frontoparietal network.

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Wessing, Ida; Rehbein, Maimu A; Romer, Georg; Achtergarde, Sandra; Dobel, Christian; Zwitserlood, Pienie; Fürniss, Tilman; Junghöfer, Markus

2015-06-01

Emotion regulation has an important role in child development and psychopathology. Reappraisal as cognitive regulation technique can be used effectively by children. Moreover, an ERP component known to reflect emotional processing called late positive potential (LPP) can be modulated by children using reappraisal and this modulation is also related to children's emotional adjustment. The present study seeks to elucidate the neural generators of such LPP effects. To this end, children aged 8-14 years reappraised emotional faces, while neural activity in an LPP time window was estimated using magnetoencephalography-based source localization. Additionally, neural activity was correlated with two indexes of emotional adjustment and age. Reappraisal reduced activity in the left dorsolateral prefrontal cortex during down-regulation and enhanced activity in the right parietal cortex during up-regulation. Activity in the visual cortex decreased with increasing age, more adaptive emotion regulation and less anxiety. Results demonstrate that reappraisal changed activity within a frontoparietal network in children. Decreasing activity in the visual cortex with increasing age is suggested to reflect neural maturation. A similar decrease with adaptive emotion regulation and less anxiety implies that better emotional adjustment may be associated with an advance in neural maturation. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

PLGA nanofibers blended with designer self-assembling peptides for peripheral neural regeneration

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Nune, Manasa; Krishnan, Uma Maheswari; Sethuraman, Swaminathan, E-mail: swami@sastra.edu

2016-05-01

Electrospun nanofibers are attractive candidates for neural regeneration due to similarity to the extracellular matrix. Several synthetic polymers have been used but they lack in providing the essential biorecognition motifs on their surfaces. Self-assembling peptide nanofiber scaffolds (SAPNFs) like RADA16 and recently, designer SAPs with functional motifs RADA16-I-BMHP1 areexamples, which showed successful spinal cord regeneration. But these peptide nanofiber scaffolds have poor mechanical properties and faster degradation rates that limit their use for larger nerve defects. Hence, we have developed a novel hybrid nanofiber scaffold of polymer poly(L-lactide-co-glycolide) (PLGA) and RADA16-I-BMHP1. The scaffolds were characterized for the presence of peptides both qualitatively and quantitatively using several techniques like SEM, EDX, FTIR, CHN analysis, Circular Dichroism analysis, Confocal and thermal analysis. Peptide self-assembly was retained post-electrospinning and formed rod-like nanostructures on PLGA nanofibers. In vitro cell compatibility was studied using rat Schwann cells and their adhesion, proliferation and gene expression levels on the designed scaffolds were evaluated. Our results have revealed the significant effects of the peptide blended scaffolds on promoting Schwann cell adhesion, extension and phenotypic expression. Neural development markers (SEM3F, NRP2 & PLX1) gene expression levels were significantly upregulated in peptide blended scaffolds compared to the PLGA scaffolds. Thus the hybrid blended novel designer scaffolds seem to be promising candidates for successful and functional regeneration of the peripheral nerve. - Highlights: • A novel blended scaffold of polymer PLGA and designer self-assembling peptide RADA16-I-BMPH1 was designed • The peptide retained the self-assembling features and formed rod like nanostructures on top of PLGA nanofibers • PLGA-peptide scaffolds have promoted the Schwann cell bipolar extension and

MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis.

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Zhao, Chunnian; Sun, GuoQiang; Ye, Peng; Li, Shengxiu; Shi, Yanhong

2013-01-01

MicroRNAs have important functions in the nervous system through post-transcriptional regulation of neurogenesis genes. Here we show that microRNA let-7d, which has been implicated in cocaine addiction and other neurological disorders, targets the neural stem cell regulator TLX. Overexpression of let-7d in vivo reduced neural stem cell proliferation and promoted premature neuronal differentiation and migration, a phenotype similar to those induced by TLX knockdown or overexpression of its negatively-regulated target, microRNA-9. We found a let-7d binding sequence in the tlx 3' UTR and demonstrated that let-7d reduced TLX expression levels in neural stem cells, which in turn, up-regulated miR-9 expression. Moreover, co-expression of let-7d and TLX lacking its 3' UTR in vivo restored neural stem cell proliferation and reversed the premature neuronal differentiation and migration. Therefore, manipulating let-7d and its downstream targets could be a novel strategy to unravel neurogenic signaling pathways and identify potential interventions for relevant neurological disorders.

Neurogenesis and Increase in Differentiated Neural Cell Survival via Phosphorylation of Akt1 after Fluoxetine Treatment of Stem Cells

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Anahita Rahmani

2013-01-01

Full Text Available Fluoxetine (FLX is a selective serotonin reuptake inhibitor (SSRI. Its action is possibly through an increase in neural cell survival. The mechanism of improved survival rate of neurons by FLX may relate to the overexpression of some kinases such as Akt protein. Akt1 (a serine/threonine kinase plays a key role in the modulation of cell proliferation and survival. Our study evaluated the effects of FLX on mesenchymal stem cell (MSC fate and Akt1 phosphorylation levels in MSCs. Evaluation tests included reverse transcriptase polymerase chain reaction, western blot, and immunocytochemistry assays. Nestin, MAP-2, and β-tubulin were detected after neurogenesis as neural markers. Ten μM of FLX upregulated phosphorylation of Akt1 protein in induced hEnSC significantly. Also FLX did increase viability of these MSCs. Continuous FLX treatment after neurogenesis elevated the survival rate of differentiated neural cells probably by enhanced induction of Akt1 phosphorylation. This study addresses a novel role of FLX in neurogenesis and differentiated neural cell survival that may contribute to explaining the therapeutic action of fluoxetine in regenerative pharmacology.

IGF-1 Promotes Brn-4 Expression and Neuronal Differentiation of Neural Stem Cells via the PI3K/Akt Pathway

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Zhang, Xinhua; Zhang, Lei; Cheng, Xiang; Guo, Yuxiu; Sun, Xiaohui; Chen, Geng; Li, Haoming; Li, Pengcheng; Lu, Xiaohui; Tian, Meiling; Qin, Jianbing; Zhou, Hui; Jin, Guohua

2014-01-01

Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs) in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1) in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002), but not MAPK inhibitor (PD98059); levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024) and mTOR (rapamycin) both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways. PMID:25474202

Upregulation of Interleukin-33 in obstructive renal injury

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Chen, Wei-Yu, E-mail: wychen624@cgmh.org.tw [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Chang, Ya-Jen [Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (China); Su, Chia-Hao [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Tsai, Tzu-Hsien [Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Chen, Shang-Der [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan (China); Hsing, Chung-Hsi [Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan (China); Yang, Jenq-Lin, E-mail: jyang@adm.cgmh.org.tw [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China)

2016-05-13

Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneys using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases. -- Highlights: •Interleukin (IL)-33 was upregulated in obstructed kidneys. •Interstitial myofibroblasts expressed IL-33 after UUO-induced renal injury. •Deficiency of IL33 reduced interstitial fibrosis and promoted tubular cell proliferation.

Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling

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Sujeong Jang

2015-01-01

Full Text Available Stem cells are a powerful resource for cell-based transplantation therapies, but understanding of stem cell differentiation at the molecular level is not clear yet. We hypothesized that the Wnt pathway controls stem cell maintenance and neural differentiation. We have characterized the transcriptional expression of Wnt during the neural differentiation of hADSCs. After neural induction, the expressions of Wnt2, Wnt4, and Wnt11 were decreased, but the expression of Wnt5a was increased compared with primary hADSCs in RT-PCR analysis. In addition, the expression levels of most Fzds and LRP5/6 ligand were decreased, but not Fzd3 and Fzd5. Furthermore, Dvl1 and RYK expression levels were downregulated in NI-hADSCs. There were no changes in the expression of ß-catenin and GSK3ß. Interestingly, Wnt5a expression was highly increased in NI-hADSCs by real time RT-PCR analysis and western blot. Wnt5a level was upregulated after neural differentiation and Wnt3, Dvl2, and Naked1 levels were downregulated. Finally, we found that the JNK expression was increased after neural induction and ERK level was decreased. Thus, this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a/JNK pathway by binding Fzd3 and Fzd5 and directing Axin/GSK-3ß in hADSCs.

Influence of neural adaptation on dynamics and equilibrium state of neural activities in a ring neural network

Science.gov (United States)

Takiyama, Ken

2017-12-01

How neural adaptation affects neural information processing (i.e. the dynamics and equilibrium state of neural activities) is a central question in computational neuroscience. In my previous works, I analytically clarified the dynamics and equilibrium state of neural activities in a ring-type neural network model that is widely used to model the visual cortex, motor cortex, and several other brain regions. The neural dynamics and the equilibrium state in the neural network model corresponded to a Bayesian computation and statistically optimal multiple information integration, respectively, under a biologically inspired condition. These results were revealed in an analytically tractable manner; however, adaptation effects were not considered. Here, I analytically reveal how the dynamics and equilibrium state of neural activities in a ring neural network are influenced by spike-frequency adaptation (SFA). SFA is an adaptation that causes gradual inhibition of neural activity when a sustained stimulus is applied, and the strength of this inhibition depends on neural activities. I reveal that SFA plays three roles: (1) SFA amplifies the influence of external input in neural dynamics; (2) SFA allows the history of the external input to affect neural dynamics; and (3) the equilibrium state corresponds to the statistically optimal multiple information integration independent of the existence of SFA. In addition, the equilibrium state in a ring neural network model corresponds to the statistically optimal integration of multiple information sources under biologically inspired conditions, independent of the existence of SFA.

IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway.

Directory of Open Access Journals (Sweden)

Xinhua Zhang

Full Text Available Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1 in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002, but not MAPK inhibitor (PD98059; levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024 and mTOR (rapamycin both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways.

Natural lecithin promotes neural network complexity and activity

Science.gov (United States)

Latifi, Shahrzad; Tamayol, Ali; Habibey, Rouhollah; Sabzevari, Reza; Kahn, Cyril; Geny, David; Eftekharpour, Eftekhar; Annabi, Nasim; Blau, Axel; Linder, Michel; Arab-Tehrany, Elmira

2016-01-01

Phospholipids in the brain cell membranes contain different polyunsaturated fatty acids (PUFAs), which are critical to nervous system function and structure. In particular, brain function critically depends on the uptake of the so-called “essential” fatty acids such as omega-3 (n-3) and omega-6 (n-6) PUFAs that cannot be readily synthesized by the human body. We extracted natural lecithin rich in various PUFAs from a marine source and transformed it into nanoliposomes. These nanoliposomes increased neurite outgrowth, network complexity and neural activity of cortical rat neurons in vitro. We also observed an upregulation of synapsin I (SYN1), which supports the positive role of lecithin in synaptogenesis, synaptic development and maturation. These findings suggest that lecithin nanoliposomes enhance neuronal development, which may have an impact on devising new lecithin delivery strategies for therapeutic applications. PMID:27228907

Natural lecithin promotes neural network complexity and activity.

Science.gov (United States)

Latifi, Shahrzad; Tamayol, Ali; Habibey, Rouhollah; Sabzevari, Reza; Kahn, Cyril; Geny, David; Eftekharpour, Eftekhar; Annabi, Nasim; Blau, Axel; Linder, Michel; Arab-Tehrany, Elmira

2016-05-27

Phospholipids in the brain cell membranes contain different polyunsaturated fatty acids (PUFAs), which are critical to nervous system function and structure. In particular, brain function critically depends on the uptake of the so-called "essential" fatty acids such as omega-3 (n-3) and omega-6 (n-6) PUFAs that cannot be readily synthesized by the human body. We extracted natural lecithin rich in various PUFAs from a marine source and transformed it into nanoliposomes. These nanoliposomes increased neurite outgrowth, network complexity and neural activity of cortical rat neurons in vitro. We also observed an upregulation of synapsin I (SYN1), which supports the positive role of lecithin in synaptogenesis, synaptic development and maturation. These findings suggest that lecithin nanoliposomes enhance neuronal development, which may have an impact on devising new lecithin delivery strategies for therapeutic applications.

The effect of cannabichromene on adult neural stem/progenitor cells.

Science.gov (United States)

Shinjyo, Noriko; Di Marzo, Vincenzo

2013-11-01

Apart from the psychotropic compound Δ(9)-tetrahydrocannabinol (THC), evidence suggests that other non-psychotropic phytocannabinoids are also of potential clinical use. This study aimed at elucidating the effect of major non-THC phytocannabinoids on the fate of adult neural stem progenitor cells (NSPCs), which are an essential component of brain function in health as well as in pathology. We tested three compounds: cannabidiol, cannabigerol, and cannabichromene (CBC), and found that CBC has a positive effect on the viability of mouse NSPCs during differentiation in vitro. The expression of NSPC and astrocyte markers nestin and Glial fibrillary acidic protein (GFAP), respectively, was up- and down-regulated, respectively. CBC stimulated ERK1/2 phosphorylation; however, this effect had a slower onset in comparison to typical MAPK stimulation. A MEK inhibitor, U0126, antagonized the up-regulation of nestin but not the down-regulation of GFAP. Based on a previous report, we studied the potential involvement of the adenosine A1 receptor in the effect of CBC on these cells and found that the selective adenosine A1 receptor antagonist, DPCPX, counteracted both ERK1/2 phosphorylation and up-regulation of nestin by CBC, indicating that also adenosine is involved in these effects of CBC, but possibly not in CBC inhibitory effect on GFAP expression. Next, we measured ATP levels as an equilibrium marker of adenosine and found higher ATP levels during differentiation of NSPCs in the presence of CBC. Taken together, our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through up-regulation of ATP and adenosine signalling. Copyright © 2013 Elsevier Ltd. All rights reserved.

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

International Nuclear Information System (INIS)

Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen

2015-01-01

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

Energy Technology Data Exchange (ETDEWEB)

Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

2015-08-14

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

Investigation of Endogenous Retrovirus Sequences in the Neighborhood of Genes Up-regulated in a Neuroblastoma Model after Treatment with Hypoxia-Mimetic Cobalt Chloride.

Science.gov (United States)

Brütting, Christine; Narasimhan, Harini; Hoffmann, Frank; Kornhuber, Malte E; Staege, Martin S; Emmer, Alexander

2018-01-01

Human endogenous retroviruses (ERVs) have been found to be associated with different diseases, e.g., multiple sclerosis (MS). Most human ERVs integrated in our genome are not competent to replicate and these sequences are presumably silent. However, transcription of human ERVs can be reactivated, e.g., by hypoxia. Interestingly, MS has been linked to hypoxia since decades. As some patterns of demyelination are similar to white matter ischemia, hypoxic damage is discussed. Therefore, we are interested in the association between hypoxia and ERVs. As a model, we used human SH-SY5Y neuroblastoma cells after treatment with the hypoxia-mimetic cobalt chloride and analyzed differences in the gene expression profiles in comparison to untreated cells. The vicinity of up-regulated genes was scanned for endogenous retrovirus-derived sequences. Five genes were found to be strongly up-regulated in SH-SY5Y cells after treatment with cobalt chloride: clusterin, glutathione peroxidase 3, insulin-like growth factor 2, solute carrier family 7 member 11, and neural precursor cell expressed developmentally down-regulated protein 9. In the vicinity of these genes we identified large (>1,000 bp) open reading frames (ORFs). Most of these ORFs showed only low similarities to proteins from retro-transcribing viruses. However, we found very high similarity between retrovirus envelope sequences and a sequence in the vicinity of neural precursor cell expressed developmentally down-regulated protein 9. This sequence encodes the human endogenous retrovirus group FRD member 1, the encoded protein product is called syncytin 2. Transfection of syncytin 2 into the well-characterized Ewing sarcoma cell line A673 was not able to modulate the low immunostimulatory activity of this cell line. Future research is needed to determine whether the identified genes and the human endogenous retrovirus group FRD member 1 might play a role in the etiology of MS.

Perfluorooctane sulfonate induces neuronal and oligodendrocytic differentiation in neural stem cells and alters the expression of PPARγ in vitro and in vivo

International Nuclear Information System (INIS)

Wan Ibrahim, Wan Norhamidah; Tofighi, Roshan; Onishchenko, Natalia; Rebellato, Paola; Bose, Raj; Uhlén, Per; Ceccatelli, Sandra

2013-01-01

Perfluorinated compounds are ubiquitous chemicals of major concern for their potential adverse effects on the human population. We have used primary rat embryonic neural stem cells (NSCs) to study the effects of perfluorooctane sulfonate (PFOS) on the process of NSC spontaneous differentiation. Upon removal of basic fibroblast growth factor, NSCs were exposed to nanomolar concentrations of PFOS for 48 h, and then allowed to differentiate for additional 5 days. Exposure to 25 or 50 nM concentration resulted in a lower number of proliferating cells and a higher number of neurite-bearing TuJ1-positive cells, indicating an increase in neuronal differentiation. Exposure to 50 nM also significantly increased the number of CNPase-positive cells, pointing to facilitation of oligodendrocytic differentiation. PPAR genes have been shown to be involved in PFOS toxicity. By q-PCR we detected an upregulation of PPARγ with no changes in PPARα or PPARδ genes. One of the downstream targets of PPARs, the mitochondrial uncoupling protein 2 (UCP2) was also upregulated. The number of TuJ1- and CNPase-positive cells increased after exposure to PPARγ agonist rosiglitazone (RGZ, 3 μM) and decreased after pre-incubation with the PPARγ antagonist GW9662 (5 μM). RGZ also upregulated the expression of PPARγ and UCP2 genes. Meanwhile GW9662 abolished the UCP2 upregulation and decreased Ca 2+ activity induced by PFOS. Interestingly, a significantly higher expression of PPARγ and UCP3 genes was also detected in mouse neonatal brain after prenatal exposure to PFOS. These data suggest that PPARγ plays a role in the alteration of spontaneous differentiation of NSCs induced by nanomolar concentrations of PFOS. - Highlights: • PFOS decreases proliferation of neural stem cells (NSCs). • PFOS induces neuronal and oligodendrocytic differentiation in NSCs. • PFOS alters expression of PPARγ and UCP2 in vitro. • PFOS alters expression of PPARγ and UCP3 in vivo. • Block of PPARγ by

Perfluorooctane sulfonate induces neuronal and oligodendrocytic differentiation in neural stem cells and alters the expression of PPARγ in vitro and in vivo

Energy Technology Data Exchange (ETDEWEB)

Wan Ibrahim, Wan Norhamidah, E-mail: hamidah@science.upm.edu.my [Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm (Sweden); Tofighi, Roshan, E-mail: Roshan.Tofighi@ki.se [Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm (Sweden); Onishchenko, Natalia, E-mail: Natalia.Onishchenko@ki.se [Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm (Sweden); Rebellato, Paola, E-mail: Paola.Rebellato@ki.se [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm (Sweden); Bose, Raj, E-mail: Raj.Bose@ki.se [Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm (Sweden); Uhlén, Per, E-mail: Per.Uhlen@ki.se [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm (Sweden); Ceccatelli, Sandra, E-mail: Sandra.Ceccatelli@ki.se [Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm (Sweden)

2013-05-15

Perfluorinated compounds are ubiquitous chemicals of major concern for their potential adverse effects on the human population. We have used primary rat embryonic neural stem cells (NSCs) to study the effects of perfluorooctane sulfonate (PFOS) on the process of NSC spontaneous differentiation. Upon removal of basic fibroblast growth factor, NSCs were exposed to nanomolar concentrations of PFOS for 48 h, and then allowed to differentiate for additional 5 days. Exposure to 25 or 50 nM concentration resulted in a lower number of proliferating cells and a higher number of neurite-bearing TuJ1-positive cells, indicating an increase in neuronal differentiation. Exposure to 50 nM also significantly increased the number of CNPase-positive cells, pointing to facilitation of oligodendrocytic differentiation. PPAR genes have been shown to be involved in PFOS toxicity. By q-PCR we detected an upregulation of PPARγ with no changes in PPARα or PPARδ genes. One of the downstream targets of PPARs, the mitochondrial uncoupling protein 2 (UCP2) was also upregulated. The number of TuJ1- and CNPase-positive cells increased after exposure to PPARγ agonist rosiglitazone (RGZ, 3 μM) and decreased after pre-incubation with the PPARγ antagonist GW9662 (5 μM). RGZ also upregulated the expression of PPARγ and UCP2 genes. Meanwhile GW9662 abolished the UCP2 upregulation and decreased Ca{sup 2+} activity induced by PFOS. Interestingly, a significantly higher expression of PPARγ and UCP3 genes was also detected in mouse neonatal brain after prenatal exposure to PFOS. These data suggest that PPARγ plays a role in the alteration of spontaneous differentiation of NSCs induced by nanomolar concentrations of PFOS. - Highlights: • PFOS decreases proliferation of neural stem cells (NSCs). • PFOS induces neuronal and oligodendrocytic differentiation in NSCs. • PFOS alters expression of PPARγ and UCP2 in vitro. • PFOS alters expression of PPARγ and UCP3 in vivo. • Block of PPAR�

Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

Energy Technology Data Exchange (ETDEWEB)

Shi, Wen-Zhu [Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Hainan 572013 (China); Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China); Miao, Yu-Liang [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Guo, Wen-Zhi [Department of Anesthesiology, Beijing Military General Hospital of Chinese People’s Liberation Army, Beijing 100700 (China); Wu, Wei, E-mail: wwzwgk@163.com [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); Li, Bao-Wei [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); An, Li-Na [Department of Anesthesiology, Armed Police General Hospital, Beijing 100039 (China); Fang, Wei-Wu [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Mi, Wei-Dong, E-mail: elite2005gg@163.com [Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China)

2014-04-25

Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

Evolvable synthetic neural system

Science.gov (United States)

Curtis, Steven A. (Inventor)

2009-01-01

An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

Neural electrical activity and neural network growth.

Science.gov (United States)

Gafarov, F M

2018-05-01

The development of central and peripheral neural system depends in part on the emergence of the correct functional connectivity in its input and output pathways. Now it is generally accepted that molecular factors guide neurons to establish a primary scaffold that undergoes activity-dependent refinement for building a fully functional circuit. However, a number of experimental results obtained recently shows that the neuronal electrical activity plays an important role in the establishing of initial interneuronal connections. Nevertheless, these processes are rather difficult to study experimentally, due to the absence of theoretical description and quantitative parameters for estimation of the neuronal activity influence on growth in neural networks. In this work we propose a general framework for a theoretical description of the activity-dependent neural network growth. The theoretical description incorporates a closed-loop growth model in which the neural activity can affect neurite outgrowth, which in turn can affect neural activity. We carried out the detailed quantitative analysis of spatiotemporal activity patterns and studied the relationship between individual cells and the network as a whole to explore the relationship between developing connectivity and activity patterns. The model, developed in this work will allow us to develop new experimental techniques for studying and quantifying the influence of the neuronal activity on growth processes in neural networks and may lead to a novel techniques for constructing large-scale neural networks by self-organization. Copyright © 2018 Elsevier Ltd. All rights reserved.

MiRNA-486 regulates angiogenic activity and survival of mesenchymal stem cells under hypoxia through modulating Akt signal

Energy Technology Data Exchange (ETDEWEB)

Shi, Xue-Feng [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Department of Respiration, Qinghai Provincial People' s Hospital, Xining (China); Wang, Hua; Xiao, Feng-Jun [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Yin, Yue [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Department of Hematology, Peking University First Hospital, Beijing (China); Xu, Qin-Qin [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Ge, Ri-Li, E-mail: geriligao@hotmail.com [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Wang, Li-Sheng, E-mail: wangls@bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China)

2016-02-12

MicroRNA-486 (miR-486) was first identified from human fetal liver cDNA library and validated as a regulator of hematopoiesis. Its roles in regulating the biological function of bone marrow-derived mesnechymal stem cells (BM-MSCs) under hypoxia have not been explored yet. In this study, we demonstrated that exposure to hypoxia upregulates miR-486 expression in BM-MSCs. Lentivirus-mediated overexpression of miR-486 resulted in increase of hepatocyte growth factor (HGF) and vascular endothelial growth factor(VEGF) in both mRNA and protein levels. MiR-486 expression also promotes proliferation and reduces apoptosis of BM-MSCs. Whereas MiR-486 knockdown downregulated the secretion of HGF and VEGF and induced apoptosis of BM-MSCs. Furthermore, PTEN-PI3K/AKT signaling was validated to be involved in changes of BM-MSC biological functions regulated by miR-486. These results suggested that MiR-486 mediated the hypoxia-induced angiogenic activity and promoted the proliferation and survival of BM-MSCs through regulating PTEN-PI3K/AKT signaling. These findings might provide a novel understanding of effective therapeutic strategy for hypoxic-ischemic diseases. - Highlights: • miR-486 is a hypoxia-induced miRNA. • miR-486 regulates the secretion of HGF and VEGF, promotes proliferation, and inhibits apoptosis of BM-MSCs. • miR-486 enhances PI3K/AKT activity signaling by targeting PTEN molecule.

Olive phenolics as c-Met inhibitors: (--Oleocanthal attenuates cell proliferation, invasiveness, and tumor growth in breast cancer models.

Directory of Open Access Journals (Sweden)

Mohamed R Akl

Full Text Available Dysregulation of the Hepatocyte growth factor (HGF/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT, angiogenesis, invasion, and metastasis. (--Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (--oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (--oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (--oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (--oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (--oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (--oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.

An investigation into the stability of commercial versus MG63-derived hepatocyte growth factor under flow cultivation conditions.

Science.gov (United States)

Meneghello, Giulia; Storm, Michael P; Chaudhuri, Julian B; De Bank, Paul A; Ellis, Marianne J

2015-03-01

The scale-up of tissue engineering cell culture must ensure that conditions are maintained while also being cost effective. Here we analyse the stability of hepatocyte growth factor (HGF) to investigate whether concentrations change under dynamic conditions, and compare commercial recombinant human HGF as an additive in 'standard medium', to HGF secreted by the osteosarcoma cell line MG63 as a 'preconditioned medium'. After 3 h under flow conditions, HGF in the standard medium degraded to 40% of its original concentration but HGF in the preconditioned medium remained at 100%. The concentration of secreted HGF was 10 times greater than the working concentration of commercially-available HGF. Thus HGF within this medium has increased stability; MG63-derived HGF should therefore be investigated as a cost-effective alternative to current lyophilised powders for use in in vitro models. Furthermore, we recommend that those intending to use HGF (or other growth factors) should consider similar stability testing before embarking on experiments with media flow.

Comprehensive quantitative comparison of the membrane proteome and PTM-ome of human embryonic stem cells and neural stem cells

DEFF Research Database (Denmark)

Braga, Marcella Nunes de Melo; Schulz, Melanie; Jakobsen, Lene

Introduction: Human embryonic stem cells (hESCs) can differentiate into all three germ layers and self-renew. Due to its ability to differentiate in vitro into human neural stem cells (hNSCs), which can further be differentiated into motor neurons and dopaminergic neurons, these cells are potential...... identified phosphorylated and SA glycosylated proteins, respectively. This study allowed us to identify several significantly regulated proteins during the differentiation process, including proteins involved in the early embryonic development as well as in the neural development. In the latter group...... of proteins we could identify a number of proteins associated with synaptic vesicles, which are vesicles that store neurotransmitters in the nerve-terminals. An example of an upregulated protein in hESCs is the gap junction alpha 1 (GJA1), a phosphorylated protein which plays a crucial role in embryonic...

Activated human neutrophils release hepatocyte growth factor/scatter factor.

LENUS (Irish Health Repository)

McCourt, M

2012-02-03

BACKGROUND: Hepatocyte growth factor or scatter factor (HGF\\/SF) is a pleiotropic cytokine that has potent angiogenic properties. We have previously demonstrated that neutrophils (PMN) are directly angiogenic by releasing vascular endothelial growth factor (VEGF). We hypothesized that the acute inflammatory response can stimulate PMN to release HGF. AIMS: To examine the effects of inflammatory mediators on PMN HGF release and the effect of recombinant human HGF (rhHGF) on PMN adhesion receptor expression and PMN VEGF release. METHODS: In the first experiment, PMN were isolated from healthy volunteers and stimulated with tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), interleukin-8 (IL-8), and formyl methionyl-leucyl-phenylalanine (fMLP). Culture supernatants were assayed for HGF using ELISA. In the second experiment, PMN were lysed to measure total HGF release and HGF expression in the PMN was detected by Western immunoblotting. Finally, PMN were stimulated with rhHGF. PMN CD 11a, CD 11b, and CD 18 receptor expression and VEGF release was measured using flow cytometry and ELISA respectively. RESULTS: TNF-alpha, LPS and fMLP stimulation resulted in significantly increased release of PMN HGF (755+\\/-216, 484+\\/-221 and 565+\\/-278 pg\\/ml, respectively) compared to controls (118+\\/-42 pg\\/ml). IL-8 had no effect. Total HGF release following cell lysis and Western blot suggests that HGF is released from intracellular stores. Recombinant human HGF did not alter PMN adhesion receptor expression and had no effect on PMN VEGF release. CONCLUSIONS: This study demonstrates that pro-inflammatory mediators can stimulate HGF release from a PMN intracellular store and that activated PMN in addition to secreting VEGF have further angiogenic potential by releasing HGF.

Neural tissue engineering scaffold with sustained RAPA release relieves neuropathic pain in rats.

Science.gov (United States)

Ding, Tan; Zhu, Chao; Kou, Zhen-Zhen; Yin, Jun-Bin; Zhang, Ting; Lu, Ya-Cheng; Wang, Li-Ying; Luo, Zhuo-Jing; Li, Yun-Qing

2014-09-01

To investigate the effect of locally slow-released rapamycin (RAPA) from bionic peripheral nerve stent to reduce the incidence of neuropathic pain or mitigate the degree of pain after nerve injury. We constructed a neural tissue engineering scaffold with sustained release of RAPA to repair 20mm defects in rat sciatic nerves. Four presurgical and postsurgical time windows were selected to monitor the changes in the expression of pain-related dorsal root ganglion (DRG) voltage-gated sodium channels 1.3 (Nav1.3), 1.7 (Nav1.7), and 1.8 (Nav1.8) through immunohistochemistry (IHC) and Western Blot, along with the observation of postsurgical pathological pain in rats by pain-related behavior approaches. Relatively small upregulation of DRG sodium channels was observed in the experimental group (RAPA+poly(lactic-co-glycolic acid) (PLGA)+stent) after surgery, along with low degrees of neuropathic pain and anxiety, which were similar to those in the Autologous nerve graft group. Autoimmune inflammatory response plays a leading role in the occurrence of post-traumatic neuropathic pain, and that RAPA significantly inhibits the abnormal upregulation of sodium channels to reduce pain by alleviating inflammatory response. Copyright © 2014 Elsevier Inc. All rights reserved.

Characterization of Proliferating Neural Progenitors after Spinal Cord Injury in Adult Zebrafish.

Directory of Open Access Journals (Sweden)

Subhra Prakash Hui

Full Text Available Zebrafish can repair their injured brain and spinal cord after injury unlike adult mammalian central nervous system. Any injury to zebrafish spinal cord would lead to increased proliferation and neurogenesis. There are presences of proliferating progenitors from which both neuronal and glial loss can be reversed by appropriately generating new neurons and glia. We have demonstrated the presence of multiple progenitors, which are different types of proliferating populations like Sox2+ neural progenitor, A2B5+ astrocyte/ glial progenitor, NG2+ oligodendrocyte progenitor, radial glia and Schwann cell like progenitor. We analyzed the expression levels of two common markers of dedifferentiation like msx-b and vimentin during regeneration along with some of the pluripotency associated factors to explore the possible role of these two processes. Among the several key factors related to pluripotency, pou5f1 and sox2 are upregulated during regeneration and associated with activation of neural progenitor cells. Uncovering the molecular mechanism for endogenous regeneration of adult zebrafish spinal cord would give us more clues on important targets for future therapeutic approach in mammalian spinal cord repair and regeneration.

Osthole Stimulated Neural Stem Cells Differentiation into Neurons in an Alzheimer's Disease Cell Model via Upregulation of MicroRNA-9 and Rescued the Functional Impairment of Hippocampal Neurons in APP/PS1 Transgenic Mice

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Shao-Heng Li

2017-06-01

Full Text Available Alzheimer's disease (AD is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost, a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD in vitro and in vivo. Recently, microRNAs (miRNAs have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP-expressing neural stem cells (NSCs as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR-9 and inhibiting the Notch signaling pathway in vitro. In addition, Ost treatment in APP/PS1 double transgenic (Tg mice markedly restored cognitive functions, reduced Aβ plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases.

Morphological neural networks

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Ritter, G.X.; Sussner, P. [Univ. of Florida, Gainesville, FL (United States)

1996-12-31

The theory of artificial neural networks has been successfully applied to a wide variety of pattern recognition problems. In this theory, the first step in computing the next state of a neuron or in performing the next layer neural network computation involves the linear operation of multiplying neural values by their synaptic strengths and adding the results. Thresholding usually follows the linear operation in order to provide for nonlinearity of the network. In this paper we introduce a novel class of neural networks, called morphological neural networks, in which the operations of multiplication and addition are replaced by addition and maximum (or minimum), respectively. By taking the maximum (or minimum) of sums instead of the sum of products, morphological network computation is nonlinear before thresholding. As a consequence, the properties of morphological neural networks are drastically different than those of traditional neural network models. In this paper we consider some of these differences and provide some particular examples of morphological neural network.

Neural Networks

International Nuclear Information System (INIS)

Smith, Patrick I.

2003-01-01

Physicists use large detectors to measure particles created in high-energy collisions at particle accelerators. These detectors typically produce signals indicating either where ionization occurs along the path of the particle, or where energy is deposited by the particle. The data produced by these signals is fed into pattern recognition programs to try to identify what particles were produced, and to measure the energy and direction of these particles. Ideally, there are many techniques used in this pattern recognition software. One technique, neural networks, is particularly suitable for identifying what type of particle caused by a set of energy deposits. Neural networks can derive meaning from complicated or imprecise data, extract patterns, and detect trends that are too complex to be noticed by either humans or other computer related processes. To assist in the advancement of this technology, Physicists use a tool kit to experiment with several neural network techniques. The goal of this research is interface a neural network tool kit into Java Analysis Studio (JAS3), an application that allows data to be analyzed from any experiment. As the final result, a physicist will have the ability to train, test, and implement a neural network with the desired output while using JAS3 to analyze the results or output. Before an implementation of a neural network can take place, a firm understanding of what a neural network is and how it works is beneficial. A neural network is an artificial representation of the human brain that tries to simulate the learning process [5]. It is also important to think of the word artificial in that definition as computer programs that use calculations during the learning process. In short, a neural network learns by representative examples. Perhaps the easiest way to describe the way neural networks learn is to explain how the human brain functions. The human brain contains billions of neural cells that are responsible for processing

Neural Based Orthogonal Data Fitting The EXIN Neural Networks

CERN Document Server

Cirrincione, Giansalvo

2008-01-01

Written by three leaders in the field of neural based algorithms, Neural Based Orthogonal Data Fitting proposes several neural networks, all endowed with a complete theory which not only explains their behavior, but also compares them with the existing neural and traditional algorithms. The algorithms are studied from different points of view, including: as a differential geometry problem, as a dynamic problem, as a stochastic problem, and as a numerical problem. All algorithms have also been analyzed on real time problems (large dimensional data matrices) and have shown accurate solutions. Wh

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis.

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Saito, Kanako; Dubreuil, Veronique; Arai, Yoko; Wilsch-Bräuninger, Michaela; Schwudke, Dominik; Saher, Gesine; Miyata, Takaki; Breier, Georg; Thiele, Christoph; Shevchenko, Andrej; Nave, Klaus-Armin; Huttner, Wieland B

2009-05-19

Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain, the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed. Here we have conditionally ablated the activity of squalene synthase (SQS), a key enzyme for endogenous cholesterol production, in the neural stem and progenitor cells of the ventricular zone (VZ) of the embryonic mouse brain. Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers, and died at birth. Analyses of the E11.5-E15.5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons, implying that this progeny of the SQS-ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival. Interestingly, the neural stem and progenitor cells of the VZ, the primary target of SQS inactivation, did not undergo significant apoptosis. Instead, vascular endothelial growth factor (VEGF) expression in these cells was strongly upregulated via a hypoxia-inducible factor-1-independent pathway, and angiogenesis in the VZ was increased. Consistent with an increased supply of lipoproteins to these cells, the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated. Our study establishes a direct link between intracellular cholesterol levels, VEGF expression, and angiogenesis. Moreover, our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis.

Transcriptional Profiling of Hypoxic Neural Stem Cells Identifies Calcineurin-NFATc4 Signaling as a Major Regulator of Neural Stem Cell Biology

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Moreno, Marta; Fernández, Virginia; Monllau, Josep M.; Borrell, Víctor; Lerin, Carles; de la Iglesia, Núria

2015-01-01

Summary Neural stem cells (NSCs) reside in a hypoxic microenvironment within the brain. However, the crucial transcription factors (TFs) that regulate NSC biology under physiologic hypoxia are poorly understood. Here we have performed gene set enrichment analysis (GSEA) of microarray datasets from hypoxic versus normoxic NSCs with the aim of identifying pathways and TFs that are activated under oxygen concentrations mimicking normal brain tissue microenvironment. Integration of TF target (TFT) and pathway enrichment analysis identified the calcium-regulated TF NFATc4 as a major candidate to regulate hypoxic NSC functions. Nfatc4 expression was coordinately upregulated by top hypoxia-activated TFs, while NFATc4 target genes were enriched in hypoxic NSCs. Loss-of-function analyses further revealed that the calcineurin-NFATc4 signaling axis acts as a major regulator of NSC self-renewal and proliferation in vitro and in vivo by promoting the expression of TFs, including Id2, that contribute to the maintenance of the NSC state. PMID:26235896

Neural systems for cognitive reappraisal in children and adolescents with autism spectrum disorder

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Naomi B. Pitskel

2014-10-01

Full Text Available Despite substantial clinical and anecdotal evidence for emotion dysregulation in individuals with autism spectrum disorder (ASD, little is known about the neural substrates underlying this phenomenon. We sought to explore neural mechanisms for cognitive reappraisal in children and adolescents with ASD using functional magnetic resonance imaging (fMRI. We studied 16 youth with ASD and 15 age- and IQ-matched typically developing (TD comparison youth. Participants were instructed in the use of cognitive reappraisal strategies to increase and decrease their emotional responses to disgusting images. Participants in both groups displayed distinct patterns of brain activity for increasing versus decreasing their emotions. TD participants showed downregulation of bilateral insula and left amygdala on decrease trials, whereas ASD participants showed no modulation of insula and upregulation of left amygdala. Furthermore, TD youth exhibited increased functional connectivity between amygdala and ventrolateral prefrontal cortex compared to ASD participants when downregulating disgust, as well as decreased functional connectivity between amygdala and orbitofrontal cortex. These findings have important implications for our understanding of emotion dysregulation and its treatment in ASD. In particular, the relative lack of prefrontal-amygdala connectivity provides a potential target for treatment-related outcome measurements.

Impact of Hepatocyte Growth Factor on Skeletal Myoblast Transplantation Late after Myocardial Infarction

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Stacy B. O'blenes

2013-01-01

Full Text Available In clinical studies, skeletal myoblast (SKMB transplantation late after myocardial infarction (MI has minimal impact on left ventricular (LV function. This may be related to our previous observation that the extent of SKMB engraftment is minimal in chronic MI when compared to acute MI, which correlates with decreased hepatocyte growth factor (HGF expression, an important regulator of SKMB function. Here, we investigated delivery of exogenous HGF as a strategy for augmenting SKMB engraftment late after MI. Rats underwent SKMB transplantation 4 weeks after coronary ligation. HGF or vehicle control was delivered intravenously during the subsequent 2 weeks. LV function was assessed by MRI before and 2 weeks after SKMB transplantation. We evaluated HGF delivery, SKMB engraftment, and expression of genes associated with post-MI remodeling. Serum HGF was 6.2 ± 2.4 ng/mL after 2 weeks of HGF infusion (n = 7, but undetectable in controls (n = 7. LV end-diastolic volume and ejection fraction did not improve with HGF treatment (321 ± 27 mm 3 , 42% ± 2% vs. 285 ± 33 mm 3 , 43% ± 2%, HGF vs. control. MIs were larger in HGF-treated animals (50 ± 7 vs. 30 ± 6 mm 3 , P = 0.046, but the volume of engrafted SKMBs or percentage of MIs occupied by SKMBs did not increase with HGF (1.7 ± 0.3 mm 3 , 4.7% ± 1.9% vs. 1.4 ± 0.4 mm 3 , 5.3% ± 1.6%, HGF vs. control. Expression of genes associated with post-infarction remodeling was not altered by HGF. Delivery of exogenous HGF failed to augment SKMB engraftment and functional recovery in chronic MI. Expression of genes associated with LV remodeling was not altered by HGF. Alternative strategies to enhance engraftment of SKMB must be explored to optimize the clinical efficacy of SKMB transplantation.

Neural networks

International Nuclear Information System (INIS)

Denby, Bruce; Lindsey, Clark; Lyons, Louis

1992-01-01

The 1980s saw a tremendous renewal of interest in 'neural' information processing systems, or 'artificial neural networks', among computer scientists and computational biologists studying cognition. Since then, the growth of interest in neural networks in high energy physics, fueled by the need for new information processing technologies for the next generation of high energy proton colliders, can only be described as explosive

Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages.

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Fattah Sotoodehnejadnematalahi

Full Text Available Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM, and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold by long term hypoxia (5 days than by 1 day of hypoxia (48 fold. We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K, LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression.

The experimental study of CT-guided hepatocyte growth factor gene therapy for cerebral ischemic diseases

International Nuclear Information System (INIS)

Zhang Xiaobo; Jin Zhengyu; Li Mingli; Wang Renzhi; Li Guilin; Kong Yanguo; Wang Jianming; Gao Shan; Guan Hongzhi; Wang Detian; Luo Yufeng

2006-01-01

Objectives: To investigate the feasibility of CT guided hepatocyte growth factor (HGF) gene therapy for cerebral ischemic diseases. Methods: Human HGF cDNA was ligated to pIRES 2 -EGFP vector. The recombinant plasmid was transfected into the penumbra tissue with liposome, guided by CT perfusion images. After seven days of transfer with recombinant plasmid, the cut sections of rat brain tissues of the treated and control groups were analyzed including immunohistochemistry, vessel count, cerebral blood flow and infarct volume etc. in order to investigate HGF gene expression and biological effect. Results: Enzymatic digestion and electrophoresis confirmed that HGF fragments had been correctly cloned into the space between the BamH I and Sal I sites of pIRES 2 -EGFP. After 7 days of HGF gene transfection, expression of HGF in transfected neurocytes of treated group was observed with immunohistochemistry. The number of vessels in penumbra tissues transfected with HGF vectors and the CBF measured by perfusion CT all were significantly increased than those of the controls (P 2 -EGFP-HGF complexes can transfect the penumbra tissues and definitely express HGF protein. The HGF gene products can stimulate angiogenesis, promote collateral circulation formation and reduce infarct volume in vivo and therefore is beneficial to the treatment of cerebral ischemia. (authors)

Marked stimulation of growth and motility of human keratinocytes by hepatocyte growth factor

International Nuclear Information System (INIS)

Matsumoto, K.; Hashimoto, K.; Yoshikawa, K.; Nakamura, T.

1991-01-01

Effect of hepatocyte growth factor (HGF) on normal human epidermal keratinocytes cultured under conditions of low Ca2+ (0.1 mM, growth-promoting condition) and physiological Ca2+ (1.8 mM, differentiation-promoting condition) was investigated. In low Ca2+, HGF markedly enhanced the migration of keratinocytes while it suppressed cell growth and DNA synthesis in a dose-dependent manner. In contrast, HGF enhanced the migration, cell growth, and DNA synthesis of keratinocytes cultured under conditions of physiological Ca2+. The maximal stimulation of DNA synthesis (2.4-fold stimulation) in physiological Ca2+ was seen at 2.5-5 ng/ml HGF and the stimulatory effect of HGF was suppressed by transforming growth factor-beta 1. Analysis of the HGF receptor using 125I-HGF as a ligand showed that human keratinocytes expressed a single class of specific, saturable receptor for HGF in both low and physiological Ca2+ conditions, exhibiting a Kd = 17.3 pM and approximately 690 binding sites/cell under physiological Ca2+. Thus, HGF is a potent factor which enhances growth and migration of normal human keratinocytes under conditions of physiological Ca2+. HGF may play an important role in epidermal tissue repair as it enhances both the migration and growth of keratinocytes

Effect of hepatocyte growth factor on radiation response of HeLa, V79, CHO and primary cultured parenchymal hepatocyte in vitro

International Nuclear Information System (INIS)

Yamazaki, Hideya; Inoue, Takehiro; Nose, Takayuki; Murayama, Shigeyuki; Teshima, Teruki; Ozeki, Syuji; Koizumi, Masahiko; Inoue, Toshihiko.

1996-01-01

Hepatocyte growth factor (HGF) is a multipotent cytokine enhancing regeneration of injured organs as liver, kidney and lung after injury. HGF enhances proliferation of various type of cells, inhibits proliferation of carcinoma cells, enhances motility of epithelial cells. We examined three cell lines (CHO, HeLa, V79) and primary cultured normal rat parenchymal hepatocytes to determine the effect of HGF on radiation response. HGF diminished survival of CHO and V79 cells determined by colony formation assay, whereas no significant change of survival was found in HeLa cells. No synergistic changes of survival were found when these three cell lines were irradiated with the addition of HGF. Thus, HGF did not enhance the radiation effect. We also analyzed the impact of irradiation with HGF on primary cultured normal rat parenchymal hepatocytes. At first, the release of glutamic-oxaloacetic amino-transaminase (GOT) in the supernatant was estimated. Irradiation (40 Gy) with or without HGF did not change GOT release in acute phase by 4 days after irradiation compared with the unirradiated control. Second, the DNA synthesis of rat parenchymal hepatocytes was analyzed using radioactive iodine-labeled deoxyuridine incorporation. HGF counteracted the suppression of DNA synthesis induced by irradiation. Thus, HGF may act as a mitogen even for irradiation-damaged normal cells. (author)

Urinary Clusterin Is Upregulated in Nephropathia Epidemica

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Ekaterina V. Martynova

2018-01-01

Full Text Available Kidney insufficiency is a hallmark of nephropathia epidemica (NE. Little is known about the mechanisms of the NE kidney pathology, with current knowledge mainly based on findings in postmortem tissue. We have analyzed kidney damage biomarkers in urine collected from early- and late-phase NE using Bio-Plex kidney toxicity panels 1 and 2. To determine the disease specificity, kidney damage biomarkers were also analyzed in urine samples from patients diagnosed with gout, type 2 diabetes, systemic lupus erythematosus, and chronic kidney insufficiency. Analysis of 12 biomarkers suggests damage to the kidney proximal tubule at the onset of NE. Also, upregulation of biomarkers of inflammation and leukocyte chemotaxis were detected in NE urine. Furthermore, increased clusterin levels were found in early- and late-phase NE urine. Comparative analysis revealed that clusterin is a biomarker, upregulated in NE urine.

Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

International Nuclear Information System (INIS)

Zhao, Liyan; Liu, Xiaolin; Zhang, Yuelin; Liang, Xiaoting; Ding, Yue; Xu, Yan; Fang, Zhen; Zhang, Fengxiang

2016-01-01

Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.

Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

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Zhao, Liyan; Liu, Xiaolin [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zhang, Yuelin [Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong (China); Liang, Xiaoting; Ding, Yue [Pudong District Clinical Translational Medical Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai (China); Xu, Yan; Fang, Zhen [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zhang, Fengxiang, E-mail: njzfx6@njmu.edu.cn [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

2016-05-15

Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.

Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model.

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Jiamin Zhang

Full Text Available Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD. ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group, as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

The Use of Endothelial Progenitor Cells for the Regeneration of Musculoskeletal and Neural Tissues

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Naosuke Kamei

2017-01-01

Full Text Available Endothelial progenitor cells (EPCs derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+ cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury.

Progesterone dose-dependently modulates hepatocyte growth factor production in 3T3-L1 mouse preadipocytes.

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Ito, Tomoki; Yamaji, Daisuke; Kamikawa, Akihiro; Abd Eldaim, Mabrouk Attia; Okamatsu-Ogura, Yuko; Terao, Akira; Saito, Masayuki; Kimura, Kazuhiro

2017-08-30

It is well documented that estrogen is predominant inducer of hepatocyte growth factor (HGF) in a variety of cell types. However, the effect of progesterone (P) remains to be elusive. Thus, in the present study, we examined the effect of P and combined effect of P and 17β-estradiol (E2) on HGF expression and production in 3T3-L1 fibroblastic preadipocytes and mature adipocytes, as a model of stromal cells. Northern blot analysis showed that hgf mRNA expressed in preadipocytes was notably higher than that of mature adipocytes, and increased by treatment of preadipocytes with E2 or 10 nM P, but not with 1,000 nM P. The E2-induced hgf mRNA expression was enhanced by 10 nM P, but suppressed by 1,000 nM P. Western blot analysis revealed that biological active forms of HGF protein was found in the preadipocyte culture medium, while the lesser amount of HGF precursor protein was detected in the mature adipocyte culture medium. The amounts of HGF were changed dependently on the hgf mRNA expression levels. These results indicate that HGF production is intricately regulated by E2 and P at the transcriptional levels in 3T3-L1 cells, and may explain the changes in the HGF production during the mammary gland development, especially decrease in HGF expression during pregnancy when P concentration is high.

A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors.

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Zhu, Xiaoyan; Fréchou, Magalie; Liere, Philippe; Zhang, Shaodong; Pianos, Antoine; Fernandez, Neïké; Denier, Christian; Mattern, Claudia; Schumacher, Michael; Guennoun, Rachida

2017-11-08

Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes. SIGNIFICANCE STATEMENT The brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5α-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the

Upregulation of NLRP3 Inflammasome in the Tears and Ocular Surface of Dry Eye Patients.

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Liangliang Niu

Full Text Available To evaluate the mRNA and protein expressions of NLRP3 inflammasome and its downstream inflammatory factors in human dry eye.We recruited 54 patients with Sjögren's syndrome dry eye (SSDE, 50 patients with non-Sjögren's syndrome dry eye (NSSDE, and 46 healthy controls. Tear film breakup time (TBUT, Schirmer I test, and fluorescein staining (FL were performed on all subjects. Tear samples were obtained to analyze the inflammatory cytokine levels of IL-1β and IL-18 via enzyme-linked immunosorbent (ELISA. Conjunctival impression cytology (CIC specimens were collected to detect the mRNA expression of NLRP3, caspase-1, IL-1β, and IL-18 using quantitative RT-PCR, and the protein expression of NLRP3 and caspase-1 by Western blotting.NLRP3 mRNA expression showed higher levels in both dry eye groups compared with controls, with a comparably significant elevation in the SSDE group (relative 2.47-fold upregulation, p<0.05. NLRP3 protein expression was also increased in SSDE group (relative1.94-fold upregulation compared with the controls. mRNA expression of caspase-1 was significantly upregulated in both SSDE (relative 1.44-fold upregulation, p<0.05 and NSSDE (relative 1.32-fold upregulation, p<0.05. Procaspase-1 protein level was increased in SSDE (relative 1.84-fold upregulation and NSSDE (relative 1.12-fold upregulation versus controls; and caspase-1 protein expression was also increased in SSDE (relative 1.49-fold upregulation and NSSDE (relative 1.17-fold upregulation compared with the controls. The patients with SSDE and NSSDE had higher IL-1β and IL-18 mRNA values and protein expressions than the controls did. The relative mRNA expression of IL-1β upregulated 3.59-fold (p<0.001 in SSDE and 2.13-fold (p<0.01 in NSSDE compared with the controls. IL-1β protein level also showed significant upregulation in SSDE (p=0.01; vs. controls groups. IL-18 mRNA expression levels were significantly upregulated in the SSDE (relative 2.97-fold upregulation, p

Evolvable Neural Software System

Science.gov (United States)

Curtis, Steven A.

2009-01-01

The Evolvable Neural Software System (ENSS) is composed of sets of Neural Basis Functions (NBFs), which can be totally autonomously created and removed according to the changing needs and requirements of the software system. The resulting structure is both hierarchical and self-similar in that a given set of NBFs may have a ruler NBF, which in turn communicates with other sets of NBFs. These sets of NBFs may function as nodes to a ruler node, which are also NBF constructs. In this manner, the synthetic neural system can exhibit the complexity, three-dimensional connectivity, and adaptability of biological neural systems. An added advantage of ENSS over a natural neural system is its ability to modify its core genetic code in response to environmental changes as reflected in needs and requirements. The neural system is fully adaptive and evolvable and is trainable before release. It continues to rewire itself while on the job. The NBF is a unique, bilevel intelligence neural system composed of a higher-level heuristic neural system (HNS) and a lower-level, autonomic neural system (ANS). Taken together, the HNS and the ANS give each NBF the complete capabilities of a biological neural system to match sensory inputs to actions. Another feature of the NBF is the Evolvable Neural Interface (ENI), which links the HNS and ANS. The ENI solves the interface problem between these two systems by actively adapting and evolving from a primitive initial state (a Neural Thread) to a complicated, operational ENI and successfully adapting to a training sequence of sensory input. This simulates the adaptation of a biological neural system in a developmental phase. Within the greater multi-NBF and multi-node ENSS, self-similar ENI s provide the basis for inter-NBF and inter-node connectivity.

Enhancement of curcumin wound healing ability by complexation with 2-hydroxypropyl-γ-cyclodextrin in sacran hydrogel film.

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Wathoni, Nasrul; Motoyama, Keiichi; Higashi, Taishi; Okajima, Maiko; Kaneko, Tatsuo; Arima, Hidetoshi

2017-05-01

Curcumin is one of promising agents to accelerate the wound-healing process. However, the efficacy of curcumin is limited due to its poor water solubility and stability. To enhance the properties of curcumin, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) can be used through complexation. Recently, we revealed that sacran has the potential to form a hydrogel film (HGF) as a wound dressing material. Therefore, in the present study, we investigated the wound healing ability of curcumin/HP-γ-CyD (Cur/HP-γ-CyD) complex in sacran-based HGF (Sac-HGF). We prepared the Cur/HP-γ-CyD complex in Sac-HGF without surface roughness. Additionally, the amorphous form in the Cur/HP-γ-CyD complex in Sac-HGF were observed. In contrast, the curcumin in Sac-HGF and curcumin/HP-γ-CyD physical mixture in Sac-HGF formed inhomogeneous films due to crystallization of curcumin. Furthermore, HP-γ-CyD played an important role to increase the elastic modulus of the Sac-HGF with high re-swelling ability. The Cur/HP-γ-CyD complex in Sac-HGF maintained antioxidant properties of curcumin. Curcumin was gradually released from the HP-γ-CyD complex in Sac-HGF. Notably, the Cur/HP-γ-CyD complex in Sac-HGF provided the highest wound healing ability in hairless mice. These results suggest that the Cur/HP-γ-CyD complex in Sac-HGF has the potential for use as a new transdermal therapeutic system to promote the wound-healing process. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of hepatocyte growth factor on secretory functions in human eosinophils.

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Yamauchi, Yumiko; Ueki, Shigeharu; Konno, Yasunori; Ito, Wataru; Takeda, Masahide; Nakamura, Yuka; Nishikawa, Junko; Moritoki, Yuki; Omokawa, Ayumi; Saga, Tomoo; Hirokawa, Makoto

2016-12-01

Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is now recognized as a humoral mediator in inflammatory and immune responses. Previous studies indicated that HGF negatively regulated allergic airway inflammation. In view of eosinophils playing a role in the pathogenesis of asthma, especially in airway remodeling as a rich source of pro-fibrogenic mediators, the effects of HGF on the different types of eosinophil secretory functions were examined in this study. We found that HGF significantly inhibited IL-5-induced secretion of TGF-β and VEGF from human eosinophils. The inhibitory effect is not associated with TGF-β transcription; rather, it is associated with ultrastructural granule emptying and loss of intracellular TGF-β contents, indicating HGF inhibits the process of piecemeal degranulation. The effect of HGF on extracellular trap cell death (ETosis) that mediates cytolytic degranulation was also investigated; however, immobilized IgG- or phorbol myristate acetate-induced ETosis was only minimally attenuated by HGF. These results reveal the effect of HGF on the distinct pathways of eosinophil secretory functions and also provide novel insights into the role of HGF in the pathogenesis of allergic inflammation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Harnessing migraines for neural regeneration

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Jonathan M Borkum

2018-01-01

Full Text Available The success of naturalistic or therapeutic neuroregeneration likely depends on an internal milieu that facilitates the survival, proliferation, migration, and differentiation of stem cells and their assimilation into neural networks. Migraine attacks are an integrated sequence of physiological processes that may protect the brain from oxidative stress by releasing growth factors, suppressing apoptosis, stimulating neurogenesis, encouraging mitochondrial biogenesis, reducing the production of oxidants, and upregulating antioxidant defenses. Thus, the migraine attack may constitute a physiologic environment conducive to stem cells. In this paper, key components of migraine are reviewed – neurogenic inflammation with release of calcitonin gene-related peptide (CGRP and substance P, plasma protein extravasation, platelet activation, release of serotonin by platelets and likely by the dorsal raphe nucleus, activation of endothelial nitric oxide synthase (eNOS, production of brain-derived neurotrophic factor (BDNF and, in migraine aura, cortical spreading depression – along with their potential neurorestorative aspects. The possibility is considered of using these components to facilitate successful stem cell transplantation. Potential methods for doing so are discussed, including chemical stimulation of the TRPA1 ion channel, conjoint activation of a subset of migraine components, invasive and noninvasive deep brain stimulation of the dorsal raphe nucleus, transcranial focused ultrasound, and stimulation of the Zusanli (ST36 acupuncture point.

Neural retina-specific Aldh1a1 controls dorsal choroidal vascular development via Sox9 expression in retinal pigment epithelial cells.

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Goto, So; Onishi, Akishi; Misaki, Kazuyo; Yonemura, Shigenobu; Sugita, Sunao; Ito, Hiromi; Ohigashi, Yoko; Ema, Masatsugu; Sakaguchi, Hirokazu; Nishida, Kohji; Takahashi, Masayo

2018-04-03

VEGF secreted from retinal pigment epithelial (RPE) cells is responsible for the choroidal vascular development; however, the molecular regulatory mechanism is unclear. We found that Aldh1a1 -/- mice showed choroidal hypoplasia with insufficient vascularization in the dorsal region, although Aldh1a1, an enzyme that synthesizes retinoic acids (RAs), is expressed in the dorsal neural retina, not in the RPE/choroid complex. The level of VEGF in the RPE/choroid was significantly decreased in Aldh1a1 -/- mice, and RA-dependent enhancement of VEGF was observed in primary RPE cells. An RA-deficient diet resulted in dorsal choroidal hypoplasia, and simple RA treatment of Aldh1a1 -/- pregnant females suppressed choroid hypoplasia in their offspring. We also found downregulation of Sox9 in the dorsal neural retina and RPE of Aldh1a1 -/- mice and RPE-specific disruption of Sox9 phenocopied Aldh1a1 -/- choroidal development. These results suggest that RAs produced by Aldh1a1 in the neural retina directs dorsal choroidal vascular development via Sox9 upregulation in the dorsal RPE cells to enhance RPE-derived VEGF secretion. © 2018, Goto et al.

Chaotic diagonal recurrent neural network

International Nuclear Information System (INIS)

Wang Xing-Yuan; Zhang Yi

2012-01-01

We propose a novel neural network based on a diagonal recurrent neural network and chaos, and its structure and learning algorithm are designed. The multilayer feedforward neural network, diagonal recurrent neural network, and chaotic diagonal recurrent neural network are used to approach the cubic symmetry map. The simulation results show that the approximation capability of the chaotic diagonal recurrent neural network is better than the other two neural networks. (interdisciplinary physics and related areas of science and technology)

Computational modeling of neural plasticity for self-organization of neural networks.

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Chrol-Cannon, Joseph; Jin, Yaochu

2014-11-01

Self-organization in biological nervous systems during the lifetime is known to largely occur through a process of plasticity that is dependent upon the spike-timing activity in connected neurons. In the field of computational neuroscience, much effort has been dedicated to building up computational models of neural plasticity to replicate experimental data. Most recently, increasing attention has been paid to understanding the role of neural plasticity in functional and structural neural self-organization, as well as its influence on the learning performance of neural networks for accomplishing machine learning tasks such as classification and regression. Although many ideas and hypothesis have been suggested, the relationship between the structure, dynamics and learning performance of neural networks remains elusive. The purpose of this article is to review the most important computational models for neural plasticity and discuss various ideas about neural plasticity's role. Finally, we suggest a few promising research directions, in particular those along the line that combines findings in computational neuroscience and systems biology, and their synergetic roles in understanding learning, memory and cognition, thereby bridging the gap between computational neuroscience, systems biology and computational intelligence. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Overexpressed Calponin3 by Subsonic Vibration Induces Neural Differentiation of hUC-MSCs by Regulating the Ionotropic Glutamate Receptor.

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Kim, Hyun-Jung; Kim, Jin-Hee; Song, Yeo-Ju; Seo, Young-Kwon; Park, Jung-Keug; Kim, Chan-Wha

2015-09-01

In this study, we used proteomics to investigate the effects of sonic vibration (SV) on mesenchymal stem cells derived from human umbilical cords (hUC-MSCs) during neural differentiation to understand how SV enhances neural differentiation of hUC-MSCs. We investigated the levels of gene and protein related to neural differentiation after 3 or 5 days in a group treated with 40-Hz SV. In addition, protein expression patterns were compared between the control and the 40-Hz SV-treated hUC-MSC groups via a proteomic approach. Among these proteins, calponin3 (CNN3) was confirmed to have 299 % higher expression in the 40-Hz SV stimulated hUC-MSCs group than that in the control by Western blotting. Notably, overexpression of CNN3-GFP in Chinese hamster ovary (CHO)-K1 cells had positive effects on the stability and reorganization of F-actin compared with that in GFP-transfected cells. Moreover, CNN3 changed the morphology of the cells by making a neurite-like form. After being subjected to SV, messenger RNA (mRNA) levels of glutamate receptors such as PSD95, GluR1, and NR1 as well as intracellular calcium levels were upregulated. These results suggest that the activity of glutamate receptors increased because of CNN3 characteristics. Taken together, these results demonstrate that overexpressed CNN3 during SV increases expression of glutamate receptors and promotes functional neural differentiation of hUC-MSCs.

Transcriptional profiling of MEF2-regulated genes in human neural progenitor cells derived from embryonic stem cells

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Shing Fai Chan

2015-03-01

Full Text Available The myocyte enhancer factor 2 (MEF2 family of transcription factors is highly expressed in the brain and constitutes a key determinant of neuronal survival, differentiation, and synaptic plasticity. However, genome-wide transcriptional profiling of MEF2-regulated genes has not yet been fully elucidated, particularly at the neural stem cell stage. Here we report the results of microarray analysis comparing mRNAs isolated from human neural progenitor/stem cells (hNPCs derived from embryonic stem cells expressing a control vector versus progenitors expressing a constitutively-active form of MEF2 (MEF2CA, which increases MEF2 activity. Microarray experiments were performed using the Illumina Human HT-12 V4.0 expression beadchip (GEO#: GSE57184. By comparing vector-control cells to MEF2CA cells, microarray analysis identified 1880 unique genes that were differentially expressed. Among these genes, 1121 genes were up-regulated and 759 genes were down-regulated. Our results provide a valuable resource for identifying transcriptional targets of MEF2 in hNPCs.

Hepatocyte growth factor secreted by ovarian cancer cells stimulates peritoneal implantation via the mesothelial-mesenchymal transition of the peritoneum.

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Nakamura, Michihiko; Ono, Yoshihiro J; Kanemura, Masanori; Tanaka, Tomohito; Hayashi, Masami; Terai, Yoshito; Ohmichi, Masahide

2015-11-01

A current working model for the metastatic process of ovarian carcinoma suggests that cancer cells are shed from the ovarian tumor into the peritoneal cavity and attach to the layer of mesothelial cells that line the inner surface of the peritoneum, and several studies suggest that hepatocyte growth factor (HGF) plays an important role in the dissemination of ovarian cancer. Our objectives were to evaluate the HGF expression of ovarian cancer using clinical data and assess the effect of HGF secreted from human ovarian cancer cells to human mesothelial cells. HGF expression was immunohistochemically evaluated in 165 epithelial ovarian cancer patients arranged as tissue microarrays. HGF expression in four ovarian cancer cell lines was evaluated by using semi-quantitative polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay. The effect of ovarian cancer cell derived HGF to the human mesothelial cells was assessed by using morphologic analysis, Western blotting and cell invasion assay. The effect of HGF on ovarian cancer metastasis was assessed by using in vivo experimental model. The clinical data showed a significantly high correlation between the HGF expression and the cancer stage. The in vivo and in vitro experimental models revealed that HGF secreted by ovarian cancer cells induces the mesothelial-to-mesenchymal transition and stimulates the invasion of mesothelial cells. Furthermore, manipulating the HGF activity affected the degree of dissemination and ascite formation. We demonstrated that HGF secreted by ovarian cancer cells plays an important role in cancer peritoneal implantation. Copyright © 2015 Elsevier Inc. All rights reserved.

Neural Parallel Engine: A toolbox for massively parallel neural signal processing.

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Tam, Wing-Kin; Yang, Zhi

2018-05-01

Large-scale neural recordings provide detailed information on neuronal activities and can help elicit the underlying neural mechanisms of the brain. However, the computational burden is also formidable when we try to process the huge data stream generated by such recordings. In this study, we report the development of Neural Parallel Engine (NPE), a toolbox for massively parallel neural signal processing on graphical processing units (GPUs). It offers a selection of the most commonly used routines in neural signal processing such as spike detection and spike sorting, including advanced algorithms such as exponential-component-power-component (EC-PC) spike detection and binary pursuit spike sorting. We also propose a new method for detecting peaks in parallel through a parallel compact operation. Our toolbox is able to offer a 5× to 110× speedup compared with its CPU counterparts depending on the algorithms. A user-friendly MATLAB interface is provided to allow easy integration of the toolbox into existing workflows. Previous efforts on GPU neural signal processing only focus on a few rudimentary algorithms, are not well-optimized and often do not provide a user-friendly programming interface to fit into existing workflows. There is a strong need for a comprehensive toolbox for massively parallel neural signal processing. A new toolbox for massively parallel neural signal processing has been created. It can offer significant speedup in processing signals from large-scale recordings up to thousands of channels. Copyright © 2018 Elsevier B.V. All rights reserved.

The emerging role of m-TOR up-regulation in brain Astrocytoma.

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Ryskalin, Larisa; Limanaqi, Fiona; Biagioni, Francesca; Frati, Alessandro; Esposito, Vincenzo; Calierno, Maria Teresa; Lenzi, Paola; Fornai, Francesco

2017-05-01

The present manuscript is an overview of various effects of mTOR up-regulation in astrocytoma with an emphasis on its deleterious effects on the proliferation of Glioblastoma Multiforme. The manuscript reports consistent evidence indicating the occurrence of mTOR up-regulation both in experimental and human astrocytoma. The grading of human astrocytoma is discussed in relationship with mTOR up-regulation. In the second part of the manuscript, the biochemical pathways under the influence of mTOR are translated to cell phenotypes which are generated by mTOR up-regulation and reverted by its inhibition. A special section is dedicated to the prominent role of autophagy in mediating the effects of mTOR in glioblastoma. In detail, autophagy inhibition produced by mTOR up-regulation determines the fate of cancer stem cells. On the other hand, biochemical findings disclose the remarkable effects of autophagy activators as powerful inducers of cell differentiation with a strong prevalence towards neuronal phenotypes. Thus, mTOR modulation acts on the neurobiology of glioblastoma just like it operates in vivo at the level of brain stem cell niches by altering autophagy-dependent cell differentiation. In the light of such a critical role of autophagy we analyzed the ubiquitin proteasome system. The merging between autophagy and proteasome generates a novel organelle, named autophagoproteasome which is strongly induced by mTOR inhibitors in glioblastoma cells. Remarkably, when mTOR is maximally inhibited the proteasome component selectively moves within autophagy vacuoles, thus making the proteasome activity dependent on the entry within autophagy compartment.

Neural chips, neural computers and application in high and superhigh energy physics experiments

International Nuclear Information System (INIS)

Nikityuk, N.M.; )

2001-01-01

Architecture peculiarity and characteristics of series of neural chips and neural computes used in scientific instruments are considered. Tendency of development and use of them in high energy and superhigh energy physics experiments are described. Comparative data which characterize the efficient use of neural chips for useful event selection, classification elementary particles, reconstruction of tracks of charged particles and for search of hypothesis Higgs particles are given. The characteristics of native neural chips and accelerated neural boards are considered [ru

Hepatocyte growth factor and chronic hepatitis C Factor de crecimiento hepatocitario y hepatitis crónica C

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E. Marín-Serrano

2010-06-01

Full Text Available Objective: the hepatocyte growth factor (HGF is a pleiotropic cytokine produced by hepatic stellate cells and implicated in liver regeneration and fibrosis. Serum levels of HGF vary in liver diseases, reflecting hepatic damage and hepatocellular dysfunction. In this study, serum levels of HGF and the relationship between HGF and biochemical, histological and virological data, have been analysed in patients suffering from chronic hepatitis C (CHC. Patients and methods: serum HGF concentration was measured by ELISA in sandwich in 45 patients with CHC. Correlation between HGF levels and histological (necroinflammatory activity and fibrosis score and biochemical (transaminases, prothrombin activity, albumin, bilirubin, or virological (hepatitis C virus load parameters was analyzed. Serum HGF concentration was also studied in a subgroup of the original sample treated with interferon and ribavirin. Results: serum HGF concentrations of patients with CHC were significantly higher than those detected in healthy controls. Patients with significant fibrosis (F ≥ 2 had a significantly older age, lower count of platelets and higher values of AST, GGT and HGF, than those patients with a fibrosis score F Objetivo: el factor de crecimiento hepatocitario (HGF es una citocina pleiotrópica producida por las células estrelladas hepáticas, que está implicada en la regeneración y la fibrosis hepática. La concentración sérica del HGF en las enfermedades hepáticas es variable, reflejando daño hepático y disfunción hepatocelular. En este estudio se ha analizado la concentración sérica del HGF en pacientes con hepatitis crónica por virus de la hepatitis C (VHC y su relación con los datos bioquímicos, histológicos y virológicos. Pacientes y métodos: se determinó la concentración sérica de HGF mediante ELISA en sándwich y se analizó la correlación entre los niveles del HGF y los datos histológicos (actividad necroinflamatoria, estadio de

Neural tissue-spheres

DEFF Research Database (Denmark)

Andersen, Rikke K; Johansen, Mathias; Blaabjerg, Morten

2007-01-01

By combining new and established protocols we have developed a procedure for isolation and propagation of neural precursor cells from the forebrain subventricular zone (SVZ) of newborn rats. Small tissue blocks of the SVZ were dissected and propagated en bloc as free-floating neural tissue...... content, thus allowing experimental studies of neural precursor cells and their niche...

Inca: a novel p21-activated kinase-associated protein required for cranial neural crest development.

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Luo, Ting; Xu, Yanhua; Hoffman, Trevor L; Zhang, Tailin; Schilling, Thomas; Sargent, Thomas D

2007-04-01

Inca (induced in neural crest by AP2) is a novel protein discovered in a microarray screen for genes that are upregulated in Xenopus embryos by the transcriptional activator protein Tfap2a. It has no significant similarity to any known protein, but is conserved among vertebrates. In Xenopus, zebrafish and mouse embryos, Inca is expressed predominantly in the premigratory and migrating neural crest (NC). Knockdown experiments in frog and fish using antisense morpholinos reveal essential functions for Inca in a subset of NC cells that form craniofacial cartilage. Cells lacking Inca migrate successfully but fail to condense into skeletal primordia. Overexpression of Inca disrupts cortical actin and prevents formation of actin "purse strings", which are required for wound healing in Xenopus embryos. We show that Inca physically interacts with p21-activated kinase 5 (PAK5), a known regulator of the actin cytoskeleton that is co-expressed with Inca in embryonic ectoderm, including in the NC. These results suggest that Inca and PAK5 cooperate in restructuring cytoskeletal organization and in the regulation of cell adhesion in the early embryo and in NC cells during craniofacial development.

Tumor necrosis factor α triggers proliferation of adult neural stem cells via IKK/NF-κB signaling

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Kaltschmidt Christian

2006-09-01

Full Text Available Abstract Background Brain inflammation has been recognized as a complex phenomenon with numerous related aspects. In addition to the very well-described neurodegenerative effect of inflammation, several studies suggest that inflammatory signals exert a potentially positive influence on neural stem cell proliferation, migration and differentiation. Tumor necrosis factor alpha (TNF-α is one of the best-characterized mediators of inflammation. To date, conclusions about the action of TNF on neural stem or progenitor cells (NSCs, NPCs have been conflicting. TNF seems to activate NSC proliferation and to inhibit their differentiation into NPCs. The purpose of the present study was to analyze the molecular signal transduction mechanisms induced by TNF and resulting in NSC proliferation. Results Here we describe for the first time the TNF-mediated signal transduction cascade in neural stem cells (NSCs that results in increased proliferation. Moreover, we demonstrate IKK-α/β-dependent proliferation and markedly up-regulated cyclin D1 expression after TNF treatment. The significant increase in proliferation in TNF-treated cells was indicated by increased neurosphere volume, increased bromodeoxyuridin (BrdU incorporation and a higher total cell number. Furthermore, TNF strongly activated nuclear factor-kappa B (NF-κB as measured by reporter gene assays and by an activity-specific antibody. Proliferation of control and TNF-treated NSCs was strongly inhibited by expression of the NF-κB super-repressor IκB-AA1. Pharmacological blockade of IκB ubiquitin ligase activity led to comparable decreases in NF-κB activity and proliferation. In addition, IKK-β gene product knock-down via siRNA led to diminished NF-κB activity, attenuated cyclin D1 expression and finally decreased proliferation. In contrast, TGFβ-activated kinase 1 (TAK-1 is partially dispensable for TNF-mediated and endogenous proliferation. Understanding stem cell proliferation is crucial

Serum Hepatocyte Growth Factor Is Associated with Small Vessel Disease in Alzheimer’s Dementia

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Yanan Zhu

2018-01-01

Full Text Available Background: While hepatocyte growth factor (HGF is known to exert cell growth, migration and morphogenic effects in various organs, recent studies suggest that HGF may also play a role in synaptic maintenance and cerebrovascular integrity. Although increased levels of HGF have been reported in brain and cerebrospinal fluid (CSF samples of patients with Alzheimer’s disease (AD, it is unclear whether peripheral HGF may be associated with cerebrovascular disease (CeVD and dementia. In this study, we examined the association of baseline serum HGF with neuroimaging markers of CeVD in a cohort of pre-dementia (cognitive impaired no dementia, CIND and AD patients.Methods: Serum samples from aged, Non-cognitively impaired (NCI controls, CIND and AD subjects were measured for HGF levels. CeVD (cortical infarcts, microinfarcts, lacunes, white matter hyperintensities (WMH and microbleeds were assessed by magnetic resonance imaging (MRI.Results: After controlling for covariates, higher levels of HGF were associated with both CIND and AD. Among the different CeVD MRI markers in CIND and AD, only small vessel disease, but not large vessel disease markers were associated with higher HGF levels.Conclusion: Serum HGF may be a useful peripheral biomarker for small vessel disease in subjects with cognitive impairment and AD.

Genes Involved in Human Ribosome Biogenesis areTranscriptionally Upregulated in Colorectal Cancer

DEFF Research Database (Denmark)

Mansilla, Francisco; Lamy, Philippe; Ørntoft, Torben Falck

2009-01-01

Microarray gene expression profiling comprising 168 colorectal adenocarcinomas and 10 normal mucosas showed that over 79% of the genes involved in human ribosome biogenesis are significantly upregulated (log2>0.5, p<10-3) when compared to normal mucosa. Overexpression was independent of microsate......Microarray gene expression profiling comprising 168 colorectal adenocarcinomas and 10 normal mucosas showed that over 79% of the genes involved in human ribosome biogenesis are significantly upregulated (log2>0.5, p... of microsatellite status. The promoters of the genes studied showed a significant enrichment for several transcription factor binding sites. There was a significant correlation between the number of binding site targets for these transcription factors and the observed gene transcript upregulation. The upregulation...

Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung.

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Carla Calvi

Full Text Available The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF, a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine-induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF-mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace.

Activation of PI3K-Akt-GSK3β pathway mediates hepatocyte growth factor inhibition of RANTES expression in renal tubular epithelial cells

International Nuclear Information System (INIS)

Gong Rujun; Rifai, Abdalla; Dworkin, Lance D.

2005-01-01

Hepatocyte growth factor (HGF) was recently reported to ameliorate renal inflammation in a rat model of chronic renal failure. HGF exerted its action through suppression of RANTES expression in renal tubules. In the present study, we utilized an in vitro model of human kidney proximal tubule epithelial cells (HKC) to elucidate the mechanisms of RANTES suppression by HGF. HGF significantly suppressed basal and TNF-α-induced mRNA and protein expression of RANTES in a time and dose dependent fashion. HGF elicited PI3K-Akt activation and inhibited GSK3, a downstream transducer of PI3K-Akt, by inhibitory phosphorylation at Ser-9. When the PI3K-Akt pathway was blocked by wortmannin, HGF inhibition of RANTES was abrogated, demonstrating that the PI3K-Akt pathway is necessary for HGF action. In addition, specific inhibition of GSK3 activity by lithium ion suppressed basal and TNF-α-induced RANTES expression, reminiscent of the action of HGF. To further investigate the role of GSK3 in modulating RANTES expression, we examined the effect of forced expression of wild type GSK3β or an uninhibitable mutant GSK3β, in which the regulatory Ser-9 residue is changed to alanine (S9A-GSK3β) in HKC. Overexpression of wild type GSK3β did not alter the inhibitory action of HGF on RANTES. In contrast, expression of S9A-GSK3β abolished HGF inhibition of basal and TNF-α stimulated RANTES expression. These findings suggest that PI3K-Akt activation and subsequent inhibitory phosphorylation of GSK3β are required for HGF-induced suppression of RANTES in HKC

Mycobacterium tuberculosis, but not vaccine BCG, specifically upregulates matrix metalloproteinase-1.

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Elkington, Paul T G; Nuttall, Robert K; Boyle, Joseph J; O'Kane, Cecilia M; Horncastle, Donna E; Edwards, Dylan R; Friedland, Jon S

2005-12-15

Pulmonary cavitation is fundamental to the global success of Mycobacterium tuberculosis. However, the mechanisms of this lung destruction are poorly understood. The biochemistry of lung matrix predicts matrix metalloproteinase (MMP) involvement in immunopathology. We investigated gene expression of all MMPs, proteins with a disintegrin and metalloproteinase domain, and tissue inhibitors of metalloproteinases in M. tuberculosis-infected human macrophages by real-time polymerase chain reaction. MMP secretion was measured by zymography and Western analysis, and expression in patients with pulmonary tuberculosis was localized by immunohistochemistry. MMP-1 and MMP-7 gene expression and secretion are potently upregulated by M. tuberculosis, and no increase in tissue inhibitor of metalloproteinase expression occurs to oppose their activity. Dexamethasone completely suppresses MMP-1 but not MMP-7 gene expression and secretion. In patients with active tuberculosis, macrophages express MMP-1 and MMP-7 adjacent to areas of tissue destruction. MMP-1 but not MMP-7 expression and secretion are relatively M. tuberculosis specific, are not upregulated by tuberculosis-associated cytokines, and are prostaglandin dependent. In contrast, the vaccine M. bovis bacillus Calmette-Guérin (BCG) does not stimulate MMP-1 secretion from human macrophages, although M. tuberculosis and BCG do upregulate MMP-7 equally. BCG-infected macrophages secrete reduced prostaglandin E2 concentrations compared with M. tuberculosis-infected macrophages, and prostaglandin pathway supplementation augments MMP-1 secretion from BCG-infected cells. M. tuberculosis specifically upregulates MMP-1 in a cellular model of human infection and in patients with tuberculosis. In contrast, vaccine BCG, which does not cause lung cavitation, does not upregulate prostaglandin E2-dependent MMP-1 secretion.

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.

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Mohamed, Hoda E; Elswefy, Sahar E; Rashed, Laila A; Younis, Nahla N; Shaheen, Mohamed A; Ghanim, Amal M H

2016-03-01

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA. © 2016 by the Society for Experimental Biology and Medicine.

Increased antigen presentation but impaired T cells priming after upregulation of interferon-beta induced by lipopolysaccharides is mediated by upregulation of B7H1 and GITRL.

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Fang Wang

Full Text Available Dendritic cells are able to present Ag-derived peptides on MHC class I and II molecules and induce T cells priming. Lipopolysaccharides (LPS, an activator of Toll-like 4 receptor (TLR4 signaling, has been demonstrated to facilitate Ag-presentation, up-regulate surface molecules expression but impair T cells priming. In this study, we investigated the effect of LPS on nicotine-enhanced DCs-dependent T cells priming and the mechanisms of LPS orchestrating the immunosuppressive program. We could demonstrate that the treatment with LPS resulted in increased surface molecules expression, enhanced Ag-presentation, up-regulated release of TGF-beta, TNF-alpha, IL-6, and IFN-beta. Concomititantly, the upregulation of IFN-beta in DCs induces the up-regulation of coinhibitory molecules B7H1 and GITRL, which cause an impaired activation of naïve Ag-specific T cells and the induction of T cell tolerance by enhancing B7H1-PD-1 interactions and promoting GITRL-GITL facilitated Treg generation, respectively. These data provide a mechanistic basis for the immunomodulatory action of IFN-beta which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune response and persistent infection.

Identifying Tmem59 related gene regulatory network of mouse neural stem cell from a compendium of expression profiles

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Guo Xiuyun

2011-09-01

Full Text Available Abstract Background Neural stem cells offer potential treatment for neurodegenerative disorders, such like Alzheimer's disease (AD. While much progress has been made in understanding neural stem cell function, a precise description of the molecular mechanisms regulating neural stem cells is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of neural stem cells. In this paper, the regulatory mechanism of mouse neural stem cell (NSC differentiation by tmem59 is explored on the genome-level. Results We identified regulators of tmem59 during the differentiation of mouse NSCs from a compendium of expression profiles. Based on the microarray experiment, we developed the parallelized SWNI algorithm to reconstruct gene regulatory networks of mouse neural stem cells. From the inferred tmem59 related gene network including 36 genes, pou6f1 was identified to regulate tmem59 significantly and might play an important role in the differentiation of NSCs in mouse brain. There are four pathways shown in the gene network, indicating that tmem59 locates in the downstream of the signalling pathway. The real-time RT-PCR results shown that the over-expression of pou6f1 could significantly up-regulate tmem59 expression in C17.2 NSC line. 16 out of 36 predicted genes in our constructed network have been reported to be AD-related, including Ace, aqp1, arrdc3, cd14, cd59a, cds1, cldn1, cox8b, defb11, folr1, gdi2, mmp3, mgp, myrip, Ripk4, rnd3, and sncg. The localization of tmem59 related genes and functional-related gene groups based on the Gene Ontology (GO annotation was also identified. Conclusions Our findings suggest that the expression of tmem59 is an important factor contributing to AD. The parallelized SWNI algorithm increased the efficiency of network reconstruction significantly. This study enables us to highlight novel genes that may be involved in NSC differentiation and provides a shortcut to

Naked gene therapy of hepatocyte growth factor for dextran sulfate sodium-induced colitis in mice

International Nuclear Information System (INIS)

Kanbe, Takamasa; Murai, Rie; Mukoyama, Tomoyuki; Murawaki, Yoshiyuki; Hashiguchi, Ko-ichi; Yoshida, Yoko; Tsuchiya, Hiroyuki; Kurimasa, Akihiro; Harada, Ken-ichi; Yashima, Kazuo; Nishimuki, Eiji; Shabana, Noriko; Kishimoto, Yukihiro; Kojyo, Haruhiko; Miura, Kunihiko; Murawaki, Yoshikazu; Kawasaki, Hironaka; Shiota, Goshi

2006-01-01

Ulcerative colitis (UC) is progressive and relapsing disease. To explore the therapeutic effects of naked gene therapy of hepatocyte growth factor (HGF) on UC, the SRα promoter driving HGF gene was intrarectally administered to the mice in which colitis was induced by dextran sulfate sodium (DSS). Expression of the transgene was seen in surface epithelium, lamina propria, and muscularis mucosae. The HGF-treated mice showed reduced colonic mucosal damage and increased body weights, compared with control mice (P < 0.01 and P < 0.05, respectively). The HGF-treated mice displayed increased number of PCNA-positive cells and decreased number of apoptotic cells than in control mice (P < 0.01, each). Phosphorylated AKT was dramatically increased after HGF gene administration, however, phosphorylated ERK1/2 was not altered. Microarray analysis revealed that HGF induced expression of proliferation- and apoptosis-associated genes. These data suggest that naked HGF gene delivery causes therapeutic effects through regulation of many downstream genes

Neural networks for aircraft control

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Linse, Dennis

1990-01-01

Current research in Artificial Neural Networks indicates that networks offer some potential advantages in adaptation and fault tolerance. This research is directed at determining the possible applicability of neural networks to aircraft control. The first application will be to aircraft trim. Neural network node characteristics, network topology and operation, neural network learning and example histories using neighboring optimal control with a neural net are discussed.

Ultrastructural evaluation of gingival connective tissue in hereditary gingival fibromatosis.

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Pêgo, Sabina Pena B; de Faria, Paulo Rogério; Santos, Luis Antônio N; Coletta, Ricardo D; de Aquino, Sibele Nascimento; Martelli-Júnior, Hercílio

2016-07-01

To describe the ultrastructural features of hereditary gingival fibromatosis (HGF) in affected family members and compare microscopic findings with normal gingival (NG) tissue. Gingival tissue samples from nine patients with HGF from five unrelated families were evaluated by transmission electron microscopy. Nine NG tissue samples were used for comparison. Areas containing collagen fibrils forming loops and folds were observed in both groups, whereas oxytalan fibers were frequently identified in the HGF group. The diameter of collagen fibrils and the interfibrillar space among them were more uniform in the NG group than in the HGF group. Fibroblasts were the most common cells found in both the HGF and NG groups and exhibited enlarged, rough endoplasmic reticulum, mitochondria with well-preserved crests, conspicuous nucleoli, and euchromatic chromatin. Other cells, such as mast cells, plasma cells, and macrophages, were also observed. HGF tissues had ultrastructural characteristics that were very similar to those of NG tissues. Oxytalan fibers were observed more frequently in the HGF samples than in the NG samples. Other studies of HGF in patients from different families should be performed to better understand the pathogenesis of this hereditary condition. Copyright © 2016 Elsevier Inc. All rights reserved.

Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

DEFF Research Database (Denmark)

Corsino, P.; Davis, B.; Law, M.

2007-01-01

) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV-cyclin D1-Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may...... sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGF beta and HGF, resulting in desmoplasia. The MMTV-DIK2 mice should provide a useful model system...

The Neural Border: Induction, Specification and Maturation of the territory that generates Neural Crest cells.

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Pla, Patrick; Monsoro-Burq, Anne H

2018-05-28

The neural crest is induced at the edge between the neural plate and the nonneural ectoderm, in an area called the neural (plate) border, during gastrulation and neurulation. In recent years, many studies have explored how this domain is patterned, and how the neural crest is induced within this territory, that also participates to the prospective dorsal neural tube, the dorsalmost nonneural ectoderm, as well as placode derivatives in the anterior area. This review highlights the tissue interactions, the cell-cell signaling and the molecular mechanisms involved in this dynamic spatiotemporal patterning, resulting in the induction of the premigratory neural crest. Collectively, these studies allow building a complex neural border and early neural crest gene regulatory network, mostly composed by transcriptional regulations but also, more recently, including novel signaling interactions. Copyright © 2018. Published by Elsevier Inc.

Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes

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Philpott Michael P

2010-02-01

Full Text Available Abstract Background The human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell carcinoma and recently reported that upregulation of FOXM1 precedes malignancy in a number of solid human cancer types including oral, oesophagus, lung, breast, kidney, bladder and uterus. This indicates that upregulation of FOXM1 may be an early molecular signal required for aberrant cell cycle and cancer initiation. Results The present study investigated the putative early mechanism of UVB and FOXM1 in skin cancer initiation. We have demonstrated that UVB dose-dependently increased FOXM1 protein levels through protein stabilisation and accumulation rather than de novo mRNA expression in human epidermal keratinocytes. FOXM1 upregulation in primary human keratinocytes triggered pro-apoptotic/DNA-damage checkpoint response genes such as p21, p38 MAPK, p53 and PARP, however, without causing significant cell cycle arrest or cell death. Using a high-resolution Affymetrix genome-wide single nucleotide polymorphism (SNP mapping technique, we provided the evidence that FOXM1 upregulation in epidermal keratinocytes is sufficient to induce genomic instability, in the form of loss of heterozygosity (LOH and copy number variations (CNV. FOXM1-induced genomic instability was significantly enhanced and accumulated with increasing cell passage and this instability was increased even further upon exposure to UVB resulting in whole chromosomal gain (7p21.3-7q36.3 and segmental LOH (6q25.1-6q25.3. Conclusion We hypothesise that prolonged and repeated UVB exposure selects for skin cells bearing stable FOXM1 protein causes aberrant cell cycle checkpoint thereby allowing ectopic cell cycle entry and subsequent genomic instability. The aberrant

Neural network regulation driven by autonomous neural firings

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Cho, Myoung Won

2016-07-01

Biological neurons naturally fire spontaneously due to the existence of a noisy current. Such autonomous firings may provide a driving force for network formation because synaptic connections can be modified due to neural firings. Here, we study the effect of autonomous firings on network formation. For the temporally asymmetric Hebbian learning, bidirectional connections lose their balance easily and become unidirectional ones. Defining the difference between reciprocal connections as new variables, we could express the learning dynamics as if Ising model spins interact with each other in magnetism. We present a theoretical method to estimate the interaction between the new variables in a neural system. We apply the method to some network systems and find some tendencies of autonomous neural network regulation.

Expression of hypoxia-inducible factor-1α and hepatocyte growth factor in development of fibrosis in the transplanted kidney

DEFF Research Database (Denmark)

Kellenberger, Terese; Marcussen, Niels; Nyengaard, Jens Randel

2014-01-01

Late renal graft loss is associated with interstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) is thought to facilitate fibrosis through interaction with TGF-β1, while hepatocyte growth factor (HGF) may act antifibrotic in the kidney allograft. The aim of this study was to investigate...... transplantation, but an inverse significant correlation between the HGF expression and the fibrosis score 1 year after transplantation was shown. Even when adjusting for human leucocyte antigen mismatches, there was a significant relationship between fibrosis and HGF expression. Graft survival...... was not significantly correlated to HIF-1α or HGF at 1 year, although the trend was towards better graft survival with high HGF. HGF may have antifibrotic effects in human renal transplants. (Central.Denmark.Region.Committee number: 1-10-72-318-13)....

Dynamics of neural cryptography.

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Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

2007-05-01

Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

Dynamics of neural cryptography

International Nuclear Information System (INIS)

Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

2007-01-01

Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible

Dynamics of neural cryptography

Science.gov (United States)

Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

2007-05-01

Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium- and high-dose groups.

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Yang, Zhi-jian; Chen, Bo; Sheng, Zhang; Zhang, Ding-guo; Jia, En-zhi; Wang, Wei; Ma, Dong-chao; Zhu, Tie-bing; Wang, Lian-sheng; Li, Chun-jian; Wang, Hui; Cao, Ke-jiang; Ma, Wen-zhu

2010-04-01

Despite advances in surgical and reperfusion therapy, there is no effective therapy currently exists to prevent the progressive decline in cardiac function following myocardial infarction. Hepatocyte growth factor has potent angiogenic and anti-apoptotic activities. The aim of this study was to investigate the therapeutic effect and dose-effect relationship on postinfarction heart failure with different doses of adenovirus-mediated human hepatocyte growth factor (Ad(5)-HGF) transference in swine models. Totally twenty swine were randomly divided into four groups: (a) control group (null- Ad(5), 1 ml); (b) low-dose group (1 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (c) medium-dose group (5 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (d) high-dose group (1 x 10(10) Pfu/ml Ad(5)-HGF, 1 ml). Four weeks after left anterior descending coronary artery (LAD) ligation, different doses of Ad(5)-HGF were transferred in three therapeutic groups via right coronary artery. Four and seven weeks after LAD ligation, gate cardiac perfusion imaging was performed to evaluate cardiac perfusion and left ventricular ejection fraction (LVEF). Seven weeks after surgery, the apoptotic index of cardiocyte was observed by TUNEL, the expression of Bcl-2, Bax, alpha-SMA and Factor VIII in the border zones were evaluated by immunohistochemistry, respectively. Four weeks after myocardial infarction, no significant difference was observed among four groups. Three weeks after Ad(5)-HGF transfer, the improvement of cardiac perfusion and LVEF was obviously observed, especially after 1 x 10(10) Pfu Ad(5)-HGF transfer. TUNEL assay showed that 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF treatment had a obvious reduction in the apoptotic index compared with the null-Ad(5) group, especially after 1 x 10(10) Pfu Ad(5)-HGF treatment. The expression of Bcl-2 protein was increased and the expression of Bax protein was inhibited in the 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF groups compared with the null-Ad(5) group. The vessel

Bioprinting for Neural Tissue Engineering.

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Knowlton, Stephanie; Anand, Shivesh; Shah, Twisha; Tasoglu, Savas

2018-01-01

Bioprinting is a method by which a cell-encapsulating bioink is patterned to create complex tissue architectures. Given the potential impact of this technology on neural research, we review the current state-of-the-art approaches for bioprinting neural tissues. While 2D neural cultures are ubiquitous for studying neural cells, 3D cultures can more accurately replicate the microenvironment of neural tissues. By bioprinting neuronal constructs, one can precisely control the microenvironment by specifically formulating the bioink for neural tissues, and by spatially patterning cell types and scaffold properties in three dimensions. We review a range of bioprinted neural tissue models and discuss how they can be used to observe how neurons behave, understand disease processes, develop new therapies and, ultimately, design replacement tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

Selective neuronal differentiation of neural stem cells induced by nanosecond microplasma agitation.

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Xiong, Z; Zhao, S; Mao, X; Lu, X; He, G; Yang, G; Chen, M; Ishaq, M; Ostrikov, K

2014-03-01

An essential step for therapeutic and research applications of stem cells is their ability to differentiate into specific cell types. Neuronal cells are of great interest for medical treatment of neurodegenerative diseases and traumatic injuries of central nervous system (CNS), but efforts to produce these cells have been met with only modest success. In an attempt of finding new approaches, atmospheric-pressure room-temperature microplasma jets (MPJs) are shown to effectively direct in vitro differentiation of neural stem cells (NSCs) predominantly into neuronal lineage. Murine neural stem cells (C17.2-NSCs) treated with MPJs exhibit rapid proliferation and differentiation with longer neurites and cell bodies eventually forming neuronal networks. MPJs regulate ~75% of NSCs to differentiate into neurons, which is a higher efficiency compared to common protein- and growth factors-based differentiation. NSCs exposure to quantized and transient (~150 ns) micro-plasma bullets up-regulates expression of different cell lineage markers as β-Tubulin III (for neurons) and O4 (for oligodendrocytes), while the expression of GFAP (for astrocytes) remains unchanged, as evidenced by quantitative PCR, immunofluorescence microscopy and Western Blot assay. It is shown that the plasma-increased nitric oxide (NO) production is a factor in the fate choice and differentiation of NSCs followed by axonal growth. The differentiated NSC cells matured and produced mostly cholinergic and motor neuronal progeny. It is also demonstrated that exposure of primary rat NSCs to the microplasma leads to quite similar differentiation effects. This suggests that the observed effect may potentially be generic and applicable to other types of neural progenitor cells. The application of this new in vitro strategy to selectively differentiate NSCs into neurons represents a step towards reproducible and efficient production of the desired NSC derivatives. Published by Elsevier B.V.

Selective neuronal differentiation of neural stem cells induced by nanosecond microplasma agitation

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Z. Xiong

2014-03-01

Full Text Available An essential step for therapeutic and research applications of stem cells is their ability to differentiate into specific cell types. Neuronal cells are of great interest for medical treatment of neurodegenerative diseases and traumatic injuries of central nervous system (CNS, but efforts to produce these cells have been met with only modest success. In an attempt of finding new approaches, atmospheric-pressure room-temperature microplasma jets (MPJs are shown to effectively direct in vitro differentiation of neural stem cells (NSCs predominantly into neuronal lineage. Murine neural stem cells (C17.2-NSCs treated with MPJs exhibit rapid proliferation and differentiation with longer neurites and cell bodies eventually forming neuronal networks. MPJs regulate ~75% of NSCs to differentiate into neurons, which is a higher efficiency compared to common protein- and growth factors-based differentiation. NSCs exposure to quantized and transient (~150 ns micro-plasma bullets up-regulates expression of different cell lineage markers as β-Tubulin III (for neurons and O4 (for oligodendrocytes, while the expression of GFAP (for astrocytes remains unchanged, as evidenced by quantitative PCR, immunofluorescence microscopy and Western Blot assay. It is shown that the plasma-increased nitric oxide (NO production is a factor in the fate choice and differentiation of NSCs followed by axonal growth. The differentiated NSC cells matured and produced mostly cholinergic and motor neuronal progeny. It is also demonstrated that exposure of primary rat NSCs to the microplasma leads to quite similar differentiation effects. This suggests that the observed effect may potentially be generic and applicable to other types of neural progenitor cells. The application of this new in vitro strategy to selectively differentiate NSCs into neurons represents a step towards reproducible and efficient production of the desired NSC derivatives.

Lack of upregulation of epidermal fatty acid binding protein in dithranol induced irritation.

NARCIS (Netherlands)

Kucharekova, M.; Vissers, W.H.P.M.; Schalkwijk, J.; Kerkhof, P.C.M. van de; Valk, P.G.M. van der

2003-01-01

The exact role of epidermal fatty acid binding protein (E-FABP) in skin is unknown. A restoration of the barrier function may be associated with an upregulation of E-FABP. Moreover, E-FABP is upregulated in a variety of cells in response to oxidative stress. A recent observation that dithranol

Cytosolic DNA Sensor Upregulation Accompanies DNA Electrotransfer in B16.F10 Melanoma Cells

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Katarina Znidar

2016-01-01

Full Text Available In several preclinical tumor models, antitumor effects occur after intratumoral electroporation, also known as electrotransfer, of plasmid DNA devoid of a therapeutic gene. In mouse melanomas, these effects are preceded by significant elevation of several proinflammatory cytokines. These observations implicate the binding and activation of intracellular DNA-specific pattern recognition receptors or DNA sensors in response to DNA electrotransfer. In tumors, IFNβ mRNA and protein levels significantly increased. The mRNAs of several DNA sensors were detected, and DAI, DDX60, and p204 tended to be upregulated. These effects were accompanied with reduced tumor growth and increased tumor necrosis. In B16.F10 cells in culture, IFNβ mRNA and protein levels were significantly upregulated. The mRNAs for several DNA sensors were present in these cells; DNA-dependent activator of interferon regulatory factor (DAI, DEAD (Asp-Glu-Ala-Asp box polypeptide 60 (DDX60, and p204 were significantly upregulated while DDX60 protein levels were coordinately upregulated. Upregulation of DNA sensors in tumors could be masked by the lower transfection efficiency compared to in vitro or to dilution by other tumor cell types. Mirroring the observation of tumor necrosis, cells underwent a significant DNA concentration-dependent decrease in proliferation and survival. Taken together, these results indicate that DNA electrotransfer may cause the upregulation of several intracellular DNA sensors in B16.F10 cells, inducing effects in vitro and potentially in vivo.

Imposed Optical Defocus Induces Isoform-Specific Up-Regulation of TGFβ Gene Expression in Chick Retinal Pigment Epithelium and Choroid but Not Neural Retina

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Zhang, Yan; Raychaudhuri, Suravi; Wildsoet, Christine F.

2016-01-01

Purpose This study investigated the gene expression of TGFβ isoforms and their receptors in chick retina, retinal pigment epithelium (RPE), and choroid and the effects of short-term imposed optical defocus. Methods The expression of TGFβ isoforms (TGF-β1, 2, 3) and TGFβ receptors (TGFBR1, 2, 3) was examined in the retina, RPE, and choroid of young White-Leghorn untreated chicks (19 days-old). The effects on the expression of the same genes of monocular +10 and -10 D defocusing lenses, worn for either 2 or 48 h by age-matched chicks, were also examined by comparing expression in treated and untreated fellow eyes. RNA was purified, characterized and then reverse transcribed to cDNA. Differential gene expression was quantified using real-time PCR. Results All 3 isoforms of TGFβ and all 3 receptor subtypes were found to be expressed in all 3 ocular tissues, with apparent tissue-dependent differences in expression profiles. Data are reported as mean normalized expression relative to GAPDH. Sign-dependent optical defocus effects were also observed. Optical defocus did not affect retinal gene expression but in the RPE, TGF-β2 expression was significantly up-regulated with +10 D lenses, worn for either 2 h (349% increase ± 88%, p < 0.01) or 48 h (752% increase ± 166%, p < 0.001), and in the choroid, the expression of TGF-β3 was up-regulated with -10 D lenses, worn for 48 h (147% increase ± 9%, p < 0.01). Conclusions The effects of short term exposure to optical defocus on TGFβ gene expression in the RPE and choroid, which were sign-dependent and isoform specific, provide further supporting evidence for important roles of members of the TGFβ family and these two tissues in local signal cascades regulating ocular growth. PMID:27214233

Neural correlates and neural computations in posterior parietal cortex during perceptual decision-making

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Alexander eHuk

2012-10-01

Full Text Available A recent line of work has found remarkable success in relating perceptual decision-making and the spiking activity in the macaque lateral intraparietal area (LIP. In this review, we focus on questions about the neural computations in LIP that are not answered by demonstrations of neural correlates of psychological processes. We highlight three areas of limitations in our current understanding of the precise neural computations that might underlie neural correlates of decisions: (1 empirical questions not yet answered by existing data; (2 implementation issues related to how neural circuits could actually implement the mechanisms suggested by both physiology and psychology; and (3 ecological constraints related to the use of well-controlled laboratory tasks and whether they provide an accurate window on sensorimotor computation. These issues motivate the adoption of a more general encoding-decoding framework that will be fruitful for more detailed contemplation of how neural computations in LIP relate to the formation of perceptual decisions.

Deep Learning Neural Networks and Bayesian Neural Networks in Data Analysis

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Chernoded Andrey

2017-01-01

Full Text Available Most of the modern analyses in high energy physics use signal-versus-background classification techniques of machine learning methods and neural networks in particular. Deep learning neural network is the most promising modern technique to separate signal and background and now days can be widely and successfully implemented as a part of physical analysis. In this article we compare Deep learning and Bayesian neural networks application as a classifiers in an instance of top quark analysis.

Neural Tube Defects

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Neural tube defects are birth defects of the brain, spine, or spinal cord. They happen in the ... that she is pregnant. The two most common neural tube defects are spina bifida and anencephaly. In ...

Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel disease.

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Arthur, L Grier; Schwartz, Marshall Z; Kuenzler, Keith A; Birbe, Ruth

2004-02-01

Transfection of the HLA-B27 gene into normal Fischer rats induces phenotypic changes similar to inflammatory bowel disease (IBD). This study investigated the benefits of 2 doses of hepatocyte growth factor (HGF) on the manifestations of IBD in this rat model. Fischer rats and HLA-B27 rats were divided into 4 groups: Fischer rats treated with saline, HLA-B27 rats treated with saline, HGF at 150 microg/kg/d, and HGF at 300 microg/kg/d. HGF or saline was infused for 14 days via an osmotic pump attached to a catheter in the internal jugular vein. After treatment, rats were evaluated for diarrhea and reduction in gross and microscopic bowel inflammation. Statistics were determined using analysis of variance (ANOVA). A P value diarrhea by 40%, gross inflammation by 41%, and microscopic inflammation by 72% (P diarrhea by 46%, gross inflammation by 45%, and microscopic inflammation by 54% (P < or =.05). HGF administration reduces the clinical manifestations of IBD in this rat model. Similar effects were seen at both doses of HGF administration, implying that there is a plateau above which further increases in HGF levels provides no added benefit. HGF administration may be clinically useful in the management of IBD.

PDGF controls contact inhibition of locomotion by regulating N-cadherin during neural crest migration.

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Bahm, Isabel; Barriga, Elias H; Frolov, Antonina; Theveneau, Eric; Frankel, Paul; Mayor, Roberto

2017-07-01

A fundamental property of neural crest (NC) migration is contact inhibition of locomotion (CIL), a process by which cells change their direction of migration upon cell contact. CIL has been proven to be essential for NC migration in amphibians and zebrafish by controlling cell polarity in a cell contact-dependent manner. Cell contact during CIL requires the participation of the cell adhesion molecule N-cadherin, which starts to be expressed by NC cells as a consequence of the switch between E- and N-cadherins during epithelial-to-mesenchymal transition (EMT). However, the mechanism that controls the upregulation of N-cadherin remains unknown. Here, we show that platelet-derived growth factor receptor alpha (PDGFRα) and its ligand platelet-derived growth factor A (PDGF-A) are co-expressed in migrating cranial NC. Inhibition of PDGF-A/PDGFRα blocks NC migration by inhibiting N-cadherin and, consequently, impairing CIL. Moreover, we identify phosphatidylinositol-3-kinase (PI3K)/AKT as a downstream effector of the PDGFRα cellular response during CIL. Our results lead us to propose PDGF-A/PDGFRα signalling as a tissue-autonomous regulator of CIL by controlling N-cadherin upregulation during EMT. Finally, we show that once NC cells have undergone EMT, the same PDGF-A/PDGFRα works as an NC chemoattractant, guiding their directional migration. © 2017. Published by The Company of Biologists Ltd.

Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA.

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Zhang, Haiyang; Wang, Yi; Bai, Ming; Wang, Junyi; Zhu, Kegan; Liu, Rui; Ge, Shaohua; Li, JiaLu; Ning, Tao; Deng, Ting; Fan, Qian; Li, Hongli; Sun, Wu; Ying, Guoguang; Ba, Yi

2018-03-01

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

DMPD: Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. [Dynamic Macrophage Pathway CSML Database

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Full Text Available 15331118 Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Wu...e-associated up-regulation in macrophage PGE2 synthesis. PubmedID 15331118 Title Mechanism of age-associated... up-regulation in macrophage PGE2 synthesis. Authors Wu D, Meydani SN. Publicatio

Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries.

Directory of Open Access Journals (Sweden)

Hilda Ahnstedt

Full Text Available BACKGROUND AND PURPOSE: Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation. EXPERIMENTAL APPROACH: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5-hydroxtryptamine type 1B (5-HT1B, angiotensin II type 1 (AT1 and endothelin-1 type A and B (ETA and ETB receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression. KEY RESULTS: Vascular sensitivity to angiotensin II and endothelin-1 was markedly lower in cultured cerebral arteries from women as compared to men. ETB receptor-mediated contraction occurred in male but not female arteries. Interestingly, there were similar upregulation in mRNA and expression of 5-HT1B, AT1, and ETB receptors and in local expression of Ang II after organ culture. CONCLUSIONS AND IMPLICATIONS: In spite of receptor upregulation after organ culture in both sexes, cerebral arteries from women were significantly less responsive to vasoconstrictors angiotensin II and endothelin-1 as compared to arteries from men. This suggests receptor coupling and/or signal transduction mechanisms involved in cerebrovascular contractility may be suppressed in females. This is the first study to demonstrate sex differences in the vascular function of human brain arteries.

A neural flow estimator

DEFF Research Database (Denmark)

Jørgensen, Ivan Harald Holger; Bogason, Gudmundur; Bruun, Erik

1995-01-01

This paper proposes a new way to estimate the flow in a micromechanical flow channel. A neural network is used to estimate the delay of random temperature fluctuations induced in a fluid. The design and implementation of a hardware efficient neural flow estimator is described. The system...... is implemented using switched-current technique and is capable of estimating flow in the μl/s range. The neural estimator is built around a multiplierless neural network, containing 96 synaptic weights which are updated using the LMS1-algorithm. An experimental chip has been designed that operates at 5 V...

Hidden neural networks

DEFF Research Database (Denmark)

Krogh, Anders Stærmose; Riis, Søren Kamaric

1999-01-01

A general framework for hybrids of hidden Markov models (HMMs) and neural networks (NNs) called hidden neural networks (HNNs) is described. The article begins by reviewing standard HMMs and estimation by conditional maximum likelihood, which is used by the HNN. In the HNN, the usual HMM probability...... parameters are replaced by the outputs of state-specific neural networks. As opposed to many other hybrids, the HNN is normalized globally and therefore has a valid probabilistic interpretation. All parameters in the HNN are estimated simultaneously according to the discriminative conditional maximum...... likelihood criterion. The HNN can be viewed as an undirected probabilistic independence network (a graphical model), where the neural networks provide a compact representation of the clique functions. An evaluation of the HNN on the task of recognizing broad phoneme classes in the TIMIT database shows clear...

NeuroMEMS: Neural Probe Microtechnologies

Directory of Open Access Journals (Sweden)

Sam Musallam

2008-10-01

Full Text Available Neural probe technologies have already had a significant positive effect on our understanding of the brain by revealing the functioning of networks of biological neurons. Probes are implanted in different areas of the brain to record and/or stimulate specific sites in the brain. Neural probes are currently used in many clinical settings for diagnosis of brain diseases such as seizers, epilepsy, migraine, Alzheimer’s, and dementia. We find these devices assisting paralyzed patients by allowing them to operate computers or robots using their neural activity. In recent years, probe technologies were assisted by rapid advancements in microfabrication and microelectronic technologies and thus are enabling highly functional and robust neural probes which are opening new and exciting avenues in neural sciences and brain machine interfaces. With a wide variety of probes that have been designed, fabricated, and tested to date, this review aims to provide an overview of the advances and recent progress in the microfabrication techniques of neural probes. In addition, we aim to highlight the challenges faced in developing and implementing ultralong multi-site recording probes that are needed to monitor neural activity from deeper regions in the brain. Finally, we review techniques that can improve the biocompatibility of the neural probes to minimize the immune response and encourage neural growth around the electrodes for long term implantation studies.

SAOS-2 osteosarcoma cells bind fibroblasts via ICAM-1 and this is increased by tumour necrosis factor-α.

Directory of Open Access Journals (Sweden)

Manu S David

Full Text Available We recently reported exchange of membrane and cytoplasmic markers between SAOS-2 osteosarcoma cells and human gingival fibroblasts (h-GF without comparable exchange of nuclear markers, while similar h-GF exchange was seen for melanoma and ovarian carcinoma cells. This process of "cellular sipping" changes phenotype such that cells sharing markers of both SAOS-2 and h-GF have morphology intermediate to that of either cell population cultured alone, evidencing increased tumour cell diversity without genetic change. TNF-α increases cellular sipping between h-GF and SAOS-2, and we here study binding of SAOS-2 to TNF-α treated h-GF to determine if increased cellular sipping can be accounted for by cytokine stimulated SAOS-2 binding. More SAOS-2 bound h-GF pe-seeded wells than culture plastic alone (p<0.001, and this was increased by h-GF pre-treatment with TNF-α (p<0.001. TNF-α stimulated binding was dose dependent and maximal at 1.16 nM (p<0.05 with no activity below 0.006 nM. SAOS-2 binding to h-GF was independent of serum, while the lipopolysaccharide antagonist Polymyxin B did not affect results, and TNF-α activity was lost on boiling. h-GF binding of SAOS-2 started to increase after 30min TNF-α stimulation and was maximal by 1.5 hr pre-treatment (p<0.001. h-GF retained maximal binding up to 6 hrs after TNF-α stimulation, but this was lost by 18 hrs (p<0.001. FACS analysis demonstrated increased ICAM-1 consistent with the time course of SAOS-2 binding, while antibody against ICAM-1 inhibited SAOS-2 adhesion (p<0.04. Pre-treating SAOS-2 with TNF-α reduced h-GF binding to background levels (p<0.003, and this opposite effect to h-GF cytokine stimulation suggests that the history of cytokine exposure of malignant cells migrating across different microenvironments can influence subsequent interactions with fibroblasts. Since cytokine stimulated binding was comparable in magnitude to earlier reported TNF-α stimulated cellular sipping, we

Anti-c-MET Nanobody - a new potential drug in multiple myeloma treatment.

Science.gov (United States)

Slørdahl, Tobias Schmidt; Denayer, Tinneke; Moen, Siv Helen; Standal, Therese; Børset, Magne; Ververken, Cedric; Rø, Torstein Baade

2013-11-01

c-MET is the tyrosine kinase receptor of the hepatocyte growth factor (HGF). HGF-c-MET signaling is involved in many human malignancies, including multiple myeloma (MM). Recently, multiple agents have been developed directed to interfere at different levels in HGF-c-MET signaling pathway. Nanobodies are therapeutic proteins based on the smallest functional fragments of heavy-chain-only antibodies. In this study, we wanted to determine the anticancer effect of a novel anti-c-MET Nanobody in MM. We examined the effects of an anti-c-MET Nanobody on thymidine incorporation, migration, adhesion of MM cells, and osteoblastogenesis in vitro. Furthermore, we investigated the effects of the Nanobody on HGF-dependent c-MET signaling by Western blotting. We show that the anti-c-MET Nanobody effectively inhibited thymidine incorporation of ANBL-6 MM cells via inhibition of an HGF autocrine growth loop and thymidine incorporation in INA-6 MM cells induced by exogenous HGF. HGF-induced migration and adhesion of INA-6 were completely and specifically blocked by the Nanobody. Furthermore, the Nanobody abolished the inhibiting effect of HGF on bone morphogenetic protein-2-induced alkaline phosphatase activity and the mineralization of human mesenchymal stem cells. Finally, we show that the Nanobody reduced phosphorylation of tyrosine residues in c-MET, MAPK, and Akt. We also compared the Nanobody with anti-c-MET monoclonal antibodies and revealed the similar or better effect. The anti-c-MET Nanobody inhibited MM cell migration, thymidine incorporation, and adhesion, and blocked the HGF-mediated inhibition of osteoblastogenesis. The anti-c-MET Nanobody might represent a novel therapeutic agent in the treatment of MM and other cancers driven by HGF-c-MET signaling. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

Energy Technology Data Exchange (ETDEWEB)

Yeom, Chul-gon; Kim, Dong-il; Park, Min-jung; Choi, Joo-hee [College of Veterinary Medicine, Chonnam National University, Gwangju 500-757 (Korea, Republic of); Jeong, Jieun; Wi, Anjin; Park, Whoashig [Jeollanamdo Forest Resources Research Institute, Naju 520-833 (Korea, Republic of); Han, Ho-jae [College of Veterinary Medicine, Seoul National University, Seoul 151-741 (Korea, Republic of); Park, Soo-hyun, E-mail: parksh@chonnam.ac.kr [College of Veterinary Medicine, Chonnam National University, Gwangju 500-757 (Korea, Republic of)

2015-06-05

Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the ‘fed’ condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. - Highlights: • Insulin treatment increases CARM1 expression in hepatocytes. • CARM1 overexpression does not increase the expression of lipogenic proteins. • CARM1 knockdown does not influence insulin sensitivity. • Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation.

Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

International Nuclear Information System (INIS)

Yeom, Chul-gon; Kim, Dong-il; Park, Min-jung; Choi, Joo-hee; Jeong, Jieun; Wi, Anjin; Park, Whoashig; Han, Ho-jae; Park, Soo-hyun

2015-01-01

Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the ‘fed’ condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. - Highlights: • Insulin treatment increases CARM1 expression in hepatocytes. • CARM1 overexpression does not increase the expression of lipogenic proteins. • CARM1 knockdown does not influence insulin sensitivity. • Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

Poly (Ethylene Glycol-Block-Brush Poly (L-Lysine Copolymer as an Efficient Nanocarrier for Human Hepatocyte Growth Factor with Enhanced Bioavailability and Anti-Ischemia Reperfusion Injury Efficacy

Directory of Open Access Journals (Sweden)

Fei Tong

2017-08-01

Full Text Available Background/Aims: The aim of this study was to assess the effect of human hepatocyte growth factor (hHGF-loaded poly (ethylene glycol-b-brush poly (l-lysine (PEG-b-P(ELG-g-PLL copolymer on ischemia/reperfusion (I/R injury to different organs. Methods: The isoelectric point (pI of hHGF is 5.5, and hHGF combined with PEG-b-P(ELG-g-PLL copolymer via electrostatic interactions at pH 7.4. The synthesized PEG-b-P(ELG-g-PLL copolymer was analyzed using 1H nuclear magnetic resonance (1H NMR and gel permeation chromatography (GPC. The hHGF/PEG-b-P(ELG-g-PLL complex was evaluated using a nanoparticle size instrument and transmission electron microscopy (TEM. In addition, vivo performance of hHGF/PEG-b-P(ELG-g-PLL complex was evaluated using plasma hHGF concentration and different organs ischemia reperfusion injury in rats. Results: An in vitro investigation showed that PEG-b-P(ELG-g-PLL could serve as a potential hHGF nanocarrier with efficient encapsulation and sustained release. An additional in vivo investigation revealed that the hHGF/PEG-b-P(ELG-g-PLL complex could prolong increases in plasma hHGF concentration and protect different organs (the brain, heart and kidney against I/R injury. Conclusion: Poly (ethylene glycol-block-brush poly (l-lysine copolymer as an efficient nanocarrier for human hepatocyte growth factor with enhanced bioavailability and anti-ischemia reperfusion injury efficacy.

The Mechanism of Gefitinib Resistance Induced by Hepatocyte Growth Factor 
in Sensitive Non-small Cell Lung Cancer Cells in Vitro

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Xianglan XUAN

2013-01-01

Full Text Available Background and objective Previous studies have reported that Met might be related to gefitinib resistance in non-small cell lung cancer (NSCLC. The present study aims to explore the mechanism of hepatocyte growth factor (HGF-induced gefitinib resistance in different gene types of sensitive NSCLC in vitro. Methods The PC-9 and H292 cell lines were chosen and induced by HGF. The cell survival was measured using MTT assay, the cell cycle distribution was measured using PI assay, and cell apoptosis with an Annexin V-PE assay, respectively. The c-Met and p-Met protein expression was determined via Western blot analysis. Results Gefitinib inhibited the growth of PC-9 and H292 cells in a dose-dependent manner. The concentration-survival curves of both cell lines shifted to the right when induced with HGF. HGF did not affect PC-9 and H292 cell proliferation. The cell also had a higher cell survival rate when treated with HGF and gefitinib compared with that under gefitinib alone (P<0.05. The apoptotic rate and cell cycle progression showed no significant difference between the HG and G group (P>0.05. HGF stimulated Met phosphorylation in the PC-9 and H292 cells. Gefitinib inhibited the HGF-induced Met phosphorylation in PC-9 cells, but not in H292 cells. Conclusion HGF induces gefitinib resistance in PC-9 and H292 cells. HGF-induced Met phosphorylation may be an important mechanism of gefitinib resistance in sensitive NSCLC.

Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary.

Science.gov (United States)

Liu, Y; Lin, L; Zarnegar, R

1994-09-01

Hepatocyte growth factor (HGF) is expressed in a variety of tissues and cell types under normal conditions and in response to various stimuli such as tissue injury. In the present study, we demonstrate that the transcription of the HGF gene is stimulated by estrogen in mouse ovary. A single injection of 17 beta-estradiol results in a dramatic and transient elevation of the levels of mouse HGF mRNA. Sequence analysis has found that two putative estrogen responsive elements (ERE) reside at -872 in the 5'-flanking region and at +511 in the first intron, respectively, of the mouse HGF gene. To test whether these ERE elements are responsible for estrogen induction of HGF gene expression, chimeric plasmids containing variable regions of the 5'-flanking sequence of HGF gene and the coding region for chloramphenicol acetyltransferase (CAT) gene were transiently transfected into both human endometrial carcinoma RL 95-2 cells and mouse fibroblast NIH 3T3 cells to assess hormone responsiveness. Transfection results indicate that the ERE elements of the mouse HGF gene can confer estrogen action to either homologous or heterologous promoters. Nuclear protein extracts either from RL95-2 cells transfected with the estrogen receptor expression vector or from mouse liver bound in vitro to ERE elements specifically, as shown by band shift assay. Therefore, our results demonstrate that the HGF gene is transcriptionally regulated by estrogen in mouse ovary; and such regulation is mediated via a direct interaction of the estrogen receptor complex with cis-acting ERE elements identified in the mouse HGF gene.

Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy

Energy Technology Data Exchange (ETDEWEB)

Chen, Ai-Lan [Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Ou, Cai-Wen [The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); He, Zhao-Chu [Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Liu, Qi-Cai [Experimental Medical Research Center, Guangzhou Medical University, Guangzhou (China); Dong, Qi [Department of Physiology, Guangzhou Medical University, Guangzhou (China); Chen, Min-Sheng [Guangzhou Key Laboratory of Cardiovascular Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou (China)

2012-10-15

Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 µM) alone, HGF (10 ng/mL) alone, and Ang II (1 µM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [{sup 3}H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of β-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 µM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 µM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 µM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy.

Insecticide-Mediated Up-Regulation of Cytochrome P450 Genes in the Red Flour Beetle (Tribolium castaneum

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Xiao Liang

2015-01-01

Full Text Available Some cytochrome P450 (CYP genes are known for their rapid up-regulation in response to insecticide exposures in insects. To date, however, limited information is available with respect to the relationships among the insecticide type, insecticide concentration, exposure duration and the up-regulated CYP genes. In this study, we examined the transcriptional response of eight selected CYP genes, including CYP4G7, CYP4Q4, CYP4BR3, CYP12H1, CYP6BK11, CYP9D4, CYP9Z5 and CYP345A1, to each of four insecticides in the red flour beetle, Tribolium castaneum. Reverse transcription quantitative PCR (RT-qPCR revealed that CYP4G7 and CYP345A1 can be significantly up-regulated by cypermethrin (1.97- and 2.06-fold, respectively, permethrin (2.00- and 2.03-fold and lambda-cyhalothrin (1.73- and 1.81-fold, whereas CYP4BR3 and CYP345A1 can be significantly up-regulated by imidacloprid (1.99- and 1.83-fold when 20-day larvae were exposed to each of these insecticides at the concentration of LC20 for 24 h. Our studies also showed that similar levels of up-regulation can be achieved for CYP4G7, CYP4BR3 and CYP345A1 by cypermethrin, permethrin, lambda-cyhalothrin or imidacloprid with approximately one fourth of LC20 in 6 h. Our study demonstrated that up-regulation of these CYP genes was rapid and only required low concentrations of insecticides, and the up-regulation not only depended on the CYP genes but also the type of insecticides. Our results along with those from previous studies also indicated that there were no specific patterns for predicting the up-regulation of specific CYP gene families based on the insecticide classification.

Neural Networks: Implementations and Applications

OpenAIRE

Vonk, E.; Veelenturf, L.P.J.; Jain, L.C.

1996-01-01

Artificial neural networks, also called neural networks, have been used successfully in many fields including engineering, science and business. This paper presents the implementation of several neural network simulators and their applications in character recognition and other engineering areas

Upregulation of LYAR induces neuroblastoma cell proliferation and survival.

Science.gov (United States)

Sun, Yuting; Atmadibrata, Bernard; Yu, Denise; Wong, Matthew; Liu, Bing; Ho, Nicholas; Ling, Dora; Tee, Andrew E; Wang, Jenny; Mungrue, Imran N; Liu, Pei Y; Liu, Tao

2017-09-01

The N-Myc oncoprotein induces neuroblastoma by regulating gene transcription and consequently causing cell proliferation. Paradoxically, N-Myc is well known to induce apoptosis by upregulating pro-apoptosis genes, and it is not clear how N-Myc overexpressing neuroblastoma cells escape N-Myc-mediated apoptosis. The nuclear zinc finger protein LYAR has recently been shown to modulate gene expression by forming a protein complex with the protein arginine methyltransferase PRMT5. Here we showed that N-Myc upregulated LYAR gene expression by binding to its gene promoter. Genome-wide differential gene expression studies revealed that knocking down LYAR considerably upregulated the expression of oxidative stress genes including CHAC1, which depletes intracellular glutathione and induces oxidative stress. Although knocking down LYAR expression with siRNAs induced oxidative stress, neuroblastoma cell growth inhibition and apoptosis, co-treatment with the glutathione supplement N-acetyl-l-cysteine or co-transfection with CHAC1 siRNAs blocked the effect of LYAR siRNAs. Importantly, high levels of LYAR gene expression in human neuroblastoma tissues predicted poor event-free and overall survival in neuroblastoma patients, independent of the best current markers for poor prognosis. Taken together, our data suggest that LYAR induces proliferation and promotes survival of neuroblastoma cells by repressing the expression of oxidative stress genes such as CHAC1 and suppressing oxidative stress, and identify LYAR as a novel co-factor in N-Myc oncogenesis.

Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration

International Nuclear Information System (INIS)

Ding, Ying; Adachi, Hiroaki; Katsuno, Masahisa; Huang, Zhe; Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki; Funakoshi, Hiroshi; Nakamura, Toshikazu; Sobue, Gen

2015-01-01

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. - Highlights: • HGF overexpression ameliorates the motor phenotypes of the SBMA mouse model. • HGF overexpression induces Akt phosphorylation in the SBMA mouse model. • This is the first report of combination therapy in a mouse model of polyQ diseases.

Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration

Energy Technology Data Exchange (ETDEWEB)

Ding, Ying [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Adachi, Hiroaki, E-mail: hadachi-ns@umin.org [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555 (Japan); Katsuno, Masahisa [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Huang, Zhe [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555 (Japan); Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Funakoshi, Hiroshi [Center for Advanced Research and Education, Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510 (Japan); Nakamura, Toshikazu [Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034 (Japan); Sobue, Gen, E-mail: sobueg@med.nagoya-u.ac.jp [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

2015-12-25

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. - Highlights: • HGF overexpression ameliorates the motor phenotypes of the SBMA mouse model. • HGF overexpression induces Akt phosphorylation in the SBMA mouse model. • This is the first report of combination therapy in a mouse model of polyQ diseases.

Effect of two different preparations of platelet-rich plasma on synoviocytes.

Science.gov (United States)

Assirelli, Elisa; Filardo, Giuseppe; Mariani, Erminia; Kon, Elizaveta; Roffi, Alice; Vaccaro, Franca; Marcacci, Maurilio; Facchini, Andrea; Pulsatelli, Lia

2015-09-01

To analyse the modifications induced by two different platelet-rich plasma (PRP) preparations on osteoarthritis (OA) synoviocytes, by documenting changes in gene expression of factors involved in joint physiopathology. OA synoviocytes were cultured for 7 days in medium with different concentrations of either P-PRP (a pure platelet concentrate without leucocytes but with a limited number of platelets), L-PRP (a higher platelet concentrate containing leucocytes) or platelet-poor plasma (PPP). Gene expression of interleukin (IL)-1beta, IL-6, IL-8/CXCL8, tumour necrosis factor alpha, IL-10, IL-4, IL-13, metalloproteinase-13, tissue inhibitor of metalloproteinase (TIMP)-1, (TIMP)-3, (TIMP)-4, vascular endothelial growth factor, transforming growth factor beta1, fibroblast growth factor (FGF)-2, hepatocyte growth factor (HGF), hyaluronic acid (HA) synthases (HAS)-1, (HAS)-2, and (HAS)-3 was analysed by RT-PCR. HA production was determined in culture supernatants by ELISA. IL-1β, IL-8 and FGF-2 were significantly induced by L-PRP compared to both P-PRP and PPP; HGF was down-modulated by L-PRP versus both P-PRP and PPP, and an inverse dose-response influence was shown for all preparations. Expression level of TIMP-4 was lower in the presence of L-PRP compared with P-PRP. HA production and HAS gene expression did not seem to be modulated by PRP. L-PRP is able to sustain the up-regulation of proinflammatory factors, (IL-1beta, IL-8 and FGF-2), together with a down-modulation of HGF and TIMP-4 expression, two factors that have been recognized as anti-catabolic mediators in cartilage, thus supporting the need to further optimize the PRP preparations to be applied in clinical practice.

Neurophysiology and neural engineering: a review.

Science.gov (United States)

Prochazka, Arthur

2017-08-01

Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s, and the present-day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied, and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. I also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight. Copyright © 2017 the American Physiological Society.

Fast and Efficient Asynchronous Neural Computation with Adapting Spiking Neural Networks

NARCIS (Netherlands)

D. Zambrano (Davide); S.M. Bohte (Sander)

2016-01-01

textabstractBiological neurons communicate with a sparing exchange of pulses - spikes. It is an open question how real spiking neurons produce the kind of powerful neural computation that is possible with deep artificial neural networks, using only so very few spikes to communicate. Building on

Interaction of adult human neural crest-derived stem cells with a nanoporous titanium surface is sufficient to induce their osteogenic differentiation

Directory of Open Access Journals (Sweden)

Matthias Schürmann

2014-07-01

Full Text Available Osteogenic differentiation of various adult stem cell populations such as neural crest-derived stem cells is of great interest in the context of bone regeneration. Ideally, exogenous differentiation should mimic an endogenous differentiation process, which is partly mediated by topological cues. To elucidate the osteoinductive potential of porous substrates with different pore diameters (30 nm, 100 nm, human neural crest-derived stem cells isolated from the inferior nasal turbinate were cultivated on the surface of nanoporous titanium covered membranes without additional chemical or biological osteoinductive cues. As controls, flat titanium without any topological features and osteogenic medium was used. Cultivation of human neural crest-derived stem cells on 30 nm pores resulted in osteogenic differentiation as demonstrated by alkaline phosphatase activity after seven days as well as by calcium deposition after 3 weeks of cultivation. In contrast, cultivation on flat titanium and on membranes equipped with 100 nm pores was not sufficient to induce osteogenic differentiation. Moreover, we demonstrate an increase of osteogenic transcripts including Osterix, Osteocalcin and up-regulation of Integrin β1 and α2 in the 30 nm pore approach only. Thus, transplantation of stem cells pre-cultivated on nanostructured implants might improve the clinical outcome by support of the graft adherence and acceleration of the regeneration process.

Artificial neural networks in NDT

International Nuclear Information System (INIS)

Abdul Aziz Mohamed

2001-01-01

Artificial neural networks, simply known as neural networks, have attracted considerable interest in recent years largely because of a growing recognition of the potential of these computational paradigms as powerful alternative models to conventional pattern recognition or function approximation techniques. The neural networks approach is having a profound effect on almost all fields, and has been utilised in fields Where experimental inter-disciplinary work is being carried out. Being a multidisciplinary subject with a broad knowledge base, Nondestructive Testing (NDT) or Nondestructive Evaluation (NDE) is no exception. This paper explains typical applications of neural networks in NDT/NDE. Three promising types of neural networks are highlighted, namely, back-propagation, binary Hopfield and Kohonen's self-organising maps. (Author)

Fractional Hopfield Neural Networks: Fractional Dynamic Associative Recurrent Neural Networks.

Science.gov (United States)

Pu, Yi-Fei; Yi, Zhang; Zhou, Ji-Liu

2017-10-01

This paper mainly discusses a novel conceptual framework: fractional Hopfield neural networks (FHNN). As is commonly known, fractional calculus has been incorporated into artificial neural networks, mainly because of its long-term memory and nonlocality. Some researchers have made interesting attempts at fractional neural networks and gained competitive advantages over integer-order neural networks. Therefore, it is naturally makes one ponder how to generalize the first-order Hopfield neural networks to the fractional-order ones, and how to implement FHNN by means of fractional calculus. We propose to introduce a novel mathematical method: fractional calculus to implement FHNN. First, we implement fractor in the form of an analog circuit. Second, we implement FHNN by utilizing fractor and the fractional steepest descent approach, construct its Lyapunov function, and further analyze its attractors. Third, we perform experiments to analyze the stability and convergence of FHNN, and further discuss its applications to the defense against chip cloning attacks for anticounterfeiting. The main contribution of our work is to propose FHNN in the form of an analog circuit by utilizing a fractor and the fractional steepest descent approach, construct its Lyapunov function, prove its Lyapunov stability, analyze its attractors, and apply FHNN to the defense against chip cloning attacks for anticounterfeiting. A significant advantage of FHNN is that its attractors essentially relate to the neuron's fractional order. FHNN possesses the fractional-order-stability and fractional-order-sensitivity characteristics.

Upregulated copper transporters in hypoxia-induced pulmonary hypertension.

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Adriana M Zimnicka

Full Text Available Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX, a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2 also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC. In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

Bidirectional neural interface: Closed-loop feedback control for hybrid neural systems.

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Chou, Zane; Lim, Jeffrey; Brown, Sophie; Keller, Melissa; Bugbee, Joseph; Broccard, Frédéric D; Khraiche, Massoud L; Silva, Gabriel A; Cauwenberghs, Gert

2015-01-01

Closed-loop neural prostheses enable bidirectional communication between the biological and artificial components of a hybrid system. However, a major challenge in this field is the limited understanding of how these components, the two separate neural networks, interact with each other. In this paper, we propose an in vitro model of a closed-loop system that allows for easy experimental testing and modification of both biological and artificial network parameters. The interface closes the system loop in real time by stimulating each network based on recorded activity of the other network, within preset parameters. As a proof of concept we demonstrate that the bidirectional interface is able to establish and control network properties, such as synchrony, in a hybrid system of two neural networks more significantly more effectively than the same system without the interface or with unidirectional alternatives. This success holds promise for the application of closed-loop systems in neural prostheses, brain-machine interfaces, and drug testing.

A new perspective on behavioral inconsistency and neural noise in aging: Compensatory speeding of neural communication

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S. Lee Hong

2012-09-01

Full Text Available This paper seeks to present a new perspective on the aging brain. Here, we make connections between two key phenomena of brain aging: 1 increased neural noise or random background activity; and 2 slowing of brain activity. Our perspective proposes the possibility that the slowing of neural processing due to decreasing nerve conduction velocities leads to a compensatory speeding of neuron firing rates. These increased firing rates lead to a broader distribution of power in the frequency spectrum of neural oscillations, which we propose, can just as easily be interpreted as neural noise. Compensatory speeding of neural activity, as we present, is constrained by the: A availability of metabolic energy sources; and B competition for frequency bandwidth needed for neural communication. We propose that these constraints lead to the eventual inability to compensate for age-related declines in neural function that are manifested clinically as deficits in cognition, affect, and motor behavior.

Prognostic implication of serum hepatocyte growth factor in stage II/III breast cancer patients who received neoadjuvant chemotherapy.

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Kim, Hyori; Youk, Jeonghwan; Yang, Yaewon; Kim, Tae-Yong; Min, Ahrum; Ham, Hye-Seon; Cho, Seongcheol; Lee, Kyung-Hun; Keam, Bhumsuk; Han, Sae-Won; Oh, Do-Youn; Ryu, Han Suk; Han, Wonshik; Park, In Ae; Kim, Tae-You; Noh, Dong-Young; Im, Seock-Ah

2016-03-01

In stage II/III breast cancer, neoadjuvant chemotherapy (NAC) is a standard treatment. Although several biomarkers are used to predict prognosis in breast cancer, there is no reliable predictive biomarker for NAC success. Recently, the hepatocyte growth factor (HGF) and cMet signaling pathway demonstrated to be involved in breast cancer tumor progression, and its potential as a biomarker is under active investigation. In this study, we assessed the potential of serum HGF as a prognostic biomarker for NAC efficacy. Venous blood samples were drawn from patients diagnosed with stage II/III breast cancer and treated with NAC in Seoul National University Hospital from August 2004 to November 2009. Serum HGF level was determined using an ELISA system. We reviewed the medical records of the patients and investigated the association of HGF level with patients' clinicopathologic characteristics. A total of 121 female patients (median age = 45 years old) were included. Median level of HGF was 934 pg/ml (lower quartile: 772, upper quartile: 1145 pg/ml). Patients with higher HGF level than median value were significantly more likely to have clinically detectable regional node metastasis (p = 0.017, Fisher's exact test). Patients with complete and partial response according to the American Joint Committee on Cancer 7th Edition criteria tended to have higher HGF level (p = 0.105 by t test). Patients with an HGF level higher than the upper quartile value had longer relapse-free survival than the other patients (106 vs. 85 months, p = 0.008). High serum HGF levels in breast cancer patients are associated with clinically detectable regional node metastasis and, paradoxically, with longer relapse-free survival in stage II/III breast cancer.

Involvement of Prohibitin Upregulation in Abrin-Triggered Apoptosis

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Yu-Huei Liu

2012-01-01

Full Text Available Abrin (ABR, a protein purified from the seeds of Abrus precatorius, induces apoptosis in various types of cancer cells. However, the detailed mechanism remains largely uncharacterized. By using a cDNA microarray platform, we determined that prohibitin (PHB, a tumor suppressor protein, is significantly upregulated in ABR-triggered apoptosis. ABR-induced upregulation of PHB is mediated by the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK pathway, as demonstrated by chemical inhibitors. In addition, ABR significantly induced the expression of Bax as well as the activation of caspase-3 and poly(ADP-ribose polymerase (PARP in Jurkat T cells, whereas the reduction of PHB by specific RNA interference delayed ABR-triggered apoptosis through the proapoptotic genes examined. Moreover, our results also indicated that nuclear translocation of the PHB-p53 complex may play a role in the transcription of Bax. Collectively, our data show that PHB plays a role in ABR-induced apoptosis, which may be helpful for the development of diagnostic or therapeutic agents.

Rottlerin upregulates DDX3 expression in hepatocellular carcinoma.

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Wang, Zhong; Shen, Gen-Hai; Xie, Jia-Ming; Li, Bin; Gao, Quan-Gen

2018-01-01

Rottlerin has been reported to exert its anti-tumor activity in various types of human cancers. However, the underlying molecular mechanism has not been fully elucidated. In the current study, we explored whether rottlerin exhibits its tumor suppressive function in hepatocellular carcinoma cells. Our MTT assay results showed that rottlerin inhibited cell growth in hepatocellular carcinoma cells. Moreover, we found that rottlerin induced cell apoptosis and caused cell cycle arrest at G1 phase. Furthermore, our wound healing assay result demonstrated that rottlerin retarded cell migration in hepatocellular carcinoma cells. Additionally, rottlerin suppressed cell migration and invasion. Notably, we found that rottlerin upregulated DDX3 expression and subsequently downregulated Cyclin D1 expression and increased p21 level. Importantly, down-regulation of DDX3 abrogated the rottlerin-mediated tumor suppressive function, whereas overexpression of DDX3 promoted the anti-tumor activity of rottlerin. Our study suggests that rottlerin exhibits its anti-cancer activity partly due to upregulation of DDX3 in hepatocellular carcinoma cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Sequential neural models with stochastic layers

DEFF Research Database (Denmark)

Fraccaro, Marco; Sønderby, Søren Kaae; Paquet, Ulrich

2016-01-01

How can we efficiently propagate uncertainty in a latent state representation with recurrent neural networks? This paper introduces stochastic recurrent neural networks which glue a deterministic recurrent neural network and a state space model together to form a stochastic and sequential neural...... generative model. The clear separation of deterministic and stochastic layers allows a structured variational inference network to track the factorization of the model's posterior distribution. By retaining both the nonlinear recursive structure of a recurrent neural network and averaging over...

Esophageal Epithelial-Derived IL-33 Is Upregulated in Patients with Heartburn.

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Sei, Hiroo; Oshima, Tadayuki; Shan, Jing; Wu, Liping; Yamasaki, Takahisa; Okugawa, Takuya; Kondo, Takashi; Tomita, Toshihiko; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2016-01-01

Interleukin-33 (IL-33) is a tissue-derived cytokine that is constitutively expressed in epithelial cells of tissues exposed to the environment and plays a role in sensing damage caused by inflammatory diseases. IL-33 acts as both a traditional cytokine and as a chromatin-associated nuclear factor in both innate and adaptive immunity. We recently showed that IL-33 in esophageal mucosa is upregulated in reflux esophagitis. However, IL-33 expression in patients with heartburn without mucosal injury and its relationship with intercellular space (ICS) have never been examined. We therefore examined the expression of cytokines and ICS in patients with heartburn. The expression of IL-33 in the middle and distal esophageal mucosa of patients with heartburn without mucosal break and control samples was examined using real-time RT-PCR and immunofluorescence. The mRNA expression of IL-6, IL-8, MCP-1, and RANTES, and ICS was also analyzed. IL-33 expression and the mean ICS were significantly increased in the mucosa of patients with heartburn compared to that of the control. IL-33 and ICS were not different between the patients who were taking a PPI and those who were not. The upregulated IL-33 expression in the heartburn group was located in the nuclei of the basal cell layer. Although IL-6, IL-8, MCP-1 and RANTES levels were not different between control and patients with heartburn samples, IL-33 mRNA levels were still significantly correlated with IL-6, IL-8, or MCP-1 mRNA levels. Nuclear IL-33 is upregulated in patients with heartburn. Upregulated IL-33 in heartburn patients is related to the symptoms.

Esophageal Epithelial-Derived IL-33 Is Upregulated in Patients with Heartburn.

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Hiroo Sei

Full Text Available Interleukin-33 (IL-33 is a tissue-derived cytokine that is constitutively expressed in epithelial cells of tissues exposed to the environment and plays a role in sensing damage caused by inflammatory diseases. IL-33 acts as both a traditional cytokine and as a chromatin-associated nuclear factor in both innate and adaptive immunity. We recently showed that IL-33 in esophageal mucosa is upregulated in reflux esophagitis. However, IL-33 expression in patients with heartburn without mucosal injury and its relationship with intercellular space (ICS have never been examined. We therefore examined the expression of cytokines and ICS in patients with heartburn.The expression of IL-33 in the middle and distal esophageal mucosa of patients with heartburn without mucosal break and control samples was examined using real-time RT-PCR and immunofluorescence. The mRNA expression of IL-6, IL-8, MCP-1, and RANTES, and ICS was also analyzed.IL-33 expression and the mean ICS were significantly increased in the mucosa of patients with heartburn compared to that of the control. IL-33 and ICS were not different between the patients who were taking a PPI and those who were not. The upregulated IL-33 expression in the heartburn group was located in the nuclei of the basal cell layer. Although IL-6, IL-8, MCP-1 and RANTES levels were not different between control and patients with heartburn samples, IL-33 mRNA levels were still significantly correlated with IL-6, IL-8, or MCP-1 mRNA levels.Nuclear IL-33 is upregulated in patients with heartburn. Upregulated IL-33 in heartburn patients is related to the symptoms.

Parallel consensual neural networks.

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Benediktsson, J A; Sveinsson, J R; Ersoy, O K; Swain, P H

1997-01-01

A new type of a neural-network architecture, the parallel consensual neural network (PCNN), is introduced and applied in classification/data fusion of multisource remote sensing and geographic data. The PCNN architecture is based on statistical consensus theory and involves using stage neural networks with transformed input data. The input data are transformed several times and the different transformed data are used as if they were independent inputs. The independent inputs are first classified using the stage neural networks. The output responses from the stage networks are then weighted and combined to make a consensual decision. In this paper, optimization methods are used in order to weight the outputs from the stage networks. Two approaches are proposed to compute the data transforms for the PCNN, one for binary data and another for analog data. The analog approach uses wavelet packets. The experimental results obtained with the proposed approach show that the PCNN outperforms both a conjugate-gradient backpropagation neural network and conventional statistical methods in terms of overall classification accuracy of test data.

Creative-Dynamics Approach To Neural Intelligence

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Zak, Michail A.

1992-01-01

Paper discusses approach to mathematical modeling of artificial neural networks exhibiting complicated behaviors reminiscent of creativity and intelligence of biological neural networks. Neural network treated as non-Lipschitzian dynamical system - as described in "Non-Lipschitzian Dynamics For Modeling Neural Networks" (NPO-17814). System serves as tool for modeling of temporal-pattern memories and recognition of complicated spatial patterns.

PPARGC1A is upregulated and facilitates lung cancer metastasis.

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Li, Jin-Dong; Feng, Qing-Chuan; Qi, Yu; Cui, Guanghui; Zhao, Song

2017-10-15

Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence it is imperative to determine reliable biomarkers for lung cancer prognosis. We performed quantitative real-time PCR (qRT-PCR) analysis to explore epithelial-mesenchymal transition (EMT) inducers that regulate EMT process in three patients with advanced lung cancer disease. Peroxisome proliferator-activated receptor gamma (PPARGC1A) was uniformly the topmost overexpressed gene in all three human non-small cell lung cancer (NSCLC) patient samples. Further evaluation in human normal lung and metastatic lung cancer cell lines revealed that the expression of PPARGC1A was upregulated in metastatic lung cancer cell lines. Metagenomic analysis revealed direct correlation among PPARGC1A, zinc-finger transcription factor snail homolog 1 (SNAI1), and metastatic lung disease. Upregulation of PPARGC1A transcript expression was independent of a differential upregulation of the upstream AMP-dependent protein kinase (AMPK) activation or steady state expression of the silent mating type information regulation 2 homolog 1 (SIRT1). Xenograft tail vein colonization assays proved that the high expression of PPARGC1A was a prerequisite for metastatic progression of lung cancer to brain. Our results indicate that PPARGC1A might be a potential biomarker for lung cancer prognosis. Copyright © 2017. Published by Elsevier Inc.

Effects of hepatocyte growth factor on glutathione synthesis, growth, and apoptosis is cell density-dependent

International Nuclear Information System (INIS)

Yang Heping; Magilnick, Nathaniel; Xia Meng; Lu, Shelly C.

2008-01-01

Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen that exerts opposing effects depending on cell density. Glutathione (GSH) is the main non-protein thiol in mammalian cells that modulates growth and apoptosis. We previously showed that GSH level is inversely related to cell density of hepatocytes and is positively related to growth. Our current work examined whether HGF can modulate GSH synthesis in a cell density-dependent manner and how GSH in turn influence HGF's effects. We found HGF treatment of H4IIE cells increased cell GSH levels only under subconfluent density. The increase in cell GSH under low density was due to increased transcription of GSH synthetic enzymes. This correlated with increased protein levels and nuclear binding activities of c-Jun, c-Fos, p65, p50, Nrf1 and Nrf2 to the promoter region of these genes. HGF acts as a mitogen in H4IIE cells under low cell density and protects against tumor necrosis factor α (TNFα)-induced apoptosis by limiting JNK activation. However, HGF is pro-apoptotic under high cell density and exacerbates TNFα-induced apoptosis by potentiating JNK activation. The increase in cell GSH under low cell density allows HGF to exert its full mitogenic effect but is not necessary for its anti-apoptotic effect

Aggravation of serum Hepatocyte Growth Factor levels during hepato carcinogenesis in Rats

International Nuclear Information System (INIS)

Abdelgawad, M.R.; Ghareeb, N.A.

2010-01-01

Hepatocyte growth factor (HGF) has an essential role during liver development and it plays an important role in the regeneration and repair of injured tissues and acting as a mitogen, motogen and morphogens for a variety of epithelial cells. The role of HGF in carcinogenesis is in straggle and so, the present study aimed to through light through the level of HGF during different steps of carcinogenesis. Forty male rats were given diethylnitrosamine (DEN) in drinking water (100 mg/l) for up to 16 weeks. Eight rats were sacrificed at 8, 12 and 16 weeks. Besides, 8 hepatoma bearing rats were exposed to a single dose gamma irradiation (3 Gy) were sacrificed after 2 weeks from exposure (2 rats died, 36 hrs post irradiation) and 8 hepatoma bearing rats were sacrificed after 4 weeks from receiving a combined antioxidant (N-acetylcysteine and Lmethionine). Serum HGF was assayed by enzyme linked immunosorbent assay (ELISA). Serum HGF level in DEN treated rats and in exposed hepatoma bearing rats was significantly higher than in control rats whereas, serum HGF level after treatment with N acetylcysteine and L-methionine for 4 weeks was significantly decreased than DEN treated rats and concluded that serum HGF may play a role during promotion and progression of hepatocellular carcinoma (HCC) and during treatment

NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects.

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Sequerra, Eduardo B; Goyal, Raman; Castro, Patricio A; Levin, Jacqueline B; Borodinsky, Laura N

2018-05-16

Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. Copyright © 2018 the authors 0270-6474/18/384762-12$15.00/0.

The effect of interferon-β on mouse neural progenitor cell survival and differentiation

International Nuclear Information System (INIS)

Hirsch, Marek; Knight, Julia; Tobita, Mari; Soltys, John; Panitch, Hillel; Mao-Draayer, Yang

2009-01-01

Interferon-β (IFN-β) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-β on the central nervous system (CNS) are not well understood. To determine whether IFN-β has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-β and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFNα/β receptor (IFNAR). In response to IFN-β treatment, no effect was observed on differentiation or proliferation. However, IFN-β treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-β treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-β can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.

The effect of interferon-{beta} on mouse neural progenitor cell survival and differentiation

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Hirsch, Marek [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States); Knight, Julia [Neuroscience Department, University of Vermont College of Medicine, Burlington, VT (United States); Tobita, Mari; Soltys, John; Panitch, Hillel [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States); Mao-Draayer, Yang, E-mail: yang.mao-draayer@vtmednet.org [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States)

2009-10-16

Interferon-{beta} (IFN-{beta}) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-{beta} on the central nervous system (CNS) are not well understood. To determine whether IFN-{beta} has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-{beta} and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFN{alpha}/{beta} receptor (IFNAR). In response to IFN-{beta} treatment, no effect was observed on differentiation or proliferation. However, IFN-{beta} treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-{beta} treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-{beta} can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.

Neural Networks in R Using the Stuttgart Neural Network Simulator: RSNNS

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Christopher Bergmeir

2012-01-01

Full Text Available Neural networks are important standard machine learning procedures for classification and regression. We describe the R package RSNNS that provides a convenient interface to the popular Stuttgart Neural Network Simulator SNNS. The main features are (a encapsulation of the relevant SNNS parts in a C++ class, for sequential and parallel usage of different networks, (b accessibility of all of the SNNSalgorithmic functionality from R using a low-level interface, and (c a high-level interface for convenient, R-style usage of many standard neural network procedures. The package also includes functions for visualization and analysis of the models and the training procedures, as well as functions for data input/output from/to the original SNNSfile formats.

Osmotic stress upregulates the transcription of thiamine (vitamin B1 ...

African Journals Online (AJOL)

Osmotic stress upregulates the transcription of thiamine (vitamin B1) ... Oil palm's responses in terms of the expression profiles of these two thiamine biosynthesis genes to an osmotic stress inducer, polyethylene glycol ... from 32 Countries:.

SAOS-2 osteosarcoma cells bind fibroblasts via ICAM-1 and this is increased by tumour necrosis factor-α.

Science.gov (United States)

David, Manu S; Kelly, Elizabeth; Cheung, Ivan; Xaymardan, Munira; Moore, Malcolm A S; Zoellner, Hans

2014-01-01

We recently reported exchange of membrane and cytoplasmic markers between SAOS-2 osteosarcoma cells and human gingival fibroblasts (h-GF) without comparable exchange of nuclear markers, while similar h-GF exchange was seen for melanoma and ovarian carcinoma cells. This process of "cellular sipping" changes phenotype such that cells sharing markers of both SAOS-2 and h-GF have morphology intermediate to that of either cell population cultured alone, evidencing increased tumour cell diversity without genetic change. TNF-α increases cellular sipping between h-GF and SAOS-2, and we here study binding of SAOS-2 to TNF-α treated h-GF to determine if increased cellular sipping can be accounted for by cytokine stimulated SAOS-2 binding. More SAOS-2 bound h-GF pe-seeded wells than culture plastic alone (pcells migrating across different microenvironments can influence subsequent interactions with fibroblasts. Since cytokine stimulated binding was comparable in magnitude to earlier reported TNF-α stimulated cellular sipping, we conclude that TNF-α stimulated cellular sipping likely reflects increased SAOS-2 binding as opposed to enhanced exchange mechanisms.

Neural fields theory and applications

CERN Document Server

Graben, Peter; Potthast, Roland; Wright, James

2014-01-01

With this book, the editors present the first comprehensive collection in neural field studies, authored by leading scientists in the field - among them are two of the founding-fathers of neural field theory. Up to now, research results in the field have been disseminated across a number of distinct journals from mathematics, computational neuroscience, biophysics, cognitive science and others. Starting with a tutorial for novices in neural field studies, the book comprises chapters on emergent patterns, their phase transitions and evolution, on stochastic approaches, cortical development, cognition, robotics and computation, large-scale numerical simulations, the coupling of neural fields to the electroencephalogram and phase transitions in anesthesia. The intended readership are students and scientists in applied mathematics, theoretical physics, theoretical biology, and computational neuroscience. Neural field theory and its applications have a long-standing tradition in the mathematical and computational ...

Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120

Science.gov (United States)

Ballester, Leomar Y.; Capó-Vélez, Coral M.; García-Beltrán, Wilfredo F.; Ramos, Félix M.; Vázquez-Rosa, Edwin; Ríos, Raymond; Mercado, José R.; Meléndez, Roberto I.; Lasalde-Dominicci, José A.

2012-01-01

Approximately 30–50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV+ individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120IIIB on the expression and function of the nicotinic receptor α7 (α7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of α7-nAChRs. Because α7-nAChRs have a high permeability to Ca2+, we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist α-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the α7-nAChR in gp120-transgenic mice brains. Specifically, α7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV+ patients. In summary, CXCR4 activation induces up-regulation of α7-nAChR, causing cell death, suggesting that α7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection. PMID:22084248

Fluoride Stimulates the Proliferation of Osteoclasts in vitro by Upregulating MCM3

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Shengbin Bai

2016-06-01

Full Text Available We have previously shown that the expression of the minichromosome maintenance protein 3 (MCM3 gene was upregulated in lymphocytes of patients with skeletal fluorosis. We speculated that increased MCM3 expression may be contribute to osteopathy in patients with skeletal fluorosis. Here, we investigated the effect of fluoride on the proliferation of osteoclasts derived from RAW264.7 cells and the involvement of MCM3. Our MTT assays showed that 0.25 mM NaF markedly stimulated the proliferation of RAW264.7 cells. The RT-PCR and immunoblotting assays revealed that 0.25 mM NaF upregulated MCM3 expression in RAW264.7 cells. The MTT assays additionally demonstrated that stimulation with MCM3 potentiated the effect of fluorine on the proliferation of RAW264.7 cells. These results demonstrated that fluoride at clinical relevant concentration upregulates MCM3 expression in osteoclasts in vitro. We are currently conducting a series of experiments to examine whether increased MCM3 in osteoclasts indeed contributes to osteopathy in skeletal fluorosis.

LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma.

Science.gov (United States)

Yun-Bo, Feng; Xiao-Po, Liu; Xiao-Li, Li; Guo-Long, Cao; Pei, Zhang; Fa-Ming, Tian

2016-01-01

To examine the expression and function of long non-coding RNA taurine up-regulated 1 ( TUG1 ) in human osteosarcoma cells. Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth-promotion activity of TUG1 , since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells.

Chondroitin sulfate effects on neural stem cell differentiation.

Science.gov (United States)

Canning, David R; Brelsford, Natalie R; Lovett, Neil W

2016-01-01

We have investigated the role chondroitin sulfate has on cell interactions during neural plate formation in the early chick embryo. Using tissue culture isolates from the prospective neural plate, we have measured neural gene expression profiles associated with neural stem cell differentiation. Removal of chondroitin sulfate from stage 4 neural plate tissue leads to altered associations of N-cadherin-positive neural progenitors and causes changes in the normal sequence of neural marker gene expression. Absence of chondroitin sulfate in the neural plate leads to reduced Sox2 expression and is accompanied by an increase in the expression of anterior markers of neural regionalization. Results obtained in this study suggest that the presence of chondroitin sulfate in the anterior chick embryo is instrumental in maintaining cells in the neural precursor state.

Neural processing of auditory signals and modular neural control for sound tropism of walking machines

DEFF Research Database (Denmark)

Manoonpong, Poramate; Pasemann, Frank; Fischer, Joern

2005-01-01

and a neural preprocessing system together with a modular neural controller are used to generate a sound tropism of a four-legged walking machine. The neural preprocessing network is acting as a low-pass filter and it is followed by a network which discerns between signals coming from the left or the right....... The parameters of these networks are optimized by an evolutionary algorithm. In addition, a simple modular neural controller then generates the desired different walking patterns such that the machine walks straight, then turns towards a switched-on sound source, and then stops near to it....

Hepatocyte growth factor profile with breast cancer

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Hoda A EL-Attar

2011-01-01

Full Text Available Background: The multifunctional hepatocyte growth factor (HGF is the ligand of c-Met receptor; it plays important role in mammary differentiation. HGF-Met signaling is a critical downstream function of c-Src-Stat3 pathway in mammalian tumorigenesis. Aim: Evaluation of tissue c-Met receptor hepatocyte growth factor receptor (HGFR and serum level of HGF in female breast ductal carcinoma. Materials and Methods: Sixty-eight premenopausal females were divided as 30 control females subdivided into: [Group 1] 15 healthy volunteer females and [Group 2] five with fibrocystic disease and 10 having fibroadenoma of the breast and patients group [Group 3] consisted of 38 female patients with breast ductal carcinoma. Thorough clinical examination, preoperative fine needle aspiration cytology, estimation of fasting serum glucose, urea, creatinine, and uric acid levels, alanine aminotransferase activities, C-reactive protein, HGF level, before surgery and histopathological examination of the breast masses, and immunohistochemical detection of HGFR were done. Results and Conclusions: Significant increase in serum HGF levels were found in patients with breast cancer as compared with controls. Significant increase was also seen in patients with breast cancer with and without lymph node metastasis when each subgroup was compared with controls. Serum level of HGF is an independent prognostic indicator of breast cancer. Fibrocystic disease of the breast showed weak HGFR expression, while in normal tissue, HGFR was scanty; meanwhile, breast invasive ductal carcinoma showed homogenous strong reaction to HGFR. HGF is only one of a number of key factors involved in breast cancer and preoperative high serum HGF levels and malignancy occur usually together.

Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases.

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Gina M Coudriet

2010-11-01

Full Text Available The generation of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β fuel the acute phase response (APR. To maintain body homeostasis, the increase of inflammatory proteins is resolved by acute phase proteins via presently unknown mechanisms. Hepatocyte growth factor (HGF is transcribed in response to IL-6. Since IL-6 production promotes the generation of HGF and induces the APR, we posited that accumulating HGF might be a likely candidate for quelling excess inflammation under non-pathological conditions. We sought to assess the role of HGF and how it influences the regulation of inflammation utilizing a well-defined model of inflammatory activation, lipopolysaccharide (LPS-stimulation of bone marrow derived macrophages (BMM. BMM were isolated from C57BL6 mice and were stimulated with LPS in the presence or absence of HGF. When HGF was present, there was a decrease in production of the pro-inflammatory cytokine IL-6, along with an increase in the anti-inflammatory cytokine IL-10. Altered cytokine production correlated with an increase in phosphorylated GSK3β, increased retention of the phosphorylated NFκB p65 subunit in the cytoplasm, and an enhanced interaction between CBP and phospho-CREB. These changes were a direct result of signaling through the HGF receptor, MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274 or when using BMM from macrophage-specific conditional MET knockout mice. Combined, these data provide compelling evidence that under normal circumstances, HGF acts to suppress the inflammatory response.

Fluoxetin Upregulates Connexin 43 Expression in Astrocyte

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Hossein Mostafavi

2014-02-01

Full Text Available Introduction: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS. Molecular target therapy studies in MS have revealed that connexin-43 (Cx43 and Aquaporin-4 (AQP4 contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte.  Methods: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 &mug/ml with or without adenyl cyclase (AC and protein kinase A (PKA inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated.  Results: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed.  Discussion: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches.

Neural overlap in processing music and speech

Science.gov (United States)

Peretz, Isabelle; Vuvan, Dominique; Lagrois, Marie-Élaine; Armony, Jorge L.

2015-01-01

Neural overlap in processing music and speech, as measured by the co-activation of brain regions in neuroimaging studies, may suggest that parts of the neural circuitries established for language may have been recycled during evolution for musicality, or vice versa that musicality served as a springboard for language emergence. Such a perspective has important implications for several topics of general interest besides evolutionary origins. For instance, neural overlap is an important premise for the possibility of music training to influence language acquisition and literacy. However, neural overlap in processing music and speech does not entail sharing neural circuitries. Neural separability between music and speech may occur in overlapping brain regions. In this paper, we review the evidence and outline the issues faced in interpreting such neural data, and argue that converging evidence from several methodologies is needed before neural overlap is taken as evidence of sharing. PMID:25646513

Atomistic mechanism of microRNA translation upregulation via molecular dynamics simulations.

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Wei Ye

Full Text Available MicroRNAs are endogenous 23-25 nt RNAs that play important gene-regulatory roles in animals and plants. Recently, miR369-3 was found to upregulate translation of TNFα mRNA in quiescent (G0 mammalian cell lines. Knock down and immunofluorescence experiments suggest that microRNA-protein complexes (with FXR1 and AGO2 are necessary for the translation upregulation. However the molecular mechanism of microRNA translation activation is poorly understood. In this study we constructed the microRNA-mRNA-AGO2-FXR1 quadruple complex by bioinformatics and molecular modeling, followed with all atom molecular dynamics simulations in explicit solvent to investigate the interaction mechanisms for the complex. A combined analysis of experimental and computational data suggests that AGO2-FXR1 complex relocalize microRNA:mRNA duplex to polysomes in G0. The two strands of dsRNA are then separated upon binding of AGO2 and FXR1. Finally, polysomes may improve the translation efficiency of mRNA. The mutation research confirms the stability of microRNA-mRNA-FXR1 and illustrates importance of key residue of Ile304. This possible mechanism can shed more light on the microRNA-dependent upregulation of translation.

Neural network to diagnose lining condition

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Yemelyanov, V. A.; Yemelyanova, N. Y.; Nedelkin, A. A.; Zarudnaya, M. V.

2018-03-01

The paper presents data on the problem of diagnosing the lining condition at the iron and steel works. The authors describe the neural network structure and software that are designed and developed to determine the lining burnout zones. The simulation results of the proposed neural networks are presented. The authors note the low learning and classification errors of the proposed neural networks. To realize the proposed neural network, the specialized software has been developed.

The effect of the neural activity on topological properties of growing neural networks.

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Gafarov, F M; Gafarova, V R

2016-09-01

The connectivity structure in cortical networks defines how information is transmitted and processed, and it is a source of the complex spatiotemporal patterns of network's development, and the process of creation and deletion of connections is continuous in the whole life of the organism. In this paper, we study how neural activity influences the growth process in neural networks. By using a two-dimensional activity-dependent growth model we demonstrated the neural network growth process from disconnected neurons to fully connected networks. For making quantitative investigation of the network's activity influence on its topological properties we compared it with the random growth network not depending on network's activity. By using the random graphs theory methods for the analysis of the network's connections structure it is shown that the growth in neural networks results in the formation of a well-known "small-world" network.

Effects of Toll-like receptor 3 on herpes simplex virus type-1-infected mouse neural stem cells.

Science.gov (United States)

Sun, Xiuning; Shi, Lihong; Zhang, Haoyun; Li, Ruifang; Liang, Ruiwen; Liu, Zhijun

2015-03-01

In this study, we aimed to investigate the effect of herpes simplex virus type-1 (HSV-1) infection on the phosphorylation of interferon regulatory factor 3 (IRF3) and the expression of interferon-β (IFN-β), as well as to clarify the functions of toll-like receptor 3 (TLR3) in mouse neural stem cells (NSCs) infected with HSV-1. In HSV-1-infected cultured NSCs, immunofluorescence, reverse transcription - polymerase chain reaction, Western blot, and ELISA were performed to reveal the expression patterns of TLR3, IRF3, and IFN-β. Then, lentivirus-mediated RNA interference (RNAi) was used to block the expression of TLR3, and its effect on host resistance to HSV-1 infection was investigated. Under uninfected conditions, NSCs expressed TLR3 and phosphorylated IRF3, but after infection, the expression level of TLR3 was upregulated and the phosphorylation level of IRF3 in the nucleus was significantly enhanced, while IFN-β was also expressed. After TLR3 expression was blocked by lentivirus-mediated RNAi, IRF3 phosphorylation and IFN-β expression were downregulated. Therefore, HSV-1 upregulated the expression of TLR3 in NSCs and promoted nuclear translocation after IRF3 was phosphorylated to induce IFN-β expression. TLR3 exhibited an anti-HSV-1 infection capacity via innate immune functions.

Neural overlap in processing music and speech.

Science.gov (United States)

Peretz, Isabelle; Vuvan, Dominique; Lagrois, Marie-Élaine; Armony, Jorge L

2015-03-19

Neural overlap in processing music and speech, as measured by the co-activation of brain regions in neuroimaging studies, may suggest that parts of the neural circuitries established for language may have been recycled during evolution for musicality, or vice versa that musicality served as a springboard for language emergence. Such a perspective has important implications for several topics of general interest besides evolutionary origins. For instance, neural overlap is an important premise for the possibility of music training to influence language acquisition and literacy. However, neural overlap in processing music and speech does not entail sharing neural circuitries. Neural separability between music and speech may occur in overlapping brain regions. In this paper, we review the evidence and outline the issues faced in interpreting such neural data, and argue that converging evidence from several methodologies is needed before neural overlap is taken as evidence of sharing. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Complex-Valued Neural Networks

CERN Document Server

Hirose, Akira

2012-01-01

This book is the second enlarged and revised edition of the first successful monograph on complex-valued neural networks (CVNNs) published in 2006, which lends itself to graduate and undergraduate courses in electrical engineering, informatics, control engineering, mechanics, robotics, bioengineering, and other relevant fields. In the second edition the recent trends in CVNNs research are included, resulting in e.g. almost a doubled number of references. The parametron invented in 1954 is also referred to with discussion on analogy and disparity. Also various additional arguments on the advantages of the complex-valued neural networks enhancing the difference to real-valued neural networks are given in various sections. The book is useful for those beginning their studies, for instance, in adaptive signal processing for highly functional sensing and imaging, control in unknown and changing environment, robotics inspired by human neural systems, and brain-like information processing, as well as interdisciplina...

Memristor-based neural networks

International Nuclear Information System (INIS)

Thomas, Andy

2013-01-01

The synapse is a crucial element in biological neural networks, but a simple electronic equivalent has been absent. This complicates the development of hardware that imitates biological architectures in the nervous system. Now, the recent progress in the experimental realization of memristive devices has renewed interest in artificial neural networks. The resistance of a memristive system depends on its past states and exactly this functionality can be used to mimic the synaptic connections in a (human) brain. After a short introduction to memristors, we present and explain the relevant mechanisms in a biological neural network, such as long-term potentiation and spike time-dependent plasticity, and determine the minimal requirements for an artificial neural network. We review the implementations of these processes using basic electric circuits and more complex mechanisms that either imitate biological systems or could act as a model system for them. (topical review)

Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.

Science.gov (United States)

Chan-Il, Choi; Young-Don, Lee; Heejaung, Kim; Kim, Seung Hyun; Suh-Kim, Haeyoung; Kim, Sung-Soo

2013-01-01

Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.

Modulation of Myostatin/Hepatocyte Growth Factor Balance by Different Hemodialysis Modalities

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Pasquale Esposito

2017-01-01

Full Text Available Background. In this study we investigated the relevance of myostatin and Hepatocyte Growth Factor (HGF in patients undergoing hemodialysis HD and the influence of different HD modalities on their levels. Methods. We performed a prospective crossover study in which HD patients were randomized to undergo 3-month treatment periods with bicarbonate hemodialysis (BHD followed by online hemodiafiltration (HDF. Clinical data, laboratory parameters, and myostatin and HGF serum levels were collected and compared. Results. Ten patients and six controls (C were evaluated. In any experimental condition myostatin and HGF levels were higher in HD than in C. At enrollment and after BHD there were not significant correlations, whereas at the end of the HDF treatment period myostatin and HGF were inversely correlated (r  -0.65, p<0.05, myostatin serum levels inversely correlated with transferrin (r  -0.73, p<0.05, and HGF levels that resulted positively correlated with BMI (r 0.67, p<0.05. Moving from BHD to HDF, clinical and laboratory parameters were unchanged, as well as serum HGF, whereas myostatin levels significantly decreased (6.3 ± 4.1 versus 4.3 ± 3.1 ng/ml, p<0.05. Conclusions. Modulation of myostatin levels and myostatin/HGF balance by the use of different HD modalities might represent a novel approach to the prevention and treatment of HD-related muscle wasting syndrome.

Neural crest contributions to the lamprey head

Science.gov (United States)

McCauley, David W.; Bronner-Fraser, Marianne

2003-01-01

The neural crest is a vertebrate-specific cell population that contributes to the facial skeleton and other derivatives. We have performed focal DiI injection into the cranial neural tube of the developing lamprey in order to follow the migratory pathways of discrete groups of cells from origin to destination and to compare neural crest migratory pathways in a basal vertebrate to those of gnathostomes. The results show that the general pathways of cranial neural crest migration are conserved throughout the vertebrates, with cells migrating in streams analogous to the mandibular and hyoid streams. Caudal branchial neural crest cells migrate ventrally as a sheet of cells from the hindbrain and super-pharyngeal region of the neural tube and form a cylinder surrounding a core of mesoderm in each pharyngeal arch, similar to that seen in zebrafish and axolotl. In addition to these similarities, we also uncovered important differences. Migration into the presumptive caudal branchial arches of the lamprey involves both rostral and caudal movements of neural crest cells that have not been described in gnathostomes, suggesting that barriers that constrain rostrocaudal movement of cranial neural crest cells may have arisen after the agnathan/gnathostome split. Accordingly, neural crest cells from a single axial level contributed to multiple arches and there was extensive mixing between populations. There was no apparent filling of neural crest derivatives in a ventral-to-dorsal order, as has been observed in higher vertebrates, nor did we find evidence of a neural crest contribution to cranial sensory ganglia. These results suggest that migratory constraints and additional neural crest derivatives arose later in gnathostome evolution.

Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL

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Han Seol

2011-07-01

Full Text Available Abstract Background At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. Methods Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C. diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay. Results In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL. Conclusion To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally

Signal Processing and Neural Network Simulator

Science.gov (United States)

Tebbe, Dennis L.; Billhartz, Thomas J.; Doner, John R.; Kraft, Timothy T.

1995-04-01

The signal processing and neural network simulator (SPANNS) is a digital signal processing simulator with the capability to invoke neural networks into signal processing chains. This is a generic tool which will greatly facilitate the design and simulation of systems with embedded neural networks. The SPANNS is based on the Signal Processing WorkSystemTM (SPWTM), a commercial-off-the-shelf signal processing simulator. SPW provides a block diagram approach to constructing signal processing simulations. Neural network paradigms implemented in the SPANNS include Backpropagation, Kohonen Feature Map, Outstar, Fully Recurrent, Adaptive Resonance Theory 1, 2, & 3, and Brain State in a Box. The SPANNS was developed by integrating SAIC's Industrial Strength Neural Networks (ISNN) Software into SPW.

The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems

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Wilfredo Blanco

2017-09-01

Full Text Available Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the “intermediate neurons.” We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes

MicroRNA-130b targets Fmr1 and regulates embryonic neural progenitor cell proliferation and differentiation

International Nuclear Information System (INIS)

Gong, Xi; Zhang, Kunshan; Wang, Yanlu; Wang, Junbang; Cui, Yaru; Li, Siguang; Luo, Yuping

2013-01-01

Highlights: •We found that the 3′ UTR of the Fmr1 mRNA is a target of miR-130b. •MiR-130b suppresses the expression of Fmr1 in mouse embryonic stem cell. •MiR-130b alters the proliferation of mouse embryonic stem cell. •MiR-130b alters fate specification of mouse embryonic stem cell. -- Abstract: Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by expansion of the CGG repeat in the 5′-untranslated region of the X-linked Fmr1 gene, which results in transcriptional silencing and loss of expression of its encoded protein FMRP. The loss of FMRP increases proliferation and alters fate specification in adult neural progenitor cells (aNPCs). However, little is known about Fmr1 mRNA regulation at the transcriptional and post-transcriptional levels. In the present study, we report that miR-130b regulated Fmr1 expression by directly targeting its 3′-untranslated region (3′ UTR). Up-regulation of miR-130b in mouse embryonic neural progenitor cells (eNPCs) decreased Fmr1 expression, markedly increased eNPC proliferation and altered the differentiation tendency of eNPCs, suggesting that antagonizing miR-130b may be a new therapeutic entry point for treating Fragile X syndrome

MicroRNA-130b targets Fmr1 and regulates embryonic neural progenitor cell proliferation and differentiation

Energy Technology Data Exchange (ETDEWEB)

Gong, Xi [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China); Zhang, Kunshan [Department of Regenerative Medicine, Stem Cell Center, Tongji University School of Medicine, Shanghai 200092 (China); Wang, Yanlu; Wang, Junbang; Cui, Yaru [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China); Li, Siguang, E-mail: siguangli@163.com [Department of Regenerative Medicine, Stem Cell Center, Tongji University School of Medicine, Shanghai 200092 (China); Luo, Yuping, E-mail: luoyuping@163.com [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China)

2013-10-04

Highlights: •We found that the 3′ UTR of the Fmr1 mRNA is a target of miR-130b. •MiR-130b suppresses the expression of Fmr1 in mouse embryonic stem cell. •MiR-130b alters the proliferation of mouse embryonic stem cell. •MiR-130b alters fate specification of mouse embryonic stem cell. -- Abstract: Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by expansion of the CGG repeat in the 5′-untranslated region of the X-linked Fmr1 gene, which results in transcriptional silencing and loss of expression of its encoded protein FMRP. The loss of FMRP increases proliferation and alters fate specification in adult neural progenitor cells (aNPCs). However, little is known about Fmr1 mRNA regulation at the transcriptional and post-transcriptional levels. In the present study, we report that miR-130b regulated Fmr1 expression by directly targeting its 3′-untranslated region (3′ UTR). Up-regulation of miR-130b in mouse embryonic neural progenitor cells (eNPCs) decreased Fmr1 expression, markedly increased eNPC proliferation and altered the differentiation tendency of eNPCs, suggesting that antagonizing miR-130b may be a new therapeutic entry point for treating Fragile X syndrome.

Establishment of a rat model of portal vein ligation combined with in situ splitting.

Science.gov (United States)

Yao, Libin; Li, Chonghui; Ge, Xinlan; Wang, Hongdong; Xu, Kesen; Zhang, Aiqun; Dong, Jiahong

2014-01-01

Portal vein ligation (PVL) combined with in situ splitting (ISS) has been shown to induce remarkable liver regeneration in patients. The purpose of this study was to establish a model of PVL+ISS in rats for exploring the possible mechanisms of liver regeneration using these techniques. Rats were randomly assigned to three experimental groups: selective PVL, selective PVL+ISS and sham operation. The hepatic regeneration rate (HRR), Ki-67, liver biochemical determinations and histopathology were assessed at 24, 48, and 72 h and 7 days after the operation. The microcirculation of the median lobes before and after ISS was examined by laser speckle contrast imaging. Meanwhile, cytokines such as TNF-α, IL-6, HGF and HSP70 in regenerating liver lobes at 24 h was investigated by RT-PCR and ELISA. The HRR of PVL+ISS was much higher than that of the PVL at 72 h and 7 days after surgery (pprotein levels of TNF-α, IL-6 and HGF in regenerating liver lobes were higher in the PVL+ISS than the PVL alone. The higher HRR in the PVL+ISS compared with the PVL confirmed that we had successfully established a PVL+ISS model in rats. The possible mechanisms included the reduced microcirculation blood perfusion of the left median lobe and up-regulation of cytokines in the regenerating lobes after ISS.

Podocalyxin Is a Novel Polysialylated Neural Adhesion Protein with Multiple Roles in Neural Development and Synapse Formation

Science.gov (United States)

Vitureira, Nathalia; Andrés, Rosa; Pérez-Martínez, Esther; Martínez, Albert; Bribián, Ana; Blasi, Juan; Chelliah, Shierley; López-Doménech, Guillermo; De Castro, Fernando; Burgaya, Ferran; McNagny, Kelly; Soriano, Eduardo

2010-01-01

Neural development and plasticity are regulated by neural adhesion proteins, including the polysialylated form of NCAM (PSA-NCAM). Podocalyxin (PC) is a renal PSA-containing protein that has been reported to function as an anti-adhesin in kidney podocytes. Here we show that PC is widely expressed in neurons during neural development. Neural PC interacts with the ERM protein family, and with NHERF1/2 and RhoA/G. Experiments in vitro and phenotypic analyses of podxl-deficient mice indicate that PC is involved in neurite growth, branching and axonal fasciculation, and that PC loss-of-function reduces the number of synapses in the CNS and in the neuromuscular system. We also show that whereas some of the brain PC functions require PSA, others depend on PC per se. Our results show that PC, the second highly sialylated neural adhesion protein, plays multiple roles in neural development. PMID:20706633

Upregulation of transmitter release probability improves a conversion of synaptic analogue signals into neuronal digital spikes

Science.gov (United States)

2012-01-01

Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners. PMID:22852823

Neural plasticity of development and learning.

Science.gov (United States)

Galván, Adriana

2010-06-01

Development and learning are powerful agents of change across the lifespan that induce robust structural and functional plasticity in neural systems. An unresolved question in developmental cognitive neuroscience is whether development and learning share the same neural mechanisms associated with experience-related neural plasticity. In this article, I outline the conceptual and practical challenges of this question, review insights gleaned from adult studies, and describe recent strides toward examining this topic across development using neuroimaging methods. I suggest that development and learning are not two completely separate constructs and instead, that they exist on a continuum. While progressive and regressive changes are central to both, the behavioral consequences associated with these changes are closely tied to the existing neural architecture of maturity of the system. Eventually, a deeper, more mechanistic understanding of neural plasticity will shed light on behavioral changes across development and, more broadly, about the underlying neural basis of cognition. (c) 2010 Wiley-Liss, Inc.

Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury

International Nuclear Information System (INIS)

Jung, Michaela; Hotter, Georgina; Vinas, Jose Luis; Sola, Anna

2009-01-01

The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process

LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma

Directory of Open Access Journals (Sweden)

Yun-Bo Feng

2016-01-01

Full Text Available Objective: To examine the expression and function of long non-coding RNA taurine up-regulated 1 (TUG1 in human osteosarcoma cells. Methods: Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. Results: Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth-promotion activity of TUG1, since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. Conclusion: Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells.

Trimaran Resistance Artificial Neural Network

Science.gov (United States)

2011-01-01

11th International Conference on Fast Sea Transportation FAST 2011, Honolulu, Hawaii, USA, September 2011 Trimaran Resistance Artificial Neural Network Richard...Trimaran Resistance Artificial Neural Network 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e... Artificial Neural Network and is restricted to the center and side-hull configurations tested. The value in the parametric model is that it is able to

Hepatocyte growth factor enhances the inflammation-alleviating effect of umbilical cord-derived mesenchymal stromal cells in a bronchiolitis obliterans model.

Science.gov (United States)

Cao, Xiao-Pei; Han, Dong-Mei; Zhao, Li; Guo, Zi-Kuan; Xiao, Feng-Jun; Zhang, Yi-Kun; Zhang, Xiao-Yan; Wang, Li-Sheng; Wang, Heng-Xiang; Wang, Hua

2016-03-01

Specific and effective therapy for prevention or reversal of bronchiolitis obliterans (BO) is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stromal cells (MSCs) on BO. A mouse model of experimental BO was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients, which were then administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using fluorescence-activated cell sorting (FACS) for lymphocyte immunophenotype of spleen, enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (rt-PCR) for cytokine expression, and histopathological analysis for the transplanted trachea. The histopathologic recovery of allograft tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGF-treated mice. Furthermore, the allo-transplantation-induced immunophenotype disorders of the spleen, including regulatory T (Treg), T helper (Th)1, Th2 and Th17, were attenuated in both cell-treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma (IFN-γ), and increased expression of anti-inflammatory cytokine interleukin (IL)-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor (TGF)-β. Treatment of BO with HGF gene modified MSCs results in reduction of local inflammation and promotion in recovery of allograft trachea histopathology. These findings might provide an effective therapeutic strategy for BO. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-"decoy" strategy.

Science.gov (United States)

Basilico, Cristina; Modica, Chiara; Maione, Federica; Vigna, Elisa; Comoglio, Paolo M

2018-04-25

MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and subsequent neutralization-we identified a single aminoacid in the extracellular domain of MET-lysine 842-that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMET K842E retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMET K842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell "scattering." The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined target therapy of MET "expedience." © 2018 UICC.

Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.

Science.gov (United States)

Kitamura, Kazuya; Fujiyoshi, Kanehiro; Yamane, Jun-Ichi; Toyota, Fumika; Hikishima, Keigo; Nomura, Tatsuji; Funakoshi, Hiroshi; Nakamura, Toshikazu; Aoki, Masashi; Toyama, Yoshiaki; Okano, Hideyuki; Nakamura, Masaya

2011-01-01

Many therapeutic interventions for spinal cord injury (SCI) using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI.

Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.

Directory of Open Access Journals (Sweden)

Kazuya Kitamura

Full Text Available Many therapeutic interventions for spinal cord injury (SCI using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF, which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI.

Training verb argument structure production in agrammatic aphasia: Behavioral and neural recovery patterns

Science.gov (United States)

Thompson, Cynthia K.; Riley, Ellyn A.; den Ouden, Dirk-Bart; Meltzer-Asscher, Aya; Lukic, Sladjana

2013-01-01

Introduction Neuroimaging and lesion studies indicate a left hemisphere network for verb and verb argument structure processing, involving both frontal and temporoparietal brain regions. Although their verb comprehension is generally unimpaired, it is well known that individuals with agrammatic aphasia often present with verb production deficits, characterized by an argument structure complexity hierarchy, indicating faulty access to argument structure representations for production and integration into syntactic contexts. Recovery of verb processing in agrammatism, however, has received little attention and no studies have examined the neural mechanisms associated with improved verb and argument structure processing. In the present study we trained agrammatic individuals on verbs with complex argument structure in sentence contexts and examined generalization to verbs with less complex argument structure. The neural substrates of improved verb production were examined using functional magnetic resonance imaging (fMRI). Methods Eight individuals with chronic agrammatic aphasia participated in the study (four experimental and four control participants). Production of three-argument verbs in active sentences was trained using a sentence generation task emphasizing the verb’s argument structure and the thematic roles of sentential noun phrases. Before and after training, production of trained and untrained verbs was tested in naming and sentence production and fMRI scans were obtained, using an action naming task. Results Significant pre- to post-training improvement in trained and untrained (one- and two-argument) verbs was found for treated, but not control, participants, with between-group differences found for verb naming, production of verbs in sentences, and production of argument structure. fMRI activation derived from post-treatment compared to pre-treatment scans revealed upregulation in cortical regions implicated for verb and argument structure processing

Consciousness and neural plasticity

DEFF Research Database (Denmark)

changes or to abandon the strong identity thesis altogether. Were one to pursue a theory according to which consciousness is not an epiphenomenon to brain processes, consciousness may in fact affect its own neural basis. The neural correlate of consciousness is often seen as a stable structure, that is...

Simplified LQG Control with Neural Networks

DEFF Research Database (Denmark)

Sørensen, O.

1997-01-01

A new neural network application for non-linear state control is described. One neural network is modelled to form a Kalmann predictor and trained to act as an optimal state observer for a non-linear process. Another neural network is modelled to form a state controller and trained to produce...

The Influence of Emotion Upregulation on the Expectation of Sexual Reward.

Science.gov (United States)

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

2016-01-01

Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also downregulate expectations of reward arising from conditioned stimuli, including sexual stimuli. However, little is known about whether such strategies can also efficiently upregulate expectations of sexual reward arising from conditioned stimuli, and possible gender differences therein. The present study examined whether a cognitive upregulatory strategy could successfully upregulate sexual arousal elicited by sexual reward-conditioned cues in men and women. Men (n = 40) and women (n = 53) participated in a study using a differential conditioning paradigm, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli. Penile circumference and vaginal pulse amplitude were assessed and ratings of US expectancy, affective value, and sexual arousal value were obtained. Also a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. Evidence was found for emotion upregulation to increase genital arousal response in the acquisition phase in both sexes, and to enhance resistance to extinction of conditioned genital responding in women. In men, the emotion upregulatory strategy resulted in increased conditioned positive affect. The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses, such as low sexual arousal and desire. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Fuzzy neural network theory and application

CERN Document Server

Liu, Puyin

2004-01-01

This book systematically synthesizes research achievements in the field of fuzzy neural networks in recent years. It also provides a comprehensive presentation of the developments in fuzzy neural networks, with regard to theory as well as their application to system modeling and image restoration. Special emphasis is placed on the fundamental concepts and architecture analysis of fuzzy neural networks. The book is unique in treating all kinds of fuzzy neural networks and their learning algorithms and universal approximations, and employing simulation examples which are carefully designed to he

Practical neural network recipies in C++

CERN Document Server

Masters

2014-01-01

This text serves as a cookbook for neural network solutions to practical problems using C++. It will enable those with moderate programming experience to select a neural network model appropriate to solving a particular problem, and to produce a working program implementing that network. The book provides guidance along the entire problem-solving path, including designing the training set, preprocessing variables, training and validating the network, and evaluating its performance. Though the book is not intended as a general course in neural networks, no background in neural works is assum

Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions

Directory of Open Access Journals (Sweden)

Li-juan Ye

2016-01-01

Full Text Available Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 105 cells/μL were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

Global Robust Stability of Switched Interval Neural Networks with Discrete and Distributed Time-Varying Delays of Neural Type

Directory of Open Access Journals (Sweden)

Huaiqin Wu

2012-01-01

Full Text Available By combing the theories of the switched systems and the interval neural networks, the mathematics model of the switched interval neural networks with discrete and distributed time-varying delays of neural type is presented. A set of the interval parameter uncertainty neural networks with discrete and distributed time-varying delays of neural type are used as the individual subsystem, and an arbitrary switching rule is assumed to coordinate the switching between these networks. By applying the augmented Lyapunov-Krasovskii functional approach and linear matrix inequality (LMI techniques, a delay-dependent criterion is achieved to ensure to such switched interval neural networks to be globally asymptotically robustly stable in terms of LMIs. The unknown gain matrix is determined by solving this delay-dependent LMIs. Finally, an illustrative example is given to demonstrate the validity of the theoretical results.

Hepatocyte growth factor promotes long-term survival and axonal regeneration of retinal ganglion cells after optic nerve injury: comparison with CNTF and BDNF.

Science.gov (United States)

Wong, Wai-Kai; Cheung, Anny Wan-Suen; Yu, Sau-Wai; Sha, Ou; Cho, Eric Yu Pang

2014-10-01

Different trophic factors are known to promote retinal ganglion cell survival and regeneration, but each had their own limitations. We report that hepatocyte growth factor (HGF) confers distinct advantages in supporting ganglion cell survival and axonal regeneration, when compared to two well-established trophic factors ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF). Ganglion cells in adult hamster were injured by cutting the optic nerve. HGF, CNTF, or BDNF was injected at different dosages intravitreally after injury. Ganglion cell survival was quantified at 7, 14, or 28 days postinjury. Peripheral nerve (PN) grafting to the cut optic nerve of the growth factor-injected eye was performed either immediately after injury or delayed until 7 days post-injury. Expression of heat-shock protein 27 and changes in microglia numbers were quantified in different growth factor groups. The cellular distribution of c-Met in the retina was examined by anti-c-Met immunostaining. Hepatocyte Growth Factor (HGF) was equally potent as BDNF in promoting short-term survival (up to 14 days post-injury) and also supported survival at 28 days post-injury when ganglion cells treated by CNTF or BDNF failed to be sustained. When grafting was performed without delay, HGF stimulated twice the number of axons to regenerate compared with control but was less potent than CNTF. However, in PN grafting delayed for 7 days after optic nerve injury, HGF maintained a better propensity of ganglion cells to regenerate than CNTF. Unlike CNTF, HGF application did not increase HSP27 expression in ganglion cells. Microglia proliferation was prolonged in HGF-treated retinas compared with CNTF or BDNF. C-Met was localized to both ganglion cells and Muller cells, suggesting HGF could be neuroprotective via interacting with both neurons and glia. Compared with CNTF or BDNF, HGF is advantageous in sustaining long-term ganglion cell survival and their propensity to respond to

Introduction to Artificial Neural Networks

DEFF Research Database (Denmark)

Larsen, Jan

1999-01-01

The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks.......The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks....

Spike Neural Models Part II: Abstract Neural Models

Directory of Open Access Journals (Sweden)

Johnson, Melissa G.

2018-02-01

Full Text Available Neurons are complex cells that require a lot of time and resources to model completely. In spiking neural networks (SNN though, not all that complexity is required. Therefore simple, abstract models are often used. These models save time, use less computer resources, and are easier to understand. This tutorial presents two such models: Izhikevich's model, which is biologically realistic in the resulting spike trains but not in the parameters, and the Leaky Integrate and Fire (LIF model which is not biologically realistic but does quickly and easily integrate input to produce spikes. Izhikevich's model is based on Hodgkin-Huxley's model but simplified such that it uses only two differentiation equations and four parameters to produce various realistic spike patterns. LIF is based on a standard electrical circuit and contains one equation. Either of these two models, or any of the many other models in literature can be used in a SNN. Choosing a neural model is an important task that depends on the goal of the research and the resources available. Once a model is chosen, network decisions such as connectivity, delay, and sparseness, need to be made. Understanding neural models and how they are incorporated into the network is the first step in creating a SNN.

[Combined assay of soluble CD30 and hepatocyte growth factor for diagnosis of acute renal allograft rejection].

Science.gov (United States)

Li, Chuan-jiang; Yu, Li-xin; Xu, Jian; Fu, Shao-jie; Deng, Wen-feng; Du, Chuan-fu; Wang, Yi-bin

2008-02-01

To study the value of detection of both preoperative soluble CD30 (sCD30) and hepatocyte growth factor (HGF) level 5 days after transplantation in the diagnosis of acute rejection of renal allograft. Preoperative serum sCD30 levels and HGF level 5 days after transplantation were determined in 65 renal-transplant recipients using enzyme-linked immunosorbent assay. The recipients were divided according to the sCD30 levels positivity. Receiver operating characteristic (ROC) curves were used to assess the value of HGF level on day 5 posttransplantation for diagnosis of acute renal allograft rejection, and the value of combined assay of the sCD30 and HGF levels was also estimated. After transplantation, 26 recipients developed graft rejection and 39 had uneventful recovery without rejection. With the cut-off value of sCD30 of 120 U/ml, the positivity rate of sCD30 was significantly higher in recipients with graft rejection than in those without (61.5% vs 17.9%, Pacute rejection showed also significantly higher HGF levels on day 5 posttransplantation than those without rejection (Pacute renal allograft rejection, and at the cut-off value of 90 ug/L, the diagnostic sensitivity was 84.6% and specificity 76.9%. Evaluation of both the sCD30 and HGF levels significantly enhanced the diagnostic accuracy of acute graft rejection. Combined assay of serum sCD30 and HGF levels offers a useful means for diagnosis of acute renal allograft rejection.

Noradrenergic modulation of neural erotic stimulus perception.

Science.gov (United States)

Graf, Heiko; Wiegers, Maike; Metzger, Coraline Danielle; Walter, Martin; Grön, Georg; Abler, Birgit

2017-09-01

We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli. Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior. Copyright © 2017 Elsevier B.V. and

Emerging trends in neuro engineering and neural computation

CERN Document Server

Lee, Kendall; Garmestani, Hamid; Lim, Chee

2017-01-01

This book focuses on neuro-engineering and neural computing, a multi-disciplinary field of research attracting considerable attention from engineers, neuroscientists, microbiologists and material scientists. It explores a range of topics concerning the design and development of innovative neural and brain interfacing technologies, as well as novel information acquisition and processing algorithms to make sense of the acquired data. The book also highlights emerging trends and advances regarding the applications of neuro-engineering in real-world scenarios, such as neural prostheses, diagnosis of neural degenerative diseases, deep brain stimulation, biosensors, real neural network-inspired artificial neural networks (ANNs) and the predictive modeling of information flows in neuronal networks. The book is broadly divided into three main sections including: current trends in technological developments, neural computation techniques to make sense of the neural behavioral data, and application of these technologie...

Active Neural Localization

OpenAIRE

Chaplot, Devendra Singh; Parisotto, Emilio; Salakhutdinov, Ruslan

2018-01-01

Localization is the problem of estimating the location of an autonomous agent from an observation and a map of the environment. Traditional methods of localization, which filter the belief based on the observations, are sub-optimal in the number of steps required, as they do not decide the actions taken by the agent. We propose "Active Neural Localizer", a fully differentiable neural network that learns to localize accurately and efficiently. The proposed model incorporates ideas of tradition...

Artificial Neural Network Analysis System

Science.gov (United States)

2001-02-27

Contract No. DASG60-00-M-0201 Purchase request no.: Foot in the Door-01 Title Name: Artificial Neural Network Analysis System Company: Atlantic... Artificial Neural Network Analysis System 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Powell, Bruce C 5d. PROJECT NUMBER 5e. TASK NUMBER...34) 27-02-2001 Report Type N/A Dates Covered (from... to) ("DD MON YYYY") 28-10-2000 27-02-2001 Title and Subtitle Artificial Neural Network Analysis

The equilibrium of neural firing: A mathematical theory

Energy Technology Data Exchange (ETDEWEB)

Lan, Sizhong, E-mail: lsz@fuyunresearch.org [Fuyun Research, Beijing, 100055 (China)

2014-12-15

Inspired by statistical thermodynamics, we presume that neuron system has equilibrium condition with respect to neural firing. We show that, even with dynamically changeable neural connections, it is inevitable for neural firing to evolve to equilibrium. To study the dynamics between neural firing and neural connections, we propose an extended communication system where noisy channel has the tendency towards fixed point, implying that neural connections are always attracted into fixed points such that equilibrium can be reached. The extended communication system and its mathematics could be useful back in thermodynamics.

Parameterization Of Solar Radiation Using Neural Network

International Nuclear Information System (INIS)

Jiya, J. D.; Alfa, B.

2002-01-01

This paper presents a neural network technique for parameterization of global solar radiation. The available data from twenty-one stations is used for training the neural network and the data from other ten stations is used to validate the neural model. The neural network utilizes latitude, longitude, altitude, sunshine duration and period number to parameterize solar radiation values. The testing data was not used in the training to demonstrate the performance of the neural network in unknown stations to parameterize solar radiation. The results indicate a good agreement between the parameterized solar radiation values and actual measured values

Neural Architectures for Control

Science.gov (United States)

Peterson, James K.

1991-01-01

The cerebellar model articulated controller (CMAC) neural architectures are shown to be viable for the purposes of real-time learning and control. Software tools for the exploration of CMAC performance are developed for three hardware platforms, the MacIntosh, the IBM PC, and the SUN workstation. All algorithm development was done using the C programming language. These software tools were then used to implement an adaptive critic neuro-control design that learns in real-time how to back up a trailer truck. The truck backer-upper experiment is a standard performance measure in the neural network literature, but previously the training of the controllers was done off-line. With the CMAC neural architectures, it was possible to train the neuro-controllers on-line in real-time on a MS-DOS PC 386. CMAC neural architectures are also used in conjunction with a hierarchical planning approach to find collision-free paths over 2-D analog valued obstacle fields. The method constructs a coarse resolution version of the original problem and then finds the corresponding coarse optimal path using multipass dynamic programming. CMAC artificial neural architectures are used to estimate the analog transition costs that dynamic programming requires. The CMAC architectures are trained in real-time for each obstacle field presented. The coarse optimal path is then used as a baseline for the construction of a fine scale optimal path through the original obstacle array. These results are a very good indication of the potential power of the neural architectures in control design. In order to reach as wide an audience as possible, we have run a seminar on neuro-control that has met once per week since 20 May 1991. This seminar has thoroughly discussed the CMAC architecture, relevant portions of classical control, back propagation through time, and adaptive critic designs.

Recycling signals in the neural crest

OpenAIRE

Taneyhill, Lisa A.; Bronner-Fraser, Marianne E.

2006-01-01

Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

Recycling signals in the neural crest.

Science.gov (United States)

Taneyhill, Lisa A; Bronner-Fraser, Marianne

2005-01-01

Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

Neural control of magnetic suspension systems

Science.gov (United States)

Gray, W. Steven

1993-01-01

The purpose of this research program is to design, build and test (in cooperation with NASA personnel from the NASA Langley Research Center) neural controllers for two different small air-gap magnetic suspension systems. The general objective of the program is to study neural network architectures for the purpose of control in an experimental setting and to demonstrate the feasibility of the concept. The specific objectives of the research program are: (1) to demonstrate through simulation and experimentation the feasibility of using neural controllers to stabilize a nonlinear magnetic suspension system; (2) to investigate through simulation and experimentation the performance of neural controllers designs under various types of parametric and nonparametric uncertainty; (3) to investigate through simulation and experimentation various types of neural architectures for real-time control with respect to performance and complexity; and (4) to benchmark in an experimental setting the performance of neural controllers against other types of existing linear and nonlinear compensator designs. To date, the first one-dimensional, small air-gap magnetic suspension system has been built, tested and delivered to the NASA Langley Research Center. The device is currently being stabilized with a digital linear phase-lead controller. The neural controller hardware is under construction. Two different neural network paradigms are under consideration, one based on hidden layer feedforward networks trained via back propagation and one based on using Gaussian radial basis functions trained by analytical methods related to stability conditions. Some advanced nonlinear control algorithms using feedback linearization and sliding mode control are in simulation studies.

Neural components of altruistic punishment

Directory of Open Access Journals (Sweden)

Emily eDu

2015-02-01

Full Text Available Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish.

Critical Branching Neural Networks

Science.gov (United States)

Kello, Christopher T.

2013-01-01

It is now well-established that intrinsic variations in human neural and behavioral activity tend to exhibit scaling laws in their fluctuations and distributions. The meaning of these scaling laws is an ongoing matter of debate between isolable causes versus pervasive causes. A spiking neural network model is presented that self-tunes to critical…

Neural computation and the computational theory of cognition.

Science.gov (United States)

Piccinini, Gualtiero; Bahar, Sonya

2013-04-01

We begin by distinguishing computationalism from a number of other theses that are sometimes conflated with it. We also distinguish between several important kinds of computation: computation in a generic sense, digital computation, and analog computation. Then, we defend a weak version of computationalism-neural processes are computations in the generic sense. After that, we reject on empirical grounds the common assimilation of neural computation to either analog or digital computation, concluding that neural computation is sui generis. Analog computation requires continuous signals; digital computation requires strings of digits. But current neuroscientific evidence indicates that typical neural signals, such as spike trains, are graded like continuous signals but are constituted by discrete functional elements (spikes); thus, typical neural signals are neither continuous signals nor strings of digits. It follows that neural computation is sui generis. Finally, we highlight three important consequences of a proper understanding of neural computation for the theory of cognition. First, understanding neural computation requires a specially designed mathematical theory (or theories) rather than the mathematical theories of analog or digital computation. Second, several popular views about neural computation turn out to be incorrect. Third, computational theories of cognition that rely on non-neural notions of computation ought to be replaced or reinterpreted in terms of neural computation. Copyright © 2012 Cognitive Science Society, Inc.

ANT Advanced Neural Tool

Energy Technology Data Exchange (ETDEWEB)

Labrador, I.; Carrasco, R.; Martinez, L.

1996-07-01

This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs.

ANT Advanced Neural Tool

International Nuclear Information System (INIS)

Labrador, I.; Carrasco, R.; Martinez, L.

1996-01-01

This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs

Serum amyloid A stimulates matrix-metalloproteinase-9 upregulation via formyl peptide receptor like-1-mediated signaling in human monocytic cells

International Nuclear Information System (INIS)

Lee, Ha Young; Kim, Mi-Kyoung; Park, Kyoung Sun; Bae, Yun Hee; Yun, Jeanho; Park, Joo-In; Kwak, Jong-Young; Bae, Yoe-Sik

2005-01-01

In the present study, we found that serum amyloid A (SAA) stimulated matrix-metalloproteinase-9 (MMP-9) upregulation at the transcription and translational levels in THP-1 cells. SAA stimulated the activation of nuclear factor κB (NF-κB), which was required for the MMP-9 upregulation by SAA. The signaling events induced by SAA included the activation of ERK and intracellular calcium rise, which were found to be required for MMP-9 upregulation. Formyl peptide receptor like 1 (FPRL1) was found to be involved in the upregulation of MMP-9 by SAA. Among several FPRL1 agonists, including Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), SAA selectively stimulated MMP-9 upregulation. With respect to the molecular mechanisms involved in the differential action of SAA and WKYMVm, we found that SAA could not competitively inhibit the binding of 125 I-labeled WKYMVm to FPRL1. Taken together, we suggest that SAA plays a role in the modulation of inflammatory and immune responses via FPRL1, by inducing MMP-9 upregulation in human monocytic cells

Dynamic decomposition of spatiotemporal neural signals.

Directory of Open Access Journals (Sweden)

Luca Ambrogioni

2017-05-01

Full Text Available Neural signals are characterized by rich temporal and spatiotemporal dynamics that reflect the organization of cortical networks. Theoretical research has shown how neural networks can operate at different dynamic ranges that correspond to specific types of information processing. Here we present a data analysis framework that uses a linearized model of these dynamic states in order to decompose the measured neural signal into a series of components that capture both rhythmic and non-rhythmic neural activity. The method is based on stochastic differential equations and Gaussian process regression. Through computer simulations and analysis of magnetoencephalographic data, we demonstrate the efficacy of the method in identifying meaningful modulations of oscillatory signals corrupted by structured temporal and spatiotemporal noise. These results suggest that the method is particularly suitable for the analysis and interpretation of complex temporal and spatiotemporal neural signals.

Neural networks with discontinuous/impact activations

CERN Document Server

Akhmet, Marat

2014-01-01

This book presents as its main subject new models in mathematical neuroscience. A wide range of neural networks models with discontinuities are discussed, including impulsive differential equations, differential equations with piecewise constant arguments, and models of mixed type. These models involve discontinuities, which are natural because huge velocities and short distances are usually observed in devices modeling the networks. A discussion of the models, appropriate for the proposed applications, is also provided. This book also: Explores questions related to the biological underpinning for models of neural networks\\ Considers neural networks modeling using differential equations with impulsive and piecewise constant argument discontinuities Provides all necessary mathematical basics for application to the theory of neural networks Neural Networks with Discontinuous/Impact Activations is an ideal book for researchers and professionals in the field of engineering mathematics that have an interest in app...

Implantable neurotechnologies: a review of integrated circuit neural amplifiers.

Science.gov (United States)

Ng, Kian Ann; Greenwald, Elliot; Xu, Yong Ping; Thakor, Nitish V

2016-01-01

Neural signal recording is critical in modern day neuroscience research and emerging neural prosthesis programs. Neural recording requires the use of precise, low-noise amplifier systems to acquire and condition the weak neural signals that are transduced through electrode interfaces. Neural amplifiers and amplifier-based systems are available commercially or can be designed in-house and fabricated using integrated circuit (IC) technologies, resulting in very large-scale integration or application-specific integrated circuit solutions. IC-based neural amplifiers are now used to acquire untethered/portable neural recordings, as they meet the requirements of a miniaturized form factor, light weight and low power consumption. Furthermore, such miniaturized and low-power IC neural amplifiers are now being used in emerging implantable neural prosthesis technologies. This review focuses on neural amplifier-based devices and is presented in two interrelated parts. First, neural signal recording is reviewed, and practical challenges are highlighted. Current amplifier designs with increased functionality and performance and without penalties in chip size and power are featured. Second, applications of IC-based neural amplifiers in basic science experiments (e.g., cortical studies using animal models), neural prostheses (e.g., brain/nerve machine interfaces) and treatment of neuronal diseases (e.g., DBS for treatment of epilepsy) are highlighted. The review concludes with future outlooks of this technology and important challenges with regard to neural signal amplification.

Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

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Xiaohong Wang

Full Text Available Insulin-like growth factor 1 (IGF-1 and hepatocyte growth factor (HGF are two potent cell survival and regenerative factors in response to myocardial injury (MI. We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31- cells formed viable grafts and improved LV ejection fraction (EF (Control, 54.5+/-2.4; MI, 17.6+/-3.1; Cell, 28.2+/-4.2, n = 9, P<0.01. IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/-2.2; n = 9, P<0.01 and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31- cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31- cells revealed that Sca-1+/CD31- cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.

Stability of a neural predictive controller scheme on a neural model

DEFF Research Database (Denmark)

Luther, Jim Benjamin; Sørensen, Paul Haase

2009-01-01

In previous works presenting various forms of neural-network-based predictive controllers, the main emphasis has been on the implementation aspects, i.e. the development of a robust optimization algorithm for the controller, which will be able to perform in real time. However, the stability issue....... The resulting controller is tested on a nonlinear pneumatic servo system.......In previous works presenting various forms of neural-network-based predictive controllers, the main emphasis has been on the implementation aspects, i.e. the development of a robust optimization algorithm for the controller, which will be able to perform in real time. However, the stability issue...... has not been addressed specifically for these controllers. On the other hand a number of results concerning the stability of receding horizon controllers on a nonlinear system exist. In this paper we present a proof of stability for a predictive controller controlling a neural network model...

Differentiation between non-neural and neural contributors to ankle joint stiffness in cerebral palsy

NARCIS (Netherlands)

De Gooijer-van de Groep, K.L.; De Vlugt, E.; De Groot, J.H.; Van der Heijden-Maessen, H.C.M.; Wielheesen, D.H.M.; Van Wijlen-Hempel, R.M.S.; Arendzen, J.H.; Meskers, C.G.M.

2013-01-01

Background Spastic paresis in cerebral palsy (CP) is characterized by increased joint stiffness that may be of neural origin, i.e. improper muscle activation caused by e.g. hyperreflexia or non-neural origin, i.e. altered tissue viscoelastic properties (clinically: “spasticity” vs. “contracture”).

Infrared neural stimulation (INS) inhibits electrically evoked neural responses in the deaf white cat

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Richter, Claus-Peter; Rajguru, Suhrud M.; Robinson, Alan; Young, Hunter K.

2014-03-01

Infrared neural stimulation (INS) has been used in the past to evoke neural activity from hearing and partially deaf animals. All the responses were excitatory. In Aplysia californica, Duke and coworkers demonstrated that INS also inhibits neural responses [1], which similar observations were made in the vestibular system [2, 3]. In deaf white cats that have cochleae with largely reduced spiral ganglion neuron counts and a significant degeneration of the organ of Corti, no cochlear compound action potentials could be observed during INS alone. However, the combined electrical and optical stimulation demonstrated inhibitory responses during irradiation with infrared light.

Neurosecurity: security and privacy for neural devices.

Science.gov (United States)

Denning, Tamara; Matsuoka, Yoky; Kohno, Tadayoshi

2009-07-01

An increasing number of neural implantable devices will become available in the near future due to advances in neural engineering. This discipline holds the potential to improve many patients' lives dramatically by offering improved-and in some cases entirely new-forms of rehabilitation for conditions ranging from missing limbs to degenerative cognitive diseases. The use of standard engineering practices, medical trials, and neuroethical evaluations during the design process can create systems that are safe and that follow ethical guidelines; unfortunately, none of these disciplines currently ensure that neural devices are robust against adversarial entities trying to exploit these devices to alter, block, or eavesdrop on neural signals. The authors define "neurosecurity"-a version of computer science security principles and methods applied to neural engineering-and discuss why neurosecurity should be a critical consideration in the design of future neural devices.

Deconvolution using a neural network

Energy Technology Data Exchange (ETDEWEB)

Lehman, S.K.

1990-11-15

Viewing one dimensional deconvolution as a matrix inversion problem, we compare a neural network backpropagation matrix inverse with LMS, and pseudo-inverse. This is a largely an exercise in understanding how our neural network code works. 1 ref.

Neural Networks in Control Applications

DEFF Research Database (Denmark)

Sørensen, O.

The intention of this report is to make a systematic examination of the possibilities of applying neural networks in those technical areas, which are familiar to a control engineer. In other words, the potential of neural networks in control applications is given higher priority than a detailed...... study of the networks themselves. With this end in view the following restrictions have been made: - Amongst numerous neural network structures, only the Multi Layer Perceptron (a feed-forward network) is applied. - Amongst numerous training algorithms, only four algorithms are examined, all...... in a recursive form (sample updating). The simplest is the Back Probagation Error Algorithm, and the most complex is the recursive Prediction Error Method using a Gauss-Newton search direction. - Over-fitting is often considered to be a serious problem when training neural networks. This problem is specifically...

Cooperating attackers in neural cryptography.

Science.gov (United States)

Shacham, Lanir N; Klein, Einat; Mislovaty, Rachel; Kanter, Ido; Kinzel, Wolfgang

2004-06-01

A successful attack strategy in neural cryptography is presented. The neural cryptosystem, based on synchronization of neural networks by mutual learning, has been recently shown to be secure under different attack strategies. The success of the advanced attacker presented here, called the "majority-flipping attacker," does not decay with the parameters of the model. This attacker's outstanding success is due to its using a group of attackers which cooperate throughout the synchronization process, unlike any other attack strategy known. An analytical description of this attack is also presented, and fits the results of simulations.

The Laplacian spectrum of neural networks

Science.gov (United States)

de Lange, Siemon C.; de Reus, Marcel A.; van den Heuvel, Martijn P.

2014-01-01

The brain is a complex network of neural interactions, both at the microscopic and macroscopic level. Graph theory is well suited to examine the global network architecture of these neural networks. Many popular graph metrics, however, encode average properties of individual network elements. Complementing these “conventional” graph metrics, the eigenvalue spectrum of the normalized Laplacian describes a network's structure directly at a systems level, without referring to individual nodes or connections. In this paper, the Laplacian spectra of the macroscopic anatomical neuronal networks of the macaque and cat, and the microscopic network of the Caenorhabditis elegans were examined. Consistent with conventional graph metrics, analysis of the Laplacian spectra revealed an integrative community structure in neural brain networks. Extending previous findings of overlap of network attributes across species, similarity of the Laplacian spectra across the cat, macaque and C. elegans neural networks suggests a certain level of consistency in the overall architecture of the anatomical neural networks of these species. Our results further suggest a specific network class for neural networks, distinct from conceptual small-world and scale-free models as well as several empirical networks. PMID:24454286

Decentralized neural control application to robotics

CERN Document Server

Garcia-Hernandez, Ramon; Sanchez, Edgar N; Alanis, Alma y; Ruz-Hernandez, Jose A

2017-01-01

This book provides a decentralized approach for the identification and control of robotics systems. It also presents recent research in decentralized neural control and includes applications to robotics. Decentralized control is free from difficulties due to complexity in design, debugging, data gathering and storage requirements, making it preferable for interconnected systems. Furthermore, as opposed to the centralized approach, it can be implemented with parallel processors. This approach deals with four decentralized control schemes, which are able to identify the robot dynamics. The training of each neural network is performed on-line using an extended Kalman filter (EKF). The first indirect decentralized control scheme applies the discrete-time block control approach, to formulate a nonlinear sliding manifold. The second direct decentralized neural control scheme is based on the backstepping technique, approximated by a high order neural network. The third control scheme applies a decentralized neural i...

Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells.

Directory of Open Access Journals (Sweden)

Laura A Genovesi

Full Text Available Medulloblastoma (MB is the most common malignant brain tumor in children and a leading cause of cancer-related mortality and morbidity. Several molecular sub-types of MB have been identified, suggesting they may arise from distinct cells of origin. Data from animal models indicate that some MB sub-types arise from multipotent cerebellar neural stem cells (NSCs. Hence, microRNA (miRNA expression profiles of primary MB samples were compared to CD133+ NSCs, aiming to identify deregulated miRNAs involved in MB pathogenesis. Expression profiling of 662 miRNAs in primary MB specimens, MB cell lines, and human CD133+ NSCs and CD133- neural progenitor cells was performed by qRT-PCR. Clustering analysis identified two distinct sub-types of MB primary specimens, reminiscent of sub-types obtained from their mRNA profiles. 21 significantly up-regulated and 12 significantly down-regulated miRNAs were identified in MB primary specimens relative to CD133+ NSCs (p<0.01. The majority of up-regulated miRNAs mapped to chromosomal regions 14q32 and 17q. Integration of the predicted targets of deregulated miRNAs with mRNA expression data from the same specimens revealed enrichment of pathways regulating neuronal migration, nervous system development and cell proliferation. Transient over-expression of a down-regulated miRNA, miR-935, resulted in significant down-regulation of three of the seven predicted miR-935 target genes at the mRNA level in a MB cell line, confirming the validity of this approach. This study represents the first integrated analysis of MB miRNA and mRNA expression profiles and is the first to compare MB miRNA expression profiles to those of CD133+ NSCs. We identified several differentially expressed miRNAs that potentially target networks of genes and signaling pathways that may be involved in the transformation of normal NSCs to brain tumor stem cells. Based on this integrative approach, our data provide an important platform for future

Hepatocyte growth factor protects human endothelial cells against advanced glycation end products-induced apoposis

International Nuclear Information System (INIS)

Zhou Yijun; Wang Jiahe; Zhang Jin

2006-01-01

Advanced glycation end products (AGEs) form by a non-enzymatic reaction between reducing sugars and biological proteins, which play an important role in the pathogenesis of atherosclerosis. In this study, we assessed AGEs effects on human umbilical vein endothelial cells (HUVECs) growth, proliferation and apoptosis. Additionally, we investigated whether hepatocyte growth factor (HGF), an anti-apoptotic factor for endothelial cells, prevents AGEs-induced apoptosis of HUVECs. HUVECs were treated with AGEs in the presence or absence of HGF. Treatment of HUVECs with AGEs changed cell morphology, decreased cell viability, and induced DNA fragmentation, leading to apoptosis. Apoptosis was induced by AGEs in a dose- and time-dependent fashion. AGEs markedly elevated Bax and decreased NF-κB, but not Bcl-2 expression. Additionally, AGEs significantly inhibited cell growth through a pro-apoptotic action involving caspase-3 and -9 activations in HUVECs. Most importantly, pretreatment with HGF protected against AGEs-induced cytotoxicity in the endothelial cells. HGF significantly promoted the expression of Bcl-2 and NF-κB, while decreasing the activities of caspase-3 and -9 without affecting Bax level. Our data suggest that AGEs induce apoptosis in endothelial cells. HGF effectively attenuate AGEs-induced endothelial cell apoptosis. These findings provide new perspectives in the role of HGF in cardiovascular disease

Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells.

Science.gov (United States)

Benkhoucha, Mahdia; Molnarfi, Nicolas; Dunand-Sauthier, Isabelle; Merkler, Doron; Schneiter, Gregory; Bruscoli, Stefano; Riccardi, Carlo; Tabata, Yasuhiko; Funakoshi, Hiroshi; Nakamura, Toshikazu; Reith, Walter; Santiago-Raber, Marie-Laure; Lalive, Patrice H

2014-09-15

Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference-directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene-deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions. Copyright © 2014 by The American Association of Immunologists, Inc.

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules.

Science.gov (United States)

Glasner, Ariella; Oiknine-Djian, Esther; Weisblum, Yiska; Diab, Mohammad; Panet, Amos; Wolf, Dana G; Mandelboim, Ofer

2017-11-15

NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus. IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus

Hyperbaric oxygen upregulates cochlear constitutive nitric oxide synthase

Directory of Open Access Journals (Sweden)

Kao Ming-Ching

2011-02-01

Full Text Available Abstract Background Hyperbaric oxygen therapy (HBOT is a known adjuvant for treating ischemia-related inner ear diseases. Controversies still exist in the role of HBOT in cochlear diseases. Few studies to date have investigated the cellular changes that occur in inner ears after HBOT. Nitric oxide, which is synthesized by nitric oxide synthase (NOS, is an important signaling molecule in cochlear physiology and pathology. Here we investigated the effects of hyperbaric oxygen on eardrum morphology, cochlear function and expression of NOS isoforms in cochlear substructures after repetitive HBOT in guinea pigs. Results Minor changes in the eardrum were observed after repetitive HBOT, which did not result in a significant hearing threshold shift by tone burst auditory brainstem responses. A differential effect of HBOT on the expression of NOS isoforms was identified. Upregulation of constitutive NOS (nNOS and eNOS was found in the substructures of the cochlea after HBOT, but inducible NOS was not found in normal or HBOT animals, as shown by immunohistochemistry. There was no obvious DNA fragmentation present in this HBOT animal model. Conclusions The present evidence indicates that the customary HBOT protocol may increase constitutive NOS expression but such upregulation did not cause cell death in the treated cochlea. The cochlear morphology and auditory function are consequently not changed through the protocol.

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model

Science.gov (United States)

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-01-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID:27617747

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

Science.gov (United States)

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-09-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction.

PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells

International Nuclear Information System (INIS)

Crosswell, Hal E; Dasgupta, Anindya; Alvarado, Carlos S; Watt, Tanya; Christensen, James G; De, Pradip; Durden, Donald L; Findley, Harry W

2009-01-01

c-Met is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been demonstrated in different tumors and linked to aggressive and metastatic tumor phenotypes. In vitro and in vivo studies have demonstrated inhibition of c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752. This study investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and tumor tissue from patients with NBL, as well as the effects of PHA665752 on growth and motility of NBL cell lines. The effect of the tumor suppressor protein PTEN on migration and proliferation of tumor cells treated with PHA665752 was also evaluated. Expression of c-Met and HGF in NBL cell lines SH-EP and SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in NBL cell proliferation and migration was evaluated in c-Met-positive cells and c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were used to measure migration and proliferation/cell-survival of tumor cells, respectively. The PPAR-γ agonist rosiglitazone was used to assess the effect of PTEN on PHA665752-induced inhibition of NBL cell proliferation/cell-survival and migration High c-Met expression was detected in SH-EP cells and primary tumors from patients with advanced-stage disease. C-Met/HGF signaling induced both migration and proliferation of SH-EP cells. Migration and proliferation/cell-survival were inhibited by PHA665752 in a dose-dependent manner. We also found that induced overexpression of PTEN following treatment with rosiglitazone significantly enhanced the inhibitory effect of PHA665752 on NBL-cell migration and proliferation. c-Met is highly expressed in most tumors from

Up-regulation of microRNA-1290 impairs cytokinesis and affects the reprogramming of colon cancer cells.

Science.gov (United States)

Wu, Jia; Ji, Xiaowei; Zhu, Linlin; Jiang, Qiaoli; Wen, Zhenzhen; Xu, Song; Shao, Wei; Cai, Jianting; Du, Qin; Zhu, Yongliang; Mao, Jianshan

2013-02-28

Abnormal cytokinesis increases the possibility of nuclear fusion in tumor cells. However, the role of microRNAs (miRNAs) in abnormal cytokinesis is unclear. Here, we found that miR-1290 was significantly up-regulated in clinical colon cancer tissues. Up-regulation of miR-1290 postponed cytokinesis and led to the formation of multinucleated cells. KIF13B was a target of miR-1290 that was involved in aberrant cytokinesis. Furthermore, enforced expression of miR-1290 activated the Wnt pathway and increased the reprogramming-related transcript factors c-Myc and Nanog. Our results suggest that up-regulation of miR-1290 in colon cancer cells impaired cytokinesis and affected reprogramming. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

22nd Italian Workshop on Neural Nets

CERN Document Server

Bassis, Simone; Esposito, Anna; Morabito, Francesco

2013-01-01

This volume collects a selection of contributions which has been presented at the 22nd Italian Workshop on Neural Networks, the yearly meeting of the Italian Society for Neural Networks (SIREN). The conference was held in Italy, Vietri sul Mare (Salerno), during May 17-19, 2012. The annual meeting of SIREN is sponsored by International Neural Network Society (INNS), European Neural Network Society (ENNS) and IEEE Computational Intelligence Society (CIS). The book – as well as the workshop-  is organized in three main components, two special sessions and a group of regular sessions featuring different aspects and point of views of artificial neural networks and natural intelligence, also including applications of present compelling interest.

Mutations in BALB mitochondrial DNA induce CCL20 up-regulation promoting tumorigenic phenotypes

Energy Technology Data Exchange (ETDEWEB)

Sligh, James [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Janda, Jaroslav [University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Jandova, Jana, E-mail: jjandova@email.arizona.edu [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States)

2014-11-15

Highlights: • Alterations in mitochondrial DNA are commonly found in various human cancers. • Mutations in BALB mitochondrial DNA induce up-regulation of chemokine CCL20. • Increased growth and motility of mtBALB cells is associated with CCL20 levels. • mtDNA changes in BALB induce in vivo tumor growth through CCL20 up-regulation. • Mutations in mitochondrial DNA play important roles in keratinocyte neoplasia. - Abstract: mtDNA mutations are common in human cancers and are thought to contribute to the process of neoplasia. We examined the role of mtDNA mutations in skin cancer by generating fibroblast cybrids harboring a mutation in the gene encoding the mitochondrial tRNA for arginine. This somatic mutation (9821insA) was previously reported in UV-induced hyperkeratotic skin tumors in hairless mice and confers specific tumorigenic phenotypes to mutant cybrids. Microarray analysis revealed and RT-PCR along with Western blot analysis confirmed the up-regulation of CCL20 and its receptor CCR6 in mtBALB haplotype containing the mt-Tr 9821insA allele compared to wild type mtB6 haplotype. Based on reported role of CCL20 in cancer progression we examined whether the hyper-proliferation and enhanced motility of mtBALB haplotype would be associated with CCL20 levels. Treatment of both genotypes with recombinant CCL20 (rmCCL20) resulted in enhanced growth and motility of mtB6 cybrids. Furthermore, the acquired somatic alteration increased the in vivo tumor growth of mtBALB cybrids through the up-regulation of CCL20 since neutralizing antibody significantly decreased in vivo tumor growth of these cells; and tumors from anti-CCL20 treated mice injected with mtBALB cybrids showed significantly decreased CCL20 levels. When rmCCL20 or mtBALB cybrids were used as chemotactic stimuli, mtB6 cybrids showed increased motility while anti-CCL20 antibody decreased the migration and in vivo tumor growth of mtBALB cybrids. Moreover, the inhibitors of MAPK signaling and NF

Airborne fine particulate matter induces an upregulation of endothelin receptors on rat bronchi

International Nuclear Information System (INIS)

Wang, Rong; Xiao, Xue; Cao, Lei; Shen, Zhen-xing; Lei, Ying; Cao, Yong-xiao

2016-01-01

Airborne fine particulate matter (PM2.5) is a risk factor for respiratory diseases. However, little is known about the effects of PM2.5 on bronchi. The present study investigated the effect of airborne PM2.5 on rat bronchi and the underlying mechanisms. Isolated rat bronchial segments were cultured for 24 h. Endothelin (ET) receptor-mediated contractile responses were recorded using a wire myograph. The mRNA and protein expression levels of ET receptors were studied using quantitative real-time PCR, Western blotting, and immunohistochemistry. The results demonstrated that ET A and ET B receptor agonists induced remarkable contractile responses on fresh and cultured bronchial segments. PM2.5 (1.0 or 3.0 μg/ml) significantly enhanced ET A and ET B receptor-mediated contractile responses in bronchi with a markedly increased maximal contraction compared to the DMSO or fresh groups. PM2.5 increased the mRNA and protein expression levels of ET A and ET B receptors. U0126 (a MEK1/2 inhibitor) and SB203580 (a p38 inhibitor) significantly suppressed PM2.5-induced increases in ET B receptor-mediated contractile responses, mRNA and protein levels. SP600125 (a JNK inhibitor) and SB203580 significantly abrogated the PM2.5-induced enhancement of ET A receptor-mediated contraction and receptor expression. In conclusion, PM2.5 upregulates ET receptors in bronchi. ET B receptor upregulation is associated with MEK1/2 and p38 pathways, and the upregulation of ET A receptor is involved in JNK and p38 pathways. - Highlights: • Airborne PM2.5 induces bronchial hyperreactivity mediated with endothelin ET B and ET A receptors in rats. • PM2.5 increases mRNA and protein expressions of endothelin ET B and ET A receptors in bronchi. • The upregulation of ET B receptor is associated with MEK1/2 and p38 pathways. • The upregulation of ET A receptor is involved in JNK and p38 pathways. • The research provides novel understanding for PM2.5-associated respiratory diseases.

Analysis of neural networks through base functions

NARCIS (Netherlands)

van der Zwaag, B.J.; Slump, Cornelis H.; Spaanenburg, L.

Problem statement. Despite their success-story, neural networks have one major disadvantage compared to other techniques: the inability to explain comprehensively how a trained neural network reaches its output; neural networks are not only (incorrectly) seen as a "magic tool" but possibly even more

Introduction to neural networks

International Nuclear Information System (INIS)

Pavlopoulos, P.

1996-01-01

This lecture is a presentation of today's research in neural computation. Neural computation is inspired by knowledge from neuro-science. It draws its methods in large degree from statistical physics and its potential applications lie mainly in computer science and engineering. Neural networks models are algorithms for cognitive tasks, such as learning and optimization, which are based on concepts derived from research into the nature of the brain. The lecture first gives an historical presentation of neural networks development and interest in performing complex tasks. Then, an exhaustive overview of data management and networks computation methods is given: the supervised learning and the associative memory problem, the capacity of networks, the Perceptron networks, the functional link networks, the Madaline (Multiple Adalines) networks, the back-propagation networks, the reduced coulomb energy (RCE) networks, the unsupervised learning and the competitive learning and vector quantization. An example of application in high energy physics is given with the trigger systems and track recognition system (track parametrization, event selection and particle identification) developed for the CPLEAR experiment detectors from the LEAR at CERN. (J.S.). 56 refs., 20 figs., 1 tab., 1 appendix

Neural Networks and Micromechanics

Science.gov (United States)

Kussul, Ernst; Baidyk, Tatiana; Wunsch, Donald C.

The title of the book, "Neural Networks and Micromechanics," seems artificial. However, the scientific and technological developments in recent decades demonstrate a very close connection between the two different areas of neural networks and micromechanics. The purpose of this book is to demonstrate this connection. Some artificial intelligence (AI) methods, including neural networks, could be used to improve automation system performance in manufacturing processes. However, the implementation of these AI methods within industry is rather slow because of the high cost of conducting experiments using conventional manufacturing and AI systems. To lower the cost, we have developed special micromechanical equipment that is similar to conventional mechanical equipment but of much smaller size and therefore of lower cost. This equipment could be used to evaluate different AI methods in an easy and inexpensive way. The proved methods could be transferred to industry through appropriate scaling. In this book, we describe the prototypes of low cost microequipment for manufacturing processes and the implementation of some AI methods to increase precision, such as computer vision systems based on neural networks for microdevice assembly and genetic algorithms for microequipment characterization and the increase of microequipment precision.

MEMBRAIN NEURAL NETWORK FOR VISUAL PATTERN RECOGNITION

Directory of Open Access Journals (Sweden)

Artur Popko

2013-06-01

Full Text Available Recognition of visual patterns is one of significant applications of Artificial Neural Networks, which partially emulate human thinking in the domain of artificial intelligence. In the paper, a simplified neural approach to recognition of visual patterns is portrayed and discussed. This paper is dedicated for investigators in visual patterns recognition, Artificial Neural Networking and related disciplines. The document describes also MemBrain application environment as a powerful and easy to use neural networks’ editor and simulator supporting ANN.

Boolean Factor Analysis by Attractor Neural Network

Czech Academy of Sciences Publication Activity Database

Frolov, A. A.; Húsek, Dušan; Muraviev, I. P.; Polyakov, P.Y.

2007-01-01

Roč. 18, č. 3 (2007), s. 698-707 ISSN 1045-9227 R&D Projects: GA AV ČR 1ET100300419; GA ČR GA201/05/0079 Institutional research plan: CEZ:AV0Z10300504 Keywords : recurrent neural network * Hopfield-like neural network * associative memory * unsupervised learning * neural network architecture * neural network application * statistics * Boolean factor analysis * dimensionality reduction * features clustering * concepts search * information retrieval Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.769, year: 2007

Non-invasive neural stimulation

Science.gov (United States)

Tyler, William J.; Sanguinetti, Joseph L.; Fini, Maria; Hool, Nicholas

2017-05-01

Neurotechnologies for non-invasively interfacing with neural circuits have been evolving from those capable of sensing neural activity to those capable of restoring and enhancing human brain function. Generally referred to as non-invasive neural stimulation (NINS) methods, these neuromodulation approaches rely on electrical, magnetic, photonic, and acoustic or ultrasonic energy to influence nervous system activity, brain function, and behavior. Evidence that has been surmounting for decades shows that advanced neural engineering of NINS technologies will indeed transform the way humans treat diseases, interact with information, communicate, and learn. The physics underlying the ability of various NINS methods to modulate nervous system activity can be quite different from one another depending on the energy modality used as we briefly discuss. For members of commercial and defense industry sectors that have not traditionally engaged in neuroscience research and development, the science, engineering and technology required to advance NINS methods beyond the state-of-the-art presents tremendous opportunities. Within the past few years alone there have been large increases in global investments made by federal agencies, foundations, private investors and multinational corporations to develop advanced applications of NINS technologies. Driven by these efforts NINS methods and devices have recently been introduced to mass markets via the consumer electronics industry. Further, NINS continues to be explored in a growing number of defense applications focused on enhancing human dimensions. The present paper provides a brief introduction to the field of non-invasive neural stimulation by highlighting some of the more common methods in use or under current development today.

Neural activation in stress-related exhaustion

DEFF Research Database (Denmark)

Gavelin, Hanna Malmberg; Neely, Anna Stigsdotter; Andersson, Micael

2017-01-01

The primary purpose of this study was to investigate the association between burnout and neural activation during working memory processing in patients with stress-related exhaustion. Additionally, we investigated the neural effects of cognitive training as part of stress rehabilitation. Fifty...... association between burnout level and working memory performance was found, however, our findings indicate that frontostriatal neural responses related to working memory were modulated by burnout severity. We suggest that patients with high levels of burnout need to recruit additional cognitive resources...... to uphold task performance. Following cognitive training, increased neural activation was observed during 3-back in working memory-related regions, including the striatum, however, low sample size limits any firm conclusions....

Chronic ethanol consumption modulates growth factor release, mucosal cytokine production, and microRNA expression in nonhuman primates.

Science.gov (United States)

Asquith, Mark; Pasala, Sumana; Engelmann, Flora; Haberthur, Kristen; Meyer, Christine; Park, Byung; Grant, Kathleen A; Messaoudi, Ilhem

2014-04-01

Chronic alcohol consumption has been associated with enhanced susceptibility to both systemic and mucosal infections. However, the exact mechanisms underlying this enhanced susceptibility remain incompletely understood. Using a nonhuman primate model of ethanol (EtOH) self-administration, we examined the impact of chronic alcohol exposure on immune homeostasis, cytokine, and growth factor production in peripheral blood, lung, and intestinal mucosa following 12 months of chronic EtOH exposure. EtOH exposure inhibited activation-induced production of growth factors hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), and vascular-endothelial growth factor (VEGF) by peripheral blood mononuclear cells (PBMC). Moreover, EtOH significantly reduced the frequency of colonic Th1 and Th17 cells in a dose-dependent manner. In contrast, we did not observe differences in lymphocyte frequency or soluble factor production in the lung of EtOH-consuming animals. To uncover mechanisms underlying reduced growth factor and Th1/Th17 cytokine production, we compared expression levels of microRNAs in PBMC and intestinal mucosa. Our analysis revealed EtOH-dependent up-regulation of distinct microRNAs in affected tissues (miR-181a and miR-221 in PBMC; miR-155 in colon). Moreover, we were able to detect reduced expression of the transcription factors STAT3 and ARNT, which regulate expression of VEGF, G-CSF, and HGF and contain targets for these microRNAs. To confirm and extend these observations, PBMC were transfected with either mimics or antagomirs of miR-181 and miR-221, and protein levels of the transcription factors and growth factors were determined. Transfection of microRNA mimics led to a reduction in both STAT3/ARNT as well as VEGF/HGF/G-CSF levels. The opposite outcome was observed when microRNA antagomirs were transfected. Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be

Neural Networks for Optimal Control

DEFF Research Database (Denmark)

Sørensen, O.

1995-01-01

Two neural networks are trained to act as an observer and a controller, respectively, to control a non-linear, multi-variable process.......Two neural networks are trained to act as an observer and a controller, respectively, to control a non-linear, multi-variable process....

Neural constructivism or self-organization?

NARCIS (Netherlands)

van der Maas, H.L.J.; Molenaar, P.C.M.

2000-01-01

Comments on the article by S. R. Quartz et al (see record 1998-00749-001) which discussed the constructivist perspective of interaction between cognition and neural processes during development and consequences for theories of learning. Three arguments are given to show that neural constructivism

Program Helps Simulate Neural Networks

Science.gov (United States)

Villarreal, James; Mcintire, Gary

1993-01-01

Neural Network Environment on Transputer System (NNETS) computer program provides users high degree of flexibility in creating and manipulating wide variety of neural-network topologies at processing speeds not found in conventional computing environments. Supports back-propagation and back-propagation-related algorithms. Back-propagation algorithm used is implementation of Rumelhart's generalized delta rule. NNETS developed on INMOS Transputer(R). Predefines back-propagation network, Jordan network, and reinforcement network to assist users in learning and defining own networks. Also enables users to configure other neural-network paradigms from NNETS basic architecture. Small portion of software written in OCCAM(R) language.

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

Directory of Open Access Journals (Sweden)

Alma Y. Galvez-Contreras

2017-07-01

Full Text Available 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.

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

Science.gov (United States)

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

Prototype-Incorporated Emotional Neural Network.

Science.gov (United States)

Oyedotun, Oyebade K; Khashman, Adnan

2017-08-15

Artificial neural networks (ANNs) aim to simulate the biological neural activities. Interestingly, many ''engineering'' prospects in ANN have relied on motivations from cognition and psychology studies. So far, two important learning theories that have been subject of active research are the prototype and adaptive learning theories. The learning rules employed for ANNs can be related to adaptive learning theory, where several examples of the different classes in a task are supplied to the network for adjusting internal parameters. Conversely, the prototype-learning theory uses prototypes (representative examples); usually, one prototype per class of the different classes contained in the task. These prototypes are supplied for systematic matching with new examples so that class association can be achieved. In this paper, we propose and implement a novel neural network algorithm based on modifying the emotional neural network (EmNN) model to unify the prototype- and adaptive-learning theories. We refer to our new model as ``prototype-incorporated EmNN''. Furthermore, we apply the proposed model to two real-life challenging tasks, namely, static hand-gesture recognition and face recognition, and compare the result to those obtained using the popular back-propagation neural network (BPNN), emotional BPNN (EmNN), deep networks, an exemplar classification model, and k-nearest neighbor.

Down-regulated miR-448 relieves spinal cord ischemia/reperfusion injury by up-regulating SIRT1

Directory of Open Access Journals (Sweden)

Yun Wang

2018-03-01

Full Text Available MicroRNAs play a crucial role in the progression of spinal cord ischemia/reperfusion injury (SCII. The role of miR-448 and SIRT1 in SCII was investigated in this study, to provide further insights into prevention and improvement of this disorder. In this study, expressions of miR-448 and SIRT1 protein were determined by qRT-PCR and western blot, respectively. Flow cytometry was used to analyze cell apoptosis. The endogenous expression of genes was modulated by recombinant plasmids and cell transfection. Dual-luciferase reporter assay was performed to determine the interaction between miR-448 and SIRT1. The Basso, Beattie, and Bresnahan score was used to measure the hind-limb function of rat. The spinal cord ischemia reperfusion injury model of adult rats was developed by abdominal aorta clamping, and the nerve function evaluation was completed by motor deficit index score. In SCII tissues and cells treated with hypoxia, miR-448 was up-regulated while SIRT1 was down-regulated. Hypoxia treatment reduced the expression of SIRT1 through up-regulating miR-448 in nerve cells. Up-regulation of miR-448 induced by hypoxia promoted apoptosis of nerve cells through down-regulating SIRT1. Down-regulated miR-448 improved neurological function and hind-limb motor function of rats with SCII by up-regulating SIRT1. Down-regulated miR-448 inhibited apoptosis of nerve cells and improved neurological function by up-regulating SIRT1, which contributes to relieving SCII.

Modular representation of layered neural networks.

Science.gov (United States)

Watanabe, Chihiro; Hiramatsu, Kaoru; Kashino, Kunio

2018-01-01

Layered neural networks have greatly improved the performance of various applications including image processing, speech recognition, natural language processing, and bioinformatics. However, it is still difficult to discover or interpret knowledge from the inference provided by a layered neural network, since its internal representation has many nonlinear and complex parameters embedded in hierarchical layers. Therefore, it becomes important to establish a new methodology by which layered neural networks can be understood. In this paper, we propose a new method for extracting a global and simplified structure from a layered neural network. Based on network analysis, the proposed method detects communities or clusters of units with similar connection patterns. We show its effectiveness by applying it to three use cases. (1) Network decomposition: it can decompose a trained neural network into multiple small independent networks thus dividing the problem and reducing the computation time. (2) Training assessment: the appropriateness of a trained result with a given hyperparameter or randomly chosen initial parameters can be evaluated by using a modularity index. And (3) data analysis: in practical data it reveals the community structure in the input, hidden, and output layers, which serves as a clue for discovering knowledge from a trained neural network. Copyright © 2017 Elsevier Ltd. All rights reserved.

38 CFR 17.149 - Sensori-neural aids.

Science.gov (United States)

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Sensori-neural aids. 17... Prosthetic, Sensory, and Rehabilitative Aids § 17.149 Sensori-neural aids. (a) Notwithstanding any other provision of this part, VA will furnish needed sensori-neural aids (i.e., eyeglasses, contact lenses...

Genetic Algorithm Optimized Neural Networks Ensemble as ...

African Journals Online (AJOL)

NJD

Improvements in neural network calibration models by a novel approach using neural network ensemble (NNE) for the simultaneous ... process by training a number of neural networks. .... Matlab® version 6.1 was employed for building principal component ... provide a fair simulation of calibration data set with some degree.

Lysophosphatidic Acid Upregulates Laminin-332 Expression during A431 Cell Colony Dispersal

Directory of Open Access Journals (Sweden)

Hironobu Yamashita

2010-01-01

Full Text Available Lysophosphatidic acid (LPA is a bioactive phospholipid that affects various biological functions, such as cell proliferation, migration, survival, wound healing, and tumor invasion through LPA receptors. Previously, we reported that LPA induces A431 colony dispersal, accompanied by disruption of cell-cell contacts and cell migration. However, it remains unclear how LPA affects cell migration and gene expression during A431 colony dispersal. In this paper, we performed cDNA microarray analysis to investigate this question by comparing gene expression between untreated and LPA-treated A431 cells. Interestingly, these results revealed that LPA treatment upregulates several TGF-β1 target genes, including laminin-332 (Ln-332 components (α3, β3, and γ2 chains. Western blot analysis also showed that LPA increased phosphorylation of Smad2, an event that is carried out by TGF-β1 interactions. Among the genes upregulated, we further addressed the role of Ln-332. Real-time PCR analysis confirmed the transcriptional upregulation of all α3, β3, and γ2 chains of Ln-332 by LPA, corresponding to the protein level increases revealed by western blot. Further, the addition of anti-Ln-332 antibody prevented LPA-treated A431 colonies from dispersing. Taken together, our results suggest that LPA-induced Ln-332 plays a significant role in migration of individual cells from A431 colonies.

Fuzzy logic and neural networks basic concepts & application

CERN Document Server

Alavala, Chennakesava R

2008-01-01

About the Book: The primary purpose of this book is to provide the student with a comprehensive knowledge of basic concepts of fuzzy logic and neural networks. The hybridization of fuzzy logic and neural networks is also included. No previous knowledge of fuzzy logic and neural networks is required. Fuzzy logic and neural networks have been discussed in detail through illustrative examples, methods and generic applications. Extensive and carefully selected references is an invaluable resource for further study of fuzzy logic and neural networks. Each chapter is followed by a question bank

Neural networks at the Tevatron

International Nuclear Information System (INIS)

Badgett, W.; Burkett, K.; Campbell, M.K.; Wu, D.Y.; Bianchin, S.; DeNardi, M.; Pauletta, G.; Santi, L.; Caner, A.; Denby, B.; Haggerty, H.; Lindsey, C.S.; Wainer, N.; Dall'Agata, M.; Johns, K.; Dickson, M.; Stanco, L.; Wyss, J.L.

1992-10-01

This paper summarizes neural network applications at the Fermilab Tevatron, including the first online hardware application in high energy physics (muon tracking): the CDF and DO neural network triggers; offline quark/gluon discrimination at CDF; ND a new tool for top to multijets recognition at CDF

Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation after Experimental Traumatic Brain Injury

Directory of Open Access Journals (Sweden)

Genevieve M. Sullivan

2017-01-01

Full Text Available Neural stem cells (NSCs delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI. To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined sonic hedgehog (Shh signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribing Shh or Gli1 after transplantation and/or TBI. Gli1 transcription is an effective readout for canonical Shh signaling. In ShhCreERT2;R26tdTomato mice, Shh was primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results in Gli1CreERT2;R26tdTomato mice demonstrated that Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSCs expressed Shh in vivo but did not increase Gli1 labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling via Gli1 transcription.

Nonequilibrium landscape theory of neural networks

Science.gov (United States)

Yan, Han; Zhao, Lei; Hu, Liang; Wang, Xidi; Wang, Erkang; Wang, Jin

2013-01-01

The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape–flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments. PMID:24145451

Nonequilibrium landscape theory of neural networks.

Science.gov (United States)

Yan, Han; Zhao, Lei; Hu, Liang; Wang, Xidi; Wang, Erkang; Wang, Jin

2013-11-05

The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape-flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments.

Application of neural network to CT

International Nuclear Information System (INIS)

Ma, Xiao-Feng; Takeda, Tatsuoki

1999-01-01

This paper presents a new method for two-dimensional image reconstruction by using a multilayer neural network. Multilayer neural networks are extensively investigated and practically applied to solution of various problems such as inverse problems or time series prediction problems. From learning an input-output mapping from a set of examples, neural networks can be regarded as synthesizing an approximation of multidimensional function (that is, solving the problem of hypersurface reconstruction, including smoothing and interpolation). From this viewpoint, neural networks are well suited to the solution of CT image reconstruction. Though a conventionally used object function of a neural network is composed of a sum of squared errors of the output data, we can define an object function composed of a sum of residue of an integral equation. By employing an appropriate line integral for this integral equation, we can construct a neural network that can be used for CT. We applied this method to some model problems and obtained satisfactory results. As it is not necessary to discretized the integral equation using this reconstruction method, therefore it is application to the problem of complicated geometrical shapes is also feasible. Moreover, in neural networks, interpolation is performed quite smoothly, as a result, inverse mapping can be achieved smoothly even in case of including experimental and numerical errors, However, use of conventional back propagation technique for optimization leads to an expensive computation cost. To overcome this drawback, 2nd order optimization methods or parallel computing will be applied in future. (J.P.N.)

Upregulation of decorin by FXR in vascular smooth muscle cells

International Nuclear Information System (INIS)

He Fengtian; Zhang Qiuhong; Kuruba, Ramalinga; Gao Xiang; Li Jiang; Li Yong; Gong Wei; Jiang, Yu; Xie Wen; Li Song

2008-01-01

Decorin is a member of the family of small leucine-rich proteoglycans that are present in blood vessels and synthesized by vascular smooth muscle cells (VSMCs). Decorin plays complex roles in both normal vascular physiology and the pathogenesis of various types of vascular disorders. However, the mechanisms of regulation of decorin expression in vasculature are not clearly understood. Particularly little information is available about a role of nuclear receptors in the regulation of decorin expression. In the present study, we report that activation of vascular FXR by a specific ligand resulted in upregulation of decorin at the levels of both mRNA and protein. FXR appears to induce decorin expression at a transcriptional level because (1) upregulation of decorin mRNA expression was abolished by the treatment of a transcription inhibitor, actinomycin D; and (2) decorin promoter activity was significantly increased by activation of FXR. Functional analysis of human decorin promoter identified an imperfect inverted repeat DNA motif, IR8 (-2313TGGTCAtagtgtcaTGACCT-2294), as a likely FXR-responsive element that is involved in decorin regulation

The p75 neurotrophin receptor: at the crossroad of neural repair and death

Science.gov (United States)

Meeker, Rick B.; Williams, Kimberly S.

2015-01-01

The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regulation of neurotrophin actions. Recently, the p75 neurotrophin receptor (p75NTR) has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by studies demonstrating 1) regulation of neural plasticity in the mature nervous system, 2) promotion of adult neurogenesis and 3) increased expression in neurons, macrophages, microglia, astrocytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and processes that support neural function. Upregulation of the p75NTR under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-peptide p75NTR ligands can selectively modify pro-survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75NTR, studies summarized in this review highlight the immense potential for development of novel neuroprotective and neurorestorative therapies. PMID:26109945

The p75 neurotrophin receptor: at the crossroad of neural repair and death

Directory of Open Access Journals (Sweden)

Rick B Meeker

2015-01-01

Full Text Available The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regulation of neurotrophin actions. Recently, the p75 neurotrophin receptor (p75 NTR has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by studies demonstrating 1 regulation of neural plasticity in the mature nervous system, 2 promotion of adult neurogenesis and 3 increased expression in neurons, macrophages, microglia, astrocytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and processes that support neural function. Upregulation of the p75 NTR under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-peptide p75 NTR ligands can selectively modify pro-survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75 NTR , studies summarized in this review highlight the immense potential for development of novel neuroprotective and neurorestorative therapies.

Fibroblast growth factor-2 up-regulates the expression of nestin through the Ras–Raf–ERK–Sp1 signaling axis in C6 glioma cells

International Nuclear Information System (INIS)

Chang, Kai-Wei; Huang, Yuan-Li; Wong, Zong-Ruei; Su, Peng-Han; Huang, Bu-Miin; Ju, Tsai-Kai; Yang, Hsi-Yuan

2013-01-01

Highlights: •Nestin expression in C6 glioma cells is induced by FGF-2. •Nestin expression is induced by FGF-2 via de novo RNA and protein synthesis. •The FGFR inhibitor SU5402 blocks the FGF-2-induced nestin expression. •The mRNA of FGFR1 and 3 are detected in C6 glioma cells. •Ras–Raf–ERK–Sp1 signaling pathway is responsibe for FGF-2-induced nestin expression. -- Abstract: Nestin is a 240-kDa intermediate filament protein expressed mainly in neural and myogenic stem cells. Although a substantial number of studies have focused on the expression of nestin during development of the central nervous system, little is known about the factors that induce and regulate its expression. Fibroblast growth factor-2 (FGF-2) is an effective mitogen and stimulates the proliferation and differentiation of a subset of nestin-expressing cells, including neural progenitor cells, glial precursor cells, and smooth muscle cells. To assess whether FGF-2 is a potent factor that induces the expression of nestin, C6 glioma cells were used. The results showed that nestin expression was up-regulated by FGF-2 via de novo RNA and protein synthesis. Our RT-PCR results showed that C6 glioma cells express FGFR1/3, and FGFRs is required for FGF-2-induced nestin expression. Further signaling analysis also revealed that FGF-2-induced nestin expression is mediated through FGFR–MAPK–ERK signaling axis and the transcriptional factor Sp1. These findings provide new insight into the regulation of nestin in glial system and enable the further studies on the function of nestin in glial cells

Fibroblast growth factor-2 up-regulates the expression of nestin through the Ras–Raf–ERK–Sp1 signaling axis in C6 glioma cells

Energy Technology Data Exchange (ETDEWEB)

Chang, Kai-Wei [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Yuan-Li [Department of Biotechnology, College of Health Science, Asia University, Taichung 413, Taiwan (China); Wong, Zong-Ruei; Su, Peng-Han [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Bu-Miin [Department of Cell Biology and Anatomy, National Cheng-Kung University, Tainan 701, Taiwan (China); Ju, Tsai-Kai [Instrumentation Center, National Taiwan University, Taipei 106, Taiwan (China); Technology Commons, College of Life Science, National Taiwan University, Taipei 106, Taiwan (China); Yang, Hsi-Yuan, E-mail: hyhy@ntu.edu.tw [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China)

2013-05-17

Highlights: •Nestin expression in C6 glioma cells is induced by FGF-2. •Nestin expression is induced by FGF-2 via de novo RNA and protein synthesis. •The FGFR inhibitor SU5402 blocks the FGF-2-induced nestin expression. •The mRNA of FGFR1 and 3 are detected in C6 glioma cells. •Ras–Raf–ERK–Sp1 signaling pathway is responsibe for FGF-2-induced nestin expression. -- Abstract: Nestin is a 240-kDa intermediate filament protein expressed mainly in neural and myogenic stem cells. Although a substantial number of studies have focused on the expression of nestin during development of the central nervous system, little is known about the factors that induce and regulate its expression. Fibroblast growth factor-2 (FGF-2) is an effective mitogen and stimulates the proliferation and differentiation of a subset of nestin-expressing cells, including neural progenitor cells, glial precursor cells, and smooth muscle cells. To assess whether FGF-2 is a potent factor that induces the expression of nestin, C6 glioma cells were used. The results showed that nestin expression was up-regulated by FGF-2 via de novo RNA and protein synthesis. Our RT-PCR results showed that C6 glioma cells express FGFR1/3, and FGFRs is required for FGF-2-induced nestin expression. Further signaling analysis also revealed that FGF-2-induced nestin expression is mediated through FGFR–MAPK–ERK signaling axis and the transcriptional factor Sp1. These findings provide new insight into the regulation of nestin in glial system and enable the further studies on the function of nestin in glial cells.

Nestin upregulation characterizes vascular remodeling secondary to hypertension in the rat.

Science.gov (United States)

Tardif, Kim; Hertig, Vanessa; Duquette, Natacha; Villeneuve, Louis; El-Hamamsy, Ismail; Tanguay, Jean-François; Calderone, Angelino

2015-05-15

Proliferation and hypertrophy of vascular smooth muscle cells represent hallmark features of vessel remodeling secondary to hypertension. The intermediate filament protein nestin was recently identified in vascular smooth muscle cells and in other cell types directly participated in proliferation. The present study tested the hypothesis that vessel remodeling secondary to hypertension was characterized by nestin upregulation in vascular smooth muscle cells. Two weeks after suprarenal abdominal aorta constriction of adult male Sprague-Dawley rats, elevated mean arterial pressure increased the media area and thickness of the carotid artery and aorta and concomitantly upregulated nestin protein levels. In the normal adult rat carotid artery, nestin immunoreactivity was observed in a subpopulation of vascular smooth muscle cells, and the density significantly increased following suprarenal abdominal aorta constriction. Filamentous nestin was detected in cultured rat carotid artery- and aorta-derived vascular smooth muscle cells and an analogous paradigm observed in human aorta-derived vascular smooth muscle cells. ANG II and EGF treatment of vascular smooth muscle cells stimulated DNA and protein synthesis and increased nestin protein levels. Lentiviral short-hairpin RNA-mediated nestin depletion of carotid artery-derived vascular smooth muscle cells inhibited peptide growth factor-stimulated DNA synthesis, whereas protein synthesis remained intact. These data have demonstrated that vessel remodeling secondary to hypertension was characterized in part by nestin upregulation in vascular smooth muscle cells. The selective role of nestin in peptide growth factor-stimulated DNA synthesis has revealed that the proliferative and hypertrophic responses of vascular smooth muscle cells were mediated by divergent signaling events. Copyright © 2015 the American Physiological Society.

Methodology of Neural Design: Applications in Microwave Engineering

Directory of Open Access Journals (Sweden)

Z. Raida

2006-06-01

Full Text Available In the paper, an original methodology for the automatic creation of neural models of microwave structures is proposed and verified. Following the methodology, neural models of the prescribed accuracy are built within the minimum CPU time. Validity of the proposed methodology is verified by developing neural models of selected microwave structures. Functionality of neural models is verified in a design - a neural model is joined with a genetic algorithm to find a global minimum of a formulated objective function. The objective function is minimized using different versions of genetic algorithms, and their mutual combinations. The verified methodology of the automated creation of accurate neural models of microwave structures, and their association with global optimization routines are the most important original features of the paper.

Differentiation between non-neural and neural contributors to ankle joint stiffness in cerebral palsy.

Science.gov (United States)

de Gooijer-van de Groep, Karin L; de Vlugt, Erwin; de Groot, Jurriaan H; van der Heijden-Maessen, Hélène C M; Wielheesen, Dennis H M; van Wijlen-Hempel, Rietje M S; Arendzen, J Hans; Meskers, Carel G M

2013-07-23

Spastic paresis in cerebral palsy (CP) is characterized by increased joint stiffness that may be of neural origin, i.e. improper muscle activation caused by e.g. hyperreflexia or non-neural origin, i.e. altered tissue viscoelastic properties (clinically: "spasticity" vs. "contracture"). Differentiation between these components is hard to achieve by common manual tests. We applied an assessment instrument to obtain quantitative measures of neural and non-neural contributions to ankle joint stiffness in CP. Twenty-three adolescents with CP and eleven healthy subjects were seated with their foot fixated to an electrically powered single axis footplate. Passive ramp-and-hold rotations were applied over full ankle range of motion (RoM) at low and high velocities. Subject specific tissue stiffness, viscosity and reflexive torque were estimated from ankle angle, torque and triceps surae EMG activity using a neuromuscular model. In CP, triceps surae reflexive torque was on average 5.7 times larger (p = .002) and tissue stiffness 2.1 times larger (p = .018) compared to controls. High tissue stiffness was associated with reduced RoM (p therapy.

Differentiation state determines neural effects on microvascular endothelial cells

International Nuclear Information System (INIS)

Muffley, Lara A.; Pan, Shin-Chen; Smith, Andria N.; Ga, Maricar; Hocking, Anne M.; Gibran, Nicole S.

2012-01-01

Growing evidence indicates that nerves and capillaries interact paracrinely in uninjured skin and cutaneous wounds. Although mature neurons are the predominant neural cell in the skin, neural progenitor cells have also been detected in uninjured adult skin. The aim of this study was to characterize differential paracrine effects of neural progenitor cells and mature sensory neurons on dermal microvascular endothelial cells. Our results suggest that neural progenitor cells and mature sensory neurons have unique secretory profiles and distinct effects on dermal microvascular endothelial cell proliferation, migration, and nitric oxide production. Neural progenitor cells and dorsal root ganglion neurons secrete different proteins related to angiogenesis. Specific to neural progenitor cells were dipeptidyl peptidase-4, IGFBP-2, pentraxin-3, serpin f1, TIMP-1, TIMP-4 and VEGF. In contrast, endostatin, FGF-1, MCP-1 and thrombospondin-2 were specific to dorsal root ganglion neurons. Microvascular endothelial cell proliferation was inhibited by dorsal root ganglion neurons but unaffected by neural progenitor cells. In contrast, microvascular endothelial cell migration in a scratch wound assay was inhibited by neural progenitor cells and unaffected by dorsal root ganglion neurons. In addition, nitric oxide production by microvascular endothelial cells was increased by dorsal root ganglion neurons but unaffected by neural progenitor cells. -- Highlights: ► Dorsal root ganglion neurons, not neural progenitor cells, regulate microvascular endothelial cell proliferation. ► Neural progenitor cells, not dorsal root ganglion neurons, regulate microvascular endothelial cell migration. ► Neural progenitor cells and dorsal root ganglion neurons do not effect microvascular endothelial tube formation. ► Dorsal root ganglion neurons, not neural progenitor cells, regulate microvascular endothelial cell production of nitric oxide. ► Neural progenitor cells and dorsal root

Proposal of a model of mammalian neural induction

Science.gov (United States)

Levine, Ariel J.; Brivanlou, Ali H.

2009-01-01

How does the vertebrate embryo make a nervous system? This complex question has been at the center of developmental biology for many years. The earliest step in this process – the induction of neural tissue – is intimately linked to patterning of the entire early embryo, and the molecular and embryological basis these processes are beginning to emerge. Here, we analyze classic and cutting-edge findings on neural induction in the mouse. We find that data from genetics, tissue explants, tissue grafting, and molecular marker expression support a coherent framework for mammalian neural induction. In this model, the gastrula organizer of the mouse embryo inhibits BMP signaling to allow neural tissue to form as a default fate – in the absence of instructive signals. The first neural tissue induced is anterior and subsequent neural tissue is posteriorized to form the midbrain, hindbrain, and spinal cord. The anterior visceral endoderm protects the pre-specified anterior neural fate from similar posteriorization, allowing formation of forebrain. This model is very similar to the default model of neural induction in the frog, thus bridging the evolutionary gap between amphibians and mammals. PMID:17585896

Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma.

Science.gov (United States)

Shahrabi-Farahani, Shokoufeh; Gallottini, Marina; Martins, Fabiana; Li, Erik; Mudge, Dayna R; Nakayama, Hironao; Hida, Kyoko; Panigrahy, Dipak; D'Amore, Patricia A; Bielenberg, Diane R

2016-04-01

Neuropilins are receptors for disparate ligands, including proangiogenic factors such as vascular endothelial growth factor and inhibitory class 3 semaphorin (SEMA3) family members. Differentiated cells in skin epithelium and cutaneous squamous cell carcinoma highly express the neuropilin-1 (NRP1) receptor. We examined the expression of NRP1 in human and mouse oral mucosa. NRP1 was significantly up-regulated in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). NRP1 receptor localized to the outer suprabasal epithelial layers in normal tongue, an expression pattern similar to the normal skin epidermis. However, dysplastic tongue epithelium and OSCC up-regulated NRP1 in basal and proliferating epithelial layers, a profile unseen in cutaneous squamous cell carcinoma. NRP1 up-regulation is observed in a mouse carcinogen-induced OSCC model and in human tongue OSCC biopsies. Human OSCC cell lines express NRP1 protein in vitro and in mouse tongue xenografts. Sites of capillary infiltration into orthotopic OSCC tumors correlate with high NRP1 expression. HSC3 xenografts, which express the highest NRP1 levels of the cell lines examined, showed massive intratumoral lymphangiogenesis. SEMA3A inhibited OSCC cell migration, suggesting that the NRP1 receptor was bioactive in OSCC. In conclusion, NRP1 is regulated in the oral epithelium and is selectively up-regulated during epithelial dysplasia. NRP1 may function as a reservoir to sequester proangiogenic ligands within the neoplastic compartment, thereby recruiting neovessels toward tumor cells. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Hepatocyte Growth Factor Levels in the Saliva and Gingival Crevicular Fluid in Smokers with Periodontitis

Directory of Open Access Journals (Sweden)

Sukumaran Anil

2014-01-01

Full Text Available Hepatocyte growth factor (HGF production by oral fibroblasts is enhanced by various molecules that are induced during inflammatory conditions including periodontitis. HGF plays an important role in the progression of periodontitis, by stimulating intense growth of epithelial cells and preventing regeneration of connective tissue attachments. Smokers have a greater risk factor in the pathogenesis and progression of periodontal disease. The objective of the study was to estimate the level of HGF in saliva and gingival crevicular fluid (GCF in smokers with periodontitis and to compare these levels with that of nonsmokers with periodontitis and healthy controls. The HGF levels were found to be significantly high in the saliva and GCF of smokers with periodontitis compared to both never-smokers with periodontitis and the healthy control group. The elevated levels of HGF in the saliva and GCF in the study population could explain the intrinsic mechanism triggering the severity of the periodontitis in smokers. Further studies are necessary to validate the current observations and to establish a sensitive marker to predict periodontal disease activity.

Serum hepatocyte growth factor levels and the effects of antidepressants in panic disorder.

Science.gov (United States)

Kanehisa, Masayuki; Ishitobi, Yoshinobu; Ando, Tomoko; Okamoto, Shizuko; Maruyama, Yoshihiro; Kohno, Kentaro; Ninomiya, Taiga; Higuma, Haruka; Tanaka, Yoshihiro; Tsuru, Jusen; Hanada, Hiroaki; Kodama, Kensuke; Akiyoshi, Jotaro

2010-10-01

Previous animal studies have suggested that hepatocyte growth factor (HGF) could be associated with depression- and anxiety-related behaviors. Our aim was to relate serum HGF levels with State-Trait Anxiety Inventory (STAI), Profile of Mood State (POMS), and Revised NEO Personality Inventory (NEO-PI-R) scores in patients with panic disorder (with or without agoraphobia) and healthy controls. We examined 67 patients with panic disorders and 97 controls. Patients were split into two groups according to whether they exhibited a 50% improvement in test scores (good/high response group: n = 26) or not (poor/low response group: n = 41). In both healthy control and panic disorder individuals, there were no significant associations between HGF serum levels and STAI or NEO-PI-R scores. However, there was a significant correlation between serum HGF levels and fatigue in healthy control subjects in as scored by POMS testing. HGF concentration in the good/high response group was significantly elevated compared to both the low/poor response group (p disorders. 2010. Published by Elsevier Ltd. All rights reserved.

Catalase activity prevents exercise-induced up-regulation of vasoprotective proteins in venous tissue.

Science.gov (United States)

Dao, Vu Thao-Vi; Floeren, Melanie; Kumpf, Stephanie; Both, Charlotte; Peter, Bärbel; Balz, Vera; Suvorava, Tatsiana; Kojda, Georg

2011-11-01

Physical activity induces favourable changes of arterial gene expression and protein activity, although little is known about its effect in venous tissue. Although our understanding of the initiating molecular signals is still incomplete, increased expression of endothelial nitric oxide synthase (eNOS) is considered a key event. This study sought to investigate the effects of two different training protocols on the expression of eNOS and extracellular superoxide dismutase (ecSOD) in venous and lung tissue and to evaluate the underlying molecular mechanisms. C57Bl/6 mice underwent voluntary exercise or forced physical activity. Changes of vascular mRNA and protein levels and activity of eNOS, ecSOD and catalase were determined in aorta, heart, lung and vena cava. Both training protocols similarly increased relative heart weight and resulted in up-regulation of aortic and myocardial eNOS. In striking contrast, eNOS expression in vena cava and lung remained unchanged. Likewise, exercise up-regulated ecSOD in the aorta and in left ventricular tissue but remained unchanged in lung tissue. Catalase expression in lung tissue and vena cava of exercised mice exceeded that in aorta by 6.9- and 10-fold, respectively, suggesting a lack of stimulatory effects of hydrogen peroxide. In accordance, treatment of mice with the catalase inhibitor aminotriazole for 6 weeks resulted in significant up-regulation of eNOS and ecSOD in vena cava. These data suggest that physiological venous catalase activity prevents exercise-induced up-regulation of eNOS and ecSOD. Furthermore, therapeutic inhibition of vascular catalase might improve pulmonary rehabilitation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Tuning Neural Phase Entrainment to Speech.

Science.gov (United States)

Falk, Simone; Lanzilotti, Cosima; Schön, Daniele

2017-08-01

Musical rhythm positively impacts on subsequent speech processing. However, the neural mechanisms underlying this phenomenon are so far unclear. We investigated whether carryover effects from a preceding musical cue to a speech stimulus result from a continuation of neural phase entrainment to periodicities that are present in both music and speech. Participants listened and memorized French metrical sentences that contained (quasi-)periodic recurrences of accents and syllables. Speech stimuli were preceded by a rhythmically regular or irregular musical cue. Our results show that the presence of a regular cue modulates neural response as estimated by EEG power spectral density, intertrial coherence, and source analyses at critical frequencies during speech processing compared with the irregular condition. Importantly, intertrial coherences for regular cues were indicative of the participants' success in memorizing the subsequent speech stimuli. These findings underscore the highly adaptive nature of neural phase entrainment across fundamentally different auditory stimuli. They also support current models of neural phase entrainment as a tool of predictive timing and attentional selection across cognitive domains.

Kernel Temporal Differences for Neural Decoding

Science.gov (United States)

Bae, Jihye; Sanchez Giraldo, Luis G.; Pohlmeyer, Eric A.; Francis, Joseph T.; Sanchez, Justin C.; Príncipe, José C.

2015-01-01

We study the feasibility and capability of the kernel temporal difference (KTD)(λ) algorithm for neural decoding. KTD(λ) is an online, kernel-based learning algorithm, which has been introduced to estimate value functions in reinforcement learning. This algorithm combines kernel-based representations with the temporal difference approach to learning. One of our key observations is that by using strictly positive definite kernels, algorithm's convergence can be guaranteed for policy evaluation. The algorithm's nonlinear functional approximation capabilities are shown in both simulations of policy evaluation and neural decoding problems (policy improvement). KTD can handle high-dimensional neural states containing spatial-temporal information at a reasonable computational complexity allowing real-time applications. When the algorithm seeks a proper mapping between a monkey's neural states and desired positions of a computer cursor or a robot arm, in both open-loop and closed-loop experiments, it can effectively learn the neural state to action mapping. Finally, a visualization of the coadaptation process between the decoder and the subject shows the algorithm's capabilities in reinforcement learning brain machine interfaces. PMID:25866504

Neural synchronization during face-to-face communication.

Science.gov (United States)

Jiang, Jing; Dai, Bohan; Peng, Danling; Zhu, Chaozhe; Liu, Li; Lu, Chunming

2012-11-07

Although the human brain may have evolutionarily adapted to face-to-face communication, other modes of communication, e.g., telephone and e-mail, increasingly dominate our modern daily life. This study examined the neural difference between face-to-face communication and other types of communication by simultaneously measuring two brains using a hyperscanning approach. The results showed a significant increase in the neural synchronization in the left inferior frontal cortex during a face-to-face dialog between partners but none during a back-to-back dialog, a face-to-face monologue, or a back-to-back monologue. Moreover, the neural synchronization between partners during the face-to-face dialog resulted primarily from the direct interactions between the partners, including multimodal sensory information integration and turn-taking behavior. The communicating behavior during the face-to-face dialog could be predicted accurately based on the neural synchronization level. These results suggest that face-to-face communication, particularly dialog, has special neural features that other types of communication do not have and that the neural synchronization between partners may underlie successful face-to-face communication.

Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease.

Science.gov (United States)

Koga, Hiroshi; Martinez-Vicente, Marta; Arias, Esperanza; Kaushik, Susmita; Sulzer, David; Cuervo, Ana Maria

2011-12-14

Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington's disease (HD), a congenital neurodegenerative disorder resulting from mutation in the huntingtin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome-associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of the lamp-2 gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.

Neural principles of memory and a neural theory of analogical insight

Science.gov (United States)

Lawson, David I.; Lawson, Anton E.

1993-12-01

Grossberg's principles of neural modeling are reviewed and extended to provide a neural level theory to explain how analogies greatly increase the rate of learning and can, in fact, make learning and retention possible. In terms of memory, the key point is that the mind is able to recognize and recall when it is able to match sensory input from new objects, events, or situations with past memory records of similar objects, events, or situations. When a match occurs, an adaptive resonance is set up in which the synaptic strengths of neurons are increased; thus a long term record of the new input is formed in memory. Systems of neurons called outstars and instars are presumably the underlying units that enable this to occur. Analogies can greatly facilitate learning and retention because they activate the outstars (i.e., the cells that are sampling the to-be-learned pattern) and cause the neural activity to grow exponentially by forming feedback loops. This increased activity insures the boost in synaptic strengths of neurons, thus causing storage and retention in long-term memory (i.e., learning).

Pim kinases are upregulated during Epstein-Barr virus infection and enhance EBNA2 activity

International Nuclear Information System (INIS)

Rainio, Eeva-Marja; Ahlfors, Helena; Carter, Kara L.; Ruuska, Marja; Matikainen, Sampsa; Kieff, Elliott; Koskinen, Paeivi J.

2005-01-01

Latent Epstein-Barr virus (EBV) infection is strongly associated with B-cell proliferative diseases such as Burkitt's lymphoma. Here we show that the oncogenic serine/threonine kinases Pim-1 and Pim-2 enhance the activity of the viral transcriptional activator EBNA2. During EBV infection of primary B-lymphocytes, the mRNA expression levels of pim genes, especially of pim-2, are upregulated and remain elevated in latently infected B-cell lines. Thus, EBV-induced upregulation of Pim kinases and Pim-stimulated EBNA2 transcriptional activity may contribute to the ability of EBV to immortalize B-cells and predispose them to malignant growth

Neural Network Based Load Frequency Control for Restructuring ...

African Journals Online (AJOL)

Neural Network Based Load Frequency Control for Restructuring Power Industry. ... an artificial neural network (ANN) application of load frequency control (LFC) of a Multi-Area power system by using a neural network controller is presented.

Neural substrates of decision-making.

Science.gov (United States)

Broche-Pérez, Y; Herrera Jiménez, L F; Omar-Martínez, E

2016-06-01

Decision-making is the process of selecting a course of action from among 2 or more alternatives by considering the potential outcomes of selecting each option and estimating its consequences in the short, medium and long term. The prefrontal cortex (PFC) has traditionally been considered the key neural structure in decision-making process. However, new studies support the hypothesis that describes a complex neural network including both cortical and subcortical structures. The aim of this review is to summarise evidence on the anatomical structures underlying the decision-making process, considering new findings that support the existence of a complex neural network that gives rise to this complex neuropsychological process. Current evidence shows that the cortical structures involved in decision-making include the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). This process is assisted by subcortical structures including the amygdala, thalamus, and cerebellum. Findings to date show that both cortical and subcortical brain regions contribute to the decision-making process. The neural basis of decision-making is a complex neural network of cortico-cortical and cortico-subcortical connections which includes subareas of the PFC, limbic structures, and the cerebellum. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

UniProt search blastx result: AK287970 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-20 ...

UniProt search blastx result: AK288287 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-18 ...

UniProt search blastx result: AK289170 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 1.00E-18 ...

UniProt search blastx result: AK287484 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-16 ...

UniProt search blastx result: AK288291 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 6.00E-14 ...

UniProt search blastx result: AK288206 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 4.00E-21 ...

Genetic algorithm for neural networks optimization

Science.gov (United States)

Setyawati, Bina R.; Creese, Robert C.; Sahirman, Sidharta

2004-11-01

This paper examines the forecasting performance of multi-layer feed forward neural networks in modeling a particular foreign exchange rates, i.e. Japanese Yen/US Dollar. The effects of two learning methods, Back Propagation and Genetic Algorithm, in which the neural network topology and other parameters fixed, were investigated. The early results indicate that the application of this hybrid system seems to be well suited for the forecasting of foreign exchange rates. The Neural Networks and Genetic Algorithm were programmed using MATLAB«.

Neural network recognition of mammographic lesions

International Nuclear Information System (INIS)

Oldham, W.J.B.; Downes, P.T.; Hunter, V.

1987-01-01

A method for recognition of mammographic lesions through the use of neural networks is presented. Neural networks have exhibited the ability to learn the shape andinternal structure of patterns. Digitized mammograms containing circumscribed and stelate lesions were used to train a feedfoward synchronous neural network that self-organizes to stable attractor states. Encoding of data for submission to the network was accomplished by performing a fractal analysis of the digitized image. This results in scale invariant representation of the lesions. Results are discussed

Brain-Derived Neurotrophic Factor Increases Synaptic Protein Levels via the MAPK/Erk Signaling Pathway and Nrf2/Trx Axis Following the Transplantation of Neural Stem Cells in a Rat Model of Traumatic Brain Injury.

Science.gov (United States)

Chen, Tao; Wu, Yu; Wang, Yuzi; Zhu, Jigao; Chu, Haiying; Kong, Li; Yin, Liangwei; Ma, Haiying

2017-11-01

Brain-derived neurotrophic factor (BDNF) plays an important role in promoting the growth, differentiation, survival and synaptic stability of neurons. Presently, the transplantation of neural stem cells (NSCs) is known to induce neural repair to some extent after injury or disease. In this study, to investigate whether NSCs genetically modified to encode the BDNF gene (BDNF/NSCs) would further enhance synaptogenesis, BDNF/NSCs or naive NSCs were directly engrafted into lesions in a rat model of traumatic brain injury (TBI). Immunohistochemistry, western blotting and RT-PCR were performed to detect synaptic proteins, BDNF-TrkB and its downstream signaling pathways, at 1, 2, 3 or 4 weeks after transplantation. Our results showed that BDNF significantly increased the expression levels of the TrkB receptor gene and the phosphorylation of the TrkB protein in the lesions. The expression levels of Ras, phosphorylated Erk1/2 and postsynaptic density protein-95 were elevated in the BDNF/NSCs-transplanted groups compared with those in the NSCs-transplanted groups throughout the experimental period. Moreover, the nuclear factor (erythroid-derived 2)-like 2/Thioredoxin (Nrf2/Trx) axis, which is a specific therapeutic target for the treatment of injury or cell death, was upregulated by BDNF overexpression. Therefore, we determined that the increased synaptic proteins level implicated in synaptogenesis might be associated with the activation of the MAPK/Erk1/2 signaling pathway and the upregulation of the antioxidant agent Trx modified by BDNF-TrkB following the BDNF/NSCs transplantation after TBI.

Effect of age on upregulation of the cardiac adrenergic beta receptors

International Nuclear Information System (INIS)

Tumer, N.; Houck, W.T.; Roberts, J.

1990-01-01

Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors

Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling.

Science.gov (United States)

Ito, Yoko; Correll, Kelly; Schiel, John A; Finigan, Jay H; Prekeris, Rytis; Mason, Robert J

2014-07-01

There are 190,600 cases of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) each year in the United States, and the incidence and mortality of ALI/ARDS increase dramatically with age. Patients with ALI/ARDS have alveolar epithelial injury, which may be worsened by high-pressure mechanical ventilation. Alveolar type II (ATII) cells are the progenitor cells for the alveolar epithelium and are required to reestablish the alveolar epithelium during the recovery process from ALI/ARDS. Lung fibroblasts (FBs) migrate and proliferate early after lung injury and likely are an important source of growth factors for epithelial repair. However, how lung FBs affect epithelial wound healing in the human adult lung has not been investigated in detail. Hepatocyte growth factor (HGF) is known to be released mainly from FBs and to stimulate both migration and proliferation of primary rat ATII cells. HGF is also increased in lung tissue, bronchoalveolar lavage fluid, and serum in patients with ALI/ARDS. Therefore, we hypothesized that HGF secreted by FBs would enhance wound closure in alveolar epithelial cells (AECs). Wound closure was measured using a scratch wound-healing assay in primary human AEC monolayers and in a coculture system with FBs. We found that wound closure was accelerated by FBs mainly through HGF/c-Met signaling. HGF also restored impaired wound healing in AECs from the elderly subjects and after exposure to cyclic stretch. We conclude that HGF is the critical factor released from FBs to close wounds in human AEC monolayers and suggest that HGF is a potential strategy for hastening alveolar repair in patients with ALI/ARDS. Copyright © 2014 the American Physiological Society.

Optical-Correlator Neural Network Based On Neocognitron

Science.gov (United States)

Chao, Tien-Hsin; Stoner, William W.

1994-01-01

Multichannel optical correlator implements shift-invariant, high-discrimination pattern-recognizing neural network based on paradigm of neocognitron. Selected as basic building block of this neural network because invariance under shifts is inherent advantage of Fourier optics included in optical correlators in general. Neocognitron is conceptual electronic neural-network model for recognition of visual patterns. Multilayer processing achieved by iteratively feeding back output of feature correlator to input spatial light modulator and updating Fourier filters. Neural network trained by use of characteristic features extracted from target images. Multichannel implementation enables parallel processing of large number of selected features.

Neutron spectrometry and dosimetry by means of Bonner spheres system and artificial neural networks applying robust design of artificial neural networks

Energy Technology Data Exchange (ETDEWEB)

Martinez B, M.R.; Ortiz R, J.M.; Vega C, H.R. [UAZ, Av. Ramon Lopez Velarde No. 801, 98000 Zacatecas (Mexico)

2006-07-01

An Artificial Neural Network has been designed, trained and tested to unfold neutron spectra and simultaneously to calculate equivalent doses. A set of 187 neutron spectra compiled by the International Atomic Energy Agency and 13 equivalent doses were used in the artificial neural network designed, trained and tested. In order to design the neural network was used the robust design of artificial neural networks methodology, which assures that the quality of the neural networks takes into account from the design stage. Unless previous works, here, for first time a group of neural networks were designed and trained to unfold 187 neutron spectra and at the same time to calculate 13 equivalent doses, starting from the count rates coming from the Bonner spheres system by using a systematic and experimental strategy. (Author)

Neutron spectrometry and dosimetry by means of Bonner spheres system and artificial neural networks applying robust design of artificial neural networks

International Nuclear Information System (INIS)

Martinez B, M.R.; Ortiz R, J.M.; Vega C, H.R.

2006-01-01

An Artificial Neural Network has been designed, trained and tested to unfold neutron spectra and simultaneously to calculate equivalent doses. A set of 187 neutron spectra compiled by the International Atomic Energy Agency and 13 equivalent doses were used in the artificial neural network designed, trained and tested. In order to design the neural network was used the robust design of artificial neural networks methodology, which assures that the quality of the neural networks takes into account from the design stage. Unless previous works, here, for first time a group of neural networks were designed and trained to unfold 187 neutron spectra and at the same time to calculate 13 equivalent doses, starting from the count rates coming from the Bonner spheres system by using a systematic and experimental strategy. (Author)

PREDIKSI FOREX MENGGUNAKAN MODEL NEURAL NETWORK

Directory of Open Access Journals (Sweden)

R. Hadapiningradja Kusumodestoni

2015-11-01

Full Text Available ABSTRAK Prediksi adalah salah satu teknik yang paling penting dalam menjalankan bisnis forex. Keputusan dalam memprediksi adalah sangatlah penting, karena dengan prediksi dapat membantu mengetahui nilai forex di waktu tertentu kedepan sehingga dapat mengurangi resiko kerugian. Tujuan dari penelitian ini dimaksudkan memprediksi bisnis fores menggunakan model neural network dengan data time series per 1 menit untuk mengetahui nilai akurasi prediksi sehingga dapat mengurangi resiko dalam menjalankan bisnis forex. Metode penelitian pada penelitian ini meliputi metode pengumpulan data kemudian dilanjutkan ke metode training, learning, testing menggunakan neural network. Setelah di evaluasi hasil penelitian ini menunjukan bahwa penerapan algoritma Neural Network mampu untuk memprediksi forex dengan tingkat akurasi prediksi 0.431 +/- 0.096 sehingga dengan prediksi ini dapat membantu mengurangi resiko dalam menjalankan bisnis forex. Kata kunci: prediksi, forex, neural network.

Artificial neural networks a practical course

CERN Document Server

da Silva, Ivan Nunes; Andrade Flauzino, Rogerio; Liboni, Luisa Helena Bartocci; dos Reis Alves, Silas Franco

2017-01-01

This book provides comprehensive coverage of neural networks, their evolution, their structure, the problems they can solve, and their applications. The first half of the book looks at theoretical investigations on artificial neural networks and addresses the key architectures that are capable of implementation in various application scenarios. The second half is designed specifically for the production of solutions using artificial neural networks to solve practical problems arising from different areas of knowledge. It also describes the various implementation details that were taken into account to achieve the reported results. These aspects contribute to the maturation and improvement of experimental techniques to specify the neural network architecture that is most appropriate for a particular application scope. The book is appropriate for students in graduate and upper undergraduate courses in addition to researchers and professionals.

Distributed Recurrent Neural Forward Models with Neural Control for Complex Locomotion in Walking Robots

DEFF Research Database (Denmark)

Dasgupta, Sakyasingha; Goldschmidt, Dennis; Wörgötter, Florentin

2015-01-01

here, an artificial bio-inspired walking system which effectively combines biomechanics (in terms of the body and leg structures) with the underlying neural mechanisms. The neural mechanisms consist of (1) central pattern generator based control for generating basic rhythmic patterns and coordinated......Walking animals, like stick insects, cockroaches or ants, demonstrate a fascinating range of locomotive abilities and complex behaviors. The locomotive behaviors can consist of a variety of walking patterns along with adaptation that allow the animals to deal with changes in environmental...... conditions, like uneven terrains, gaps, obstacles etc. Biological study has revealed that such complex behaviors are a result of a combination of biomechanics and neural mechanism thus representing the true nature of embodied interactions. While the biomechanics helps maintain flexibility and sustain...

In-vitro differentiation induction of neural stem cells

NARCIS (Netherlands)

Balasubramaniyan, Veerakumar

2006-01-01

Neurale stamcellen maken de drie belangrijkste celtypes van ons zenuwstelsel aan. Veerakumar Balasubramaniyan onderzocht hoe neurale stamcellen kunnen worden aangezet tot het aanmaken van specifieke neurale celtypes. Met behulp van genetische technieken lukte het hem oligodendrocyten te verkrijgen:

Neural entrainment to the rhythmic structure of music.

Science.gov (United States)

Tierney, Adam; Kraus, Nina

2015-02-01

The neural resonance theory of musical meter explains musical beat tracking as the result of entrainment of neural oscillations to the beat frequency and its higher harmonics. This theory has gained empirical support from experiments using simple, abstract stimuli. However, to date there has been no empirical evidence for a role of neural entrainment in the perception of the beat of ecologically valid music. Here we presented participants with a single pop song with a superimposed bassoon sound. This stimulus was either lined up with the beat of the music or shifted away from the beat by 25% of the average interbeat interval. Both conditions elicited a neural response at the beat frequency. However, although the on-the-beat condition elicited a clear response at the first harmonic of the beat, this frequency was absent in the neural response to the off-the-beat condition. These results support a role for neural entrainment in tracking the metrical structure of real music and show that neural meter tracking can be disrupted by the presentation of contradictory rhythmic cues.

Adaptive optimization and control using neural networks

Energy Technology Data Exchange (ETDEWEB)

Mead, W.C.; Brown, S.K.; Jones, R.D.; Bowling, P.S.; Barnes, C.W.

1993-10-22

Recent work has demonstrated the ability of neural-network-based controllers to optimize and control machines with complex, non-linear, relatively unknown control spaces. We present a brief overview of neural networks via a taxonomy illustrating some capabilities of different kinds of neural networks. We present some successful control examples, particularly the optimization and control of a small-angle negative ion source.

Calibration technique and study on metrological characteristics of a high-voltage inverse square-law function generator

International Nuclear Information System (INIS)

Popov, V.P.; Semenov, A.L.

1987-01-01

The calibration technique is described, and the metrological characteristics of a high-voltage generator of the inverse-quadratic function (HGF), being a functional unit of the diagnostic system of an electrodynamic analyser of a ionic component of a laser plasma, is analysed. The results of HGF testing in the range of time constants of the τ=(5-25)μs function are given. Analysis of metrologic and experimental characteristics shows, that HGF with automatic calibration has quite high accurate parameters. The high accuracy of function generation is provided with the possibility of calibration and adjustment conduction under experimental working conditions. Increase of the generated pulse amplitude to several tens of kilovelts is possible. Besides, the possibility of timely function adjustment to the necessary parameter (τ) increases essentially the HGF functional possibilities

Intelligent neural network diagnostic system

International Nuclear Information System (INIS)

Mohamed, A.H.

2010-01-01

Recently, artificial neural network (ANN) has made a significant mark in the domain of diagnostic applications. Neural networks are used to implement complex non-linear mappings (functions) using simple elementary units interrelated through connections with adaptive weights. The performance of the ANN is mainly depending on their topology structure and weights. Some systems have been developed using genetic algorithm (GA) to optimize the topology of the ANN. But, they suffer from some limitations. They are : (1) The computation time requires for training the ANN several time reaching for the average weight required, (2) Slowness of GA for optimization process and (3) Fitness noise appeared in the optimization of ANN. This research suggests new issues to overcome these limitations for finding optimal neural network architectures to learn particular problems. This proposed methodology is used to develop a diagnostic neural network system. It has been applied for a 600 MW turbo-generator as a case of real complex systems. The proposed system has proved its significant performance compared to two common methods used in the diagnostic applications.

Myostatin signaling is up-regulated in female patients with advanced heart failure.

Science.gov (United States)

Ishida, Junichi; Konishi, Masaaki; Saitoh, Masakazu; Anker, Markus; Anker, Stefan D; Springer, Jochen

2017-07-01

Myostatin, a negative regulator of skeletal muscle mass, is up-regulated in the myocardium of heart failure (HF) and increased myostatin is associated with weight loss in animal models with HF. Although there are disparities in pathophysiology and epidemiology between male and female patients with HF, it remains unclear whether there is gender difference in myostatin expression and whether it is associated with weight loss in HF patients. Heart tissue samples were collected from patients with advanced heart failure (n=31, female n=5) as well as healthy control donors (n=14, female n=6). Expression levels of myostatin and its related proteins in the heart were evaluated by western blotting analysis. Body mass index was significantly lower in female HF patients than in male counterparts (20.0±4.2 in female vs 25.2±3.8 in male, p=0.04). In female HF patients, both mature myostatin and pSmad2 were significantly up-regulated by 1.9 fold (p=0.05) and 2.5 fold (pmyostatin was not. There was no significant difference in protein expression related to myostatin signaling between male and female patients. In this study, myostatin and pSmad2 were significantly up-regulated in the failing heart of female patients, but not male patients, and female patients displayed lower body mass index. Enhanced myostatin signaling in female failing heart may causally contribute to pathogenesis of HF and cardiac cachexia. Copyright © 2017 Elsevier B.V. All rights reserved.

Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury.

Science.gov (United States)

Llorens-Bobadilla, Enric; Zhao, Sheng; Baser, Avni; Saiz-Castro, Gonzalo; Zwadlo, Klara; Martin-Villalba, Ana

2015-09-03

Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. Copyright © 2015 Elsevier Inc. All rights reserved.

Prickly pear induces upregulation of liver LDL binding in familial heterozygous hypercholesterolemia

International Nuclear Information System (INIS)

Palumbo, B.; Palumbo, R.; Efthimiou, Y.; Stamatopoulos, J.; Sinzinger, H.; Oguogho, A.; Budinsky, A.; Sinzinger, H.

2003-01-01

The hypoglycemic effect of prickly pear is well known by native local Indian population since a long time. Beside the beneficial effects on lipid metabolism, oxidation injury and platelet function has been claimed in experimental animals. We recently found an upregulation of apo-B/E receptor. We therefore examined 10 patients with isolated heterozygous familial hypercholesterolemia (FH) being enrolled in a dietary run-in phase of 6 weeks after dietary counselling and a further 6 weeks of prickly pear addition. Uptake of autologous 123 I-radiolabeled LDL was determined at entry as well as after 6 weeks of daily prickly pear ingestion. We found a significant (p 176.4 mg/dl; p 123 I-LDL binding by prickly pear in FH-patients in vivo and indicate that prickly pear exerts a significant hypolipidemic action via receptor upregulation. (author)

Neural Networks for the Beginner.

Science.gov (United States)

Snyder, Robin M.

Motivated by the brain, neural networks are a right-brained approach to artificial intelligence that is used to recognize patterns based on previous training. In practice, one would not program an expert system to recognize a pattern and one would not train a neural network to make decisions from rules; but one could combine the best features of…

Recent Advances in Neural Recording Microsystems

Directory of Open Access Journals (Sweden)

Benoit Gosselin

2011-04-01

Full Text Available The accelerating pace of research in neuroscience has created a considerable demand for neural interfacing microsystems capable of monitoring the activity of large groups of neurons. These emerging tools have revealed a tremendous potential for the advancement of knowledge in brain research and for the development of useful clinical applications. They can extract the relevant control signals directly from the brain enabling individuals with severe disabilities to communicate their intentions to other devices, like computers or various prostheses. Such microsystems are self-contained devices composed of a neural probe attached with an integrated circuit for extracting neural signals from multiple channels, and transferring the data outside the body. The greatest challenge facing development of such emerging devices into viable clinical systems involves addressing their small form factor and low-power consumption constraints, while providing superior resolution. In this paper, we survey the recent progress in the design and the implementation of multi-channel neural recording Microsystems, with particular emphasis on the design of recording and telemetry electronics. An overview of the numerous neural signal modalities is given and the existing microsystem topologies are covered. We present energy-efficient sensory circuits to retrieve weak signals from neural probes and we compare them. We cover data management and smart power scheduling approaches, and we review advances in low-power telemetry. Finally, we conclude by summarizing the remaining challenges and by highlighting the emerging trends in the field.

International Conference on Artificial Neural Networks (ICANN)

CERN Document Server

Mladenov, Valeri; Kasabov, Nikola; Artificial Neural Networks : Methods and Applications in Bio-/Neuroinformatics

2015-01-01

The book reports on the latest theories on artificial neural networks, with a special emphasis on bio-neuroinformatics methods. It includes twenty-three papers selected from among the best contributions on bio-neuroinformatics-related issues, which were presented at the International Conference on Artificial Neural Networks, held in Sofia, Bulgaria, on September 10-13, 2013 (ICANN 2013). The book covers a broad range of topics concerning the theory and applications of artificial neural networks, including recurrent neural networks, super-Turing computation and reservoir computing, double-layer vector perceptrons, nonnegative matrix factorization, bio-inspired models of cell communities, Gestalt laws, embodied theory of language understanding, saccadic gaze shifts and memory formation, and new training algorithms for Deep Boltzmann Machines, as well as dynamic neural networks and kernel machines. It also reports on new approaches to reinforcement learning, optimal control of discrete time-delay systems, new al...

Neural neworks in a management information systems

Directory of Open Access Journals (Sweden)

Jana Weinlichová

2009-01-01

Full Text Available For having retrospection for all over the data which are used, analyzed, evaluated and for a future incident predictions are used Management Information Systems and Business Intelligence. In case of not to be able to apply standard methods of data processing there can be with benefit applied an Artificial Intelligence. In this article will be referred to proofed abilities of Neural Networks. The Neural Networks is supported by many software products related to provide effective solution of manager issues. Those products are given as primary support for manager issues solving. We were tried to find reciprocally between products using Neural Networks and between Management Information Systems for finding a real possibility of applying Neural Networks as a direct part of Management Information Systems (MIS. In the article are presented possibilities to apply Neural Networks on different types of tasks in MIS.

Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

DEFF Research Database (Denmark)

Xu, Cang-Bao; Zheng, Jian-Pu; Zhang, Wei

2014-01-01

Vasoconstrictive endothelin type B (ET(B)) receptors promote vasospasm and ischemic cerebro- and cardiovascular diseases. The present study was designed to examine if low density lipoprotein (LDL) induces upregulation of vasoconstrictive ET(B) receptor expression and if extracellular signal...

Neural Networks in Mobile Robot Motion

Directory of Open Access Journals (Sweden)

Danica Janglová

2004-03-01

Full Text Available This paper deals with a path planning and intelligent control of an autonomous robot which should move safely in partially structured environment. This environment may involve any number of obstacles of arbitrary shape and size; some of them are allowed to move. We describe our approach to solving the motion-planning problem in mobile robot control using neural networks-based technique. Our method of the construction of a collision-free path for moving robot among obstacles is based on two neural networks. The first neural network is used to determine the “free” space using ultrasound range finder data. The second neural network “finds” a safe direction for the next robot section of the path in the workspace while avoiding the nearest obstacles. Simulation examples of generated path with proposed techniques will be presented.

Optimal neural computations require analog processors

Energy Technology Data Exchange (ETDEWEB)

Beiu, V.

1998-12-31

This paper discusses some of the limitations of hardware implementations of neural networks. The authors start by presenting neural structures and their biological inspirations, while mentioning the simplifications leading to artificial neural networks. Further, the focus will be on hardware imposed constraints. They will present recent results for three different alternatives of parallel implementations of neural networks: digital circuits, threshold gate circuits, and analog circuits. The area and the delay will be related to the neurons` fan-in and to the precision of their synaptic weights. The main conclusion is that hardware-efficient solutions require analog computations, and suggests the following two alternatives: (i) cope with the limitations imposed by silicon, by speeding up the computation of the elementary silicon neurons; (2) investigate solutions which would allow the use of the third dimension (e.g. using optical interconnections).

Learning from neural control.

Science.gov (United States)

Wang, Cong; Hill, David J

2006-01-01

One of the amazing successes of biological systems is their ability to "learn by doing" and so adapt to their environment. In this paper, first, a deterministic learning mechanism is presented, by which an appropriately designed adaptive neural controller is capable of learning closed-loop system dynamics during tracking control to a periodic reference orbit. Among various neural network (NN) architectures, the localized radial basis function (RBF) network is employed. A property of persistence of excitation (PE) for RBF networks is established, and a partial PE condition of closed-loop signals, i.e., the PE condition of a regression subvector constructed out of the RBFs along a periodic state trajectory, is proven to be satisfied. Accurate NN approximation for closed-loop system dynamics is achieved in a local region along the periodic state trajectory, and a learning ability is implemented during a closed-loop feedback control process. Second, based on the deterministic learning mechanism, a neural learning control scheme is proposed which can effectively recall and reuse the learned knowledge to achieve closed-loop stability and improved control performance. The significance of this paper is that the presented deterministic learning mechanism and the neural learning control scheme provide elementary components toward the development of a biologically-plausible learning and control methodology. Simulation studies are included to demonstrate the effectiveness of the approach.

Sacred or Neural?

DEFF Research Database (Denmark)

Runehov, Anne Leona Cesarine

Are religious spiritual experiences merely the product of the human nervous system? Anne L.C. Runehov investigates the potential of contemporary neuroscience to explain religious experiences. Following the footsteps of Michael Persinger, Andrew Newberg and Eugene d'Aquili she defines...... the terminological bounderies of "religious experiences" and explores the relevant criteria for the proper evaluation of scientific research, with a particular focus on the validity of reductionist models. Runehov's theis is that the perspectives looked at do not necessarily exclude each other but can be merged....... The question "sacred or neural?" becomes a statement "sacred and neural". The synergies thus produced provide manifold opportunities for interdisciplinary dialogue and research....

On the neural mechanisms subserving consciousness and attention

Directory of Open Access Journals (Sweden)

Catherine eTallon-Baudry

2012-01-01

Full Text Available Consciousness, as described in the experimental literature, is a multi-faceted phenomenon, that impinges on other well-studied concepts such as attention and control. Do consciousness and attention refer to different aspects of the same core phenomenon, or do they correspond to distinct functions? One possibility to address this question is to examine the neural mechanisms underlying consciousness and attention. If consciousness and attention pertain to the same concept, they should rely on shared neural mechanisms. Conversely, if their underlying mechanisms are distinct, then consciousness and attention should be considered as distinct entities. This paper therefore reviews neurophysiological facts arguing in favor or against a tight relationship between consciousness and attention. Three neural mechanisms that have been associated with both attention and consciousness are examined (neural amplification, involvement of the fronto-parietal network, and oscillatory synchrony, to conclude that the commonalities between attention and consciousness at the neural level may have been overestimated. Last but not least, experiments in which both attention and consciousness were probed at the neural level point toward a dissociation between the two concepts. It therefore appears from this review that consciousness and attention rely on distinct neural properties, although they can interact at the behavioral level. It is proposed that a "cumulative influence model", in which attention and consciousness correspond to distinct neural mechanisms feeding a single decisional process leading to behavior, fits best with available neural and behavioral data. In this view, consciousness should not be considered as a top-level executive function but should rather be defined by its experiential properties.

First Ph.D. Student Workshop of the Hermann von Helmholtz Association of National Research Centers (HGF) on ''Nuclear Safety Research''

International Nuclear Information System (INIS)

Knebel, J.U.; Sanchez Espinoza, V.H.

2006-03-01

The First Ph.D. Student Workshop ''Nuclear Safety Research'' of the Helmholtz Association of National Research Centers (HGF)'' was jointly organized by the Research Center Karlsruhe GmbH and the Energie Baden-Wuerttemberg AG (EnBW) from Wednesday 9th to Friday 11th March 2005. The workshop was opened with welcome greetings by Dr. Peter Fritz, Forschungszentrum Karlsruhe. Subsequently Dr. Joachim U. Knebel explained the main goals and the content of the workshop. The young scientists reported in 28 high-level presentations about their research work which covered a wide spectrum from reactor safety, partitions and transmutation, and innovative reactor systems, to safety research for nuclear waste disposal. The junior researchs showed excellent professional competence and demonstrated presentation qualities at the highest level. The successful funding of two Virtual Institutes, namely: the ''Competence in Nuclear Technologies'' and ''Functional Characteristics of Aquatic Interfaces both co-ordinated by Forschungszentrum Karlsruhe'', by the President of the Helmholtz Association Prof. Walter Kroell was the motivation for the organization of this first Ph.D. Student Workshop. Thanks to these two Virtual Institutes, the Reseach Center Karlsruhe and Juelich together with several univer-sities i.e. RWTH Aachen, Heidelberg, Karlsruhe, Muenster, and Stuttgart, have successfully financed eight Ph.D. and two post-doctoral students. Moreover, young scientists of the European Institute for Transuranium Elements (ITU) and additional seven Ph.D. Students, who are sponsored by the German nuclear industry (Framatome ANP, RWE Power, EnBW) in the frame of the Alliance Competence in on Nuclear Technology, and who are trained at Forschungszentrum Karlsruhe, actively contributed to this workshop. The EnBW-Award was handed over by Dr. Hans-Josef Zimmer, member of the board of directors of the EnBW-Kraftwerksgesellschaft, to Mrs. Ayelet Walter from the University of Stuttgart for the best

Adaptive nonlinear control using input normalized neural networks

International Nuclear Information System (INIS)

Leeghim, Henzeh; Seo, In Ho; Bang, Hyo Choong

2008-01-01

An adaptive feedback linearization technique combined with the neural network is addressed to control uncertain nonlinear systems. The neural network-based adaptive control theory has been widely studied. However, the stability analysis of the closed-loop system with the neural network is rather complicated and difficult to understand, and sometimes unnecessary assumptions are involved. As a result, unnecessary assumptions for stability analysis are avoided by using the neural network with input normalization technique. The ultimate boundedness of the tracking error is simply proved by the Lyapunov stability theory. A new simple update law as an adaptive nonlinear control is derived by the simplification of the input normalized neural network assuming the variation of the uncertain term is sufficiently small

Antenna analysis using neural networks

Science.gov (United States)

Smith, William T.

1992-01-01

Conventional computing schemes have long been used to analyze problems in electromagnetics (EM). The vast majority of EM applications require computationally intensive algorithms involving numerical integration and solutions to large systems of equations. The feasibility of using neural network computing algorithms for antenna analysis is investigated. The ultimate goal is to use a trained neural network algorithm to reduce the computational demands of existing reflector surface error compensation techniques. Neural networks are computational algorithms based on neurobiological systems. Neural nets consist of massively parallel interconnected nonlinear computational elements. They are often employed in pattern recognition and image processing problems. Recently, neural network analysis has been applied in the electromagnetics area for the design of frequency selective surfaces and beam forming networks. The backpropagation training algorithm was employed to simulate classical antenna array synthesis techniques. The Woodward-Lawson (W-L) and Dolph-Chebyshev (D-C) array pattern synthesis techniques were used to train the neural network. The inputs to the network were samples of the desired synthesis pattern. The outputs are the array element excitations required to synthesize the desired pattern. Once trained, the network is used to simulate the W-L or D-C techniques. Various sector patterns and cosecant-type patterns (27 total) generated using W-L synthesis were used to train the network. Desired pattern samples were then fed to the neural network. The outputs of the network were the simulated W-L excitations. A 20 element linear array was used. There were 41 input pattern samples with 40 output excitations (20 real parts, 20 imaginary). A comparison between the simulated and actual W-L techniques is shown for a triangular-shaped pattern. Dolph-Chebyshev is a different class of synthesis technique in that D-C is used for side lobe control as opposed to pattern

Neural networks in economic modelling : An empirical study

NARCIS (Netherlands)

Verkooijen, W.J.H.

1996-01-01

This dissertation addresses the statistical aspects of neural networks and their usability for solving problems in economics and finance. Neural networks are discussed in a framework of modelling which is generally accepted in econometrics. Within this framework a neural network is regarded as a

Efficient computation in adaptive artificial spiking neural networks

NARCIS (Netherlands)

D. Zambrano (Davide); R.B.P. Nusselder (Roeland); H.S. Scholte; S.M. Bohte (Sander)

2017-01-01

textabstractArtificial Neural Networks (ANNs) are bio-inspired models of neural computation that have proven highly effective. Still, ANNs lack a natural notion of time, and neural units in ANNs exchange analog values in a frame-based manner, a computationally and energetically inefficient form of

Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries

DEFF Research Database (Denmark)

Ahnstedt, Hilda; Cao, Lei; Krause, Diana N

2013-01-01

Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which...

Neural Networks

Directory of Open Access Journals (Sweden)

Schwindling Jerome

2010-04-01

Full Text Available This course presents an overview of the concepts of the neural networks and their aplication in the framework of High energy physics analyses. After a brief introduction on the concept of neural networks, the concept is explained in the frame of neuro-biology, introducing the concept of multi-layer perceptron, learning and their use as data classifer. The concept is then presented in a second part using in more details the mathematical approach focussing on typical use cases faced in particle physics. Finally, the last part presents the best way to use such statistical tools in view of event classifers, putting the emphasis on the setup of the multi-layer perceptron. The full article (15 p. corresponding to this lecture is written in french and is provided in the proceedings of the book SOS 2008.

Interpretable neural networks with BP-SOM

NARCIS (Netherlands)

Weijters, A.J.M.M.; Bosch, van den A.P.J.; Pobil, del A.P.; Mira, J.; Ali, M.

1998-01-01

Artificial Neural Networks (ANNS) are used successfully in industry and commerce. This is not surprising since neural networks are especially competitive for complex tasks for which insufficient domain-specific knowledge is available. However, interpretation of models induced by ANNS is often

A high-speed analog neural processor

NARCIS (Netherlands)

Masa, P.; Masa, Peter; Hoen, Klaas; Hoen, Klaas; Wallinga, Hans

1994-01-01

Targeted at high-energy physics research applications, our special-purpose analog neural processor can classify up to 70 dimensional vectors within 50 nanoseconds. The decision-making process of the implemented feedforward neural network enables this type of computation to tolerate weight

Neural cryptography with feedback.

Science.gov (United States)

Ruttor, Andreas; Kinzel, Wolfgang; Shacham, Lanir; Kanter, Ido

2004-04-01

Neural cryptography is based on a competition between attractive and repulsive stochastic forces. A feedback mechanism is added to neural cryptography which increases the repulsive forces. Using numerical simulations and an analytic approach, the probability of a successful attack is calculated for different model parameters. Scaling laws are derived which show that feedback improves the security of the system. In addition, a network with feedback generates a pseudorandom bit sequence which can be used to encrypt and decrypt a secret message.

Requirement of mouse BCCIP for neural development and progenitor proliferation.

Directory of Open Access Journals (Sweden)

Yi-Yuan Huang

Full Text Available Multiple DNA repair pathways are involved in the orderly development of neural systems at distinct stages. The homologous recombination (HR pathway is required to resolve stalled replication forks and critical for the proliferation of progenitor cells during neural development. BCCIP is a BRCA2 and CDKN1A interacting protein implicated in HR and inhibition of DNA replication stress. In this study, we determined the role of BCCIP in neural development using a conditional BCCIP knock-down mouse model. BCCIP deficiency impaired embryonic and postnatal neural development, causing severe ataxia, cerebral and cerebellar defects, and microcephaly. These development defects are associated with spontaneous DNA damage and subsequent cell death in the proliferative cell populations of the neural system during embryogenesis. With in vitro neural spheroid cultures, BCCIP deficiency impaired neural progenitor's self-renewal capability, and spontaneously activated p53. These data suggest that BCCIP and its anti-replication stress functions are essential for normal neural development by maintaining an orderly proliferation of neural progenitors.

Neural crest cells: from developmental biology to clinical interventions.

Science.gov (United States)

Noisa, Parinya; Raivio, Taneli

2014-09-01

Neural crest cells are multipotent cells, which are specified in embryonic ectoderm in the border of neural plate and epiderm during early development by interconnection of extrinsic stimuli and intrinsic factors. Neural crest cells are capable of differentiating into various somatic cell types, including melanocytes, craniofacial cartilage and bone, smooth muscle, and peripheral nervous cells, which supports their promise for cell therapy. In this work, we provide a comprehensive review of wide aspects of neural crest cells from their developmental biology to applicability in medical research. We provide a simplified model of neural crest cell development and highlight the key external stimuli and intrinsic regulators that determine the neural crest cell fate. Defects of neural crest cell development leading to several human disorders are also mentioned, with the emphasis of using human induced pluripotent stem cells to model neurocristopathic syndromes. © 2014 Wiley Periodicals, Inc.